Contents SECTION I: DISORDERS OF WATER, ELECTROLYTES, AND ACID-BASE CHAPTER 1 DISEASES OF WATER METABOLISM Sumit Kumar and Tomas

Berl CHAPTER 2 DISO RDERS OF SODIUM BALANCE David H. Ellison CHAPTER 3 DISORDERS OF POTASSIUM METABO LISM Fredrick V. Osorio and Stuart L.Linas CHAPTER 4 DIVALENT CATION METABOLISM: MAGNESIUM James T. McCarthy and Rajiv Kumar CHAPTER 5 DIVALENT CATION METABOLIS M: CALCIUM James T. McCarthy and Rajiv Kumar CHAPTER 6 DISORDERS OF ACID-BASE BA LANCE Horacio J. Androgu and Nicolas E. Madias CHAPTER 7 DISORDERS OF PHOSPHATE B ALANCE Moshe Levi and Mordecai Popovtzer SECTION II: ACUTE RENAL FAILURE CHAPTER 8 ACUTE RENAL FAILURE Fernando Liao CHAPTER 9 RENAL HISTOPATHOLOGY, URINE CYTOLOGY, AND CYTOPATHOLOGY OF ACUTE RENAL FAILURE Lorraine C. Racusen and Cynt hia C. Nast CHAPTER 10 ACUTE RENAL FAILURE IN THE TRANSPLANTED KIDNEY Kim Solez and Lorraine C. Racusen CHAPTER 11 RENAL INJURY DUE TO ENVIRONMENTAL TOXINS, DRU GS, AND CONTRAST AGENTS Marc E. De Broe CHAPTER 12 DIAGNOSTIC EVALUATION OF THE PATIENT WITH ACUTE RENAL FAILURE Brian G. Dwinnell and Robert J. Anderson CHAPTE R 13 PATHOPHYSIOLOGY OF ISCHEMIC ACUTE RENAL FAILURE: CYTOSKELETAL ASPECTS Bruce A. Molitoris and Robert Bacallao CHAPTER 14

PATHOPHYSIOLOGY OF ISCHEMIC ACUTE RENAL FAILURE Michael S. Goligorsky and Wilfre d Lieberthal CHAPTER 15 PATHOPHYSIOLOGY OF NEPHROTOXIC ACUTE RENAL FAILURE Rick G. Schnellmann and Katrina J. Kelly CHAPTER 16 ACUTE RENAL FAILURE: CELLULAR FEA TURES OF INJURY AND REPAIR Kevin T. Bush, Hiroyuki Sakurai, Tatsuo Tsukamoto, an d Sanjay K. Nigam CHAPTER 17 MOLECULAR RESPONSES AND GROWTH FACTORS Steven B. Mi ller and Babu J. Padanilam CHAPTER 18 NUTRITION AND METABOLISM IN ACUTE RENAL FA ILURE Wilfred Druml CHAPTER 19 SUPPORTIVE THERAPIES: INTERMITTENT HEMODIALYSIS, CONTINUOUS RENAL REPLACEMENT THERAPIES, AND PERITONEAL DIALYSIS Ravindra L. Meht a

VOLUME TWO Edited by Richard J. Glassock, Arthur H. Cohen and Jean Perre Grnfeld Contents SECTION I: GLOMERULONEPHRITIS AND VASCULITIS CHAPTER 1 NORMAL VASCULAR AND GLOMERULAR ANATOMY Arthur H. Cohen and Richard J. Glassock CHAPTER 2 THE PRIMARY GLOMERULOPATHIES Arthur H. Cohen and Richard J. G lassock CHAPTER 3 HEREDOFAMILIAL AND CONGENITAL Arthur H. Cohen and Richard J. G lassock CHAPTER 4 INFECTION-ASSOCIATED GLOMERULOPATHIES Arthur H. Cohen and Rich ard J. Glassock CHAPTER 5 VASCULAR DISORDERS Arthur H. Cohen and Richard J. Glas sock SECTION II: TUBULOINTERSTITIAL DISEASE CHAPTER 6 RENAL INTERSTITIUM AND MAJOR FEATURES OF CHRONIC TUBULOINTERSTITIAL NE PHRITIS Garabed Eknoyan and Luan D. Truong CHAPTER 7 URINARY TRACT INFECTION Ala in Meyrier CHAPTER 8 REFLUX AND OBSTRUCTIVE NEPHROPATHY James M. Gloor and Vicen te E. Torres CHAPTER 9 CYSTIC DISEASE OF THE KIDNEY Yves Pirson and Dominique Ch auveau CHAPTER 10 TOXIC NEPHROPATHIES Jean-Louis Vanherweghem CHAPTER 11 METABOL IC CAUSES OF TUBULOINTERSTITIAL DISEASE Steven J. Scheinman

CHAPTER 12 RENAL TUBULAR DISORDERS Lisa M. Guay-Woodford VOLUME THREE Edited by Christopher S. Wilcox Contents CHAPTER 1 THE KIDNEY IN BLOOD PRESSURE REGULATION L. Gabriel Navar and L. Lee Ha mm CHAPTER 2 RENAL PARENCHYMAL DISEASE AND HYPERTENSION Stephen C. Textor CHAPTE R 3 RENOVASCULAR HYPERTENSION AND ISCHEMIC NEPHROPATHY Marc A. Pohl CHAPTER 4 AD RENAL CAUSES OF HYPERTENSION Myron H. Weinberger CHAPTER 5 INSULIN RESISTANCE AN D HYPERTENSION Theodore A. Kotchen CHAPTER 6 THE ROLE OF HYPERTENSION IN PROGRES SION OF CHRONIC RENAL DISEASE Lance D. Dworkin and Douglas G. Shemin CHAPTER 7 P HARMACOLOGIC TREATMENT OF HYPERTENSION Garry P. Reams and John H. Bauer CHAPTER 8 HYPERTENSIVE CRISES Charles R. Nolan

VOLUME FOUR Edited by Saulo Klahr Contents CHAPTER 1 DIABETIC NEPHROPATHY: IMPACT OF COMORBIDITY Eli A. Friedman CHAPTER 2 VASCULITIS (POLYARTERITIS, NODOSA, MICROSCOPIC POLYANGITIS, WEGENER'S GRANULOMAT OSIS, HENOCH-SCHONLEIN PURPURA) J. Charles Jennette and Ronald J. Falk CHAPTER 3 AMYLOIDOSIS Robert A. Kyle and Morie A. Gertz CHAPTER 4 SICKLE CELL DISEASE L. W. Statius van Eps CHAPTER 5 RENAL INVOLVEMENT IN MALIGNANCY Richard E. Rieselba ch, A. Vishnu Moorthy and Marc B. Garnick CHAPTER 6 RENAL INVOLVEMENT IN TROPICA L DISEASES Rashad S Barsoum, Magdi R. Francis and Visith Sitprija CHAPTER 7 RENA L DISEASE IN PATIENTS INFECTED WITH HEPATITIS AND HUMAN IMMUNODEFICIENCY VIRUS J acques Bourgoignie, T.K. Sreepada Rao, David Roth CHAPTER 8 RENAL INVOLVEMENT IN SARCOIDOSIS Garabed Eknoyan CHAPTER 9 RENAL INVOLVEMENT IN ESSENTIAL MIXED CRYO GLOBULINEMIA Giuseppe D'Amico and Franco Ferrario CHAPTER 10 KIDNEY DISEASE AND HYPERTENSION IN PREGNANCY Phyllis August CHAPTER 11 RENAL INVOLVEMENT IN COLLAGE N VASCULAR DISEASES AND DYSPROTEINEMIAS Jo H. M. Berden and Karel J. M. Assmann

VOLUME FIVE Edited by William L Henrich and William M. Bennet Contents Section I: DIALYSIS AS TREATMENT OF END-STAGE RENAL DISEASE CHAPTER 1 PRINCIPLES OF DIALYSIS: DIFFUSION, CONVECTION, AND DIALYSIS MACHINES R obert W. Hamilton CHAPTER 2 DIALYSATE COMPOSITION IN HEMODIALYSIS AND PERITONEAL DIALYSIS Biff F. Palmer CHAPTER 3 HIGH-EFFICIENCY AND HIGH-FLUX HEMODIALYSIS Si vasankaran Ambalavanan, Gary M. Rabetoy and Alfred K. Cheung CHAPTER 4 PRINCIPLE S OF PERITONEAL DIALYSIS Ramesh Khanna and Karl D. Nolph CHAPTER 5 DIALYSIS ACCE SS AND RECIRCULATION Toros Kapoian, Jeffrey L. Kaufman, John L. Nosher, and Rich ard A. Sherman CHAPTER 6 THE DIALYSIS PRESCRIPTION AND UREA MODELING Biff F. Pal mer CHAPTER 7 COMPLICATIONS OF DIALYSIS: SELECTED TOPICS Robert W. Hamilton SECTION II: TRANSPLANTATION AS TREATMENT OF END-STAGE RENAL DISEASE CHAPTER 8 HISTOCOMPATIBILITY TESTING AND ORGAN SHARING Lauralynn K. Lebeck and M arvin R. Garovoy CHAPTER 9 TRANSPLANT REJECTION AND ITS TREATMENT Laurence Chan CHAPTER 10 POST-TRANSPLANT INFECTIONS Connie L. Davis CHAPTER 11 IMMUNOSUPPRESSI VE THERAPY AND PROTOCOLS Angelo M. de Mattos CHAPTER 12 EVALUATION OF PROSPECTIV E DONORS AND RECIPIENTS

Bertram L. Kasiske CHAPTER 13 MEDICAL COMPLICATIONS OF RENAL TRANSPLANTATION Rob ert S. Gaston CHAPTER 14 TECHNICAL ASPECTS OF RENAL TRANSPLANTATION John M. Barr y CHAPTER 15 KIDNEY-PANCREAS-TRANSPLANTATION John D. Pirsch, Jon S Odorico, and Hans W. Sollinger CHAPTER 16 TRANSPLANTATION IN CHILDREN Jeanne A. Mowry CHAPTER 17 RECURRENT DISEASE IN THE TRANSPLANTED KIDNEY Jeremy B. Levy

Diseases of Water Metabolism Sumit Kumar Tomas Berl T he maintenance of the tonicity of body fluids within a very narrow physiologic r ange is made possible by homeostatic mechanisms that control the intake and excr etion of water. Critical to this process are the osmoreceptors in the hypothalam us that control the secretion of antidiuretic hormone (ADH) in response to chang es in tonicity. In turn, ADH governs the excretion of water by its end-organ eff ect on the various segments of the renal collecting system. The unique anatomic and physiologic arrangement of the nephrons brings about either urinary concentr ation or dilution, depending on prevailing physiologic needs. In the first secti on of this chapter, the physiology of urine formation and water balance is descr ibed. The kidney plays a pivotal role in the maintenance of normal water homeost asis, as it conserves water in states of water deprivation, and excretes water i n states of water excess. When water homeostasis is deranged, alterations in ser um sodium ensue. Disorders of urine dilution cause hyponatremia. The pathogenesi s, causes, and management strategies are described in the second part of this ch apter. When any of the components of the urinary concentration mechanism is disr upted, hypernatremia may ensue, which is universally characterized by a hyperosm olar state. In the third section of this chapter, the pathogenesis, causes, and clinical settings for hypernatremia and management strategies are described. CHAPTER 1

1.2 Disorders of Water, Electrolytes, and Acid-Base Physiology of the Renal Diluting and Concentrating Mechanisms FIGURE 1-1 Principles of normal water balance. In most steady-state situations, human water intake matches water losses through all sources. Water intake is det ermined by thirst (see Fig. 1-12) and by cultural and social behaviors. Water in take is finely balanced by the need to maintain physiologic serum osmolality bet ween 285 to 290 mOsm/kg. Both water that is drunk and that is generated through metabolism are distributed in the extracellular and intracellular compartments t hat are in constant equilibrium. Total body water equals approximately 60% of to tal body weight in young men, about 50% in young women, and less in older person s. Infants' total body water is between 65% and 75%. In a 70-kg man, in temperate conditions, total body water equals 42 L, 65% of which (22 L) is in the intracel lular compartment and 35% (19 L) in the extracellular compartment. Assuming norm al glomerular filtration rate to be about 125 mL/min, the total volume of blood filtered by the kidney is about 180 L/24 hr. Only about 1 to 1.5 L is excreted a s urine, however, on account of the complex interplay of the urine concentrating and diluting mechanism and the effect of antidiuretic hormone to different segm ents of the nephron, as depicted in the following figures. Normal water intake (1.01.5 L/d) Water of cellular metabolism (350500 mL/d) Intracellular compartment (27 L) Extra cellular compartment (15 L) Total body water 42L (60% body weight in a 70-kg man ) Fixed water excretion Variable water excretion Filtrate/d 180L Stool 0.1 L/d Sweat 0.1 L/d Pulmonary 0.3 L/d Total insensible losses ~0.5 L/d Total urine output 1.01.5 L/d Water excretion Water intake and distribution

Diseases of Water Metabolism 1.3 GFR Determinants of delivery of NaCl to distal tubule: GFR Proximal tubular fluid an d solute (NaCl) reabsorption ;; ;; Water delivery NaCl movement Solute concentration ;;;;;;;;;;;;;;; ;;;;;;;;;;; ;;;;;;;;;;;;;;; ;;;;;;;;;;;;;;; ;;;;;;;;;;;;;;; ;;;; ;;;;;;;;;;; ;;;;;;;;;;;;;;; ;;;;;;;;;;;;;;; ;;;;;;;;;;;;;;; ;;;; ;;;;;;;;;;;;;;; ;;;; ;;;;;;;;;;; ;;;; ;;;;;;;;;;; ;;;; ;;; ;;;;;;;;;;; ;;;; ;;; ;;;;;;;;;;; ;;; ; ;;; ;;;;;;;;;;; ;;;; ;;; ;;;; ;;; ;;; NaCl H 2O H 2O Generation of medullary hypertonicity Normal function of the thick ascending lim b of loop of Henle Urea delivery Normal medullary blood flow ADH ADH H 2O NaCl NaCl NaCl NaCl NaCl NaCl H 2O ADH H 2O H 2O H 2O H 2O Collecting system water permeability determined by Presence of arginine vasopres sin Normal collecting system FIGURE 1-2 Determinants of the renal concentrating mechanism. Human kidneys have two populations of nephrons, superficial and juxtamedullary. This anatomic arra ngement has important bearing on the formation of urine by the countercurrent me chanism. The unique anatomy of the nephron [1] lays the groundwork for a complex yet logical physiologic arrangement that facilitates the urine concentration an d dilution mechanism, leading to the formation of either concentrated or dilute urine, as appropriate to the person's needs and dictated by the plasma osmolality. After two thirds of the filtered load (180 L/d) is isotonically reabsorbed in t he proximal convoluted tubule, water is handled by three interrelated processes: 1) the delivery of fluid to the diluting segments; 2) the separation of solute and water (H2O) in the diluting segment; and 3) variable reabsorption of water i n the collecting duct. These processes participate in the renal concentrating me chanism [2]. 1. Delivery of sodium chloride (NaCl) to the diluting segments of the nephron (t hick ascending limb of the loop of Henle and the distal convoluted tubule) is de termined by glomerular filtration rate (GFR) and proximal tubule function. 2. Ge

neration of medullary interstitial hypertonicity, is determined by normal functi oning of the thick ascending limb of the loop of Henle, urea delivery from the m edullary collecting duct, and medullary blood flow. 3. Collecting duct permeabil ity is determined by the presence of antidiuretic hormone (ADH) and normal anato my of the collecting system, leading to the formation of a concentrated urine.

1.4 Disorders of Water, Electrolytes, and Acid-Base FIGURE 1-3 Determinants of the urinary dilution mechanism include 1) delivery of water to the thick ascending limb of the loop of Henle, distal convoluted tubul e, and collecting system of the nephron; 2) generation of maximally hypotonic fl uid in the diluting segments (ie, normal thick ascending limb of the loop of Hen le and cortical diluting segment); 3) maintenance of water impermeability of the collecting system as determined by the absence of antidiuretic hormone (ADH) or its action and other antidiuretic substances. GFRglomerular filtration rate; NaC lsodium chloride; H2Owater. GFR Determinants of delivery of H2O to distal parts of the nephron GFR Proximal tubu lar H2O and NaCl reabsorption ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;; ;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;; ; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;; ;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; ;;;; ;;;;;;;;;;;; NaCl H 2O NaCl NaCl NaCl NaCl H 2O H 2O H 2O H 2O Collecting duct impermeability depends on Absence of ADH Absence of other antidiuretic substances H 2O Distal tubule Urea Normal functioning of Thick ascending limb of loop of Henle Cortical diluting se gment Impermeable collecting duct Cortex Na+ K+ 2Cl2 NaCl Na+ K+ 2Cl2 H 2O Urea H 2O 2 H 2O Na+ 1 K+ 2Cl2 Na+ K+ 2Cl2 Urea Outer medullary collecting duct Outer medulla H 2O 4 3 H 2O Urea NaCl NaCl 5 NaCl Inner medulla Loop of Henle Inner medullary collecting duct Urea Collecting tubule FIGURE 1-4 Mechanism of urine concentration: overview of the passive model. Seve ral models of urine concentration have been put forth by investigators. The pass ive model of urine concentration described by Kokko and Rector [3] is based on p ermeability characteristics of different parts of the nephron to solute and wate r and on the fact that the active transport is limited to the thick ascending li mb. 1) Through the Na+, K+, 2 Cl cotransporter, the thick ascending limb activel y transports sodium chloride (NaCl), increasing the interstitial tonicity, resul ting in tubular fluid dilution with no net movement of water and urea on account of their low permeability. 2) The hypotonic fluid under antidiuretic hormone ac tion undergoes osmotic equilibration with the interstitium in the late distal tu bule and cortical and outer medullary collecting duct, resulting in water remova l. Urea concentration in the tubular fluid rises on account of low urea permeabi

lity. 3) At the inner medullary collecting duct, which is highly permeable to ur ea and water, especially in response to antidiuretic hormone, the urea enters th e interstitium down its concentration gradient, preserving interstitial hyperton icity and generating high urea concentration in the interstitium. (Legend contin ued on next page)

Diseases of Water Metabolism FIGURE 1-4 (continued) 4) The hypertonic interstitium causes abstraction of wate r from the descending thin limb of loop of Henle, which is relatively impermeabl e to NaCl and urea, making the tubular fluid hypertonic with high NaCl concentra tion as it arrives at the bend of the loop of 1.5 Henle. 5) In the thin ascending limb of the loop of Henle, NaCl moves passively down its concentration gradient into the interstitium, making tubular fluid less concentrated with little or no movement of water. H2Owater. FIGURE 1-5 Pathways for urea recycling. Urea plays an important role in the generation of medullary interstitial hypertonicity. A recycling mechanism operates to minimize urea loss . The urea that is reabsorbed into the inner medullary stripe from the terminal inner medullary collecting duct (step 3 in Fig. 1-4) is carried out of this regi on by the ascending vasa recta, which deposits urea into the adjacent descending thin limbs of a short loop of Henle, thus recycling the urea to the inner medul lary collecting tubule (pathway A). Some of the urea enters the descending limb of the loop of Henle and the thin ascending limb of the loop of Henle. It is the n carried through to the thick ascending limb of the loop of Henle, the distal c ollecting tubule, and the collecting duct, before it reaches the inner medullary collecting duct (pathway B). This process is facilitated by the close anatomic relationship that the hairpin loop of Henle and the vasa recta share [4]. Cortex Urea Urea Urea Urea Outer stripe Inner stripe Urea Outer medulla Urea Collecting duct Urea Urea Ascending vasa recta Pathway A Pathway B Urea Inner medulla 1500 20 mL 0.3 mL 1200 Osmolality, mOsm/kg H2O 900 600 300 100 mL 30 mL 20 mL Maximal ADH 2.0 mL no ADH 16 mL 0 Proximal tubule Loop of Henle Distal tubule and cortical collecting tubule Out er and inner medullary collecting ducts FIGURE 1-6 Changes in the volume and osmolality of tubular fluid along the nephr on in diuresis and antidiuresis. The osmolality of the tubular fluid undergoes s everal changes as it passes through different segments of the tubules. Tubular f

luid undergoes marked reduction in its volume in the proximal tubule; however, t his occurs iso-osmotically with the glomerular filtrate. In the loop of Henle, b ecause of the aforementioned countercurrent mechanism, the osmolality of the tub ular fluid rises sharply but falls again to as low as 100 mOsm/kg as it reaches the thick ascending limb and the distal convoluted tubule. Thereafter, in the la te distal tubule and the collecting duct, the osmolality depends on the presence or absence of antidiuretic hormone (ADH). In the absence of ADH, very little wa ter is reabsorbed and dilute urine results. On the other hand, in the presence o f ADH, the collecting duct, and in some species, the distal convoluted tubule, b ecome highly permeable to water, causing reabsorption of water into the intersti tium, resulting in concentrated urine [5].

1.6 Disorders of Water, Electrolytes, and Acid-Base Paraventricular neurons Baroreceptors Supraoptic neuron SON Osmoreceptors Pineal Third ventricle VP,NP Tanycyte Optic chiasm Superior hypophysial artery Portal capillaries in zona externa of m edian eminence Long portal vein Systemic venous system Anterior pituitary Short portal vein VP,NP Mammilary body Posterior pituitary VP,NP FIGURE 1-7 Pathways of antidiuretic hormone release. Antidiuretic hormone is res ponsible for augmenting the water permeability of the cortical and medullary col lecting tubules, thus promoting water reabsorption via osmotic equilibration wit h the isotonic and hypertonic interstitium, respecively. The hormone is formed i n the supraoptic and paraventricular nuclei, under the stimulus of osmoreceptors and baroreceptors (see Fig. 1-11), transported along their axons and secreted a t three sites: the posterior pituitary gland, the portal capillaries of the medi an eminence, and the cerebrospinal fluid of the third ventricle. It is from the posterior pituitary that the antidiuretic hormone is released into the systemic circulation [6]. SONsupraoptic nucleus; VPvasopressin; NPneurophysin. Exon 1 Exon 2 Exon 3 Pre-pro-vasopressin (164 AA) AVP Signal peptide Gly Lys Arg Neurophysin II Arg Glycopeptide (Cleavage site) Pro-vasopressin AVP Gly Lys Arg Neurophysin II

Arg Glycopeptide Products of pro-vasopressin AVP NH2 + Neurophysin II + Glycopeptide FIGURE 1-8 Structure of the human arginine vasopressin (AVP/antidiuretic hormone ) gene and the prohormone. Antidiuretic hormone (ADH) is a cyclic hexapeptide (m ol. wt. 1099) with a tail of three amino acids. The biologically inactive macrom olecule, pre-pro-vasopressin is cleaved into the smaller, biologically active pr otein. The protein of vasopressin is translated through a series of signal trans duction pathways and intracellular cleaving. Vasopressin, along with its binding protein, neurophysin II, and the glycoprotein, are secreted in the form of neur osecretory granules down the axons and stored in nerve terminals of the posterio r lobe of the pituitary [7]. ADH has a short half-life of about 15 to 20 minutes and is rapidly metabolized in the liver and kidneys. Glyglycine; Lyslysine; Argarg inine.

Diseases of Water Metabolism 1.7 AQP-3 Recycling vesicle Endocytic retrieval AQP-2 AQP-2 PKA Gas Gas AQP-2 Exocytic i nsertion Recycling vesicle H 2O cAMP ATP AVP AQP-4 Basolateral Luminal FIGURE 1-9 Intracellular action of antidiuretic hormone. The multiple actions of vasopressin can be accounted for by its interaction with the V2 receptor found in the kidney. After stimulation, vasopressin binds to the V2 receptor on the ba solateral membrane of the collecting duct cell. This interaction of vasopressin with the V2 receptor leads to increased adenylate cyclase activity via the stimu latory G protein (Gs), which catalyzes the formation of cyclic adenosine 3', 5'monop hosphte (cAMP) from adenosine triphosphate (ATP). In turn, cAMP activates a ser ine threonine kinase, protein kinase A (PKA). Cytoplasmic vesicles carrying the water channel proteins migrate through the cell in response to this phosphorylat ion process and fuse with the apical membrane in response to increasing vasopres sin binding, thus increasing water permeability of the collecting duct cells. Th ese water channels are recyled by endocytosis once the vasopressin is removed. T he water channel responsible for the high water permeability of the luminal memb rane in response to vasopressin has recently been cloned and designated as aquap orin-2 (AQP-2) [8]. The other members of the aquaporin family, AQP-3 and AQP-4 a re located on the basolateral membranes and are probably involved in water exit from the cell. The molecular biology of these channels and of receptors responsi ble for vasopressin action have contributed to the understanding of the syndrome s of genetically transmitted and acquired forms of vasopressin resistance. AVParg inine vasopressin. AQUAPORINS AND THEIR CHARACTERISTICS AQP-1 Size (amino acids) Permeability to small solutes Regulation by antidiurectic hor mone Site Cellular localization Mutant phenotype 269 No No Proximal tubules; des cending thin limb Apical and basolateral membrane Normal AQP-2 271 No Yes Collecting duct; principal cells Apical membrane and intracellular ve sicles Nephrogenic diabetes insipidus AQP-3 285 Urea glycerol No Medullary collecting duct; colon Basolateral membrane Unkno wn AQP-4 301 No No Hypothalamicsupraoptic, paraventricular nuclei; ependymal, granular, an d Purkinje cells Basolateral membrane of the prinicpal cells Unknown FIGURE 1-10 Aquaporins and their characteristics. An ever growing family of aqua porin (AQP) channels are being described. So far, about seven different channels have been cloned and characterized; however, only four have b een found to have any definite physiologic role.

1.8 Disorders of Water, Electrolytes, and Acid-Base FIGURE 1-11 Osmotic and nonosmotic regulation of antidiuretic hormone (ADH) secr etion. ADH is secreted in response to changes in osmolality and in circulating a rterial volume. The osmoreceptor cells are located in the anterior hypothalamus cl ose to the supraoptic nuclei. Aquaporin-4 (AQP-4), a candidate osmoreceptor, is a member of the water channel family that was recently cloned and characterized and is found in abundance in these neurons. The osmoreceptors are sensitive to c hanges in plasma osmolality of as little as 1%. In humans, the osmotic threshold for ADH release is 280 to 290 mOsm/kg. This system is so efficient that the pla sma osmolality usually does not vary by more than 1% to 2% despite wide fluctuat ions in water intake [9]. There are several other nonosmotic stimuli for ADH sec retion. In conditions of decreased arterial circulating volume (eg, heart failur e, cirrhosis, vomiting), decrease in inhibitory parasympathetic afferents in the carotid sinus baroreceptors affects ADH secretion. Other nonosmotic stimuli inc lude nausea, which can lead to a 500-fold rise in circulating ADH levels, postop erative pain, and pregnancy. Much higher ADH levels can be achieved with hypovol emia than with hyperosmolarity, although a large fall in blood volume is require d before this response is initiated. In the maintenance of tonicity the interpla y of these homeostatic mechanisms also involves the thirst mechanism, that under normal conditions, causes either intake or exclusion of water in an effort to r estore serum osmolality to normal. 50 45 40 Plasma AVP, pg/mL 35 30 25 20 15 10 5 0 Isotonic volume depletion Isovolemic osmotic increase 0 5 10 15 Change, % 20 Control of Water Balance and Serum Sodium Concentration Increased plasma osmolality or decreased arterial circulating volume Decreased p lasma osmolality or increased arterial circulating blood volume Increased thirst Increased ADH release Decreased thirst Decreased ADH release Increased water intake Water retention Decreased water excretion Decreased water intake Water excretion Decreased water excretion Decreased plasma osmolality or increased arterial circulating volume Increased plasma osmolality and decreased arterial circulating volume

A Decreased ADH release and thirst B Increased ADH release and thirst FIGURE 1-12 Pathways of water balance (conservation, A, and excretion, B). In hu mans and other terrestrial animals, the thirst mechanism plays an important role in water (H2O) balance. Hypertonicity is the most potent stimulus for thirst: o nly 2% to 3 % changes in plasma osmolality produce a strong desire to drink wate r. This absolute level of osmolality at which the sensation of thirst arises in healthy persons, called the osmotic threshold for thirst, usually averages about 290 to 295 mOsm/kg H2O (approximately 10 mOsm/kg H2O above that of antidiuretic hormone [ADH] release). The socalled thirst center is located close to the osmo receptors but is anatomically distinct. Between the limits imposed by the osmotic thresholds for thirst and ADH release, plasma osmolality may be regulated still more precisely by small osmoregulated adjustments in urine flow and water intake. The exact lev el at which balance occurs depends on various factors such as insensible losses through skin and lungs, and the gains incurred from eating, normal drinking, and fat metabolism. In general, overall intake and output come into balance at a pl asma osmolality of 288 mOsm/kg, roughly halfway between the thresholds for ADH r elease and thirst [10].

Diseases of Water Metabolism 1.9 Plasma osmolality 280 to 290 mOsm/kg H2O Decrease Supression of thirst Supressio n of ADH release Increase Stimulation of thirst Stimulation of ADH release Dilute urine Concentrated urine FIGURE 1-13 Pathogenesis of dysnatremias. The countercurrent mechanism of the ki dneys in concert with the hypothalamic osmoreceptors via antidiuretic hormone (A DH) secretion maintain a very finely tuned balance of water (H2O). A defect in t he urine-diluting capacity with continued H2O intake results in hyponatremia. Co nversely, a defect in urine concentration with inadequate H2O intake culminates in hypernatremia. Hyponatremia reflects a disturbance in homeostatic mechanisms characterized by excess total body H2O relative to total body sodium, and hypern atremia reflects a deficiency of total body H2O relative to total body sodium [1 1]. (From Halterman and Berl [12]; with permission.) Disorder involving urine dilution with H2O intake Disorder involving urine concentration with inadequate H2O intake Hypernatremia Hyponatremia Approach to the Hyponatremic Patient EFFECTS OF OSMOTICALLY ACTIVE SUBSTANCES ON SERUM SODIUM Substances that increase osmolality and decrease serum sodium (translocational h yponatremia) Glucose Mannitol Glycine Maltose Substances the increase osmolality without changing serum sodium Urea Ethanol Ethylene glycol Isopropyl alcohol Methanol FIGURE 1-14 Evaluation of a hyponatremic patient: effects of osmotically active substances on serum sodium. In the evaluation of a hyponatremic patient, a deter mination should be made about whether hyponatremia is truly hypo-osmotic and not a consequence of translocational or pseudohyponatremia, since, in most but not all situations, hyponatremia reflects hypo-osmolality. The nature of the solute plays an important role in determinin g whether or not there is an increase in measured osmolality or an actual increa se in effective osmolality. Solutes that are permeable across cell membranes (eg , urea, methanol, ethanol, and ethylene glycol) do not cause water movement and cause hypertonicity without causing cell dehydration. Typical examples are an ur emic patient with a high blood urea nitrogen value and an ethanolintoxicated per son. On the other hand, in a patient with diabetic ketoacidosis who is insulinop enic the glucose is not permeant across cell membranes and, by its presence in t he extracellular fluid, causes water to move from the cells to extracellular spa ce, thus leading to cell dehydration and lowering serum sodium. This can be view ed as translocational at the cellular level, as the serum sodium level does not reflect changes in total body water but rather movement of water from intracellu lar to extracellular space. Glycine is used as an irrigant solution during trans urethral resection of the prostate and in endometrial surgery. Pseudohyponatremi a occurs when the solid phase of plasma (usually 6% to 8%) is much increased by large increments of either lipids or proteins (eg, in hypertriglyceridemia or pa raproteinemias).

1.10 Disorders of Water, Electrolytes, and Acid-Base FIGURE 1-15 Pathogenesis of hyponatremia. The normal components of the renal dil uting mechanism are depicted in Figure 1-3. Hyponatremia results from disorders of this diluting capacity of the kidney in the following situations: 1. Intrarenal factors such as a diminished glomerular filtration rate (GFR), or an increase in proximal tubule fluid and sodium reabsorption, or both, which dec rease distal delivery to the diluting segments of the nephron, as in volume depl etion, congestive heart failure, cirrhosis, or nephrotic syndrome. 2. A defect i n sodium chloride transport out of the water-impermeable segments of the nephron s (ie, in the thick ascending limb of the loop of Henle). This may occur in pati ents with interstitial renal disease and administration of thiazide or loop diur etics. 3. Continued secretion of antidiuretic hormone (ADH) despite the presence of serum hypo-osmolality mostly stimulated by nonosmotic mechanisms [12]. Reabsorption of sodium chloride in distal convoluted tubule Thiazide diuretics GFR diminished Age Renal disease Congestive heart failure Cirrhosis Nephrotic sy ndrome Volume depletion Reabsorption of sodium chloride in thick ascending limb of loop of Henle Loop di uretics Osmotic diuretics Interstitial disease NaCl - ADH release or action Drugs Syndrome of inappropriate antidiuretic hormone secre tion, etc. NaClsodium chloride. Assessment of volume status Hypovolemia Total body water Total body sodium Euvolemia (no edema) Total body water - Total body sodium Hypervolemia Total body water -- Total body sodium UNa >20 UNa <20 UNa >20 UNa >20 UNa <20 Renal losses Diuretic excess Mineralcorticoid deficiency Salt-losing deficiency Bicarbonaturia with renal tubal acidosis and metabolic alkalosis Ketonuria Osmot ic diuresis Extrarenal losses Vomiting Diarrhea Third spacing of fluids Burns Pancreatitis T rauma Glucocorticoid deficiency Hypothyroidism Stress Drugs Syndrome of inappropriate antidiuretic hormone secretion Acute or chronic renal failure

Nephrotic syndrome Cirrhosis Cardiac failure FIGURE 1-16 Diagnostic algorithm for hyponatremia. The next step in the evaluati on of a hyponatremic patient is to assess volume status and identify it as hypov olemic, euvolemic or hypervolemic. The patient with hypovolemic hyponatremia has both total body sodium and water deficits, with the sodium deficit exceeding th e water deficit. This occurs with large gastrointestinal and renal losses of wat er and solute when accompanied by free water or hypotonic fluid intake. In patie nts with hypervolemic hyponatremia, total body sodium is increased but total body water is increased even more than sodium, causing hypon atremia. These syndromes include congestive heart failure, nephrotic syndrome, a nd cirrhosis. They are all associated with impaired water excretion. Euvolemic h yponatremia is the most common dysnatremia in hospitalized patients. In these pa tients, by definition, no physical signs of increased total body sodium are dete cted. They may have a slight excess of volume but no edema [12]. (Modified from Halterman and Berl [12]; with permission.)

Diseases of Water Metabolism 1.11 DRUGS ASSOCIATED WITH HYPONATREMIA Antidiuretic hormone analogues Deamino-D-arginine vasopressin (DDAVP) Oxytocin D rugs that enhance release of antidiuretic hormone Chlorpropamide Clofibrate Carb amazepine-oxycarbazepine Vincristine Nicotine Narcotics Antipsychotics Antidepre ssants Ifosfamide Drugs that potentiate renal action of antidiuretic hormone Chl orpropamide Cyclophosphamide Nonsteroidal anti-inflammatory drugs Acetaminophen Drugs that cause hyponatremia by unknown mechanisms Haloperidol Fluphenazine Ami triptyline Thioradazine Fluoxetine CAUSES OF THE SYNDROME OF INAPPROPRIATE DIURETIC HORMONE SECRETION Pulmonary Disorders Viral pneumonia Bacterial pneumonia Pulmonary abscess Tuberculosis Aspergillosis Positive-pressure breathing Asthma Pneumothorax Mesothelioma Cystic fibrosis Carcinomas Bronchogenic Duodenal Pancreatic Thymoma Gastric Lymphoma Ewing's sarcoma Bladder Carcinoma of the ureter Prostatic Oropharyngeal Central Nervous System Disorders Encephalitis (viral or bacterial) Meningitis (viral, bacterial, tuberculous, fun gal) Head trauma Brain abscess Brain tumor Guillain-Barr syndrome Acute intermitt ent porphyria Subarachnoid hemorrhage or subdural hematoma Cerebellar and cerebr al atrophy Cavernous sinus thrombosis Neonatal hypoxia Hydrocephalus Shy-Drager syndrome Rocky Mountain spotted fever Delirium tremens Cerebrovascular accident (cerebral thrombosis or hemorrhage) Acute psychosis Multiple sclerosis FIGURE 1-17 Drugs that cause hyponatremia. Drug-induced hyponatremia is mediated by antidiuretic hormone analogues like deamino-D-arginine-vasopressin (DDAVP), or antidiuretic hormone release, or by potentiating the action of antidiuretic h ormone. Some drugs cause hyponatremia by unknown mechanisms [13]. (From Veis and Berl [13]; with permission.) FIGURE 1-18 Causes of the syndrome of inappropriate antidiuretic hormone secreti on (SIADH). Though SIADH is the commonest cause of hyponatremia in hospitalized patients, it is a diagnosis of exclusion. It is characterized by a defect in osm oregulation of ADH in which plasma ADH levels are not appropriately suppressed f or the degree of hypotonicity, leading to urine concentration by a variety of me chanisms. Most of these fall into one of three categories (ie, malignancies, pul monary diseases, central nervous system disorders) [14]. FIGURE 1-19 Diagnostic criteria for the syndrome of inappropriate antidiuretic hormone secretion (SIADH ). Clinically, SIADH is characterized by a decrease in the effective extracellul ar fluid osmolality, with inappropriately concentrated urine. Patients with SIAD H are clinically euvolemic and are consuming normal amounts of sodium and water (H2O). They have elevated urinary sodium excretion. In the evaluation of these p atients, it is important to exclude adrenal, thyroid, pituitary, and renal disea se and diuretic use. Patients with clinically suspected SIADH can be tested with a water load. Upon administration of 20 mL/kg of H2O, patients with SIADH are u nable to excrete 90% of the H2O load and are unable to dilute their urine to an osmolality less than 100 mOsm/kg [15]. (Modified from Verbalis [15]; with permis sion.) DIAGNOSTIC CRITERIA FOR THE SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRE TION Essential Decreased extracellular fluid effective osmolality (< 270 mOsm/kg H2O) Inappropriate urinary concentration (> 100 mOsm/kg H2O) Clinical euvolemia Elev ated urinary sodium concentration (U[Na]), with normal salt and H2O intake Absen

ce of adrenal, thyroid, pituitary, or renal insufficiency or diuretic use Supple mental Abnormal H2O load test (inability to excrete at least 90% of a 20mL/kg H2O load in 4 hrs or failure to dilute urinary osmolality to < 100 mOsm/kg) Plasma antidiuretic hormone level inappropriately elevated relative to plasma osmolalit y No significant correction of plasma sodium with volume expansion, but improvem ent after fluid restriction

1.12 Disorders of Water, Electrolytes, and Acid-Base FIGURE 1-20 Signs and symptoms of hyponatremia. In evaluating hyponatremic patie nts, it is important to assess whether or not the patient is symptomatic, becaus e symptoms are a better determinant of therapy than the absolute value itself. M ost patients with serum sodium values above 125 mEq/L are asymptomatic. The rapi dity with which hyponatremia develops is critical in the initial evaluation of s uch patients. In the range of 125 to 130 mEq/L, the predominant symptoms are gas trointestinal ones, including nausea and vomiting. Neuropsychiatric symptoms dom inate the picture once the serum sodium level drops below 125 mEq/L, mostly beca use of cerebral edema secondary to hypotonicity. These include headache, letharg y, reversible ataxia, psychosis, seizures, and coma. Severe manifestations of ce rebral edema include increased intracerebral pressure, tentorial herniation, res piratory depression and death. Hyponatremia-induced cerebral edema occurs princi pally with rapid development of hyponatremia, typically in patients managed with hypotonic fluids in the postoperative setting or those receiving diuretics, as discussed previously. The mortality rate can be as great as 50%. Fortunately, th is rarely occurs. Nevertheless, neurologic symptoms in a hyponatremic patient ca ll for prompt and immediate attention and treatment [16,17]. SIGNS AND SYMPTOMS OF HYPONATREMIA Central Nervous System Mild Apathy Headache Lethargy Moderate Agitation Ataxia Confusion Disorientation Psychosis Severe Stupor Coma Pseudobulbar palsy Tentorial herniation Cheyne-Sto kes respiration Death Gastrointestinal System Anorexia Nausea Vomiting Musculoskeletal System Cramps Diminished deep tendon reflexes FIGURE 1-21 Cerebral adaptation to hyponatremia. 3 Na+/H2O Na+/-H2O Na+/-H2O A, Decrea ses in extracellular osmolality 2 cause movement of water (H2O) into the cells, increasing intracellular volume and K+, Na+ K+, Na+ K+, Na+ thus causing tissue ed ema. This cellular H 2O -H2O H 2O osmolytes osmolytes osmolytes edema within the fi xed confines of the cranium causes increased intracranial pressure, leading to n eurologic symptoms. To prevent this from happening, mechanisms geared toward vol ume regulation come into operaNormonatremia Acute hyponatremia Chronic hyponatre mia A tion, to prevent cerebral edema from developing in the vast majority of pa tients with hyponatremia. After induction of extracellular fluid hypo-osmolality , H2O moves into the brain in response to osmotic gradients, producing cerebral edema (middle panel, 1). However, within 1 to 3 hours, a decrease in cerebral ex tracellular volume occurs by movement of K+ fluid into the cerebrospinal fluid, which is then shunted back into the systemic circulation. Glutamate This happens very promptly and is evident by the loss of extracellular and intracellular sol utes (sodium and chloride ions) as early as 30 minutes after the onset of hypona tremia. Na+ As H2O losses accompany the losses of brain solute (middle panel, 2) , the expanded brain Urea volume decreases back toward normal (middle panel, 3) [15]. B, Relative decreases in individual osmolytes during adaptation to chronic hyponatremia. Thereafter, if hyponatremia persists, other organic osmolytes suc h as phosphocreatine, myoinositol, and amino acids Inositol like glutamine, and taurine are lost. The loss of these solutes markedly decreases cerebral Cl swelli ng. Patients who have had a slower onset of hyponatremia (over 72 to 96 hours or Taurine longer), the risk for osmotic demyelination rises if hyponatremia is co rrected too rapidly Other B [18,19]. Na+sodium; K+potassium; Cl-chloride. 1

Diseases of Water Metabolism 1.13 HYPONATREMIC PATIENTS AT RISK FOR NEUROLOGIC COMPLICATIONS Complication Acute cerebral edema SYMPTOMS OF CENTRAL PONTINE MYELINOLYSIS Initial symptoms Mutism Dysarthria Lethargy and affective changes Classic sympto ms Spastic quadriparesis Pseudobulbar palsy Lesions in the midbrain, medulla obl ongata, and pontine tegmentum Pupillary and oculomotor abnormalities Altered sen sorium Cranial neuropathies Extrapontine myelinolysis Ataxia Behavioral abnormal ities Parkinsonism Dystonia Persons at Risk Postoperative menstruant females Elderly women taking thiazides Children Psychia tric polydipsic patients Hypoxemic patients Alcoholics Malnourished patients Hyp okalemic patients Burn victims Elderly women taking thiazide diuretics Osmotic demyelination syndrome FIGURE 1-22 Hyponatremic patients at risk for neurologic complications. Those at risk for cerebral edema include postoperative menstruant women, elderly women t aking thiazide diuretics, children, psychiatric patients with polydipsia, and hy poxic patients. In women, and, in particular, menstruant ones, the risk for deve loping neurologic complications is 25 times greater than that for nonmenstruant women or men. The increased risk was independent of the rate of development, or the magnitude of the hyponatremia [21]. The osmotic demyelination syndrome or ce ntral pontine myelinolysis seems to occur when there is rapid correction of low osmolality (hyponatremia) in a brain already chronically adapted (more than 72 t o 96 hours). It is rarely seen in patients with a serum sodium value greater tha n 120 mEq/L or in those who have hyponatremia of less than 48 hours' duration [20, 21]. (Adapted from Lauriat and Berl [21]; with permission.) FIGURE 1-23 Symptoms of central pontine myelinolysis. This condition has been de scribed all over the world, in all age groups, and can follow correction of hypo natremia of any cause. The risk for development of central pontine myelinolysis is related to the severity and chronicity of the hyponatremia. Initial symptoms include mutism and dysarthria. More than 90% of patients exhibit the classic sym ptoms of myelinolysis (ie, spastic quadriparesis and pseudobulbar palsy), reflec ting damage to the corticospinal and corticobulbar tracts in the basis pontis. O ther symptoms occur on account of extension of the lesion to other parts of the midbrain. This syndrome follows a biphasic course. Initially, a generalized ence phalopathy, associated with a rapid rise in serum sodium, occurs. This is follow ed by the classic symptoms 2 to 3 days after correction of hyponatremia, however , this pattern does not always occur [22]. (Adapted from Laureno and Karp [22]; with permission.) A B images, hypointense. These lesions do not enhance with gadolinium. They may not be apparent on imaging until 2 weeks into the illness. Other diagnostic tests ar e brainstem auditory evoked potentials, electroencephalography, and cerebrospina l fluid protein and myelin basic proteins [22]. B, Gross appearance of the pons in central pontine myelinolysis. (From Laureno and Karp [22]; with permission.) FIGURE 1-24 A, Imaging of central pontine myelinolysis. Brain imaging is the mos t useful diagnostic technique for central pontine myelinolysis. Magnetic resonan

ce imaging (MRI) is more sensitive than computed tomography (CT). On CT, central pontine and extrapontine lesions appear as symmetric areas of hypodensity (not shown). On T2 images of MRI, the lesions appear as hyperintense and on T1

1.14 Disorders of Water, Electrolytes, and Acid-Base FIGURE 1-25 Treatment of severe euvolemic hyponatremia (<125 mmol/L). The evalua tion of a hyponatremic patient involves an assessment of whether the patient is symptomatic, and if so, the duration of hyponatremia should be ascertained. The therapeutic approach to the hyponatremic patient is determined more by the prese nce or absence of symptoms than by the absolute level of serum sodium. Acutely h yponatremic patients are at great risk for permanent neurologic sequelae from ce rebral edema if the hyponatremia is not promptly corrected. On the other hand, c hronic hyponatremia carries the risk of osmotic demyelination syndrome if correc ted too rapidly. The next step involves a determination of whether the patient h as any risk factors for development of neurologic complications. The commonest s etting for acute, symptomatic hyponatremia is hospitalized, postoperative patien ts who are receiving hypotonic fluids. In these patients, the risk of cerebral e dema outweighs the risk for osmotic demyelination. In the presence of seizures, obtundation, and coma, rapid infusion of 3% sodium chloride (4 to 6 mL/kg/h) or even 50 mL of 29.2% sodium chloride has been used safely. Ongoing careful neurol ogic monitoring is imperative [20]. Severe hyponatremia (<125 mmol/L) Symptomatic Asymptomatic Acute Duration <48 h Chronic Duration >48 h Chronic Rarely <48 h Emergency correction needed Hypertonic saline 12 mL/kg/h Coadministration of furo semide Some immediate correction needed Hypertonic saline 12 mL/kg/h Coadministration of furosemide Change to water restriction upon 10% increase of sodium or if sympto ms resolve Perform frequent measurement of serum and urine electrolytes Do not e xceed 1.5 mmol/L/hr or 20 mmol/d No immediate correction needed Long-term management Identification and treatment of reversible causes Water res triction Demeclocycline, 300600 mg bid Urea, 1560 g/d V2 receptor antagonists A. GENERAL GUIDELINES FOR THE TREATMENT OF SYMPTOMATIC HYPONATREMIA* Acute hyponatremia (duration < 48 hrs) Increase serum sodium rapidly by approxim ately 2 mmol/L/h until symptoms resolve Full correction probably safe but not ne cessary Chronic hyponatremia (duration > 48 hrs) Initial increase in serum sodiu m by 10% or 10 mmol/L Perform frequent neurologic evaluations; correction rate m ay be reduced with improvement in symptoms At no time should correction exceed r ate of 1.5 mmol/L/h, or increments of 15 mmol/d Measure serum and urine electrol ytes every 12 h *The sum of urinary cations (UNa + UK) should be less than the co ncentration of infused sodium, to ensure excretion of electrolyte-free water. B. TREATMENT OF CHRONIC SYMPTOMATIC HYPONATREMIA Calculate the net water loss needed to raise the serum sodium (SNa) from 110 mEq /L to 120 mEq/L in a 50 kg person. Example Current SNa Total body water (TBW) = Desired SNa New TBW Assume that TBW = 60% o f body weight Therefore TBW of patient = 50 0.6 = 30 L 110 mEq/L 30 L New TBW = = 27.5 L 120 mEq/L Thus the electrolyte-free water loss needed to raise the SNa to 120 mEq/L = Present TBW New TBW = 2.5 L FIGURE 1-26 General guidelines for the treatment of symptomatic hyponatremia, A.

Included herein are general guidelines for treatment of patients with acute and chronic symptomatic hyponatremia. In the treatment of chronic symptomatic hypon atremia, since cerebral water is increased by approximately 10%, a prompt increa se in serum sodium by 10% or 10 mEq/L is permissible. Thereafter, the patient's fl uids should be restricted. The total correction rate should not Calculate the time course in which to achieve the desired correction (1 mEq/h)in this case, 250 mL/h Administer furosemide, monitor urine output, and replace sod ium, potassium, and excess free water lost in the urine Continue to monitor urin e output and replace sodium, potassium, and excess free water lost in the urine exceed 1.0 to 1.5 mEq/L/h, and the total increment in 24 hours should not exceed 15 mmol/d [12]. A specific example as to how to increase a patient's serum sodium is illustrated in B.

Diseases of Water Metabolism 1.15 MANAGEMENT OPTIONS FOR CHRONIC ASYMPTOMATIC HYPONATREMIA Treatment Fluid restriction Pharmacologic inhibition of antidiuretic hormone action Lithiu m Demeclocycline V2-receptor antagonist Increased solute intake Furosemide Urea Mechanism of Action Decreases availability of free water Dose Variable Advantages Effective and inexpensive Limitations Noncompliance Inhibits the kidney's response to antidiuretic hormone Inhibits the kidney's respons e to antidiurectic hormone Antagonizes vasopressin action Increases free water c learance Osmotic diuresis 9001200 mg/d 1200 mg/d initially; then, 300900 mg/d Unrestricted water intake Effective; unrestricted water intake Ongoing trials Ef fective Effective; unrestricted water intake Polyuria, narrow therapeutic range, neurotoxicity Neurotoxicity, polyuria, photo sensitivity, nephrotoxicity Titrate to optimal dose; coadminister 23 g sodium chloride 3060 g/d Ototoxicity, K+ and Mg2+ depletion Polyuria, unpalatable gastrointestinal sympto ms FIGURE 1-27 Management options for patients with chronic asymptomatic hyponatrem ia. If the patient has chronic hyponatremia and is asymptomatic, treatment need not be intensive or emergent. Careful scrutiny of likely causes should be follow ed by treatment. If the cause is determined to be the syndrome of inappropriate antidiuretic hormone (ADH) secretion, it must be treated as a chronic disorder. As summarized here, the treatment strategies involve fluid restriction, pharmaco logic inhibition of ADH action, and increased solute intake. Fluid restriction i s frequently successful in normalizing serum sodium and preventing symptoms [23] . FIGURE 1-28 Management of noneuvolemic hyponatremia. Hypovolemic hyponatremia results from the loss of both water and solute, with relatively greater loss of solute. The nonosmotic release of antidiuretic hormone stimulated by decreased a rterial circulating blood volume causes antidiuresis and perpetuates the hyponat remia. Most of these patients are asymptomatic. The keystone of therapy is isoto nic saline administration, which corrects the hypovolemia and removes the stimul us of antidiuretic hormone to retain fluid. Hypervolemic hyponatremia occurs whe n both solute and water are increased, but water more than solute. This occurs w ith heart failure, cirrhosis and nephrotic syndrome. The cornerstones of treatme nt include fluid restriction, salt restriction, and loop diuretics [20]. (Adapte d from Lauriat and Berl [20]; with permission.) MANAGEMENT OF NONEUVOLEMIC HYPONATREMIA

Hypovolemic hyponatremia Volume restoration with isotonic saline Identify and co rrect causes of water and sodium losses Hypervolemic hyponatremia Water restrict ion Sodium restriction Substitiute loop diuretics for thiazide diurectics Treatm ent of timulus for sodium and water retention V2-receptor antagonist

1.16 Disorders of Water, Electrolytes, and Acid-Base Approach to the Hypernatremic Patient ADH release or action Nephrogenic DI Central DI (see Fig. 1-) GFR diminished Age Renal disease Reabsorption of sodium chloride in thick ascending limb of loop of Henle Loop di uretics Osmotic diuretics Interstitial disease Urea NaCl Urea in the medulla Water diuresis Decreased dietary protein intake FIGURE 1-29 Pathogenesis of hypernatremia. The renal concentrating mechanism is the first line of defense against water depletion and hyperosmolality. When rena l concentration is impaired, thirst becomes a very effective mechanism for preve nting further increases in serum osmolality. The components of the normal urine concentrating mechanism are shown in Figure 1-2. Hypernatremia results from dist urbances in the renal concentrating mechanism. This occurs in interstitial renal disease, with administration of loop and osmotic diuretics, and with protein ma lnutrition, in which less urea is available to generate the medullary interstiti al tonicity. Hypernatremia usually occurs only when hypotonic fluid losses occur in combination with a disturbance in water intake, typically in elders with alt ered consciousness, in infants with inadequate access to water, and, rarely, wit h primary disturbances of thirst [24]. GFRglomerular filtration rate; ADHantidiure tic hormone; DIdiabetes insipidus. Assessment of volume status Hypovolemia Total body water Total body sodium UNa>20 R enal losses Osmotic or loop diuretic Postobstruction Intrinsic renal disease UNa <20 Extrarenal losses Excessive sweating Burns Diarrhea Fistulas Euvolemia (no e dema) Total body water Total body sodium UNa variable Renal losses Diabetes insipid us Hypodipsia Extrarenal losses Insensible losses Respiratory Dermal Hypervolemi a Total body water - Total body sodium -- UNa>20 Sodium gains Primary Hyperaldosteronism Cushing's sydrome Hypertonic dialysis Hypertonic sodium bicarbonate Sodium chlo ride tablets FIGURE 1-30 Diagnostic algorithm for hypernatremia. As for hyponatremia, the ini tial evaluation of the patient with hypernatremia involves assessment of volume status. Patients with hypovolemic hypernatremia lose both sodium and water, but relatively more water. On physical examination, they exhibit signs of hypovolemi a. The causes listed reflect principally hypotonic water losses from the kidneys or the gastrointestinal tract. Euvolemic hyponatremia reflects water losses acc ompanied by inadequate water intake. Since such hypodipsia is uncommon, hypernat remia usually supervenes in persons who have no access to water or who have a ne urologic deficit that impairs thirst perceptionthe very young and the very old. E xtrarenal water loss occurs from the skin and respiratory tract, in febrile or other hypermetabolic states. Very high urin e osmolality reflects an intact osmoreceptorantidiuretic hormonerenal response. Th us, the defense against the development of hyperosmolality requires appropriate stimulation of thirst and the ability to respond by drinking water. The urine so dium (UNa) value varies with the sodium intake. The renal water losses that lead to euvolemic hypernatremia are a consequence of either a defect in vasopressin production or release (central diabetes insipidus) or failure of the collecting duct to respond to the hormone (nephrogenic diabetes insipidus) [23]. (Modified from Halterman and Berl [12]; with permission.)

Diseases of Water Metabolism 1.17 Urine volume = CH2O + COsm COsm Isotonic or hypertonic urine CH2O Hypotonic urine Polyuria due to increased solute excretion Sodium chloride Diuretics Renal sodiu m wasting Excessive salt intake Bicarbonate Vomiting/metabolic alkalosis Alkali administration Mannitol Diuretics Bladder lavage Treatment of cerebral edema Polyuria due to increased free water clearance Excessive water intake Psychogeni c polydipsia Defect in thirst Hyper-reninemia Potassium depletion Renal vascular disease Renal tumors Renal hypoperfusion Increased renal water excretion Impair ed renal water concentrating mechanism Decreased ADH secretion Increased ADH deg radation Resistance to ADH action FIGURE 1-31 Physiologic approach to polyuric disorders. Among euvolemic hypernat remic patients, those affected by polyuric disorders are an important subcategor y. Polyuria is arbitrarily defined as urine output of more than 3 L/d. Urine vol ume can be conceived of as having two components: the volume needed to excrete s olutes at the concentration of solutes in plasma (called the osmolar clearance) and the other being the free water clearance, which is the volume of solute-free water that has been added to (positive free water clearance [CH2O]) or subtract ed (negative CH2O) from the isotonic portion of the urine osmolar clearance (Cos m) to create either a hypotonic or hypertonic urine. Consumption of an average A merican diet requires the kidneys to excrete 600 to 800 mOsm of solute each day. The urine volume in which this solute is excreted is determined by fluid intake . If the urine is maximally diluted to 60 mOsm/kg of water, the 600 mOsm will ne ed 10 L of urine for effective osmotic clearance. If the concentrating mechanism is maximally stimulated to 1200 mOsm/kg of water, osmotic clearance will occur in a minimum of 500 mL of urine. This flexibility is affected when drugs or dise ases alter the renal concentrating mechanism. Polyuric disorders can be secondar y to an increase in solute clearance, free water clearance, or a combination of both. ADHantidiuretic hormone. WATER DEPRIVATION TEST Urine Osmolality with Water Deprivation (mOsm/kg H2O) > 800 < 300 300800 < 300500 > 500 CLINICAL FEATURES OF DIABETES INSIPIDUS Plasma Arginine Vasopressin (AVP) after Dehydration > 2 pg/mL Indetectable < 1.5 pg/mL > 5 pg/mL < 5 pg/mL Diagnosis Normal Complete central diabetes insipidus Partial central diabetes insipidus Ne phrogenic diabetes insipidus Primary polydipsia Increase in Urine Osmolality with Exogenous AVP Little or none Substantial > 10% of urine osmolality after water deprivation Lit tle or none Little or none Abrupt onset Equal frequency in both sexes Rare in infancy, usual in second deca de of life Predilection for cold water Polydipsia Urine output of 3 to 15 L/d Ma rked nocturia but no diurnal variation Sleep deprivation leads to fatigue and ir ritability Severe life-threatening hypernatremia can be associated with illness or water deprivation

* Water intake is restricted until the patient loses 3%5% of weight or until thre e consecutive hourly determinations of urinary osmolality are within 10% of each other. (Caution must be exercised to ensure that the patient does not become ex cessively dehydrated.) Aqueous AVP (5 U subcutaneous) is given, and urine osmola lity is measured after 60 minutes. The expected responses are given above. FIGURE 1-32 Water deprivation test. Along with nephrogenic diabetes insipidus an d primary polydipsia, patients with central diabetes insipius present with polyu ria and polydipsia. Differentiating between these entities can be accomplished b y measuring vasopressin levels and determining the response to water deprivation followed by vasopressin administration [25]. (From Lanese and Teitelbaum [26]; with permission.) FIGURE 1-33 Clinical features of diabetes insipidus. Other clinical features can distinguish compulsive water drinkers from patients with central diabetes insip idus. The latter usually has abrupt onset, whereas compulsive water drinkers may give a vague history of the onset. Unlike compulsive water drinkers, patients w ith central diabetes insipidus have a constant need for water. Compulsive water drinkers exhibit large variations in water intake and urine output. Nocturia is common with central diabetes insipidus and unusual in compulsive water drinkers. Finally, patients with central diabetes insipidus have a predilection for drink ing cold water. Plasma osmolality above 295 mOsm/kg suggests central diabetes in sipidus and below 270 mOsm/kg suggests compulsive water drinking [23].

1.18 Disorders of Water, Electrolytes, and Acid-Base FIGURE 1-34 Causes of diabetes insipidus. The causes of diabetes insipidus can b e divided into central and nephrogenic. Most (about 50%) of the central causes a re idiopathic; the rest are caused by central nervous system involvement with in fection, tumors, granuloma, or trauma. The nephrogenic causes can be congenital or acquired [23]. CAUSES OF DIABETES INSIPIDUS Central diabetes insipidus Congenital Autosomal-dominant Autosomal-recessive Acquired Post-traumatic Iatrog enic Tumors (metastatic from breast, craniopharyngioma, pinealoma) Cysts Histioc ytosis Granuloma (tuberculosis, sarcoid) Aneurysms Meningitis Encephalitis Guill ain-Barr syndrome Idiopathic Nephrogenic diabetes insipidus Congenital X-linked Autosomal-recessive Acquired Renal diseases (medullary cysti c disease, polycystic disease, analgesic nephropathy, sickle cell nephropathy, o bstructive uropathy, chronic pyelonephritis, multiple myeloma, amyloidosis, sarc oidosis) Hypercalcemia Hypokalemia Drugs (lithium compounds, demeclocycline, met hoxyflurane, amphotericin, foscarnet) SP VP Exon 1 NP NP Exon 2 NP Exon 3 83 CP 19..16 47 50 14 17 20 57 61 62 65 Missense mutation Stop codon Deletion 79 87 FIGURE 1-35 Congenital central diabetes insipidus (DI), autosomal-dominant form. This condition has been described in many families in Europe and North America. It is an autosomal dominant inherited disease associated with marked loss of ce lls in the supraoptic nuclei. Molecular biology techniques have revealed multipl e point mutations in the vasopressin-neurophysin II gene. This condition usually presents early in life [25]. A rare autosomal-recessive form of central DI has been described that is characterized by DI, diabetes mellitus (DM), optic atroph y (OA), and deafness (DIDMOAD or Wolfram's syndrome). This has been linked to a de fect in chromosome-4 and involves abnormalities in mitochondrial DNA [27]. SPsign al peptide; VPvasopressin; NPneurophysin; GPglycoprotein. 3 1 24 67

Diseases of Water Metabolism 1.19 TREATMENT OF CENTRAL DIABETES INSIPIDUS Condition Complete central DI Partial central DI Drug dDAVP Vasopressin tannate Aqueous vasopressin Chlorpropamide Clofibrate Carbamaz epine

Dose 1020 (g intranasally q 1224 h 25 U IM q 2448 h 510 U SC q 46 h 250500 mg/d 500 mg tid 400600 mg/d FIGURE 1-36 Treatment of central diabetes insipidus (DI). Central DI may be trea ted with hormone replacement or drugs. In acute settings when renal water losses are extensive, aqueous vasopressin (pitressin) is useful. It has a short durati on of action that allows for careful monitoring and avoiding complications like water intoxication. This drug should be used with caution in patients with under lying coronary artery disease and peripheral vascular disease, as it can cause v ascular spasm and prolonged vasoconstriction. For the patient with established c entral DI, desmopressin acetate (dDAVP) is the agent of choice. It has a long ha lf-life and does not have significant vasoconstrictive effects like those of aqu eous vasopressin. It can be conveniently administered intranasally every 12 to 2 4 hours. It is usually tolerated well. It is safe to use in pregnancy and resist s degradation by circulating vasopressinase. In patients with partial DI, agents that potentiate release of antidiuretic hormone can be used. These include chlo rpropamide, clofibrate, and carbamazepine. They work effectively only if combine d with hormone therapy, decreased solute intake, or diuretic administration [23] . FIGURE 1-37 Congenital nephrogenic diabetes insipidus, X-linkedrecessive form. This is a rare disease of male patients who do not concentrate their urine after administration of antidiuretic hormone. The pedigrees of affected families have been linked to a group of Ulster Scots who emigrated to Halifax, Nova Scotia in 1761 aboard the ship called Hopewell. According to the Hopewell hypothesis, most North American patients with this disease are descendants of a common ancestor w ith a single gene defect. Recent studies, however, disproved this hypothesis [28 ]. The gene defect has now been traced to 87 different mutations in the gene for the vasopressin receptor (AVP-R2) in 106 presumably unrelated families [29]. (F rom Bichet, et al. [29]; with permission.) S N S S P S L S P L P H * G P V A S T T S A M L M 1

NH2 Extracellular Q E R P L D L A R A L P D R T E L * L A F S I L A V A V L G S V A L V N A L L * * A R R G R R G V A D L F I P A W H D T A K W A L Q L P Q L F V L A A C L H I G H V R F Intracellular R F Y C G V A H P K A A A I M V E A I R P L L A W Y C G F I Q * G L A P D Q W P C M V G R V A S A L V M S F L G G P M L G Q T E A M L G R F I P G V F A E V L Y W L V R L G P H T M D G V A E S C P R E V S R R C Y I * Y T H P * L R G D A H G T L R R N R V R A T W A Q L S S G I S L A F N A A W S I H V L R

P E D W A W A Q L L V F F A P C W V L V Y V V V I L M T R V T K A S A V A A P L E G A L L N N V S V L * L T I S F S S S S E L R S P F L M A S S C P W Y A L L C C A R G R T P P C S E D Q P G L P S G T T T R A S S R G R S S 371 L A K D T S S COOH

1.20 Urinary lumen Disorders of Water, Electrolytes, and Acid-Base FIGURE 1-38 Congenital nephrogenic diabetes insipidus (NDI), autosomalrecessive form. In the autosomal recessive form of NDI, mutations have been found in the g ene for the antiiuretic hormone (ADH) sensitive water channel, AQP-2. This form o f NDI is exceedingly rare as compared with the X-linked form of NDI [30]. Thus f ar, a total of 15 AQP-2 mutations have been described in total of 13 families [3 1]. The acquired form of NDI occurs in various kidney diseases and in associatio n with various drugs, such as lithium and amphotericin B. (From Canfield et al. [31]; with permission.) L A P A S 11 V 9,12 R V L A V N A D T A G G 8 P R L K N I S F M D N D S S A D 13 C P T H G T 6 T W T I A V Y E Q A L P S G H F H Q I W L V G I A P V L L L G T W L A P A G 4 E V I Q M A N L G H L V A L A L A G V F G S F A L G V A A G L I S L G L F F L L T L I G T G G G V F Q Q A I F L S 12 S L A V L 13 V L L L L V Q T L Y C A Y F A A N P T A I Y G F A G L F L V A P E L R 7 H S N A F L I T F E P D G V S V P E R R S 1 G A A A V R K S H S H F L I C P Q S L A S S 2 N H P G E I 11 R L R P V G S M L E T W E L R A L K A V C 3 V A V T V A S L Q R K R G V E Princi pal cell R E L E W D T D P E -intracellular ACQUIRED NEPHROGENIC DIABETES INSIPIDUS: CAUSES AND MECHANISMS Defect in Generation of Medullary Defect in cAMP Downregulation Interstitial Ton icity Generation of AQP-2 Other Downregulation of V2 receptor message PATIENT GROUPS AT INCREASED RISK FOR SEVERE HYPERNATREMIA Elders and infants Hospitalized patients receiving Hypertonic infusions Tube fee dings Osmotic diuretics Lactulose Mechanical ventilation Altered mental status U ncontrolled diabetes mellitus Underlying polyuria Disease State Chronic renal failure Hypokalemia Hypercalcemia Sickle cell disease Protein maln utrition Demeclocycline Lithium Pregnancy Placental secretion of vasopressinase FIGURE 1-39 Causes and mechanisms of acquired nephrogenic diabetes insidpidus. A cquired nephrogenic diabetes insipidus occurs in chronic renal failure, electrol yte imbalances, with certain drugs, in sickle cell disease and pregnancy. The ex act mechanism involved has been the subject of extensive investigation over the past decade and has now been carefully elucidated for most of the etiologies. FIGURE 1-40 Patient groups at increased risk for severe hypernatremia. Hypernatr emia always reflects a hyperosmolar state. It usually occurs in a hospital setti ng (reported incidence 0.65% to 2.23% of all hospitalized patients) with very hi gh morbidity and mortality (estimates of 42% to over 70%) [12].

Diseases of Water Metabolism 1.21 SIGNS AND SYMPTOMS OF HYPERNATREMIA Central Nervous System Mild Restlessness Lethargy Altered mental status Irritability Moderate Disorient ation Confusion Severe Stupor Coma Seizures Death Hypovolemic hypernatremia Euvolemic hypernatremia Hypervolemic hypernatremia Correction of volume deficit Administer isotonic saline until hypovolemia improv es Treat causes of losses (insulin, relief of urinary tract obstruction, removal of osmotic diuretics) Correction of water deficit Calculate water deficit Admin ister 0.45% saline, 5% dextrose or oral water replacing deficit and ongoing loss es Correction of water deficit Calculate water deficit Administer 0.45% saline, 5% dextrose or oral water to replace the deficit and ongoing losses In central diab etes insipidus with severe losses, aqueous vasopressin (pitressin) 5 U SC q 6 hr Follow serum sodium concentration carefully to avoid water intoxication Removal of sodium Discontinue offending agents Administer furosemide Provide hem odialysis, as needed, for renal failure Respiratory System Labored respiration Gastrointestinal System Intense thirst Nausea Vomiting Long term therapy Central diabetes insipidus (see Table 112) Nephrogenic diabetes insipidus Correct plasma potassium and calcium concentration Remove offending d rugs Low-sodium diet Thiazide diuretics Amiloride (for lithium-induced nephrogen ic diabetes insipidus) Musculoskeletal System Muscle twitching Spasticity Hyperreflexia FIGURE 1-41 Signs and symptoms of hypernatremia. Hypernatremia always reflects a hyperosmolar state; thus, central nervous system symptoms are prominent in affe cted patients [12]. FIGURE 1-42 Management options for patients with hypernatremia. The primary goal in the treatment of hypernatremia is restoration of serum tonicity. Hypovolemic hypernatremia in the context of low total body sodium and orthostatic blood pre ssure changes should be managed with isotonic saline until blood pressure normal izes. Thereafter, fluid management generally involves administration of 0.45% so dium chloride or 5% dextrose solution. The goal of therapy for hypervolemic hype rnatremias is to remove the excess sodium, which is achieved with diuretics plus 5% dextrose. Patients who have renal impairment may need dialysis. In euvolemic hypernatremic patients, water losses far exceed solute losses, and the mainstay of therapy is 5% dextrose. To correct the hypernatremia, the total body water d eficit must be estimated. This is based on the serum sodium concentration and on the assumption that 60% of the body weight is water [24]. (Modified from Halter man and Berl [12]; with permission.)

GUIDELINES FOR THE TREATMENT OF SYMPTOMATIC HYPERNATREMIA* Correct at a rate of 2 mmol/L/h Replace half of the calculated water deficit ove r the first 1224 hrs Replace the remaining deficit over the next 2436 hrs Perform serial neurologic examinations (prescribed rate of correction can be decreased a s symptoms improve) Measure serum and urine electrolytes every 12 hrs *If UNa + U K is less than the concentration of PNa, then water loss is ongoing and needs t o be replaced. FIGURE 1-43 Guidelines for the treatment of symptomatic hypernatremia. Patients with severe symptomatic hypernatremia are at high risk of dying and should be tr eated aggressively. An initial step is estimating the total body free water defi cit, based on the weight (in kilograms) and the serum sodium. During correction of the water deficit, it is important to perform serial neurologic examinations.

1.22 Disorders of Water, Electrolytes, and Acid-Base References 1. Jacobson HR: Functional segmentation of the mammalian nephron. Am J Physiol 1 981, 241:F203. 2. Goldberg M: Water control and the dysnatremias. In The Sea Wit hin Us. Edited by Bricker NS. New York: Science and Medicine Publishing Co., 197 5:20. 3. Kokko J, Rector F: Countercurrent multiplication system without active transport in inner medulla. Kidney Int 1972, 114. 4. Knepper MA, Roch-Ramel F: P athways of urea transport in the mammalian kidney. Kidney Int 1987, 31:629. 5. V ander A: In Renal Physiology. New York: McGraw Hill, 1980:89. 6. Zimmerman E, Ro bertson AG: Hypothalamic neurons secreting vasopressin and neurophysin. Kidney I nt 1976, 10(1):12. 7. Bichet DG: Nephrogenic and central diabetes insipidus. In Diseases of the Kidney, edn. 6. Edited by Schrier RW, Gottschalk CW. Boston: Lit tle, Brown, and Co., 1997:2430 8. Bichet DG : Vasopressin receptors in health an d disease. Kidney Int 1996, 49:1706. 9. Dunn FL, Brennan TJ, Nelson AE, Robertso n GL: The role of blood osmolality and volume in regulating vasopressin secretio n in the rat. J Clin Invest 1973, 52:3212. 10. Rose BD: Antidiuretic hormone and water balance. In Clinical Physiology of Acid Base and Electrolyte Disorders, e dn. 4. New York: McGraw Hill, 1994. 11. Cogan MG: Normal water homeostasis. In F luid & Electrolytes, Physiology and Pathophysiology. Edited by Cogan MG. Norwalk : Appleton & Lange, 1991:98. 12. Halterman R, Berl T: Therapy of dysnatremic dis orders. In Therapy in Nephrology and Hypertension. Edited by Brady H, Wilcox C. Philadelphia: WB Saunders, 1998, in press. 13. Veis JH, Berl T, Hyponatremia: In The Principles and Practice of Nephrology, edn. 2. Edited by Jacobson HR, Strik er GE, Klahr S. St.Louis: Mosby, 1995:890. 14. Berl T, Schrier RW: Disorders of water metabolism. In Renal and Electrolyte Disorders, edn 4. Philadelphia: Lippi ncott-Raven, 1997:52. 15. Verbalis JG: The syndrome of ianappropriate diuretic h ormone secretion and other hypoosmolar disorders. In Diseases of the Kidney, edn . 6. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown, and Co., 1997:2 393. 16. Berl T, Schrier RW: Disorders of water metabolism. In Renal and Electro lyte Disorders, edn. 4. Edited by Schrier RW. Philadelphia: Lippincott-Raven, 19 97:54. 17. Berl T, Anderson RJ, McDonald KM, Schreir RW: Clinical Disorders of w ater metabolism. Kidney Int 1976, 10:117. 18. Gullans SR, Verbalis JG: Control o f brain volume during hyperosmolar and hypoosmolar conditions. Annu Rev Med 1993 , 44:289. 19. Zarinetchi F, Berl T: Evaluation and management of severe hyponatr emia. Adv Intern Med 1996, 41:251. 20. Lauriat SM, Berl T: The Hyponatremic Pati ent: Practical focus on therapy. J Am Soc Nephrol 1997, 8(11):1599. 21. Ayus JC, Wheeler JM, Arieff AI: Postoperative hyponatremic encephalopathy in menstruant women. Ann Intern Med 1992,117:891. 22. Laureno R, Karp BI: Myelinolysis after c orrection of hyponatremia. Ann Intern Med 1997, 126:57. 23. Kumar S, Berl T: Dis orders of serum sodium concentration. Lancet 1998. in press. 24. Cogan MG: Norma l water homeostasis. In Fluid & Electrolytes, Physiology and Pathophysiology. Ed ited by Cogan MG. Norwalk: Appleton & Lange, 1991:94. 25. Rittig S, Robertson G, Siggaard C, et al.: Identification of 13 new mutations in the vasopressin-neuro physin II gene in 17 kindreds with familial autosomal dominant neurohypophyseal diabetes insipidus. Am J Hum Genet 1996, 58:107. 26. Lanese D, Teitelbaum I: Hyp ernatremia. In The Principles and Practice of Nephrology, edn. 2. Edited by Jaco bson HR, Striker GE, Klahr S. St. Louis: Mosby, 1995:895. 27. Barrett T, Bundey S: Wolfram (DIDMOAD) syndrome. J Med Genet 1997, 29:1237. 28. Holtzman EJ, Ausie llo DA: Nephrogenic Diabetes insipidus: Causes revealed. Hosp Pract 1994, Mar 15 :89104. 29. Bichet D, Oksche A, Rosenthal W: Congential Nephrogenic Diabetes Insi pidus. J Am Soc Nephrol 1997, 8:1951. 30. Lieburg van, Verdjik M, Knoers N, et a l.: Patients with autosomal nephrogenic diabetes insipidus homozygous for mutati ons in the aquaporin 2 water channel. Am J Hum Genet 1994, 55:648. 31. Canfield MC, Tamarappoo BK, Moses AM, et al.: Identification and characterization of aqua porin-2 water channel mutations causing nephrogenic diabetes insipidus with part ial vasopressin response. Hum Mol Genet 1997, 6(11):1865.

Disorders of Sodium Balance David H. Ellison S odium is the predominant cation in extracellular fluid (ECF); the volume of ECF is directly proportional to the content of sodium in the body. Disorders of sodi um balance, therefore, may be viewed as disorders of ECF volume. The body must m aintain ECF volume within acceptable limits to maintain tissue perfusion because plasma volume is directly proportional to ECF volume. The plasma volume is a cr ucial component of the blood volume that determines rates of organ perfusion. Ma ny authors suggest that ECF volume is maintained within narrow limits despite wi de variations in dietary sodium intake. However, ECF volume may increase as much as 18% when dietary sodium intake is increased from very low to moderately high levels [1,2]. Such variation in ECF volume usually is well tolerated and leads to few short-term consequences. In contrast, the same change in dietary sodium i ntake causes only a 1% change in mean arterial pressure (MAP) in normal persons [3]. The body behaves as if the MAP, rather than the ECF volume, is tightly regu lated. Under chronic conditions, the effect of MAP on urinary sodium excretion d isplays a remarkable gain; an increase in MAP of 1 mm Hg is associated with incr eases in daily sodium excretion of 200 mmol [4]. Guyton [4] demonstrated the imp ortance of the kidney in control of arterial pressure. Endogenous regulators of vascular tone, hormonal vasoconstrictors, neural inputs, and other nonrenal mech anisms are important participants in short-term pressure homeostasis. Over the l ong term, blood pressure is controlled by renal volume excretion, which is adjus ted to a set point. Increases in arterial pressure lead to natriuresis (called p ressure natriuresis), which reduces blood volume. A decrease in blood volume red uces venous return to the heart and cardiac output. Urinary volume excretion exc eeds dietary intake until the blood volume decreases sufficiently to return the blood pressure to the set point. Disorders of sodium balance resulting from prim ary renal sodium retention lead only to modest volume expansion without edema be cause increases in MAP quickly return sodium excretion to baseline CHAPTER 2

2.2 Disorders of Water, Electrolytes, and Acid-Base (see Chapter 1). Disorders of sodium balance are disorders of ECF volume. This c onstruct has a physiologic basis because water balance and sodium balance can be controlled separately and by distinct hormonal systems. It should be emphasized , however, that disorders of sodium balance frequently lead to or are associated with disorders of water balance. This is evident from Figure 2-24 in which hypo natremia is noted to be a sign of either ECF volume expansion or contraction. Th us, the distinction between disorders of sodium and water balance is useful in c onstructing differential diagnoses; however, the close interrelationships betwee n factors that control sodium and water balance should be kept in mind. The figu res herein describe characteristics of sodium homeostasis in normal persons and also describe several of the regulatory systems that are important participants in controlling renal sodium excretion. Next, mechanisms of sodium transport alon g the nephron are presented, followed by examples of disorders of sodium balance that illuminate current understanding of their pathophysiology. Recently, rapid progress has been made in unraveling mechanisms of renal volume homeostasis. Mo st of the hormones that regulate sodium balance have been cloned and sequenced. Intracellular signaling mechanisms responsible for their effects have been chara cterized. The renal transport proteins that mediate sodium reabsorption also hav e been cloned and sequenced. The remaining challenges are to integrate this info rmation into models that describe systemic volume homeostasis and to determine h ow alterations in one or more of the well-characterized systems lead to volume e xpansion or contraction. levels. Examples of these disorders include chronic renal failure and states of mineralocorticoid excess. In this case, the price of a return to sodium balance is hypertension. Disorders of sodium balance that result from secondary renal so dium retention, as in congestive heart failure, lead to more profound volume exp ansion owing to hypotension. In mild to moderates cases, volume expansion eventu ally returns the MAP to its set point; the price of sodium balance in this case is edema. In more severe cases, volume expansion never returns blood pressure to normal, and renal sodium retention is unremitting. In still other situations, s uch as nephrotic syndrome, volume expansion results from changes in both the ren al set point and body volume distribution. In this case, the price of sodium bal ance may be both edema and hypertension. In each of these cases, renal sodium (a nd chloride) retention results from a discrepancy between the existing MAP and t he renal set point. The examples listed previously emphasize that disorders of s odium balance do not necessarily abrogate the ability to achieve sodium balance. When balance is defined as the equation of sodium intake and output, most patie nts with ECF expansion (and edema or hypertension) or ECF volume depletion achie ve sodium balance. They do so, however, at the expense of expanded or contracted ECF volume. The failure to achieve sodium balance at normal ECF volumes charact erizes these disorders. Frequently, distinguishing disorders of sodium balance f rom disorders of water balance is useful. According to this scheme, disorders of water balance are disorders of body osmolality and usually are manifested by al terations in serum sodium concentration Normal Extracellular Fluid Volume Homeostasis Adult male Extravascular (15%) Plasma (5%) Blood volume (9%) RBC (4%) Adult fema le ECF volume (20%) Blood volume (7%) ICF volume (40%) Extravascular (11%) Plasm a (4%) RBC (3%) ICF volume (35%) ECF volume (15%) A B FIGURE 2-1 Fluid volumes in typical adult men and women, given as percentages of body weight. In men (A), total body water typically is 60% of body weight (Tota

l body water = Extracellular fluid [ECF] volume + Intracellular fluid [ICF] volu me). The ECF volume comprises the plasma volume and the extravascular volume. Th e ICF volume comprises the water inside erythrocytes (RBCs) and inside other cel ls. The blood volume comprises the plasma volume plus the RBC volume. Thus, the RBC volume is a unique component of ICF volume that contributes directly to card iac output and blood pressure. Typically, water comprises a smaller percentage o f the body weight in a woman (B) than in a man; thus, when expressed as a percen tage of body weight, fluid volumes are smaller. Note, however, that the percenta ge of total body water that is intracellular is approximately 70% in both men an d women [5].

Disorders of Sodium Balance 2.3 14 ECF volume, L 13 12 11 10 0 5 10 15 Days 20 25 10 9 8 7 6 5 4 3 2 1 0 FIGURE 2-2 Effects of changes in dietary sodium (Na) intake on extracellular flu id (ECF) volume. The dietary intake of Na was increased from 2 to 5 g, and then returned to 2 g. The relationship between dietary Na intake (dashed line) and EC F volume (solid line) is derived from the model of Walser [1]. In this model the rate of Na excretion is assumed to be proportional to the content of Na in the body (At) above a zero point (A0) at which Na excretion ceases. This relation ca n be expressed as dAt/dt = I - k(At - A0), where I is the dietary Na intake and t is time. The ECF volume is approximated as the total body Na content divided b y the plasma Na concentration. (This assumption is strictly incorrect because ap proximately 25% of Na is tightly bound in bone; however, this amount is nearly i nvariant and can be ignored in the current analysis.) According to this construc t, when dietary Na intake changes from level 1 to level 2, the ECF volume approa ches a new steady state exponentially with a time constant of k according to the following equation: I I I A2 A1 = 2 + 1 2 e kt k k 0 18 17 1 Urinary sodium excretion, g/d 2 3 4 Dietary sodium intake, g 5 6 100 98 96 Mean arterial pressure, mmHg 94 92 90 88 86 84 82 80 0 1 Urinary sodium excretion, g/d 2 3 4 5 6 16 ECF volume, L 15 14 13 12 11 10 0 1 2 18% 1% A 3 4 Sodium intake, g/d 5 6 0

1 2 B 3 4 Sodium intake, g/d 5 6 FIGURE 2-3 Relation between dietary sodium (Na), extracellular fluid (ECF) volum e, and mean arterial pressure (MAP). A, Relation between the dietary intake of N a, ECF volume, and urinary Na excretion at steady state in a normal person. Note that 1 g of Na equals 43 mmol (43 mEq) of Na. At steady state, urinary Na excre tion essentially is identical to the dietary intake of Na. As discussed in Figur e 2-2, ECF volume increases linearly as the dietary intake of Na increases. At a n ECF volume of under about 12 L, urinary Na excretion ceases. The gray bar indi cates a normal dietary intake of Na when consuming a typical Western diet. The d ark blue bar indicates the range of Na intake when consuming a no added salt diet. The light blue bar indicates that a low -salt diet generally contains about 2 g/d of Na. Note that increasing the dietary intake of Na from very low to normal levels leads to an 18% increase in ECF vol ume. B, Relation between the dietary intake of Na and MAP in normal persons. MAP is linearly dependent on Na intake; however, increasing dietary Na intake from very low to normal levels increases the MAP by only 1%. Thus, arterial pressure is regulated much more tightly than is ECF volume. (A, Data from Walser [1]; B, Data from Luft and coworkers [3].)

2.4 6 5 4 3 2 1 0 0 + Disorders of Water, Electrolytes, and Acid-Base in extracellular fluid (ECF) volume result from increases in sodium chloride (Na Cl) and fluid intake or decreases in kidney volume output. An increase in ECF vo lume increases the blood volume, thereby increasing the venous return to the hea rt and cardiac output. Increases in cardiac output increase arterial pressure bo th directly and by increasing peripheral vascular resistance (autoregulation). I ncreased arterial pressure is sensed by the kidney, leading to increased kidney volume output (pressure diuresis and pressure natriuresis), and thus returning t he ECF volume to normal. The inset shows this relation between mean arterial pre ssure (MAP), renal volume, and sodium excretion [4]. The effects of acute increa ses in arterial pressure on urinary excretion are shown by the solid curve. The chronic effects are shown by the dotted curve; note that the dotted line is iden tical to the curve in Figure 2-3. Thus, when the MAP increases, urinary output i ncreases, leading to decreased ECF volume and return to the original pressure se t point. UNaVurinary sodium excretion volume. UNaV, X normal + Net volume intake + 50 100 150 200 MAP, mm Hg Kidney volume output Rate of cha nge of extracellular fluid volume + NaCl and fluid intake Nonrenal fluid loss Arterial pressure + + Extracellular fluid volume + Total peripheral resistance Autoregulation + Cardiac output + + Venous return Blood volume + Mean circulatory filling pressure FIGURE 2-4 Schema for the kidney blood volume pressure feedback mechanism adapte d from the work of Guyton and colleagues [6]. Positive relations are indicated b y a plus sign; inverse relations are indicated by a minus sign. The block diagra m shows that increases Lumen Na Cl Blood DCT 5-7% CD 3-5% PROX 60% Na Lumen Lumen Na HCO3 H2CO3 CA H 2O CO2 Na H 2O H H+ OH HCO3 Blood K Blood + CO2 Lumen + Na K Cl K Blood FIGURE 2-5 Sodium (Na) reabsorption along the mammalian nephron. About 25 moles of Na in 180 L of fluid daily is delivered into the glomerular filtrate of a nor mal person. About 60% of this load is reabsorbed along the proximal tubule (PROX ), indicated in dark blue; about 25% along the loop of Henle (LOH), including th e thick ascending limb indicated in light blue; about 5% to 7% along the distal convoluted tubule (DCT), indicated in dark gray; and 3% to 5% along the collecti

ng duct (CD) system, indicated in light gray. All Na transporting cells along th e nephron express the ouabain-inhibitable sodium-potassium adenosine triphosphat ase (Na-K ATPase) pump at their basolateral (blood) cell surface. (The pump is n ot shown here for clarity.) Unique pathways are expressed at the luminal membran e that permit Na to enter cells. The most quantitatively important of these lumi nal Na entry pathways are shown here. These pathways are discussed in more detai l in Figures 2-15 to 2-19. CAcarbonic anhydrase; Clchloride; CO2carbon dioxide; Hhyd rogen; H2CO3carbonic acid; HCO3bicarbonate; Kpotassium; OHhydroxyl ion. LOH 25%

Disorders of Sodium Balance 2.5 Mechanisms of Extracellular Fluid Volume Control - Renal tubular sodium reabsoption - ERSNA - Activation of baroreceptors - Angiotensin I I - Aldosterone - FF - Renin Arterial pressure ECFV contraction Normal ECF volume FIGURE 2-6 Integrated response of the kidneys to changes in extracellular fluid (ECF) volume. This composite figure illustrates natriuretic and antinatriuretic mechanisms. For simplicity, the systems are shown operating only in one directio n and not all pathways are shown. The major antinatriuretic systems are the reni n-angiotensin-aldosterone axis and increased efferent renal sympathetic nerve ac tivity (ERSNA). The most important natriuretic mechanism is pressure natriuresis , because the level of renal perfusion pressure (RPP) determines the magnitude o f the response to all other natriuretic systems. Renal interstitial hydrostatic pressure (RIHP) is a link between the circulation and renal tubular sodium reabs orption. Atrial natriuretic peptide (ANP) is the major systemic natriuretic horm one. Within the kidney, kinins and renomedullary prostaglandins are important mo dulators of the natriuretic response of the kidney. AVParginine vasopressin; FFfil tration fraction. (Modified from Gonzalez-Campoy and Knox [7].) ECFV expansion - ANP - Arterial pressure - RIHP Renal tubular sodium reabsoption - Kinin s - Prostaglandins ACE SVR + Angiotensinogen DRVYIHPFHL + DRVYIHPF Angiotensin I + Aldo Angiotensin II + FIGURE 2-7 Overview of the renin-angiotensin-aldosterone system [8,9]. Angiotens inogen (or renin substrate) is a 56-kD glycoprotein produced and secreted by the liver. Renin is produced by the juxtaglomerular apparatus of the kidney, as sho wn in Figures 2-8 and 2-9. Renin cleaves the 10 N-terminal amino acids from angi otensinogen. This decapeptide (angiotensin I) is cleaved by angiotensin converti ng enzyme (ACE). The resulting angiotensin II comprises the 8 N-terminal amino a cids of angiotensin I. The primary amino acid structures of angiotensins I and I I are shown in single letter codes. Angiotensin II increases systemic vascular r esistance (SVR), stimulates aldosterone secretion from the adrenal gland (indica ted in gray), and increases sodium (Na) absorption by renal tubules, as shown in Figures 2-15 and 2-17. These effects decrease urinary Na (and chloride excretio n; UNaV).

Renin UNaV

2.6 Disorders of Water, Electrolytes, and Acid-Base FIGURE 2-8 The juxtaglomerular (JG) apparatus. This apparatus brings into close apposition the afferent (A) and efferent (E) arterioles with the macula densa (M D), a specialized region of the thick ascending limb (TAL). The extraglomerular mesangium (EM), or lacis Goormaghtigh apparatus (cells), forms at the interface of these components. MD cells express the Na-K-2Cl (sodium-potassium-chloride) cot ransporter (NKCC2) at the apical membrane [10,11]. By way of the action of this transporter, MD cells sense the sodium chloride concentration of luminal fluid. By way of mechanisms that are unclear, this message is communicated to JG cells located in and near the arterioles (especially the afferent arteriole). These JG cells increase renin secretion when the NaCl concentration in the lumen is low [12]. Cells in the afferent arteriole also sense vascular pressure directly, by way of the mechanisms discussed in Figure 2-9. Both the vascular and tubular com ponents are innervated by sympathetic nerves (N). BBowman's space, Gglomerular capil lary; IMintraglomerular mesangium. (From Barajas [13]; with permission.) B N JG A N G IM MD G JG E N ANP Prorenin Renin Renin + NO -cAMP AC AT1 b1 Sympthetic nerves All -Ca + -Ca + PGE2 PGI2 + Membrane stretch Membrane depolarization + + Arterial pressure MD NaCl FIGURE 2-9 Schematic view of a (granular) juxtaglomerular cell showing secretion mechanisms of renin [8]. Renin is generated from prorenin. Renin secretion is i nhibited by increases in and stimulated by decreases in intracellular calcium (C a) concentrations. Voltage-sensitive Ca channels in the plasma membrane are acti vated by membrane stretch, which correlates with arterial pressure and is assume

d to mediate baroreceptor-sensitive renin secretion. Renin secretion is also sti mulated when the concentration of sodium (Na) and chloride (Cl) at the macula de nsa (MD) decreases [12,14]. The mediators of this effect are less well character ized; however, some studies suggest that the effect of Na and Cl in the lumen is more potent than is the baroreceptor mechanism [15]. Many other factors affect rates of renin release and contribute to the physiologic regulation of renin. Re nal nerves, by way of receptors coupled to adenylyl cyclase (AC), stimulate reni n release by increasing the production of cyclic adenosine monophosphate (cAMP), which reduces Ca release. Angiotensin II (AII) receptors (AT1 receptors) inhibi t renin release, as least in vitro. Prostaglandins E2 and I2 (PGE2 and PGI2, res pectively) strongly stimulate renin release through mechanisms that remain uncle ar. Atrial natriuretic peptide (ANP) strongly inhibits renin secretion. Constitu tive nitric oxide (NO) synthase is expressed by macula densa (MD) cells [16]. NO appears to stimulate renin secretion, an effect that may counteract inhibition of the renin gene by AII [17,18].

Disorders of Sodium Balance AME or Licorice Basolateral Cortisone 11b HSD Cortisol Cortisol GR - ENaC - Na/K ATPase 2.7 Apical Cortisone 11b HSD Cortisol MR Aldo Aldo MR Distal nephron cell FIGURE 2-10 Mechanism of aldosterone action in the distal nephron [19]. Aldoster one, the predominant human mineralocorticoid hormone, enters distal nephron cell s through the plasma membrane and interacts with its receptor (the mineralocorti coid receptor [MR], or Type I receptor). Interaction between aldosterone and thi s receptor initiates induction of new proteins that, by way of mechanisms that r emain unclear, increase the number of sodium channels (ENaC) and sodium-potassiu m adenosine triphosphatase (Na-K ATPase) pumps at the cell surface. This increas es transepithelial Na (and potassium) transport. Cortisol, the predominant human glucocorticoid hormone, also enters cells through the plasma membrane and inter acts with its receptor (the glucocorticoid receptor [GR]). Cortisol, however, al so interacts with mineralocorticoid receptors; the affinity of cortisol and aldo sterone for mineralocorticoid receptors is approximately equal. In distal nephro n cells, this interaction also stimulates electrogenic Na transport [20]. Cortis ol normally circulates at concentrations 100 to 1000 times higher than the circu lating concentration of aldosterone. In aldosterone-responsive tissues, such as the distal nephron, expression of the enzyme 11 -hydroxysteroid dehydrogenase (1 1 -HSD) permits rapid metabolism of cortisol so that only aldosterone can stimul ate Na transport in these cells. An inherited deficiency of the enzyme 11 -HSD ( the syndrome of apparent mineralocorticoid excess, AME), or inhibition of the en zyme by ingestion of licorice, leads to hypertension owing to chronic stimulatio n of distal Na transport by endogenous glucocorticoids [21]. FIGURE 2-11 Control of systemic hemodynamics by the atrial natriuretic peptide (ANP) system. Increa ses in atrial stretch (PRELOAD) increase ANP secretion by cardiac atria. The pri mary amino acid sequence of ANP is shown in single letter code with its disulfid e bond indicated by the lines. The amino acids highlighted in blue are conserved between ANP, brain natriuretic peptide, and C-type natriuretic peptide. ANP has diverse functions that include but are not limited to the following: stimulatin g vagal afferent activity, increasing capillary permeability, inhibiting renal s odium (Na) and water reabsorption, inhibiting renin release, and inhibiting arte riolar contraction. These effects reduce sympathetic nervous activity, reduce an giotensin II generation, reduce aldosterone secretion, reduce total peripheral r esistance, and shift fluid out of the vasculature into the interstitium. The net effect of these actions is to decrease cardiac output, vascular volume, and per ipheral resistance, thereby returning preload toward baseline. Many effects of A NP (indicated by solid arrows) are diminished in patients with edematous disorde rs (there is an apparent resistance to ANP). Effects indicated by dashed arrows may not be diminished in edematous disorders; these effects contribute to shifti ng fluid from vascular to extravascular tissue, leading to edema. This observati on may help explain the association between elevated right-sided filling pressur es and the tendency for Na retention [22]. (Modified from Brenner and coworkers [23].) - Preload + SLRRSSCFGGRLDRIGAQSGLGCNSFRY Plasma ANP + Vagal afferent activity Sympathetic efferent activity + Cardiac out

put + + Renal NaCl reabsoption + Arteriolar contraction Capillary permeability + + Renin secretion + + Fluid shift into interstitium Angiotensin II + Aldosterone + + Vascular volume + Preload + Blood pressure + Peripheral vascular resistance

2.8 20 18 16 UNAV, mmol/min/g body wt 14 12 10 8 6 4 2 0 15 30 Disorders of Water, Electrolytes, and Acid-Base Afferent Wild type Knockout ANP infusion Efferent Cerebral cortex Hypothalamus Medulla X X Carotid sinus IX Carotid bodies 45 60 75 90 105 120 135 150 165 180 Time, min Lumbar Thoracic Blood vessel Adrenal FIGURE 2-12 Mechanism of atrial natriuretic peptide (ANP) action on the kidney. Animals with disruption of the particulate form of guanylyl cyclase (GC) manifes t increased mean arterial pressure that is independent of dietary intake of sodi um chloride. To test whether ANP mediates its renal effects by way of the action of GC, ANP was infused into wild-type and GC-Adeficient mice. In wild-type anima ls, ANP led to prompt natriuresis. In GC-Adeficient mice, no effect was observed. UNaVurinary sodium excretion volume. (Modified from Kishimoto [24].) Other somatic (eg, muscle, splanchnic viscera, joint receptors) Sacral Spinal cord Kidney Splanchnic viscera FIGURE 2-13 Schematic diagram of neural connections important in circulatory con trol. Although the system is bilaterally symmetric, afferent fibers are shown to the left and efferent fibers to the right. Sympathetic fibers are shown as soli d lines and parasympathetic fibers as dashed lines. The heart receives both symp athetic and parasympathetic innervation. Sympathetic fibers lead to vasoconstric tion and renal sodium chloride retention. X indicates the vagus nerve; IX indica tes glossopharyngeal. (From Korner [25]; with permission.) FIGURE 2-14 Cellular mechanisms of increased solute and water reabsorption by the proximal tubule in patients with effective arterial volume depletion. A, Normal effective arterial vo lume in normal persons. B, Low effective arterial volume in patients with both d ecreased glomerular filtration rates (GFR) and renal plasma flow (RPF). In contr ast to normal persons, patients with low effective arterial volume have decrease d GFR and RPF, yet the filtration fraction is increased because the RPF decrease s more than does the GFR. The increased filtration fraction concentrates the pla sma protein (indicated by the dots) in the peritubular capillaries leading to in creased plasma oncotic pressure ( onc). Increased plasma oncotic pressure reduce s the amount of backleak from the peritubular capillaries. Simultaneously, the i ncrease in filtration fraction reduces volume delivery to the (Legend continued on next page) Normal effective arterial volume GFR =Filtration fraction RPF Filtration A E A Low effective arterial volume GFR =-Filtration fraction RPF Filtration E

onc Reabsorption Pt Pi onc Reabsorption Pt Pi A Backleak B Backleak

Disorders of Sodium Balance FIGURE 2-14 (continued) peritubular capillary, decreasing its hydrostatic pressu re, and thereby reducing the renal interstitial hydrostatic pressure (Pi). Even though the proximal tubule hydrostatic pressure (Pt) may be 2.9 reduced, owing to diminished GFR, the hydrostatic gradient from tubule to inters titium is increased, favoring increased volume reabsorption. Aafferent arteriole; Eefferent arteriole. Mechanisms of Sodium and Chloride Transport along the Nephron Lumen Na+ H+ + + AT1 a Renl nerves See figure 2-13 All See figure 2-7 + DA1 Dopamine H 2O 3Na+ ~ 2K+ + Na+ Cl-FF See figure 2-14 Pi + onc Interstitum FIGURE 2-15 Cellular mechanisms and regulation of sodium chloride (NaCl) and vol ume reabsorption along the proximal tubule. The sodium-potassium adenosine triph osphate (Na-K ATPase) pump (shown as white circle with light blue outline) at th e basolateral cell membrane keeps the intracellular Na concentration low; the K concentration high; and the cell membrane voltage oriented with the cell interio r negative, relative to the exterior. Many pathways participate in Na entry acro ss the luminal membrane. Only the sodiumhydrogen (Na-H) exchanger is shown becau se its regulation in states of volume excess and depletion has been characterize d extensively. Activity of the Na-H exchanger is increased by stimulation of ren al nerves, acting by way of receptors and by increased levels of circulating ang iotensin II (AII), as shown in Figures 2-7 and 2-13 [2528]. Increased levels of d opamine (DA1) act to inhibit activity of the Na-H exchanger [29,30]. Dopamine al so acts to inhibit activity of the Na-K ATPase pump at the basolateral cell memb rane [30]. As described in Figure 2-14, increases in the filtration fraction (FF ) lead to increases in oncotic pressure ( onc) in peritubular capillaries and de creases in peritubular and interstitial hydrostatic pressure (Pi). These changes increase solute and volume absorption and decrease solute backflux. Water flows through water channels (Aquaporin-1) Na and Cl also traverse the paracellular p athway.

2.10 Disorders of Water, Electrolytes, and Acid-Base FIGURE 2-16 Cellular mechanisms and regulation of sodium (Na) and chloride (Cl) transport by thick ascending limb (TAL) cells. Na, Cl, and potassium (K) enter c ells by way of the bumetanide-sensitive Na-K2Cl cotransporter (NKCC2) at the api cal membrane. K recycles back through apical membrane K channels (ROMK) to permi t continued operation of the transporter. In this nephron segment, the asymmetri c operations of the luminal K channel and the basolateral chloride channel gener ate a transepithelial voltage, oriented with the lumen positive. This voltage dr ives paracellular Na absorption. Although arginine vasopressin (AVP) is known to stimulate Na reabsorption by TAL cells in some species, data from studies in hu man subjects suggest AVP has minimal or no effect [31,32]. The effect of AVP is mediated by way of production of cyclic adenosine monophosphate (cAMP). Prostagl andin E2 (PGE2) and cytochrome P450 (c-P450) metabolites of arachidonic acid (20 -HETE [hydroxy-eicosatetraenoic acid] and 20-COOH-AA) inhibit transepithelial Na Cl transport, at least in part by inhibiting the Na-K-2Cl cotransporter [3335]. P GE2 also inhibits vasopressin-stimulated Na transport, in part by activating Gi and inhibiting adenylyl cyclase [36]. Increases in medullary NaCl concentration may activate transepithelial Na transport by increasing production of PGE2. Inse t A, Regulation of NKCC2 by chronic Na delivery. Animals were treated with 0.16 mol NaCl or water as drinking fluid for 2 weeks. The Western blot shows upregula tion of NKCC2 in the group treated with saline [37]. Giinhibitory G protein; PRpro staglandin receptor; V2 AVP receptors. (Modified from Ecelbarger [37].) Lumen Na + cAMP ? V2 AVP 2Cl K K PR PGE2 20-HETE 20-COOH-AA Cl c-P450 Arachidonic acid ~ 3Na+ 2K+ + Na Interstitum A kD 19912087480.16 mol NaCl H 2O Lumen + Na Cl + + ~ 3Na+ AT1

Aldo receptor + Aldo See figure Y + a 2K+ All See figure 2-7 FIGURE 2-17 Mechanisms and regulation of sodium (Na) and chloride (Cl) transport by the distal nephron. As in other nephron segments, intracellular Na concentra tion is maintained low by the action of the Na-K ATPase (sodium-potassium adenos ine triphosphatase) pump at the basolateral cell membrane. Na enters distal conv oluted tubule (DCT) cells across the luminal membrane coupled directly to chlori de by way of the thiazide-sensitive Na-Cl cotransporter. Activity of the Na-Cl c otransporter appears to be stimulated by both aldosterone and angiotensin II (AI I) [3840]. Transepithelial Na transport in this segment is also stimulated by sym pathetic nerves acting by way of receptors [41,42]. The DCT is impermeable to wa ter. DCT + Interstitum

Disorders of Sodium Balance 2.11 Lumen + Interstitum -GFR Na + Aldo receptor + + ~ Aldo Na Na Na Na Na Na Na cGMP GC AR ANP + K + H 2O ATP CCT cAMP 3Na+ 2K+ PGE2 a Lumen PGE2 3Na+ + V2 ~ 2K+ AVP R Gi AC Gs V2 + AVP H 2O MCT FIGURE 2-18 Principal cortical collecting tubule (CCT) cells. In these cells, so dium (Na) enters across the luminal membrane through Na channels (ENaC). The mov ement of cationic Na from lumen to cell depolarizes the luminal membrane, genera ting a transepithelial electrical gradient oriented with the lumen negative with respect to interstitium. This electrical gradient permits cationic potassium (K ) to diffuse preferentially from cell to lumen through K channels (ROMK). Na tra nsport is stimulated when aldosterone interacts with its intracellular receptor [43]. This effect involves both increases in the number of Na channels at the lu minal membrane and increases in the number of Na-K ATPase (Sodium-potassium aden osine triphosphatase) pumps at the basolateral cell membrane. Arginine vasopress in (AVP) stimulates both Na absorption (by interacting with V2 receptors and, pe rhaps, V1 receptors) and water transport (by interacting with V2 receptors) [4446 ]. V2 receptor stimulation leads to insertion of water channels (aquaporin 2) in to the luminal membrane [47]. V2 receptor stimulation is modified by PGE2 and 2 agonists that interact with a receptor that stimulates Gi [48]. ACadenylyl cyclas e; ATPadenosine triphosphate; cAMPcyclic adenosine monophosphate; CCTcortical colle

cting tubule; Giinhibitory G protein; Gsstimulatory G protein; RRi receptor. FIGURE 2-19 Cellular mechanism of the medullary collecting tubule (MCT). Sodium (Na) and water are reabsorbed along the MCT. Atrial natriuretic peptide (ANP) is the best-characterized hormone that affects Na absorption along this segment [2 2]. Data on the effects of arginine vasopressin (AVP) and aldosterone are not as consistent [46,49]. Prostaglandin E2 (PGE2) inhibits Na transport by inner medu llary collecting duct cells and may be an important intracellular mediator for t he actions of endothelin and interleukin-1 [50,51]. ANP inhibits medullary Na tr ansport by interacting with a G-proteincoupled receptor that generates cyclic gua nosine monophosphate (cGMP). This second messenger inhibits a luminal Na channel that is distinct from the Na channel expressed by the principal cells of the co rtical collecting tubule, as shown in Figure 2-18 [52,53]. Under normal circumst ances, ANP also increases the glomerular filtration rate (GFR) and inhibits Na t ransport by way of the effects on the renin-angiotensin-aldosterone axis, as sho wn in Figures 2-7 to 2-10. These effects increase Na delivery to the MCT. The co mbination of increased distal Na delivery and inhibited distal reabsorption lead s to natriuresis. In patients with congestive heart failure, distal Na delivery remains depressed despite high levels of circulating ANP. Thus, inhibition of ap ical Na entry does not lead to natriuresis, despite high levels of MCT cGMP. ARAN P receptor; GCguanylyl cyclase; Kpotassium; V2receptors.

2.12 Disorders of Water, Electrolytes, and Acid-Base Causes, Signs, and Symptoms of Extracellular Fluid Volume Expansion and Contract ion CAUSES OF VOLUME EXPANSION Primary renal sodium retention (with hypertension but without edema) Hyperaldost eronism (Conn's syndrome) Cushing's syndrome Inherited hypertension (Liddle's syndrome , glucocorticoid remediable hyperaldosteronism, pseudohypoaldosteronism Type II, others) Renal failure Nephrotic syndrome (mixed disorder) Secondary renal sodiu m retention Hypoproteinemia Nephrotic syndrome Protein-losing enteropathy Cirrho sis with ascites Low cardiac output Hemodynamically significant pericardial effu sion Constrictive pericarditis Valvular heart disease with congestive heart fail ure Severe pulmonary disease Cardiomyopathies Peripheral vasodilation Pregnancy Gram-negative sepsis Anaphylaxis Arteriovenous fistula Trauma Cirrhosis Idiopath ic edema (?) Drugs: minoxidil, diazoxide, calcium channel blockers (?) Increased capillary permeability Idiopathic edema (?) Burns Allergic reactions, including certain forms of angioedema Adult respiratory distress syndrome Interleukin-2 t herapy Malignant ascites Sequestration of fluid (3rd spacing, urine sodium concent ration low) Peritonitis Pancreatitis Small bowel obstruction Rhabdomyolysis, cru sh injury Bleeding into tissues Venous occlusion CAUSES OF VOLUME DEPLETION Extrarenal losses (urine sodium concentration low) Gastrointestinal salt losses Vomiting Diarrhea Nasogastric or small bowel aspiration Intestinal fistulae or o stomies Gastrointestinal bleeding Skin and respiratory tract losses Burns Heat e xposure Adrenal insufficiency Extensive dermatologic lesions Cystic fibrosis Pul monary bronchorrhea Drainage of large pleural effusion Renal losses (urine sodiu m concentration normal or elevated) Extrinsic Solute diuresis (glucose, bicarbon ate, urea, mannitol, dextran, contrast dye) Diuretic agents Adrenal insufficienc y Selective aldosterone deficiency Intrinsic Diuretic phase of oliguric acute re nal failure Postobstructive diuresis Nonoliguric acute renal failure Salt-wastin g nephropathy Medullary cystic disease Tubulointerstitial disease Nephrocalcinos is FIGURE 2-21 In volume depletion, total body sodium is decreased. FIGURE 2-20 In volume expansion, total body sodium (Na) content is increased. In primary renal Na retention, volume expansion is modest and edema does not devel op because blood pressure increases until Na excretion matches intake. In second ary Na retention, blood pressure may not increase sufficiently to increase urina ry Na excretion until edema develops.

Disorders of Sodium Balance 2.13 CLINICAL SIGNS OF VOLUME EXPANSION Edema Pulmonary crackles Ascites Jugular venous distention Hepatojugular reflux Hypertension CLINICAL SIGNS OF VOLUME DEPLETION Orthostatic decrease in blood pressure and increase in pulse rate Decreased puls e volume Decreased venous pressure Loss of axillary sweating Decreased skin turg or Dry mucous membranes LABORATORY SIGNS OF VOLUME DEPLETION OR EXPANSION Hypernatremia Hyponatremia Acid-base disturbances Abnormal plasma potassium Decr ease in glomerular filtration rate Elevated blood urea nitrogencreatinine ratio L ow functional excretion of sodium (FENa) FIGURE 2-22 Clinical signs of volume expansion. FIGURE 2-23 Clinical signs of volume depletion. FIGURE 2-24 Note that laboratory test results for volume expansion and contracti on are similar. Serum sodium (Na) concentration may be increased or decreased in either volume expansion or contraction, depending on the cause and intake of fr ee water (see Chapter 1). Acid-base disturbances, such as metabolic alkalosis, a nd hypokalemia are common in both conditions. The similarity of the laboratory t est results of volume depletion and expansion results from the fact that the effe ctive arterial volume is depleted in both states despite dramatic expansion of th e extracellular fluid volume in one. Unifying Hypothesis of Renal Sodium Excretion Myocardial dysfunction Extracellular fluid volume AV fistula Cardiac output High output failure Cirrhosis Pregnancy Systemic vascular resistance = Mean arterial pressure + Sodium excretion (pressure natriuresis) FIGURE 2-25 Summary of mechanisms of sodium (Na) retention in volume contraction and in depletion of the effective arterial volume. In secondary Na retention, Na retention results primarily from a reduction in mean arterial pressure (MAP). Some disorders decrease cardia c output, such as congestive heart failure owing to myocardial dysfunction; othe rs decrease systemic vascular resistance, such as high-output cardiac failure, a triovenous fistulas, and cirrhosis. Because MAP is the product of systemic vascu lar resistance and cardiac output, all causes lead to the same result. As shown in Figures 2-3 and 2-4, small changes in MAP lead to large changes in urinary Na excretion. Although edematous disorders usually are characterized as resulting from contraction of the effective arterial volume, the MAP, as a determinant of renal perfusion pressure, may be the crucial variable (Figs. 2-26 and 2-28 provi de supportive data). The mechanisms of edema in nephrotic syndrome are more comp lex and are discussed in Figures 2-36 to 2-39.

2.14 Disorders of Water, Electrolytes, and Acid-Base Mechanisms of Extracellular Fluid Volume Expansion in Congestive Heart Failure 130 125 Mean arterial pressure, mmHg 120 115 110 105 100 95 90 Control Small MI MI AVF 130 125 Mean arterial pressure, mmHg 120 115 110 105 100 95 90 Large MI AVF Cont rol Balance J Lab Clin Med 1978 Am J Physiol 1977 A B Na Ret. Cirrhosis Ascites FIGURE 2-26 Role of renal perfusion pressure in sodium (Na) retention. A, Result s from studies in rats that had undergone myocardial infarction (MI) or placemen t of an arteriovenous fistula (AVF) [54]. Rats with small and large MIs were ide ntified. Both small and large MIs induced significant Na retention when challeng ed with Na loads. Renal Na retention occurred in the setting of mild hypotension . AVF also induced significant Na retention, which was associated with a decreas e in mean arterial pressure (MAP) [55,56]. Figure 2-3 has shown that Na excretio n decreases greatly for each mm Hg decrease in MAP. B, Results of two groups of experiments performed by Levy and Allotey [57,58] in which experimental cirrhosis was induced in dogs by sporadic feeding with dimeth ylnitrosamine. Three cirrhotic stages were identified based on the pattern of Na retention. In the first, dietary Na intake was balanced by Na excretion. In the second, renal Na retention began, but still without evidence of ascites or edem a. In the last, ascites were detected. Because Na was retained before the appear ance of ascites, primary renal Na retention was inferred. An alternative interpret ation of these data suggests that the modest decrease in MAP is responsible for Na retention in this model. Note that in both heart failure and cirrhosis, Na re tention correlates with a decline in MAP. FIGURE 2-27 Mechanism of sodium (Na) r etention in high-output cardiac failure. Effects of high-output heart failure in duced in dogs by arteriovenous (AV) fistula [59]. After induction of an AV fistu la (day 0), plasma renin activity (PRA; thick solid line) increased greatly, cor relating temporally with a reduction in urinary Na excretion (UNaV; thin solid l ine). During this period, mean arterial pressure (MAP; dotted line) declined mod estly. After day 5, the plasma atrial natriuretic peptide concentration (ANP; da shed line) increased because of volume expansion, returning urinary Na excretion to baseline levels. Thus, Na retention, mediated in part by the renin-angiotens in-aldosterone system, led to volume expansion. The volume expansion suppressed the renin-angiotensin-aldosterone system and stimulated ANP secretion, thereby r eturning Na excretion to normal. These experiments suggest that ANP secretion pl ays an important role in maintaining Na excretion in compensated congestive hear t failure. This effect of ANP has been confirmed directly in experiments using a nti-ANP antibodies [60]. AIangiotensin I. 600 UNaV, mmol/d or plasma ANP, pg/mL or MAP, mmHg; 500 UNaV ANP MAP PRA

10 8 PRA, ng ANG I mL-1h-1 400 6 300 4 200 2 100 0 -5 0 5 10 15 20 Days 25 30 35 40 0

Disorders of Sodium Balance 400 UNaV, mol/min 300 200 100 0 Baseline TIVCC Infusion 2.15 ANP ANP & SAR ANP & AII ANP & AII & SAR AII & SAR FIGURE 2-28 Mechanism of renal resistance to atrial natriuretic peptide (ANP) in experimental low-output heart failure. Low-output heart failure was induced in dogs by thoracic inferior vena caval constriction (TIVCC), which also led to a s ignificant decrease in renal perfusion pressure (RPP) (from 127 to 120 mm Hg). A NP infusion into dogs with TIVCC did not increase urinary sodium (Na) excretion (UNaV, ANP group). In contrast, when the RPP was returned to baseline by infusin g angiotensin II (AII), urinary Na excretion increased greatly (ANP + AII). To e xclude a direct effect of AII on urinary Na excretion, intrarenal saralasin (SAR ) was infused to block renal AII receptors. SAR did not significantly affect the natriuresis induced by ANP plus AII. An independent effect of SAR on urinary Na excretion was excluded by infusing ANP plus SAR and AII plus SAR. These treatme nts were without effect. These results were interpreted as indicating that the p redominant cause of resistance to ANP in dogs with low-output congestive heart f ailure is a reduction in RPP. (Data from Redfield and coworkers [61].) FIGURE 229 Mechanism of extracellular fluid (ECF) volume expansion in congestive heart f ailure. A primary decrease in cardiac output (indicated by dark blue arrow) lead s to a decrease in arterial pressure, which decreases pressure natriuresis and v olume excretion. These decreases expand the ECF volume. The inset graph shows th at the ratio of interstitial volume (solid line) to plasma volume (dotted line) increases as the ECF volume expands because the interstitial compliance increase s [62]. Thus, although expansion of the ECF volume increases blood volume and ve nous return, thereby restoring cardiac output toward normal, this occurs at the expense of a disproportionate expansion of interstitial volume, often manifested as edema. 30 Fluid intake Nonrenal fluid loss + Net volume intake + Blood volume, L 30 20 10 0 0 Arterial pressure + Kidney volume output Rate of change of extracellular fluid volume + 10 20 ECF volume, L Extracellular fluid volume + + Total peripher al resistance Autoregulation + Cardiac output + + Venous return Blood volume + M ean circulatory filling pressure 30 20 10 0 Intersititial volume, L

2.16 Disorders of Water, Electrolytes, and Acid-Base Mechanisms of Extracellular Fluid Volume Expansion in Cirrhosis Underfill theory Hepatic venous outflow obstruction + Vasodilation theory SVR Ov erflow theory Hepatic venous outflow obstruction Transudation Transudation + ? + Renin Blood volume ? - ECF volume UNaV FIGURE 2-30 Three theories of ascites formation in hepatic cirrhosis. Hepatic ve nous outflow obstruction leads to portal hypertension. According to the underfil l theory, transudation from the liver leads to reduction of the blood volume, th ereby stimulating sodium (Na) retention by the kidney. As indicated by the quest ion mark near the term blood volume, a low blood volume is rarely detected in cl inical or experimental cirrhosis. Furthermore, this theory predicts that ascites would develop before renal Na retention, when the reverse generally occurs. Acc ording to the overflow theory, increased portal pressure stimulates renal Na ret ention through incompletely defined mechanisms. As indicated by the question mar k near the arrow from hepatic venous outflow obstruction to UNaV, the nature of the portal hypertensioninduced signals for renal Na retention remains unclear. Th e vasodilation theory suggests that portal hypertension leads to vasodilation an d relative arterial hypotension. Evidence for vasodilation in cirrhosis that pre cedes renal Na retention is now convincing, as shown in Figures 2-31 and 2-33 [6 3]. Vasodilators Nitric oxide Glucagon CGRP ANP VIP Substance P Prostaglandin E2 Enc ephalins TNF Andrenomedullin Vasoconstrictors SNS RAAS Vasopressin ET-1 FIGURE 2-31 Alterations in cardiovascular hemodynamics in hepatic cirrhosis. Hep atic dysfunction and portal hypertension increase the production and impair the metabolism of several vasoactive substances. The overall balance of vasoconstric tion and vasodilation shifts in favor of dilation. Vasodilation may also shift b lood away from the central circulation toward the periphery and away from the ki dneys. Some of the vasoactive substances postulated to participate in the hemody namic disturbances of cirrhosis include those shown here. ANPatrial natrivretic p eptide; ET-1endothelin-1; CGRPcalcitonin gene related peptide; RAASrenin/angiotensi n/aldosterone system; TNFtumor necrosis factor; VIP vasoactive intestinal peptide. (Data from Mller and Henriksen [64].) C.O.=5.22 L/min 3.64 L C.O.=6.41 L/min 4.34 L 1.31 L Central blood volume 1.81 L Central blood volume Noncentral blood volume

FIGURE 2-32 Effects of cirrhosis on central and noncentral blood volumes. The ce ntral blood volume is defined as the blood volume in the heart, lungs, and centr al arterial tree. Compared with control subjects (A), patients with cirrhosis (B ) have decreased central and increased noncentral blood volumes. The higher card iac output (CO) results from peripheral vasodilation. Perfusion of the kidney is reduced significantly in patients with cirrhosis. (Data from Hillarp and cowork ers [65].) A B Noncentral blood volume Control subjects, n=16 Cirrhotic patients, n=60

Disorders of Sodium Balance 15 15 2.17 Control Cirrhosis Cirrhosis & L-name 10 10 5 5 FIGURE 2-33 Contribution of nitric oxide to vasodilation and sodium (Na) retenti on in cirrhosis. Compared with control rats, rats having cirrhosis induced by ca rbon tetrachloride and phenobarbital exhibited increased plasma renin activity ( PRA) and plasma arginine vasopressin (AVP) concentrations. At steady state, the urinary Na excretion (UNaV) was similar in both groups. After treatment with LNA ME for 7 days, plasma renin activity decreased to normal levels, AVP concentrati ons decreased toward normal levels, and urinary Na excretion increased by threef old. These changes were associated with a normalization of mean arterial pressur e and cardiac output. (Data compiled from Niederberger and coworkers [66,67] and Martin and Schrier [68].) PRA, ng/min/h or AVP, pg/mL UNaV, mmol/d 0 PRA AVP UNaV 0 30 Fluid intake Nonrenal fluid loss + Net volume intake + Blood volume, L 30 20 10 0 0 + Rate of change of extracellular fluid volume + 10 20 ECF volume, L Extr acellular fluid volume + 30 20 10 0 Arterial pressure Kidney volume output + Total peripheral resistance + Cardiac output Venous return Central blood volume + + Peripheral blood volume Mean circulatory filling pressure FIGURE 2-34 Mechanisms of sodium (Na) retention in cirrhosis. A primary decrease in systemic vascular resistance (indicated by dark blue arrow), induced by medi ators shown in Figure 2-31, leads to a decrease in arterial pressure. The reduct ion in systemic vascular resistance, however, is not uniform and favors movement of blood from the central (effective) circulation into the peripheral circulation , as shown in Figure 2-32. Hypoalbuminemia shifts the interstitial to blood volu me ratio upward (compare the interstitial volume with normal [dashed line], and low [solid line], protein levels in the inset graph). Because cardiac output inc

reases and venous return must equal cardiac output, dramatic expansion of the ex tracellular fluid (ECF) volume occurs. Mechanisms of Extracellular Fluid Volume Expansion in Nephrotic Syndrome 14 12 mmHg 10 8 6 4 2 0 2 4 6 8 Plasma protein concentration, g/dL FIGURE 2-35 Changes in plasma protein concentration affect the net oncotic press ure difference across capillaries ( c - i) in humans. Note that moderate reducti ons in plasma protein concentration have little effect on differences in transca pillary oncotic pressure. Only when plasma protein concentration decreases below 5 g/dL do changes become significant. (Data from Fadnes and coworkers [69].) Intersititial volume, L (with low albumin) Ci,

2.18 300 UNaV, mmol/24 hrs ( ) 250 Disorders of Water, Electrolytes, and Acid-Base 20 35 PRA 30 25 ANP, fmol/mL 20 15 30 15 Albumin, g/L ( ) PRA, ng/L sec 25 20 15 10 5 ANP 200 150 100 5 50 0 -6 -5 -4 -3 -2 -1 0 Days 1 2 3 4 5 6 0 10 10 5 0 20 mEq 300 mEq Controls AGN NS 0 FIGURE 2-36 Time course of recovery from minimal change nephrotic syndrome in fi ve children. Note that urinary Na excretion (squares) increases before serum alb umin concentration increases. The data suggest that the natriuresis reflects a c hange in intrinsic renal Na retention. The data also emphasize that factors othe r than hypoalbuminemia must contribute to the Na retention that occurs in nephro sis. UNaVurinary Na excretion volume. (Data from Oliver and Owings [70].) FIGURE 2-37 Plasma renin activity (PRA) and atrial natriuretic peptide (ANP) con centration in the nephrotic syndrome. Shown are PRA and ANP concentration ( stan dard error) in normal persons ingesting diets high (300 mEq/d) and low (20 mEq/d ) in sodium (Na) and in patients with acute glomerulonephritis (AGN), predominan tly poststreptococcal, or nephrotic syndrome (NS). Note that PRA is suppressed i n patients with AGN to levels below those in normal persons on diets high in Na. PRA suppression suggests that primary renal NaCl retention plays an important r ole in the pathogenesis of volume expansion in AGN. Although plasma renin activi ty in patients with nephrotic syndrome is not suppressed to the same degree, the absence of PRA elevation in these patients suggests that primary renal Na reten tion plays a significant role in the pathogenesis of Na retention in NS as well. (Data from Rodrgeuez-Iturbe and coworkers [71].) FIGURE 2-38 Sites of sodium (Na ) reabsorption along the nephron in control and nephrotic rats (induced by purom ycin aminonucleoside [PAN]). The glomerular filtration rates (GFR) in normal and nephrotic rats are shown by the hatched bars. Note the modest reduction in GFR in the nephrotic group, a finding that is common in human nephrosis. Fractional reabsorption rates along the proximal tubule, the loop of Henle, and the superfi cial distal tubule are indicated. The fractional reabsorption along the collecti ng duct (CD) is estimated from the difference between the end distal and urine d eliveries. The data suggest that the predominant site of increased reabsorption is the collecting duct. Because superficial and deep nephrons may differ in reab sorptive rates, these data would also be consistent with enhanced reabsorption b y deep nephrons. Asteriskdata inferred from the difference between distal and uri ne samples. (Data from Ichikawa and coworkers [72].) 100 Control PAN 100 80 GFR, % of control 80 Fractional absorption, %

60 60 40 40 20 20 0 GFR Proximal Loop Distal CD (*) 0

Disorders of Sodium Balance 30 Fluid intake Nonrenal fluid loss + Net volume intake + Blood volume, L 30 20 10 0 0 + Rate of change of extracellular fluid volume + 10 20 ECF volume, L Extr acellular fluid volume + + Total peripheral resistance + Cardiac output Venous r eturn + Blood volume + Mean circulatory filling pressure 30 20 10 0 2.19 Arterial pressure Kidney volume output FIGURE 2-39 Mechanisms of extracellular fluid (ECF) volume expansion in nephroti c syndrome. Nephrotic syndrome is characterized by hypoalbuminemia, which shifts the relation between blood and interstitial volume upward (dashed to solid line s in inset). As discussed in Figure 2-35, these effects of hypoalbuminemia are e vident when serum albumin concentrations decrease by more than half. In addition , however, hypoalbuminemia may induce vasodilation and arterial hypotension that lead to sodium (Na) retention, independent of transudation of fluid into the in terstitium [73,74]. Unlike other states of hypoproteinemia and vasodilation, how ever, nephrotic syndrome usually is associated with normotension or hypertension . Coupled with the observation made in Figure 2-36 that natriuresis may take pla ce before increases in serum albumin concentration in patients with nephrotic sy ndrome, these data implicate an important role for primary renal Na retention in this disorder (dark blue arrow). As suggested by Figure 237, the decrease in ur inary Na excretion may play a larger role in patients with acute glomerulonephri tis than in patients with minimal change nephropathy [71]. Intersititial volume, L Extracellular Fluid Volume Homeostasis in Chronic Renal Failure 35 30 25 FENA, % 20 15 10 5 0 0 20 40 60 80 GFR, mL/min 100 120 FIGURE 2-40 Relation between glomerular filtration rate (GFR) and fractional sod ium (Na) excretion (FENa). The normal FENa is less than 1%. Adaptations in chron ic renal failure maintain urinary Na excretion equal to dietary intake until end -stage renal disease is reached. To achieve this, the FENa must increase as the GFR decreases.

2.20 18 17 16 ECF volume, L 15 14 13 12 11 10 0 5 Disorders of Water, Electrolytes, and Acid-Base FIGURE 2-41 Effects of dietary sodium (Na) intake on extracellular fluid (ECF) v olume in chronic renal failure (CRF) [75]. Compared with normal persons, patient s with CRF have expanded ECF volume at normal Na intake. Furthermore, the time n ecessary to return to neutral balance on shifting from one to another level of N a intake is increased. Thus, whereas urinary Na excretion equals dietary intake of Na within 3 to 5 days in normal persons, this process may take up to 2 weeks in patients with CRF. This time delay means that not only are these patients sus ceptible to volume overload, but also to volume depletion. This phenomenon can b e modeled simply by reducing the time constant (k) given in the equation in Figu re 2-2, and leaving the set point (A0) unchanged. The curves here represent time constants of 0.79 0.05 day-1 (normal), 0.5 day-1 (mild CRF), and 0.25 day-1 (sev ere CRF). Normal Mild CRF Severe CRF 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Dietary sodium intake, g 10 Days 15 20 25 References 1. 2. 3. 4. 5. Walser M: Phenomenological analysis of renal regulation of sodium and potassium balance. Kidney Int 1985, 27:837841. Simpson FO: Sodium intake, bo dy sodium, and sodium excretion. Lancet 1990, 2:2529. Luft FC, Weinberger MH, Gri m CE: Sodium sensitivity and resistance in normotensive humans. Am J Med 1982, 7 2:726736. Guyton AC: Blood pressure control: special role of the kidneys and body fluids. Science 1991, 252:18131816. Lassiter WE: Regulation of sodium chloride d istribution within the extracellular space. In The Regulation of Sodium and Chlo ride Balance. Edited by Seldin DW, Giebisch G. New York: Raven Press; 1990:2358. Hall JE, Jackson TE: The basic kidney-blood volume-pressure regulatory system: t he pressure diuresis and natriuresis phenomena. In Arterial Pressure and Hyperte nsion. Edited by Guyton AC. Philadelphia: WB Saunders Co, 1998:8799. Gonzalez-Cam poy JM, Knox FG: Integrated responses of the kidney to alterations in extracellu lar fluid volume. In The Kidney: Physiology and Pathophysiology, edn 2. Edited b y Seldin DW, Giebisch G. New York: Raven Press; 1992:20412097. Hall JE, Brands MW : The renin-angiotensin-aldosterone systems. In The Kidney: Physiology and Patho physiology, edn 2. Edited by Seldin DW, Giebisch G. New York: Raven Press; 1992: 14551504. Laragh JH, Sealey JE: The intergrated regulation of electrolyte balance and blood pressure by the renin system. In The Regulation of Sodium and Chlorid e Balance. Edited by Seldin DW, Giebisch G. New York: Raven Press, 1990:133193. 1 2. Briggs JP: Whys and the wherefores of juxtaglomerular apparatus functions.Kid ney Int 1996, 49:17241726. 13. Barajas L: Architecture of the juxtaglomerular app aratus. In Hypertension: Pathophysiology, Diagnosis and Treatment. Edited by Lar agh JH, Brenner BM. New York: Raven Press; 1990:XXXX. 14. Skott O, Briggs JP: Dir ect demonstration of macula densa mediated renin secretion. Science 1987, 237:16 181620. 15. Hall JE, Guyton AC: Changes in renal hemodynamics and renin release c aused by increased plasma oncotic pressure. Am J Physiol 1976, 231:1550. 16. Bac hmann S, Bosse HM, Mundel P: Topography of nitric oxide synthesis by localizing constitutive NO synthetases in mammalian kidney. Am J Physiol 1995, 268:F885F898. 17. Johnson RA, Freeman RH: Renin release in rats during blockade of nitric oxi de synthesis. Am J Physiol 1994, 266:R1723R1729. 18. Schricker K, Hegyi I, Hamann

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Disorders of Sodium Balance 24. Kishimoto I, Dubois SK, Garbers DL: The heart communicates with the kidney e xclusively through the guanylyl cyclase-A receptor: Acute handling of sodium and water in response to volume expansion. Proc Natl Acad Sci USA 1996, 93:62156219. 25. Korner PI: Integrative neural cardiovascular control. Physiol Rev 1971, 51: 312367. 26. Cogan MG: Neurogenic regulation of proximal bicarbonate and chloride reabsorption. Am J Physiol 1986, 250:F22F26. 27. Geibel J, Giebisch G, Boron WF: Angiotensin II stimulates both Na+H+ exchange and Na+/HCO-3 cotransport in the r abbit proximal tubule. Proc Natl Acad Sci USA 1990, 87:79177920. 28. Block RD, Zi kos D, Fisher KA, et al.: Peterson DR: Activation of proximal tubular Na+-H+ exc hanger by angiotensin II. Am J Physiol 1992, 263:F135F143. 29. Bertorello A, Aper ia A: Regulation of Na+-K+-ATPase activity in kidney proximal tubules: involveme nt of GTP binding proteins. Am J Physiol 1989, 256:F57F62. 30. Aperia AC: Regulat ion of sodium transport. Curr Opinion Nephrol Hypertens 1995, 4:416420. 31. Bouby N, Bankir L, Trinh-Trang-Tan MM, et al.: Selective ADHinduced hypertrophy of th e medullary thick ascending limb in Brattleboro rats. Kidney Int 1985, 28:456466. 32. Chabards D, Gagnan-Brunette M, Imbert-Tbol M: Adenylate cyclase responsivenes s to hormones in various portions of the human nephron. J Clin Invest 1980, 65:4 39448. 33. Stokes JB: Effects of prostaglandin E2 on chloride transport across th e rabbit thick ascending limb of Henle. J Clin Invest 1979, 64:495502. 34. Escala nte B, Erlij D, Falck JR, McGiff JC: Effect of cytochrome P450 arachidonate meta bolites on ion transport in rabbit kidney loop of Henle. Science 1991, 251:799802 . 35. Amlal H, Legoff C, Vernimmen C, et al.: Na(+)-K+(NH4+)-2Clcotransport in m edullary thick ascending limb: control by PKA, PKC, and 20-HETE. Am J Physiol 19 96, 271:C455C463. 36. Culpepper RM, Adreoli TE: Interactions among prostaglandin E2, antidiuretic hormone and cyclic adenosine monophosphate in modulating Cl- ab sorption in single mouse medullary thick ascending limbs of Henle. J Clin Invest 1983, 71:15881601. 37. Ecelbarger CA, Terris J, Hoyer JR, et al.: Localization a nd regulation of the rat renal Na+-K+-2Cl-, cotransporter, BSC-1. Am J Physiol R enal Fluid Electrolyte Physiol 1996, 271:F619F628. 38. Chen Z, Vaughn DA, Blakele y P, Fanestil DD: Adrenocortical steroids increase renal thiazide diuretic recep tor density and response. J Am Soc Nephrol 1994, 5:13611368. 39. Velzquez H, Barti ss A, Bernstein PL, Ellison DH: Adrenal steroids stimulate thiazide-sensitive Na Cl transport by the rat renal distal tubule. Am J Physiol 1996, 39:F211F219. 40. Wang T, Giebisch G: Effects of angiotensin II on electrolyte transport in the ea rly and late distal tubule in rat kidney. Am J Physiol Renal Fluid Electrolyte P hysiol 1996, 271:F143F149. 41. Wang T, Chan YL: Neural control of distal tubular bicarbonate and fluid transport. Am J Physiol 1989, 257:F72F76. 42. Bencsth P, Sznsi G, Takcs L: Water and electrolyte transport in Henle's loop and distal tubule afte r renal sympathectomy in the rat. Am J Physiol 1985, 249:F308F314. 43. Rossier BC , Palmer LG: Mechanisms of aldosterone action on sodium and potassium transport. In The Kidney: Physiology and Pathophysiology, edn 2. Edited by Seldin DW, Gieb isch G. New York: Raven Press, 1992:13731409. 44. Breyer MD, Ando Y: Hormonal sig nalling and regulation of salt and water transport in the collecting duct. Ann R ev Physiol 1994, 56:711739. 45. Schafer JA, Hawk CT: Regulation of Na+ channels i n the cortical collecting duct by AVP and mineralocorticoids. Int Kidney 1992, 4 1:255268. 2.21 46. Kudo LH, Van Baak AA, Rocha AS: Effects of vasopressin on sodium transport a cross inner medullary collecting duct. Am J Physiol 1990, 258:F1438F1447. 47. Nie lsen S, Chou C-L, Marples D, et al.: Vasopressin increases water permeability of kidney collecting duct by inducing translocation of aquaporin: CD water channel s to plasma membrane. Proc Natl Acad Sci USA 1995, 92:10131017. 48. Schafer JA: S alt and water homeostasis: Is it just a matter of good bookkeeping? J Am Soc Nep hrol 1994, 4:19331950. 49. Husted RF, Laplace JR, Stokes JB: Enhancement of elect rogenic Na+ transport across rat inner medullary collecting duct cells in cultur e. J Clin Invest 1990, 86:498506. 50. Zeidel ML, Jabs K, Kikeri D, Silva P: Kinin s inhibit conductive Na+ uptake by rabbit inner medullary collecting duct cells.

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2.22 Disorders of Water, Electrolytes, and Acid-Base 71. Rodrgeuez-Iturbe B, Colic D, Parra G, Gutkowska J: Atrial natriuretic factor in the acute nephritic and nephrotic syndromes. Kidney Int 1990, 38:512517. 72. I chikawa I, Rennke HG, Hoyer JR, et al.: Role for intrarenal mechanisms in the im paired salt excretion of experimental nephrotic syndrome. J Clin Invest 1983, 71 :91103. 73. Manning RD Jr: Effects of hypoproteinemia on renal hemodynamics, arte rial pressure, and fluid volume. Am J Physiol 1997, 252:F91F98. 74. Manning RD Jr , Guyton AC: Effects of hypoproteinemia on fluid volumes and arterial pressure. Am J Physiol 1983, 245:H284H293. 75. Mitch WE, Wilcox CS: Disorders of body fluid s, sodium and potassium in chronic renal failure. Am J Med 1982, 72:536550. 67. Niederberger M, Gins P, Tsai P, et al.: Increased aortic cyclic guanosine mon ophosphate concentration in experimental cirrhosis in rats: evidence for a role of nitric oxide in the pathogenesis of arterial vasodilation in cirrhosis. Hepat ology 1995, 21:16251631. 68. Martin P-Y, Schrier RW: Pathogenesis of water and so dium retention in cirrhosis. Kidney Int 1997, 51(suppl 59):S-43S-49. 69. Fadnes H O, Pape JF, Sundsfjord JA: A study on oedema mechanism in nephrotic syndrome. Sc and J Clin Lab Invest 1986, 46:533538. 70. Oliver WJ, Owings CL: Sodium excretion in the nephrotic syndrome: relation to serum albumin concentration, glomerular filtration rate, and aldosterone secretion rate. Am J Dis Child 1967, 113:352362.

Disorders of Potassium Metabolism Fredrick V. Osorio Stuart L. Linas P otassium, the most abundant cation in the human body, regulates intracellular en zyme function and neuromuscular tissue excitability. Serum potassium is normally maintained within the narrow range of 3.5 to 5.5 mEq/L. The intracellular-extra cellular potassium ratio (Ki/Ke) largely determines neuromuscular tissue excitab ility [1]. Because only a small portion of potassium is extracellular, neuromusc ular tissue excitability is markedly affected by small changes in extracellular potassium. Thus, the body has developed elaborate regulatory mechanisms to maint ain potassium homeostasis. Because dietary potassium intake is sporadic and it c annot be rapidly excreted renally, short-term potassium homeostasis occurs via t ranscellular potassium shifts [2]. Ultimately, long-term maintenance of potassiu m balance depends on renal excretion of ingested potassium. The illustrations in this chapter review normal transcellular potassium homeostasis as well as mecha nisms of renal potassium excretion. With an understanding of normal potassium ba lance, disorders of potassium metabolism can be grouped into those that are due to altered intake, altered excretion, and abnormal transcellular distribution. T he diagnostic algorithms that follow allow the reader to limit the potential cau ses of hyperkalemia and hypokalemia and to reach a diagnosis as efficiently as p ossible. Finally, clinical manifestations of disorders of potassium metabolism a re reviewed, and treatment algorithms for hypokalemia and hyperkalemia are offer ed. Recently, the molecular defects responsible for a variety of diseases associ ated with disordered potassium metabolism have been discovered [38]. Hypokalemia and Liddle's syndrome [3] and hyperkalemia and pseudohypoaldosteronism type I [4] result from mutations at different sites on the epithelial sodium channel in the distal tubules. The hypokalemia of Bartter's syndrome can be accounted for by two separate ion transporter defects in the thick ascending limb of Henle's loop [5]. Gitelman's syndrome, a clinical variant of Bartter's CHAPTER 3

3.2 Disorders of Water, Electrolytes, and Acid-Base apparent mineralocorticoid excess [7] and glucocorticoidremediable aldosteronism [8] have recently been elucidated and are illustrated below. syndrome, is caused by a mutation in an ion cotransporter in a completely differ ent segment of the renal tubule [6]. The genetic mutations responsible for hypok alemia in the syndrome of Overview of Potassium Physiology PHYSIOLOGY OF POTASSIUM BALANCE: DISTRIBUTION OF POTASSIUM ECF 350 mEq (10%) Plasma 15 mEq (0.4%) Interstitial fluid 35 mEq (1%) Bone 300 mEq (8.6%) [K+] = 3 .55.0 mEq/L Urine 9095 mEq/d Stool 510mEq/d Sweat < 5 mEq/d ICF 3150 mEq (90%) Muscle 2650 mEq (76%) Liver 250 mEq (7%) Erythrocytes 250 mEq (7%) [K+] = 140150 mEq/L Urine 9095 mEq/d Stool 510mEq/d Sweat < 5 mEq/d FIGURE 3-1 External balance and distribution of potassium. The usual Western die t contains approximately 100 mEq of potassium per day. Under normal circumstance s, renal excretion accounts for approximately 90% of daily potassium elimination , the remainder being excreted in stool and (a negligible amount) in sweat. Abou t 90% of total body potassium is located in the intracellular fluid (ICF), the m ajority in muscle. Although the extracellular fluid (ECF) contains about 10% of total body potassium, less than 1% is located in the plasma [9]. Thus, disorders of potassium metabolism can be classified as those that are due 1) to altered i ntake, 2) to altered elimination, or 3) to deranged transcellular potassium shif ts. FACTORS CAUSING TRANSCELLULAR POTASSIUM SHIFTS Factor Acid-base status Metabolic acidosis Hyperchloremic acidosis Organic acidosis Res piratory acidosis Metabolic alkalosis Respiratory alkalosis Pancreatic hormones Insulin Glucagon Catecholamines -Adrenergic -Adrenergic Hyperosmolarity Aldoster one Exercise FIGURE 3-2 Factors that cause transcellular potassium shifts. Plasma K+ -- - - - - , -

Diseases of Potassium Metabolism 3.3 FIGURE 3-3 Extrarenal potassium homeostasis: insulin and catecholamines. Schemat ic representation of the cellular mechanisms by which insulin and -adrenergic st imulation promote potassium uptake by extrarenal tissues. Insulin binding to its receptor results in hyperpolarization of cell membranes (1), which facilitates potassium uptake. After binding to its receptor, insulin also activates Na+-K+-A TPase pumps, resulting in cellular uptake of potassium (2). The second messenger that mediates this effect has not yet been identified. Catecholamines stimulate cellular potassium uptake via the 2 adrenergic receptor ( 2R). The generation o f cyclic adenosine monophosphate (3 , 5 cAMP) activates Na+-K+-ATPase pumps (3), causing an influx of potassium in exchange for sodium [10]. By inhibiting the d egradation of cyclic AMP, theophylline potentiates catecholaminestimulated potas sium uptake, resulting in hypokalemia (4). FIGURE 3-4 Renal potassium handling. More than half of filtered potassium is pas sively reabsorbed by the end of the proximal convolted tubule (PCT). Potassium i s then added to tubular fluid in the descending limb of Henle's loop (see below). The major site of active potassium reabsorption is the thick ascending limb of t he loop of Henle (TAL), so that, by the end of the distal convoluted tubule (DCT ), only 10% to 15% of filtered potassium remains in the tubule lumen. Potassium is secreted mainly by the principal cells of the cortical collecting duct (CCD) and outer medullary collecting duct (OMCD). Potassium reabsorption occurs via th e intercalated cells of the medullary collecting duct (MCD). Urinary potassium r epresents the difference between potassium secreted and potassium reabsorbed [11 ]. During states of total body potassium depletion, potassium reabsorption is en hanced. Reabsorbed potassium initially enters the medullary interstitium, but th en it is secreted into the pars recta (PR) and descending limb of the loop of He nle (TDL). The physiologic role of medullary potassium recycling may be to minim ize potassium backleak out of the collecting tubule lumen or to enhance renal pota ssium secretion during states of excess total body potassium [12]. The percentag e of filtered potassium remaining in the tubule lumen is indicated in the corres ponding nephron segment.

3.4 Disorders of Water, Electrolytes, and Acid-Base FIGURE 3-5 Cellular mechanisms of renal potassium transport: proximal tubule and thick ascending limb. A, Proximal tubule potassium reabsorption is closely coup led to proximal sodium and water transport. Potassium is reabsorbed through both paracellular and cellular pathways. Proximal apical potassium channels are norm ally almost completely closed. The lumen of the proximal tubule is negative in t he early proximal tubule and positive in late proximal tubule segments. Potassiu m transport is not specifically regulated in this portion of the nephron, but ne t potassium reabsorption is closely coupled to sodium and water reabsorption. B, In the thick ascending limb of Henle's loop, potassium reabsorption proceeds by e lectroneutral Na+-K+-2Cl- cotransport in the thick ascending limb, the low intra cellular sodium and chloride concentrations providing the driving force for tran sport. In addition, the positive lumen potential allows some portion of luminal potassium to be reabsorbed via paracellular pathways [11]. The apical potassium channel allows potassium recycling and provides substrate to the apical Na+-K+-2 Cl- cotransporter [12]. Loop diuretics act by competing for the Cl- site on this carrier. FIGURE 3-6 Cellular mechanisms of renal potassium transport: cortical collecting tubule. A, Principal cells of the cortical collecting duct: apical sodium chann els play a key role in potassium secretion by increasing the intracellular sodiu m available to Na+-K+-ATPase pumps and by creating a favorable electrical potent ial for potassium secretion. Basolateral Na+-K+-ATPase creates a favorable conce ntration gradient for passive diffusion of potassium from cell to lumen through potassium-selective channels. B, Intercalated cells. Under conditions of potassi um depletion, the cortical collecting duct becomes a site for net potassium reab sorption. The H+-K+-ATPase pump is regulated by potassium intake. Decreases in t otal body potassium increase pump activity, resulting in enhanced potassium reab sorption. This pump may be partly responsible for the maintenance of metabolic a lkalosis in conditions of potassium depletion [11].

Diseases of Potassium Metabolism 3.5 Hypokalemia: Diagnostic Approach that, during some conditions (eg, ketoacidosis), transcellular shifts and potass ium depletion exist simultaneously. Spurious hypokalemia results when blood spec imens from leukemia patients are allowed to stand at room temperature; this resu lts in leukocyte uptake of potassium from serum and artifactual hypokalemia. Pat ients with spurious hypokalemia do not have clinical manifestations of hypokalem ia, as their in vivo serum potassium values are normal. Theophylline poisoning p revents cAMP breakdown (see Fig. 3-3). Barium poisoning from the ingestion of so luble barium salts results in severe hypokalemia by blocking channels for exit o f potassium from cells. Episodes of hypokalemic periodic paralysis can be precip itated by rest after exercise, carbohydrate meal, stress, or administration of i nsulin. Hypokalemic periodic paralysis can be inherited as an autosomal-dominant disease or acquired by patients with thyrotoxicosis, especially Chinese males. Therapy of megaloblastic anemia is associated with potassium uptake by newly for med cells, which is occasionally of sufficient magnitude to cause hypokalemia [1 3]. concentration of less than 20 mEq/L indicates renal potassium conservation. In certain circumstances (eg, diuretics abuse), renal potassium losses may not b e evident once the stimulus for renal potassium wasting is removed. In this circ umstance, urinary potassium concentrations may be deceptively low despite renal potassium losses. Hypokalemia due to colonic villous adenoma or laxative abuse m ay be associated with metabolic acidosis, alkalosis, or no acid-base disturbance . Stool has a relatively high potassium content, and fecal potassium losses coul d exceed 100 mEq per day with severe diarrhea. Habitual ingestion of clay (pica) , encountered in some parts of the rural southeastern United States, can result in potassium depletion by binding potassium in the gut, much as a cation exchang e resin does. Inadequate dietary intake of potassium, like that associated ith a norexia or a tea and toast diet, can lead to hypokalemia, owing to delayed renal c onservation of potassium; however, progressive potassium depletion does not occu r unless intake is well below 15 mEq of potassium per day. FIGURE 3-7 Overview of diagnostic approach to hypokalemia: hypokalemia without t otal body potassium depletion. Hypokalemia can result from transcellular shifts of potassium into cells without total body potassium depletion or from decreases in total body potassium. Perhaps the most dramatic examples occur in catecholam ine excess states, as after administration of 2adreneric receptor ( 2AR) agonist s or during stress. It is important to note FIGURE 3-8 Diagnostic approach to hypokalemia: hypokalemia with total body potas sium depletion secondary to extrarenal losses. In the absence of redistribution, measurement of urinary potassium is helpful in determining whether hypokalemia is due to renal or to extrarenal potassium losses. The normal kidney responds to several (3 to 5) days of potassium depletion with appropriate renal potassium c onservation. In the absence of severe polyuria, a spot urinary potassium

3.6 Disorders of Water, Electrolytes, and Acid-Base uropathy, presumably secondary to increased delivery of sodium and water to the distal nephrons. Patients with acute monocytic and myelomonocytic leukemias occa sionally excrete large amounts of lysozyme in their urine. Lysozyme appears to h ave a direct kaliuretic effect on the kidneys (by an undefined mechanism). Penic illin in large doses acts as a poorly reabsorbable anion, resulting in obligate renal potassium wasting. Mechanisms for renal potassium wasting associated with aminoglycosides and cisplatin are illdefined. Hypokalemia in type I renal tubula r acidosis is due in part to secondary hyperaldosteronism, whereas type II renal tubular acidosis can result in a defect in potassium reabsorption in the proxim al nephrons. Carbonic anhydrase inhibitors result in an acquired form of renal t ubular acidosis. Ureterosigmoidostomy results in hypokalemia in 10% to 35% of pa tients, owing to the sigmoid colon's capacity for net potassium secretion. The osm otic diuresis associated with diabetic ketoacidosis results in potassium depleti on, although patients may initially present with a normal serum potassium value, owing to altered transcellular potassium distribution. FIGURE 3-9 Diagnostic approach to hypokalemia: hypokalemia due to renal losses w ith normal acidbase status or metabolic acidosis. Hypokalemia is occasionally ob served during the diuretic recovery phase of acute tubular necrosis (ATN) or aft er relief of acute obstructive FIGURE 3-10 Hypokalemia and magnesium depletion. Hypokalemia and magnesium deple tion can occur concurrently in a variety of clinical settings, including diureti c therapy, ketoacidosis, aminoglycoside therapy, and prolonged osmotic diuresis (as with poorly controlled diabetes mellitus). Hypokalemia is also a common find ing in patients with congenital magnesium-losing kidney disease. The patient dep icted was treated with cisplatin 2 months before presentation. Attempts at oral and intravenous potassium replacement of up to 80 mEq/day were unsuccessful in c orrecting the hypokalemia. Once serum magnesium was corrected, however, serum po tassium quickly normalized [14].

Diseases of Potassium Metabolism 3.7 FIGURE 3-11 Diagnostic approach to hypokalemia: hypokalemia due to renal losses with metabolic alkalosis. The urine chloride value is helpful in distinguishing the causes of hypokalemia. Diuretics are a common cause of hypokalemia; however, after discontinuing diuretics, urinary potassium and chloride may be appropriat ely low. Urine diuretic screens are warranted for patients suspected of surrepti ous diuretic abuse. Vomiting results in chloride and sodium depletion, hyperaldo steronism, and renal potassium wasting. Posthypercapnic states are often associa ted with chloride depletion (from diuretics) and sodium avidity. If hypercapnia is corrected without replacing chloride, patients develop chloride-depletion alk alosis and hypokalemia. FIGURE 3-12 Mechanisms of hypokalemia in Bartter's syndrome and Gitelman's syndrome. A, A defective Na+-K+-2Cl- cotransporter in the thick ascending limb (TAL) of H enle's loop can account for virtually all features of Bartter's syndrome. Since appr oximately 30% of filtered sodium is reabsorbed by this segment of the nephron, d efective sodium reabsorption results in salt wasting and elevated renin and aldosterone levels. The hyperaldo steronism and increased distal sodium delivery account for the characteristic hy pokalemic metabolic alkalosis. Moreover, impaired sodium reabsorption in the TAL results in the hypercalciuria seen in these patients, as approximately 25% of f iltered calcium is reabsorbed in this segment in a process coupled to sodium rea bsorption. Since potassium levels in the TAL are much lower than levels of sodiu m or chloride, luminal potassium concentrations are rate limiting for Na+-K+-2Cl - co-transporter activity. Defects in ATP-sensitive potassium channels would be predicted to alter potassium recycling and diminish Na+-K+-2Cl- cotransporter ac tivity. Recently, mutations in the gene that encodes for the Na+-K+-2Clcotranspo rter and the ATP-sensitive potassium channel have been described in kindreds wit h Bartter's syndrome. Because loop diuretics interfere with the Na+-K+-2Clcotransp orter, surrepititious diuretic abusers have a clinical presentation that is virt ually indistinguishable from that of Bartter's syndrome. B, Gitelman's syndrome, whi ch typically presents later in life and is associated with hypomagnesemia and hy pocalciuria, is due to a defect in the gene encoding for the thiazide-sensitive Na+-Cl- cotransporter. The mild volume depletion results in more avid sodium and calcium reabsorption by the proximal nephrons.

3.8 Disorders of Water, Electrolytes, and Acid-Base FIGURE 3-13 Diagnostic approach to hypokalemia: hypokalemia due to renal losses with hypertension and metabolic alkalosis. FIGURE 3-14 Distinguishing characteri stics of hypokalemia associated with hypertension and metabolic alkalosis. Respo nse to Dexamethasone + + CHARACTERISTICS OF HYPOKALEMIA WITH HYPERTENSION AND METABOLIC ALKALOSIS Aldosterone Primary aldosteronism 11 -hydroxysteroid dehydrogenase deficiency Glucocorticoid remediable aldosteronism Liddle's syndrome - - Renin

Diseases of Potassium Metabolism 3.9 FIGURE 3-15 Mechanism of hypokalemia in Liddle's syndrome. The amiloridesensitive sodium channel on the apical membrane of the distal tubule consists of homologou s , , and subunits. Each subunit is composed of two transmembrane-spanning domai ns, an extracellular loop, and intracellular amino and carboxyl terminals. Trunc ation mutations of either the or subunit carboxyl terminal result in greatly inc reased sodium conductance, which creates a favorable electrochemical gradient fo r potassium secretion. Although patients with Liddle's syndrome are not universall y hypokalemic, they may exhibit severe potassium wasting with thiazide diuretics . The hypokalemia, hypertension, and metabolic alkalosis that typify Liddle's synd rome can be corrected with amiloride or triamterene or restriction of sodium. FIGURE 3-16 Mechanism of hypokalemia in the syndrome of apparent mineralocortico id excess (AME). Cortisol and aldosterone have equal affinity for the intracellu lar mineralocorticoid receptor (MR); however, in aldosterone-sensitive tissues s uch as the kidney, the enzyme 11 -hydroxysteroid dehydrogenase (11 -HSD) convert s cortisol to cortisone. Since cortisone has a low affinity for the MR, the enzy me 11 -HSD serves to protect the kidney from the effects of glucocorticoids. In hereditary or acquired AME, 11 -HSD is defective or is inactiveted (by licorice or carbenoxalone). Cortisol, which is present at concentrations approximately 10 00-fold that of aldosterone, becomes a mineralocorticoid. The hypermineralocorti coid state results in increased transcription of subunits of the sodium channel and the Na+-K+-ATPase pump. The favorable electrochemical gradient then favors p otassium secretion [7,15].

3.10 Disorders of Water, Electrolytes, and Acid-Base produced in the zona glomerulosa and cortisol, in the zona fasciculata. These en zymes have identical intron-extron structures and are closely linked on chromoso me 8. If unequal crossover occurs, a new hybrid gene is produced that includes t he 5' segment of the 11 -OHase gene (ACTH-response element and the 11 -OHase segme nt) plus the 3' segment of the Aldo S gene (aldosterone synthase segment). The chi meric gene is now under the contol of ACTH, and aldosterone secretion is enhance d, thus causing hypokalemia and hypertension. By inhibiting pituitary release of ACTH, glucocorticoid administration leads to a fall in aldosterone levels and c orrection of the clinical and biochemical abnormalities of GRA. The presence of Aldo S activity in the zona fasciculata gives rise to characteristic elevations in 18-oxidation products of cortisol (18-hydroxycortisol and 18-oxocortisol), wh ich are diagnostic for GRA [8]. FIGURE 3-17 Genetics of glucocorticoid-remediable aldosteronism (GRA): schematic representation of unequal crossover in GRA. The genes for aldosterone synthase (Aldo S) and 11 -hydroxylase (11 -OHase) are normally expressed in separate zone s of the adrenal cortex. Aldosterone is Hypokalemia: Clinical Manifestations CLINICAL MANIFESTATIONS OF HYPOKALEMIA Cardiovascular Abnormal electrocardiogram Predisposition for digitalis toxicity Atrial ventricular arrhythmias Hypertension Neuromuscular Smooth muscle Constipa tion/ileus Bladder dysfunction Skeletal muscle Weakness/cramps Tetany Paralysis Myalgias/rhabdomyolysis Renal/electrolyte Functional alterations Decreased glome rular filtration rate Decreased renal blood flow Renal concentrating defect Incr eased renal ammonia production Chloride wasting Metabolic alkalosis Hypercalciur ia Phosphaturia Structural alterations Dilation and vacuolization of proximal tu bules Medullary cyst formation Interstitial nephritis Endocrine/metabolic Decrea sed insulin secretion Carbohydrate intolerance Increased renin Decreased aldoste rone Altered prostaglandin synthesis Growth retardation FIGURE 3-18 Clinical manifestations of hypokalemia. FIGURE 3-19 Electrocardiographic changes associated with hypokalemia. A, The U w ave may be a normal finding and is not specific for hypokalemia. B, When the amp litude of the U wave exceeds that of the T wave, hypokalemia may be present. The QT interval may appear to be prolonged; however, this is often due to mistaking the QU interval for the QT interval, as the latter does not change in duration with hypokalemia. C, Sagging of the ST segment, flattening of the T wave, and a prominent U wave are seen with progressive hypokalemia. D, The QRS complex may w iden slightly, and the PR interval is often prolonged with severe hypokalemia. H ypokalemia promotes the appearance of supraventricular and ventricular ectopic r hythms, especially in patients taking digitalis [16].

Diseases of Potassium Metabolism 3.11 FIGURE 3-20 Renal lesions associated with hypokalemia. The predominant pathologi c finding accompanying potassium depletion in humans is vacuolization of the epi thelium of the proximal convoluted tubules. The vacoules are large and coarse, a nd staining for lipids is usually negative. The tubular vacuolation is reversibl e with sustained correction of the hypokalemia; however, in patients with long-s tanding hypokalemia, lymphocytic infiltration, interstitial scarring, and tubule atrophy have been described. Increased renal ammonia production may promote com plement activation via the alternate pathway and can contribute to the interstit ial nephritis [17,18]. Hypokalemia: Treatment FIGURE 3-21 Treatment of hypokalemia: estimation of potassium deficit. In the ab sence of stimuli that alter intracellular-extracellular potassium distribution, a decrease in the serum potassium concentration from 3.5 to 3.0 mEq/L correspond s to a 5% reduction (~175 mEq) in total body potassium stores. A decline from 3. 0 to 2.0 mEq/L signifies an additional 200 to 400-mEq deficit. Factors such as t he rapidity of the fall in serum potassium and the presence or absence of sympto ms dictate the aggressiveness of replacement therapy. In general, hypokalemia du e to intracellular shifts can be managed by treating the underlying condition (h yperinsulinemia, theophylline intoxication). Hypokalemic periodic paralysis and hypokalemia associated with myocardial infarction (secondary to endogenous -adre nergic agonist release) are best managed by potassium supplementation [19].

3.12 Disorders of Water, Electrolytes, and Acid-Base FIGURE 3-22 Treatment of hypokalemia. Hyperkalemia: Diagnostic Approach either leukocytes or platelets results in leakage of potassium from these cells. Familial pseudohyperkalemia is a rare condition of increased potassium efflux f rom red blood cells in vitro. Ischemia due to tight or prolonged tourniquet appl ication or fist clenching increases serum potassium concentrations by as much as 1.0 to 1.6 mEq/L. Hyperkalemia can also result from decreases in K movement int o cells or increases in potassium movement from cells. Hyperchloremic metabolic acidosis (in contrast to organic acid, anion-gap metabolic acidosis) causes pota ssium ions to flow out of cells. Hypertonic states induced by mannitol, hyperton ic saline, or poor blood sugar control promote movement of water and potassium o ut of cells. Depolarizing muscle relaxants such as succinylcholine increase perm eability of muscle cells and should be avoided by hyperkalemic patients. The mec hanism of hyperkalemia with -adrenergic blockade is illustrated in Figure 3-3. D igitalis impairs function of the Na+-K+-ATPase pumps and blocks entry of potassi um into cells. Acute fluoride intoxication can be treated with cation-exchange r esins or dialysis, as attempts at shifting potassium back into cells may not be successful. FIGURE 3-23 Approach to hyperkalemia: hyperkalemia without total body potassium excess. Spurious hyperkalemia is suggested by the absence of electrocardiographi c (ECG) findings in patients with elevated serum potassium. The most common caus e of spurious hyperkalemia is hemolysis, which may be apparent on visual inspect ion of serum. For patients with extreme leukocytosis or thrombocytosis, potassiu m levels should be measured in plasma samples that have been promptly separated from the cellular components since extreme elevations in

Diseases of Potassium Metabolism 3.13 FIGURE 3-24 Approach to hyperkalemia: hyperkalemia with reduced glomerular filtr ation rate (GFR). Normokalemia can be maintained in patients who consume normal quantities of potassium until GFR decreases to less than 10 mL/min; however, dim inished GFR predisposes patients to hyperkalemia from excessive exogenous or end ogenous potassium loads. Hidden sources of endogenous and exogenous potassiumand drugs that predispose to hyperkalemiaare listed. FIGURE 3-25 Approach to hyperkalemia: hyporeninemic hypoaldosteronism. Hyporenin emic hypoaldosteronism accounts for the majority of cases of unexplained hyperka lemia in patients with reduced glomerular filtration rate (GFR) whose level of r enal insufficiency is not what would be expected to cause hyperkalemia. Intersti tial renal disease is a feature of most of the diseases listed. The transtubular potassium gradient (see Fig. 3-26) can be used to distinguish between primary t ubule defects and hyporeninemic hypoaldosteronism. Although the transtubular pot assium gradient should be low in both disorders, exogenous mineralocorticoid wou ld normalize transtubular potassium gradient in hyporeninemic hypoaldosteronism.

3.14 Disorders of Water, Electrolytes, and Acid-Base FIGURE 3-26 Physiologic basis of the transtubular potassium concentration gradie nt (TTKG). Secretion of potassium in the cortical collecting duct and outer medu llary collecting duct accounts for the vast majority of potassium excreted in th e urine. Potassium secretion in these segments is influenced mainly by aldostero ne, plasma potassium concentrations, and the anion composition of the fluid in t he lumen. Use of the TTKG assumes that negligible amounts of potassium are secre ted or reabsorbed distal to these sites. The final urinary potassium concentrati on then depends on water reabsorption in the medullary collecting ducts, which r esults in a rise in the final urinary potassium concentration without addition o f significant amounts of potassium to the urine. The TTKG is calculated as follo ws: TTKG = ([K+]urine/(U/P)osm)/[K+]plasma The ratio of (U/P)osm allows for corre ction of the final urinary potassium concentration for the amount of water reabso rbed in the medullary collecting duct. In effect, the TTKG is an index of the gr adient of potassium achieved at potassium secretory sites, independent of urine flow rate. The urine must at least be iso-osmolal with respect to serum if the T TKG is to be meaningful [20]. CAUSES FOR HYPERKALEMIA WITH AN INAPPROPRIATELY LOW TTKG THAT IS UNRESPONSIVE TO MINERALOCORTICOID CHALLENGE Potassium-sparing diuretics Amiloride Triamterene Spironolactone Tubular resista nce to aldosterone Interstitial nephritis Sickle cell disease Urinary tract obst ruction Pseudohypoaldosteronism type I Drugs Trimethoprim Pentamidine Increased distal nephron potassium reabsorption Pseudohypoaldosteronism type II Urinary tr act obstruction FIGURE 3-27 Clinical application of the transtubular potassium gradient (TTKG). The TTKG in normal persons varies much but is genarally within the the range of 6 to 12. Hypokalemia from extrarenal causes results in renal potassium conservat ion and a TTKG less than 2. A higher value suggests renal potassium losses, as t hrough hyperaldosteronism. The expected TTKG during hyperkalemia is greater than 10. An inappropriately low TTKG in a hyperkalemic patient suggests hypoaldoster onism or a renal tubule defect. Administration of the mineralocorticoid 9 -fludr ocortisone (0.05 mg) should cause TTKG to rise above 7 in cases of hypoaldostero nism. Circumstances are listed in which the TTKG would not increase after minera locorticoid challenge, because of tubular resistance to aldosterone [21].

Diseases of Potassium Metabolism 3.15 FIGURE 3-28 Approach to hyperkalemia: low aldosterone with normal to increased p lasma renin. Heparin impairs aldosterone synthesis by inhibiting the enzyme 18-h ydroxylase. Despite its frequent use, heparin is rarely associated with overt hy perkalemia; this suggests that other mechanisms (eg, reduced renal potassium sec retion) must be present simultaneously for hyperkalemia to manifest itself. Both angiotensin-converting enzyme inhibitors and the angiotensin type 1 receptor bl ockers (AT1) receptor blockers interfere with adrenal aldosterone synthesis. Gen eralized impairment of adrenal cortical function manifested by combined glucocor ticoid and mineralocorticoid deficiencies are seen in Addison's disease and in def ects of aldosterone biosynthesis. FIGURE 3-29 Approach to hyperkalemia: pseudohypoaldosteronism. The mechanism of decreased potassium excretion is caused either by failure to secrete potassium i n the cortical collecting tubule or enhanced reabsorption of potassium in the me dullary or papillary collecting tubules. Decreased secretion of potassium in the cortical and medullary collecting duct results from decreases in either apical sodium or potassium channel function or diminished basolateral Na+-K+-ATPase act ivity. Alternatively, potassium may be secreted normally but hyperkalemia can de velop because potassium reabsorption is enhanced in the intercalated cells of th e medullary collecting duct (see Fig. 3-4). The transtubule potassium gradient ( TTKG) in both situations is inappropriately low and fails to normalize in respon se to mineralocorticoid replacement.

3.16 Disorders of Water, Electrolytes, and Acid-Base FIGURE 3-30 Mechanism of hyperkalemia in pseudohypoaldosteronism type I (PHA I). This rare autosomally transmitted disease is characterized by neonatal dehydrat ion, failure to thrive, hyponatremia, hyperkalemia, and metabolic acidosis. Kidn ey and adrenal function are normal, and patients do not respond to exogenous min eralocorticoids. Genetic mutations responsible for PHA I occur in the and subuni ts of the amiloride-sensitive sodium channel of the collecting tubule. Frameshif t or premature stop codon mutations in the cytoplasmic amino terminal or extrace llular loop of either subunit disrupt the integrity of the sodium channel and re sult in loss of channel activity. Failure to reabsorb sodium results in volume d epletion and activation of the renin-aldosterone axis. Furthermore, since sodium reabsorption is indirectly coupled to potassium and hydrogen ion secretion, hyp erkalemia and metabolic acidosis ensue. Interestingly, when mutations are introd uced into the cytoplasmic carboxyl terminal, sodium channel activity is increase d and Liddle's syndrome is observed [4]. Hyperkalemia: Clinical Manifestations CLINICAL MANIFESTATIONS OF HYPERKALEMIA FIGURE 3-31 Clinical manifestations of hyperkalemia. Cardiac Abnormal electrocardiogram Atrial/ventricular arrhythmias Pacemaker dysf unction Neuromuscular Paresthesias Weakness Paralysis Renal electrolyte Decreased renal NH4+ production Natriuresis Endocrine Increase d aldosterone secretion Increased insulin secretion

Diseases of Potassium Metabolism 3.17 FIGURE 3-32 Electrocardiographic (ECG) changes associated with hyperkalemia. A, Normal ECG pattern. B, Peaked, narrow-based T waves are the earliest sign of hyp erkalemia. C, The P wave broadens and the QRS complex widens when the plamsa pot assium level is above 7 mEq/L. D, With higher elevations in potassium, the P wav e becomes difficult to identify. E, Eventually, an undulating sinusoidal pattern is evident. Although the ECG changes are depicted here as correlating to the se verity of hyperkalemia, patients with even mild ECG changes may abruptly progres s to terminal rhythm disturbances. Thus, hyperkalemia with any ECG changes shoul d be treated as an emergency. Hyperkalemia: Treatment FIGURE 3-33 Treatment of hyperkalemia. References 1. 2. 3. MacNight ADC: Epithelial transport of potassium. Kidney Int 1977, 11:39 1397. Bia MJ, DeFronzo RA: Extrarenal potassium homeostasis. Am J Physiol 1981, 2 40:F257262. Hansson JH, Nelson-Williams C, Suzuki H, et al.: Hypertension caused by a truncated epithelial sodium channel gamma subunit: Genetic heterogeneity of Liddle's syndrome. Nature Genetics 1995, 11:7682. 4. Chang SS, Grunder S, Hanukogl u A, et al.: Mutations in subunits of the epithelial sodium channel cause salt w asting with hyperkalemic acidosis, pseudohypoaldosteronism type I. Nature Geneti cs 1996, 12:248253. Simon DB, Karet FE, Rodriguez-Soriano J, et al.: Genetic hete rogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK. Nat ure Genetics 1996, 14:152156. 5.

3.18 6. Disorders of Water, Electrolytes, and Acid-Base 14. Whang R, Flink EB, Dyckner T, et al.: Magnesium depletion as a cause of refr actory potassium repletion. Arch Int Med 1985, 145:16861689. 15. Funder JW: Corti costeroid receptors and renal 11 -hydroxysteroid dehydrogenase activity. Semin N ephrol 1990, 10:311319. 16. Marriott HJL: Miscellaneous conditions: Hypokalemia. In Practical Electrocardiography, edn 8. Baltimore: Williams and Wilkins; 1988. 17. Riemanschneider TH, Bohle A: Morphologic aspects of low-potassium and low-so dium nephropathy. Clin Nephrol 1983, 19:271279. 18. Tolins JP, Hostetter MK, Host etter TH: Hypokalemic nephropathy in the rat: Role of ammonia in chronic tubular injury. J Clin Invest 1987, 79:14471458. 19. Sterns RH, Cox M, Fieg PU, et al.: Internal potassium balance and the control of the plasma potassium concentration . Medicine 1981, 60:339344. 20. Kamel KS, Quaggin S, Scheich A, Halperin ML: Diso rders of potassium homeostasis: an approach based on pathophysiology. Am J Kidne y Dis 1994, 24:597613. 21. Ethier JH, Kamel SK, Magner PO, et al.: The transtubul ar potassium concentration gradient in patients with hypokalemia and hyperkalemi a. Am J Kidney Dis 1990, 15:309315. 7. 8. 9. 10. 11. 12. 13. Pollack MR, Delaney VB, Graham RM, Hebert SC. Gitelman's syndrome (Bartter's variant ) maps to the thiazide-sensitive co-transporter gene locus on chromosome 16q13 i n a large kindred. J Am Soc Nephrol 1996, 7:22442248. Sterwart PM, Krozowski ZS, Gupta A, et al.: Hypertension in the syndrome of apparent mineralocorticoid exce ss due to a mutation of the 11 (-hydroxysteroid dehydrogenase type 2 gene. Lance t 1996, 347:8891. Pascoe L, Curnow KM, Slutsker L, et al.: Glucocorticoid suppres sable hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2. Proc Natl Acad Sci USA 1992, 89:82378331. Welt LG, Blyth WB. Potassium in clinical medicine. In A Primer on Potassium Metabolism. C hicago: Searle & Co.; 1973. DeFronzo RA: Regulation of extrarenal potassium home ostasis by insulin and catecholamines. In Current Topics in Membranes and Transp ort, vol. 28. Edited by Giebisch G. San Diego: Academic Press; 1987:299329. Giebi sch G, Wang W: Potassium transport: from clearance to channels and pumps. Kidney Int 1996, 49:16421631. Jamison RL: Potassium recycling. Kidney Int 1987, 31:69570 3. Nora NA, Berns AS: Hypokalemic, hypophosphatemic thyrotoxic periodic paralysi s. Am J Kidney Dis 1989, 13:247251.

Divalent Cation Metabolism: Magnesium James T. McCarthy Rajiv Kumar M agnesium is an essential intracellular cation. Nearly 99% of the total body magn esium is located in bone or the intracellular space. Magnesium is a critical cat ion and cofactor in numerous intracellular processes. It is a cofactor for adeno sine triphosphate; an important membrane stabilizing agent; required for the str uctural integrity of numerous intracellular proteins and nucleic acids; a substr ate or cofactor for important enzymes such as adenosine triphosphatase, guanosin e triphosphatase, phospholipase C, adenylate cyclase, and guanylate cyclase; a r equired cofactor for the activity of over 300 other enzymes; a regulator of ion channels; an important intracellular signaling molecule; and a modulator of oxid ative phosphorylation. Finally, magnesium is intimately involved in nerve conduc tion, muscle contraction, potassium transport, and calcium channels. Because tur nover of magnesium in bone is so low, the short-term body requirements are met b y a balance of gastrointestinal absorption and renal excretion. Therefore, the k idney occupies a central role in magnesium balance. Factors that modulate and af fect renal magnesium excretion can have profound effects on magnesium balance. I n turn, magnesium balance affects numerous intracellular and systemic processes [112]. In the presence of normal renal function, magnesium retention and hypermag nesemia are relatively uncommon. Hypermagnesemia inhibits magnesium reabsorption in both the proximal tubule and the loop of Henle. This inhibition of reabsorpt ion leads to an increase in magnesium excretion and prevents the development of dangerous levels of serum magnesium, even in the presence of above-normal intake . However, in familial hypocalciuric hypercalcemia, there appears to be an abnor mality of the thick ascending limb of the loop of Henle that prevents excretion of calcium. This abnormality may also extend to Mg. In familial hypocalciuric hy percalcemia, mild hypermagnesemia does not increase the renal excretion of magne sium. A similar abnormality may be caused by lithium [1,2,6,10]. The renal excre tion of magnesium also is below normal in states of hypomagnesemia, decreased di etary magnesium, dehydration and volume depletion, hypocalcemia, hypothyroidism, and hyperparathyroidism [1,2,6,10]. CHAPTER 4

4.2 Disorders of Water, Electrolytes, and Acid-Base Magnesium Distribution TOTAL BODY MAGNESIUM (MG) DISTRIBUTION Location Bone Muscle Soft tissue Erythrocyte Serum Total *data typical for a 70 kg adult Percent of Total 53 27 19.2 0.5 0.3 Mg Content, mmol* 530 270 192 5 3 1000 Mg Content, mg* 12720 6480 4608 120 72 24000 FIGURE 4-1 Total distribution of magnesium (Mg) in the body. Mg (molecular weigh t, 24.305 D) is predominantly distributed in bone, muscle, and soft tissue. Tota l body Mg content is about 24 g (1 mol) per 70 kg. Mg in bone is adsorbed to the surface of hydroxyapatite crystals, and only about one third is readily availab le as an exchangeable pool. Only about 1% of the total body Mg is in the serum a nd interstitial fluid [1,2,8,9,11,12]. Intracellular magnesium (Mg) Proteins, enzymes, citrate, ATP, ADP Membrane proteins Endoplasmic reticulum Mg2+ DNA Mg2+ RNA Ca Mg ATPase Mitochondria FIGURE 4-2 Intracellular distribution of magnesium (Mg). Only 1% to 3% of the to tal intracellular Mg exists as the free ionized form of Mg, which has a closely regulated concentration of 0.5 to 1.0 mmol. Total cellular Mg concentration can vary from 5 to 20 mmol, depending on the type of tissue studied, with the highes t Mg concentrations being found in skeletal and cardiac muscle cells. Our unders tanding of the concentration and distribution of intracellular Mg has been facil itated by the development of electron microprobe analysis techniques and fluores cent dyes using microfluorescence spectrometry. Intracellular Mg is predominantl y complexed to organic molecules (eg, adenosine triphosphatase [ATPase], cell an d nuclear membrane-associated proteins, DNA and RNA, enzymes, proteins, and citr ates) or sequestered within subcellular organelles (mitochondria and endoplasmic reticulum). A heterogeneous distribution of Mg occurs within cells, with the hi ghest concentrations being found in the perinuclear areas, which is the predomin ant site of endoplasmic reticulum. The concentration of intracellular free ioniz ed Mg is tightly regulated by intracellular sequestration and complexation. Very little change occurs in the concentration of intracellular free Mg, even with l arge variations in the concentrations of total intracellular or extracellular Mg [1,3,11]. ADP adenosine diphosphate; ATPadenosine triphosphate; Ca+ionized calcium .

Divalent Cation Metabolism: Magnesium 4.3 Intracellular Magnesium Metabolism -Adrenergic receptor +? + Cellular Mg 2+ Extracellular Mg2+ ? Mg2+ ATP+Mg2+ ATPMg Mg2+ +? ? Na+ (Ca2+?) Extracellular Pi + + Ca2+ pK C Ca2+ +? [Mg2+] = 0.7-1.2mmol Na+ (Ca2+?) Plasma membrane Mg2+? E.R. or S.R. Ca2+ Mg2+? [ Mg2+] = 0.5mmol Adenylyl cyclase Mitochondrion ADP ? Mg2+? cAMP Nucleus D.G. + IP3 Muscarinic receptor or vasopressin receptor Plasma membrane FIGURE 4-3 Regulation of intracellular magnesium (Mg2+) in the mammalian cell. S hown is an example of Mg2+ movement between intracellular and extracellular spac es and within intracellular compartments. The stimulation of adenylate cyclase a ctivity (eg, through stimulation of -adrenergic receptors) increases cyclic aden osine monophosphate (cAMP). The increase in cAMP induces extrusion of Mg from mi tochondria by way of mitochondrial adenine nucleotide translocase, which exchang es 1 Mg2+-adenosine triphosphate (ATP) for adenosine diphosphate (ADP). This sli ght increase in cytosolic Mg2+ can then be extruded through the plasma membrane by way of a Mg-cation exchange mechanism, which may be activated by either cAMP or Mg. Activation of other cell receptors (eg, muscarinic receptor or vasopressi n receptor) may alter cAMP levels or produce diacylglycerol (DAG). DAG activates Mg influx by way of protein kinase C (pK C) activi ty. Mitochondria may accumulate Mg by the exchange of a cytosolic Mg2+-ATP for a mitochondrial matrix Pi molecule. This exchange mechanism is Ca2+-activated and bidirectional, depending on the concentrations of Mg2+-ATP and Pi in the cytoso l and mitochondria. Inositol 1,4,5-trisphosphate (IP3) may also increase the rel ease of Mg from endoplasmic reticulum or sarcoplasmic reticulum (ER or SR, respe ctively), which also has a positive effect on this Mg2+-ATP-Pi exchanger. Other potential mechanisms affecting cytosolic Mg include a hypothetical Ca2+-Mg2+ exc hanger located in the ER and transport proteins that can allow the accumulation of Mg within the nucleus or ER. A balance must exist between passive entry of Mg into the cell and an active efflux mechanism because the concentration gradient favors the movement of extracellular Mg (0.71.2 mmol) into the cell (free Mg, 0. 5 mmol). This Mg extrusion process may be energyrequiring or may be coupled to t he movement of other cations. The cellular movement of Mg generally is not invol ved in the transepithelial transport of Mg, which is primarily passive and occur s between cells [13,7]. (From Romani and coworkers [3]; with permission.)

4.4 Disorders of Water, Electrolytes, and Acid-Base Mg2+ Outer membrane Mg CorA MgtB Mg2+ Cytosol Mg2+ ATP MgtA ATP ADP Mg2+ 37 kDa? ADP 2+ Extracellular Mg2+ N Mg2+ Periplasm Mg2+ 1 2 3 4 Periplasm 5 6 7 8 9 10 Periplasm 12 3 N Cytoplasm C Cytoplasm C A B MgtA and MgtB CorA FIGURE 4-4 A, Transport systems of magnesium (Mg). Specific membraneassociated M g transport proteins only have been described in bacteria such as Salmonella. Al though similar transport proteins are believed to be present in mammalian cells based on nucleotide sequence analysis, they have not yet been demonstrated. Both MgtA and MgtB (molecular weight, 91 and 101 kDa, respectively) are members of t he adenosine triphosphatase (ATPase) family of transport proteins. B, Both of th ese transport proteins have six C-terminal and four N-terminal membrane-spanning segments, with both the N- and C-terminals within the cytoplasm. Both proteins transport Mg with its electrochemical gradient, in contrast to other known ATPas e proteins that usually transport ions against their chemical gradient. Low levels of extracellular Mg are capable of i ncreasing transcription of these transport proteins, which increases transport o f Mg into Salmonella. The CorA system has three membrane-spanning segments. This system mediates Mg influx; however, at extremely high extracellular Mg concentr ations, this protein can also mediate Mg efflux. Another cell membrane Mg transp ort protein exists in erythrocytes (RBCs). This RBC Na+-Mg2+ antiporter (not sho wn here) facilitates the outward movement of Mg from erythrocytes in the presenc e of extracellular Na+ and intracellular adenosine triphosphate (ATP) [4,5]. ADPa denosine diphosphate; Ccarbon; Nnitrogen. (From Smith and Maguire [4]). Gastrointestinal Absorption of Magnesium FIGURE 4-5 Gastrointestinal absorption of dietary intake of magnesium (Mg). The normal adult dietary intake of Mg is 300 to 360 mg/d (12.515 mmol/d). A Mg intake of about 3.6 mg/kg/d is necessary to maintain Mg balance. Foods high in Mg cont ent include green leafy vegetables (rich in Mg-containing chlorophyll), legumes, nuts, seafoods, and meats. Hard water contains about 30 mg/L of Mg. Dietary int ake is the only source by which the body can replete Mg stores. Net intestinal M g absorption is affected by the fractional Mg absorption within a specific segme nt of intestine, the length of that intestinal segment, and transit time of the food bolus. Approximately 40% to 50% of dietary Mg is absorbed. Both the duodenu m and jejunum have a high fractional absorption of Mg. These segments of intesti ne are relatively short, however, and the transit time is rapid. Therefore, thei

r relative contribution to total Mg absorption is less than that of the ileum. I n the intact animal, most of the Mg absorption occurs in the ileum and colon. 1, 25-dihydroxy-vitamin D3 may mildly increase the intestinal absorption of Mg; how ever, this effect may be an indirect result of increased calcium absorption indu ced by the vitamin. Secretions of the upper intestinal tract contain approximate ly 1 mEq/L of Mg, whereas secretions from the lower intestinal tract contain 15 mEq/L of Mg. In states of nausea, vomiting, or nasogastric suction, mild to mode rate losses of Mg occur. In diarrheal states, Mg depletion can occur rapidly owi ng to both high intestinal secretion and lack of Mg absorption [2,6,813]. Gastrointestinal absorption of dietary magnesium (Mg) Mg absorption % of intake mmol/day mg/day absorption 0 0.63 1.25 1.88 1.25 0.63 5.6 0 15 30 45 30 15 135 0 5 10 15 10 5 45 Site Stomach Duodenum Jejunum Proximal Ileum Distal Ileum Colon Total* *Normal dietary Mg intake = 300 mg (12.5 mmol) per day

Divalent Cation Metabolism: Magnesium 10 9 Magnesium absorbed M Mg , mmol 8 Mg transported, Eq/h 7 6 5 4 3 2 1 0 0 3 6 9 12 15 18 21 24 3 12 0 0 10 20 30 40 [Mg] in bicarbonate saline, mEq/L 22 3 13 3 6 6 5 4 3 2 1 4.5 7 Physiological Mg-intake, mmol/d A B Oral magnesium dose m, mmol 10 Net Mg absorption, mEq/10 hrs 8 6 4 2 0 0 20 FIGURE 4-6 Intestinal magnesium (Mg) absorption. In rats, the intestinal Mg abso rption is related to the luminal Mg concentration in a curvilinear fashion (A). This same phenomenon has been observed in humans (B and C). The hyperbolic curve (dotted line in B and C) seen at low doses and concentrations may reflect a sat urable transcellular process; whereas the linear function (dashed line in B and C) at higher Mg intake may be a concentration-dependent passive intercellular Mg absorption. Alternatively, an intercellular process that can vary its permeabil ity to Mg, depending on the luminal Mg concentration, could explain these findin gs (see Fig. 4-7) [1315]. (A, From Kayne and Lee [13]; B, from Roth and Wermer [1 4]; C, from Fine and coworkers [15]; with permission.) C 40 Mg intake, mEq/meal 60 80 Mechanism of intestinal magnesium absorption Nucleus Lumen Mg2+ A Mg2+ B Mg2+ K+ Na+ ATPase Mg2+ FIGURE 4-7 Proposed pathways for movement of magnesium (Mg) across the intestina l epithelium. Two possible routes exist for the absorption of Mg across intestin al epithelial cells: the transcellular route and the intercellular pathway. Alth ough a transcellular route has not yet been demonstrated, its existence is infer red from several observations. No large chemical gradient exists for Mg movement across the cell membrane; however, a significant uphill electrical gradient exi sts for the exit of Mg from cells. This finding suggests the existence and parti cipation of an energy-dependent mechanism for extrusion of Mg from intestinal ce lls. If such a system exists, it is believed it would consist of two stages. 1) Mg would enter the apical membrane of intestinal cells by way of a passive carri er or facilitated diffusion. 2) An active Mg pump in the basolateral section of the cell would extrude Mg. The intercellular movement of Mg has been demonstrate d to occur by both gradient-driven and solvent-drag mechanisms. This intercellul ar path may be the only means by which Mg moves across the intestinal epithelium . The change in transport rates at low Mg concentrations would reflect changes i n the openness of this pathway. High concentrations of luminal Mg (eg, after a mea l) are capable of altering the morphology of the tight junction complex. High lo cal Mg concentrations near the intercellular junction also can affect the activi ties of local membrane-associated proteins (eg, sodium-potassium adenosine triph

osphate [Na-K ATPase]) near the tight junction and affect its permeability (see Fig. 4-6) [1315].

4.6 Disorders of Water, Electrolytes, and Acid-Base Renal Handling of Magnesium Afferent arteriole Efferent arteriole FIGURE 4-8 The glomerular filtration of magnesium (Mg). Total serum Mg consists of ionized, complexed, and protein bound fractions, 60%, 7%, and 33% of total, r espectively. The complexed Mg is bound to molecules such as citrate, oxalate, an d phosphate. The ultrafilterable Mg is the total of the ionized and complexed fr actions. Normal total serum Mg is approximately 1.7 to 2.1 mg/dL (about 0.700.90 mmol/L) [1,2,79,11,12]. Glomerular capillary Mg2+-protein Mg2+ionized Bowman's space Mg2+complexed Mg2+-ultrafilterable % of total serum Mg2+ Mg2+ Ionized Mg 60% Protein-bound Mg 33% Complexed Mg 7% *Normal total serum Mg = 1.72.1 mg/dL (0.700.9 mmol/L) Proximal tubule Juxtamedullary nephron 05% Filtered Mg2+ (100%) Superficial cortical nephron 510% Filtered Mg2+ (100%) 20% 65% 65% 20% Excreted (5%) FIGURE 4-9 The renal handling of magnesium (Mg2+). Mg is filtered at the glomeru lus, with the ultrafilterable fraction of plasma Mg entering the proximal convol uted tubule (PCT). At the end of the PCT, the Mg concentration is approximately 1.7 times the initial concentration of Mg and about 20% of the filtered Mg has been reabsorbed. Mg reabsorption occurs passively through paracellular pathways. Hydrated Mg has a very large ra dius that decreases its intercellular permeability in the PCT when compared with sodium. The smaller hydrated radius of sodium is 50% to 60% reabsorbed in the P CT. No clear evidence exists of transcellular reabsorption or secretion of Mg wi thin the mammalian PCT. In the pars recta of the proximal straight tubule (PST), Mg reabsorption can continue to occur by way of passive forces in the concentra ting kidney. In states of normal hydration, however, very little Mg reabsorption occurs in the PST. Within the thin descending limb of the loop of Henle, juxtam edullary nephrons are capable of a small amount of Mg reabsorption in a state of antidiuresis or Mg depletion. This reabsorption does not occur in superficial c ortical nephrons. No data exist regarding Mg reabsorption in the thin ascending limb of the loop of Henle. No Mg reabsorption occurs in the medullary portion of the thick ascending limb of the loop of Henle; whereas nearly 65% of the filter ed load is absorbed in the cortical thick ascending limb of the loop of Henle in both juxtamedullary and superficial cortical nephrons. A small amount of Mg is absorbed in the distal convoluted tubule. Mg transport in the connecting tubule has not been well quantified. Little reabsorption occurs and no evidence exists of Mg secretion within the collecting duct. Normally, 95% of the filtered Mg is reabsorbed by the nephron. In states of Mg depletion the fractional excretion of Mg can decrease to less than 1%; whereas Mg excretion can increase in states of

above-normal Mg intake, provided no evidence of renal failure exists [1,2,69,11, 12].

Divalent Cation Metabolism: Magnesium Mg absorption in cTAL +8mV 78mV 0mV 4.7 6 1Cl 4 3Na+ 6Cl 3K+ 1 2K+ 2 3 5 Mg 2Na+ 3Na+ 2K+ 2Cl 4Cl 3K+ FIGURE 4-10 Magnesium (Mg) reabsorption in the cortical thick ascending limb (cT AL) of the loop of Henle. Most Mg reabsorption within the nephron occurs in the cTAL owing primarily to voltage-dependent Mg flux through the intercellular tigh t junction. Transcellular Mg movement occurs only in response to cellular metabo lic needs. The sequence of events necessary to generate the lumen-positive elect rochemical gradient that drives Mg reabsorption is as follows: 1) A basolateral sodium-potassium-adenosine triphosphatase (Na+-K+ATPase) decreases intracellular sodium, generating an inside-negative electrical potential difference; 2) Intra cellular K is extruded by an electroneutral K-Cl (chloride) cotransporter; 3) Cl is extruded by way of conductive pathways in the basolateral membrane; 4) The a pical-luminal Na-2Cl-K (furosemide-sensitive) cotransport mechanism is driven by the inside-negative potential difference and decrease in intracellular Na; 5) P otassium is recycled back into the lumen by way of an apical K conductive channe l; 6) Passage of approximately 2 Na molecules for every Cl molecule is allowed b y the paracellular pathway (intercellular tight junction), which is cation perms elective; 7) Mg reabsorption occurs passively, by way of intercellular channels, as it moves down its electrical gradient [1,2,6,7]. (Adapted from de Rouffignac and Quamme [1].) Mg ~1.0mmol Mg ~1.0mmol A Mg 0.5mmol JMg, pmol.min1.mm1 0.8 0.6 0.4 (7) 0.2 Vt, mV 18 15 12 9 6 3 0.2 0.4 (8) 0.6 0.8 12 15 18 FIGURE 4-11 Voltage-dependent net magnesium (Mg) flux in the cortical thick asce nding limb (cTAL). Within the isolated mouse cTAL, Mg flux (JMg) occurs in respo nse to voltage-dependent mechanisms. With a relative lumen-positive transepithel ial potential difference (Vt), Mg reabsorption increases (positive JMg). Mg reab sorption equals zero when no voltage-dependent difference exists, and Mg is capa ble of moving into the tubular lumen (negative JMg) when a lumen-negative voltag e difference exists [1,16]. (From di Stefano and coworkers [16]).

4.8 Disorders of Water, Electrolytes, and Acid-Base FIGURE 4-12 Effect of hormones on magnesium (Mg) transport in the cortical thick ascending limb (cTAL). In the presence of arginine vasopressin (AVP), glucagon (GLU), human calcitonin (HCT), parathyroid hormone (PTH), 1,4,5-isoproteronol (I SO), and insulin (INS), increases occur in Mg reabsorption from isolated segment s of mouse cTALs. These hormones have no effect on medullary TAL segments. As al ready has been shown in Figure 4-3, these hormones affect intracellular second me ssengers and cellular Mg movement. These hormone-induced alterations can affect t he paracellular permeability of the intercellular tight junction. These changes may also affect the transepithelial voltage across the cTAL. Both of these force s favor net Mg reabsorption in the cTAL [1,2,7,8]. Asterisksignificant change fro m preceding period; JMgMg flux; Ccontrol, absence of hormone. (Adapted from de Rou ffignac and Quamme [1].) JMg2+ Net fluxes, pmol min1 mm1 1.0 0.8 AVP * GLU * HCT PTH * ISO INS * 0.6 * 0.4 0.2 0 C C C C C C C C C C C C * Magnesium Depletion CAUSES OF MAGNESIUM (Mg) DEPLETION FIGURE 4-13 The causes of magnesium (Mg) depletion. Depletion of Mg can develop as a result of low intake or increased losses by way of the gastrointestinal tra ct, the kidneys, or other routes [1,2,813]. Poor Mg intake Starvation Anorexia Protein calorie malnutrition No Mg in intrave nous fluids Renal losses see Fig. 4-14 Increased gastrointestinal Mg losses Naso gastric suction Vomiting Intestinal bypass for obesity Short-bowel syndrome Infl ammatory bowel disease Pancreatitis Diarrhea Laxative abuse Villous adenoma Other Lactation Extensive burns Exchange transfusions

Divalent Cation Metabolism: Magnesium Renal magnesium (Mg) wasting Thiazides(?) Volume expansion Osmotic diuresis Gluc ose Mannitol Urea Diuretic phase acute renal failure* Post obstructive diuresis* Hypercalcemia* Phosphate depletion* Chronic renal disease* ? Aminoglycosides* R enal transplant* Interstitial nephritis* Tubular defects Bartter's syndrome Gite lman's syndrome Renal tubular acidosis Medullary calcinosis Drugs/toxins Cis-pla tinum Amphotericin B Cyclosporine Pentamidine ? Aminoglycosides* Foscarnet (?ATN ) Ticarcillin/carbenicillin ? Digoxin Electrolyte imbalances Hypercalcemia* Phos phate depletion* Metabolic acidosis Starvation Ketoacidosis Alcoholism Hormonal changes Hyperaldosteronism Primary hyperparathyroidism Hyperthyroidism Uncontrol led diabetes mellitus 4.9 FIGURE 4-14 Renal magnesium (Mg) wasting. Mg is normally reabsorbed in the proxi mal tubule (PT), cortical thick ascending limb (cTAL), and distal convoluted tub ule (DCT) (see Fig. 4-9). Volume expansion and osmotic diuretics inhibit PT reab sorption of Mg. Several renal diseases and electrolyte disturbances (asterisks) inhibit Mg reabsorption in both the PT and cTAL owing to damage to the epithelia l cells and the intercellular tight junctions, plus disruption of the electroche mical forces that normally favor Mg reabsorption. Many drugs and toxins directly damage the cTAL. Thiazides have little direct effect on Mg reabsorption; howeve r, the secondary hyperaldosteronism and hypercalcemia effect Mg reabsorption in CD and/or cTAL. Aminoglycosides accumulate in the PT, which affects sodium reabs orption, also leading to an increase in aldosterone. Aldosterone leads to volume expansion, decreasing Mg reabsorption. Parathyroid hormone has the direct effec t of increasing Mg reabsorption in cTAL; however, hypercalcemia offsets this ten dency. Thyroid hormone increases Mg loss. Diabetes mellitus increases Mg loss by way of both hyperglycemic osmotic diuresis and insulin abnormalities (deficienc y and resistance), which decrease Mg reabsorption in the proximal convoluted tub ule and cTAL, respectively. Cisplatin causes a Gitelman-like syndrome, which oft en can be permanent [1,2,812]. SIGNS AND SYMPTOMS OF HYPOMAGNESEMIA Cardiovascular Electrocardiographic results Prolonged P-R and Q-T intervals, U w aves Angina pectoris ?Congestive heart failure Atrial and ventricular arrhythmia s ?Hypertension Digoxin toxicity Atherogenesis Neuromuscular Central nervous sys tem Seizures Obtundation Depression Psychosis Coma Ataxia Nystagmus Choreiform a nd athetoid movements Muscular Cramps Weakness Carpopedal spasm Chvostek's sign Trousseau's sign Fascicula tions Tremulous Hyperactive reflexes Myoclonus Dysphagia Skeletal Osteoporosis O steomalacia FIGURE 4-15 Signs and symptoms of hypomagnesemia. Symptoms of hypomagnesemia can develop when the serum magnesium (Mg) level falls below 1.2 mg/dL. Mg is a crit ical cation in nerves and muscles and is intimately involved with potassium and calcium. Therefore, neuromuscular symptoms predominate and are similar to those seen in hypocalcemia and hypokalemia. Electrocardiographic changes of hypomagnes emia include an increased P-R interval, increased Q-T duration, and development of U waves. Mg deficiency increases the mortality of patients with acute myocard ial infarction and congestive heart failure. Mg depletion hastens atherogenesis by increasing total cholesterol and triglyceride levels and by decreasing high-d ensity lipoprotein cholesterol levels. Hypomagnesemia also increases hypertensiv e tendencies and impairs insulin release, which favor atherogenesis. Low levels of Mg impair parathyroid hormone (PTH) release, block PTH action on bone, and de crease the activity of renal 1- -hydroxylase, which converts 25-hydroxy-vitamin D3 into 1,25-dihydroxy-vitamin D3, all of which contribute to hypocalcemia. Mg i s an integral cofactor in cellular sodium-potassium-adenosine triphosphatase act

ivity, and a deficiency of Mg impairs the intracellular transport of K and contr ibutes to renal wasting of K, causing hypokalemia [6,812].

4.10 Disorders of Water, Electrolytes, and Acid-Base Magnesium deficiency Total serum Mg (On normal diet of 250350 mg/d of Mg) Enhanced AII action Normal ( 1.72.1 mg/dL) 24 hour urine Mg -Aldosterone Low (<1.7 mg/dL) 24 hour urine Mg Insulin resistance Altered synthesis of eicosanoids (PGI2 , : -TXA2 , and 12-HETE) -Platelet aggregation Normal (> 24 mg/24 hrs) Low (< 24 mg/24 hrs) Low (< 24 mg/24 hrs) High (> 24 mg/24 hrs) Increased vasomotor tone -Na+ reabsorption No Mg deficiency Mg deficiency present Check for nonrenal causes Mg deficiency present Renal Mg w asting Hypertension Tolerance Mg test (see Figure 418) FIGURE 4-16 Mechanism whereby magnesium (Mg) deficiency could lead to hypertensi on. Mg deficiency does the following: increases angiotensin II (AII) action, dec reases levels of vasodilatory prostaglandins (PGs), increases levels of vasocons trictive PGs and growth factors, increases vascular smooth muscle cytosolic calc ium, impairs insulin release, produces insulin resistance, and alters lipid prof ile. All of these results of Mg deficiency favor the development of hypertension and atherosclerosis [10,11]. Na+ionized sodium; 12-HETEhydroxy-eicosatetraenoic [ acid]; TXA2thromboxane A2. (From Nadler and coworkers [17].) Normal Mg retention No Mg deficiency Normal Mg retention Mg deficiency present Check for nonrenal causes FIGURE 4-17 Evaluation in suspected magnesium (Mg) deficiency. Serum Mg levels m ay not always indicate total body stores. More refined tools used to assess the status of Mg in erythrocytes, muscle, lymphocytes, bone, isotope studies, and in dicators of intracellular Mg, are not routinely available. Screening for Mg defi ciency relies on the fact that urinary Mg decreases rapidly in the face of Mg de pletion in the presence of normal renal function [2,6,815,18]. (Adapted from Al-G hamdi and coworkers [11].) FIGURE 4-18 The magnesium (Mg) tolerance test, in var ious forms [2,6,812,18], has been advocated to diagnose Mg depletion in patients with normal or near-normal serum Mg levels. All such tests are predicated on the fact that patients with normal Mg status rapidly excrete over 50% of an acute M g load; whereas patients with depleted Mg retain Mg in an effort to replenish Mg stores. (From Ryzen and coworkers [18].) MAGNESIUM (Mg) TOLERANCE TEST FOR PATIENTS WITH NORMAL SERUM MAGNESIUM

Time 0 (baseline) 04 h 024 h End %M=1 (24-h urine Mg) Action Urine (spot or timed) for molar Mg:Cr ratio IV infusion of 2.4 mg (0.1 mmol) of Mg/kg lean body wt in 50 mL of 50% dextrose Collect urine (staring with Mg infus ion) for Mg and Cr Calculate % Mg retained (%M) ([Preinfusion urine Mg:Cr] Total Mg infused [24-h urine Cr]) 100 Mg retained, % >50 2050 <20 Mg deficiency Definite Probable None Crcreatinine; IVintravenous; Mgmagnesium.

Divalent Cation Metabolism: Magnesium 4.11 MAGNESIUM SALTS USED IN MAGNESIUM REPLACEMENT THERAPY Magnesium salt Gluconate Chloride Lactate Citrate Hydroxide Oxide Chemical formula Cl2H22MgO14 MgCl2 . (H2O)6 C6H10MgO6 C12H10Mg3O14 Mg(OH)2 MgO Mg content, mg/g 58 120 120 53 410 600 Examples* Magonate Mag-L-100 MagTab SR* Multiple Maalox, Mylanta, Gelusil Riopan Mag-Ox 400 UroMag Beelith IV IV Oral epsom salt Phillips' Milk of Magnesia Mg content 27-mg tablet 54 mg/5 mL 100-mg capsule 84-mg caplet 4756 mg/5 mL 83 mg/ 5 mL and 63-mg tablet 96 mg/5 mL 241-mg tablet 84.5-mg tablet 362-mg tablet 10%9.9 mg/mL 5 0%49.3 mg/mL 97 mg/g 168 mg/ 5 mL Diarrhea + + ++ ++ ++ Sulfate MgSO4 . (H2O)7 100 ++ ++ ++ Milk of Magnesia Data from McLean [9], Al-Ghamdi and coworkers [11], Oster and Epstein [19], and Physicians' Desk Reference [20]. *Magonate, Fleming & Co, Fenton, MD; MagTab Sr, Nic he Pharmaceuticals, Roanoke, TX; Maalox, Rhone-Poulenc Rorer Pharmaceutical, Coll egeville, PA; Mylanta, J & J-Merck Consumer Pharm, Ft Washinton, PA; Riopan, White hall Robbins Laboratories, Madison, NJ; Mag-Ox 400 and Uro-Mag, Blaine, Erlanger, KY; Beelith, Beach Pharmaceuticals, Conestee, SC; Phillips' Milk of Magnesia, Bayer Corp, Parsippany, NJ. FIGURE 4-19 Magnesium (Mg) salts that may be used in Mg replacement therapy. FIG URE 4-20 Acute Mg replacement for life-threatening events such as seizures or po tentially lethal cardiac arrhythmias has been described [812,19]. Acute increases in the level of serum Mg can cause nausea, vomiting, cutaneous flushing, muscul ar weakness, and hyporeflexia. As Mg levels increase above 6 mg/dL (2.5 mmol/L), electrocardiographic changes are followed, in sequence, by hyporeflexia, respir atory paralysis, and cardiac arrest. Mg should be administered with caution in p atients with renal failure. In the event of an emergency the acute Mg load shoul d be followed by an intravenous (IV) infusion, providing no more than 1200 mg (5 0 mmol) of Mg on the first day. This treatment can be followed by another 2 to 5 days of Mg repletion in the same dosage, which is used in less urgent situation s. Continuous IV infusion of Mg is preferred to both intramuscular (which is pai nful) and oral (which causes diarrhea) administration. A continuous infusion avo ids the higher urinary fractional excretion of Mg seen with intermittent adminis tration of Mg. Patients with mild Mg deficiency may be treated with oral Mg salt s rather than parenteral Mg and may be equally efficacious [8]. Administration o

f Mg sulfate may cause kaliuresis owing to excretion of the nonreabsorbable sulf ate anion; Mg oxide administration has been reported to cause significant acidos is and hyperkalemia [19]. Parenteral Mg also is administered (often in a manner different from that shown here) to patients with preeclampsia, asthma, acute myo cardial infarction, and congestive heart failure. GUIDELINES FOR MAGNESIUM (Mg) REPLACEMENT Life-threatening event, eg, seizures and cardiac arrhythmia I. 24 g MgSO4 IV or IM stat (24 vials [2 mL each] of 50% MgSO4) Provides 200400 mg of Mg (8.316.7 mmol Mg) Closely monitor: Deep tendon reflexes Heart rate Blood pr essure Respiratory rate Serum Mg (<2.5 mmol/L [6.0 mg/dL]) Serum K II. IV drip o ver first 24 h to provide no more than 1200 mg (50 mmol) Mg/24 h Subacute and chronic Mg replacement I. 400600 mg (16.725 mmol Mg daily for 25 d) IV: continuous infusion IM: painful Or al: use divided doses to minimize diarrhea

4.12 Disorders of Water, Electrolytes, and Acid-Base References 1. de Rouffignac C, Quamme G: Renal magnesium handling and its hormonal control. Physiol Rev 1994, 74:305322. 2. Quamme GA: Magnesium homeostasis and renal magne sium handling. Miner Electrolyte Metab 1993, 19:218225. 3. Romani A, Marfella C, Scarpa A: Cell magnesium transport and homeostasis: role of intracellular compar tments. Miner Electrolyte Metab 1993, 19:282289. 4. Smith DL, Maguire ME: Molecul ar aspects of Mg2+ transport systems. Miner Electrolyte Metab 1993, 19:266276. 5. Roof SK, Maguire ME: Magnesium transport systems: genetics and protein structur e (a review). J Am Coll Nutr 1994, 13:424428. 6. Sutton RAL, Domrongkitchaiporn S : Abnormal renal magnesium handling. Miner Electrolyte Metab 1993, 19:232240. 7. de Rouffignac C, Mandon B, Wittner M, di Stefano A: Hormonal control of magnesiu m handling. Miner Electrolyte Metab 1993, 19:226231. 8. Whang R, Hampton EM, Whan g DD: Magnesium homeostasis and clinical disorders of magnesium deficiency. Ann Pharmacother 1994, 28:220226. 9. McLean RM: Magnesium and its therapeutic uses: a review. Am J Med 1994, 96:6376. 10. Abbott LG, Rude RK: Clinical manifestations of magnesium deficiency. Miner Electrolyte Metab 1993, 19:314322. 11. Al-Ghamdi S MG, Cameron EC, Sutton RAL: Magnesium deficiency: pathophysiologic and clinical overview. Am J Kid Dis 1994, 24:737752. 12. Nadler JL, Rude RK: Disorders of magn esium metabolism. Endocrinol Metab Clin North Am 1995, 24:623641. 13. Kayne LH, L ee DBN: Intestinal magnesium absorption. Miner Electrolyte Metab 1993, 19:210217. 14. Roth P, Werner E: Intestinal absorption of magnesium in man. Int J Appl Rad iat Isotopes 1979, 30:523526. 15. Fine KD, Santa Ana CA, Porter JL, Fordtran JS: Intestinal absorption of magnesium from food and supplements. J Clin Invest 1991 , 88:396402. 16. di Stefano A, Roinel N, de Rouffignac C, Wittner M: Transepithel ial Ca+ and Mg+ transport in the cortical thick ascending limb of Henle's loop of the mouse is a voltage-dependent process. Renal Physiol Biochem 1993, 16:157166. 17. Nadler JL, Buchanan T, Natarajan R, et al.: Magnesium deficiency produces in sulin resistance and increased thromboxane synthesis. Hypertension 1993, 21:10241 029. 18. Ryzen E, Elbaum N, Singer FR, Rude RK: Parenteral magnesium tolerance t esting in the evaluation of magnesium deficiency. Magnesium 1985, 4:137147. 19. O ster JR, Epstein M: Management of magnesium depletion. Am J Nephrol 1988, 8:34935 4. 20. Physicians' Desk Reference (PDR). Montvale, NJ: Medical Economics Company; 1996.

Divalent Cation Metabolism: Calcium James T. McCarthy Rajiv Kumar C alcium is an essential element in the human body. Although over 99% of the total body calcium is located in bone, calcium is a critical cation in both the extra cellular and intracellular spaces. Its concentration is held in a very narrow ra nge in both spaces. In addition to its important role in the bone mineral matrix , calcium serves a vital role in nerve impulse transmission, muscular contractio n, blood coagulation, hormone secretion, and intercellular adhesion. Calcium als o is an important intracellular second messenger for processes such as exocytosi s, chemotaxis, hormone secretion, enzymatic activity, and fertilization. Calcium balance is tightly regulated by the interplay between gastrointestinal absorpti on, renal excretion, bone resorption, and the vitamin Dparathyroid hormone (PTH) system [17]. CHAPTER 5

5.2 Disorders of Water, Electrolytes, and Acid-Base Calcium Distribution TOTAL DISTRIBUTION OF CALCIUM IN THE BODY Ca Content* Location Bone Extracellular fluid Intracellular fluid Total *data for a 70 kg person Concentration 99% 2.4 mmol 0.1 mol mmol ~31.4 103 35 <1 ~31.5 103 mg ~1255 103 ~1400 <40 ~1260 103 FIGURE 5-1 Total distribution of calcium (Ca) in the body. Ca (molecular weight, 40.08 D) is predominantly incorporated into bone. Total body Ca content is abou t 1250 g (31 mol) in a person weighing 70 kg. Bone Ca is incorporated into the h ydroxyapatite crystals of bone, and about 1% of bone Ca is available as an excha ngeable pool. Only 1% of the total body calcium exists outside of the skeleton. Intracellular Calcium Metabolism Ca2+o [Ca2+]o1-3mM +8-0mV -50mV Ca2+-binding proteins; phosphate, citrate, etc. c omplexes Ca2+i Mitochondria VOC ROC SOC [Ca2+]i<10-3mM Nucleus ~ 2+ SRCa Ca s ATPase Ca2+ Plasma membrane ATPase Na+ ~ Ca2+ Ca2+ Sarcoplasmic or endoplasmic reticulum InsP3 receptor 3Na+: Ca2+exchanger FIGURE 5-2 General scheme of the distribution and movement of intracellular calc ium (Ca). In contrast to magnesium, Ca has a particularly adaptable coordination sphere that facilitates its binding to the irregular geom etry of proteins, a binding that is readily reversible. Low intracellular Ca con centrations can function as either a first or second messenger. The extremely lo w concentrations of intracellular Ca are necessary to avoid Ca-phosphate micropr ecipitation and make Ca an extremely sensitive cellular messenger. Less than 1% of the total intracellular Ca exists in the free ionized form, with a concentrat ion of approximately 0.1 mol/L. Technical methods available to investigate intrac ellular free Ca concentration include Ca-selective microelectrodes, bioluminesce nt indicators, metallochromic dyes, Ca-sensitive fluorescent indicators, electro n-probe radiographic microanalysis, and fluorine-19 nuclear magnetic resonance i maging. Intracellular Ca is predominantly sequestered within the endoplasmic ret iculum (ER) and sarcoplasmic reticulum (SR). Some sequestration of Ca occurs wit hin mitochondria and the nucleus. Ca can be bound to proteins such as calmodulin and calbindin, and Ca can be complexed to phosphate, citrate, and other anions. Intracellular Ca is closely regulated by balancing Ca entry by way of voltage-o perated channels (VOC), receptoroperated channels (ROC), and store-operated chan nels (SOC), with active Ca efflux by way of plasma membraneassociated Ca-adenosin e triphosphatase (ATPase) and a Na-Ca exchanger. Intracellular Ca also is closel y regulated by balancing Ca movement into the SR (SR Ca-ATPase) and efflux from

the SR by an inositol 1,4,5-trisphosphate (InsP3) receptor [17]. The highest conc entration of intracellular Ca is found in the brush border of epithelial cells, where there is also the highest concentration of Ca-binding proteins such as act in-myosin and calbindin. Intracellular Ca messages are closely modulated by the phospholipase C-InsP3 pathway and also the phospholipase A2arachidonic acid pathw ay, along with intracellular Ca, which itself modulates the InsP3 receptor.

Divalent Cation Metabolism: Calcium 5.3 Vitamin D and Parathyroid Hormone Actions FIGURE 5-3 Metabolism of vitamin D. The compound 7dehydrocholesterol, through th e effects of heat (37C) and (UV) light (wavelength 280305 nm), is converted into v itamin D3 in the skin. Vitamin D3 is then transported on vitamin D binding prote ins (VDBP) to the liver. In the liver, vitamin D3 is converted to 25-hydroxyvita min D3 by the hepatic microsomal and mitochondrial cytochrome P450containing vita min D3 25-hydroxylase enzyme. The 25hydroxy-vitamin D3 is transported on VDBP to the proximal tubular cells of the kidney, where it is converted to 1,25-dihydro xy-vitamin D3 by a 1- -hydroxylase enzyme, which also is a cytochrome P450contain ing enzyme. The genetic information for this enzyme is encoded on the 12q14 chro mosome. Alternatively, 25-hydroxy-vitamin D3 can be converted to 24R,25-dihydrox y-vitamin D3, a relatively inactive vitamin D metabolite. 1,25dihydroxy-vitamin D3 can then be transported by VDBP to its most important target tissues in the d istal tubular cells of the kidney, intestinal epithelial cells, parathyroid cell s, and bone cells. VDBP is a 58 kD -globulin that is a member of the albumin and -fetoprotein gene family. The DNA sequence that encodes for this protein is on chromosome 4q11-13. 1,25dihydroxy-vitamin D3 is eventually metabolized to hydrox ylated and conjugated polar metabolites in the enterohepatic circulation. Occasi onally, 1,25-dihydroxy-vitamin D3 also may be produced in extrarenal sites, such as monocyte-derived cells, and may have an antiproliferative effect in certain lymphocytes and keratinocytes [1,79]. (Adapted from Kumar [1].) 7-dehydrocholesterol HO UV light Skin Vitamin D3 Liver 25-hydroxylase HO OH + PTH PTHrP Hypophosphatemia Hypocalcemia 24R, 25(OH) 2D3 IGF-1 Hypercalcemia Hyperphosphatemia 1, 25(OH)2D3 Acidosis HO Kidney 1-alph ahydroxylase OH 1, 25-hydroxyvitamin D3 24, 25-hydroxyvitamin D3 25-hydroxyvitam in D3 + 1, 25(OH)2D3 Hypercalcemia Hyperphosphatemia Kidney, intestine, other ti ssue 24-hydroxylase OH OH HO OH Various tissue enzymes HO Hydroxylated and conjugated polar metabolites Oral calcium intake ~1000 mg/d Intestine 400 mg 200 mg Soft tissue and intracellular calcium Extracellular fluid and plasma 10,000 mg 9800 mg 500 mg 500 mg FIGURE 5-4 Calcium (Ca) flux between body compartments. Ca balance is a complex process involving bone, intestinal absorption of dietary Ca, and renal excretion

of Ca. The parathyroid glands, by their production of parathyroid hormone, and the liver, through its participation in vitamin D metabolism, also are integral organs in the maintenance of Ca balance. (From Kumar [1]; with permission.) Feces 800 mg Kidney Bone Urine 200 mg

5.4 ??? Osteoblast precusor Disorders of Water, Electrolytes, and Acid-Base 1,25(OH)2D3 T-lymphocyte Monoblast FIGURE 5-5 Effects of 1,25-dihydroxy-vitamin D3 (calcitriol) on bone. In additio n to the effects on parathyroid cells, the kidney, and intestinal epithelium, ca lcitriol has direct effects on bone metabolism. Calcitriol can promote osteoclas t differentiation and activity from monocyte precursor cells. Calcitriol also pr omotes osteoblast differentiation into mature cells. (From Holick [8]; with perm ission.) Osteoblast Cytokines Osteocalcin Osteopontin Alkaline Phosphatase Osteoclast Bone DNA binding glyasp 30 hisgln 32 arggln 42 Hinge region Calcitiriol binding arggln 70 arggln 77 cystrp 187 tyrstop 292 COOH NH2 18 42 44 lysglu pheile 149 glnstop 271 argleu 424 ZN Mutant amino acid FIGURE 5-6 The vitamin D receptor (VDR). Within its target tissues, calcitriol b inds to the VDR. The VDR is a 424 amino acid polypeptide. Its genomic informatio n is encoded on the 12q12-14 chromosome, near the gene for the 1- -hydroxylase enzyme. The VDR is fo und in the intestinal epithelium, parathyroid cells, kidney cells, osteoblasts, and thyroid cells. VDR also can be detected in keratinocytes, monocyte precursor cells, muscle cells, and numerous other tissues. The allele variations for the vitamin D receptor. Two allele variations exist for the vitamin D receptor (VDR) : the b allele and the B allele. In general, normal persons with the b allele se em to have a higher bone mineral density [9]. Among patients on dialysis, those with the b allele may have higher levels of circulating parathyroid hormone (PTH ) [7,9,10,11]. COOHcarboxy terminal; NH2amino terminal. (From Root [7]; with permi ssion.)

VDBP VDR-D3 complex 1,25 (OH)2D3 VDR RAF Pi VDRE Regulation mRNA transcription FIGURE 5-7 Mechanism of action of 1-25-dihydroxy-vitamin D3 (1,25(OH)2D3). 1,25( OH)2D3 is transported to the target cell bound to the vitamin Dbinding protein (V DBP). The free form of 1,25(OH)2D3 enters the target cell and interacts with the vitamin D receptor (VDR) at the nucleus. This complex is phosphorylated and com bined with the nuclear accessory factor (RAF). This forms a heterodimer, which t hen interacts with the vitamin D responsive element (VDRE). The VDRE then either promotes or inhibits the transcription of messenger RNA (mRNA) for proteins reg ulated by 1,25(OH)2D3, such as Ca-binding proteins, the 25-hydroxy-vitamin D3 24 -hydroxylase enzyme, and parathyroid hormone. Piinorganic phosphate. (Adapted fro m Holick [8].) Nucleus CaBP 24-OHase PTH Osteocalcin Osteopontin Alkaline phosphatase

Divalent Cation Metabolism: Calcium 5.5 Parathyroid cell Cell membrane Ca2+ Sensing receptor Ca2+ DNA G-protein VDR VDRE Nucleus OH PTH mRNA HO OH PTH PTH mRNA Degradation PTH Secretory granules Golgi apparatus proPTH preproPTH 1,25 (OH)2D3 or Calcitriol Rough endoplasmic reticulum FIGURE 5-8 Metabolism of parathyroid hormone (PTH). The PTH gene is located on c hromosome 11p15. PTH messenger RNA (mRNA) is transcribed from the DNA fragment a nd then translated into a 115 amino acid containing molecule of prepro-PTH. In th e rough endoplasmic reticulum, this undergoes hydrolysis to a 90 amino acidcontai ning molecule, pro-PTH, which undergoes further hydrolysis to the 84 amino acidco ntaining PTH molecule. PTH is then stored within secretory granules in the cytop lasm for release. PTH is metabolized by hepatic Kupffer cells and renal tubular cells. Transcription of the PTH gene is inhibited by 1,25-dihydroxy-vitamin D3, calcitonin, and hypercalcemia. PTH gene transcription is increased by hypocalcem ia, glucocorticoids, and estrogen. Hypercalcemia also can increase the intracell ular degradation of PTH. PTH release is increased by hypocalcemia, -adrenergic a gonists, dopamine, and prostaglandin E2. Hypomagnesemia blocks the secretion of PTH [7,12]. VDR vitamin D receptor; VDREvitamin D responsive element. (Adapted fro m Tanaka and coworkers [12].) FIGURE 5-9 Parathyroid-hormonerelated protein (PTHr P). PTHrP was initially described as the causative circulating factor in the hum oral hypercalcemia of malignancy, particularly in breast cancer, squamous cell c ancers of the lung, renal cell cancer, and other tumors. It is now clear that PT HrP can be expressed not only in cancer but also in many normal tissues. It may play an important role in the regulation of smooth muscle tone, transepithelial Ca transport (eg, in the mammary gland), and the differentiation of tissue and o rgan development [7,13]. Note the high degree of homology between PTHrP and PTH at the amino end of the polypeptides. MWmolecular weight; Namino terminal; Ccarboxy terminal. (From Root [7]; with permission.) 1 PTH (mw 9600) PTH-like peptide (mw 16,000) N 1 N 34 84 C 141 C -2 -1 1 2 3 4 5

6 7 8 9 10 11 12 13 PTH LYS ARG SER VAL SER GLU ILE GLN LEU MET HIS ASN LEU GLY LYS PTH-like peptide LYS ARG ALA VAL SER GLU HIS GLN LEU LEU HIS ASP LYS GLY LYS

5.6 Disorders of Water, Electrolytes, and Acid-Base SP NH2 100 * X 300 X 350 HS Inactivating Arg186Gln Asp216Glu Tyr219Glu Glu298Lys Ser608Stop Ser658Tyr Gly670Arg Pro749Arg Arg796Trp Val818Ile Stop Activating Gl u128Ala 50 X 250 X 200 X 400 550 450 600 500 S * S X 614 671 684 746 771 829 829 Cell membrane 636 651 701 726 P P 793 808 863 X P P Cysteline Conserved Acidic P PKC phosphorylation site N-glycosylation HOOC FIGURE 5-10 The calcium-ion sensing receptor (CaSR). The CaSR is a guanosine tri phosphate (GTP) or G-proteincoupled polypeptide receptor. The human CaSR has appr oximately 1084 amino acid residues. The CaSR mediates the effects of Ca on parat hyroid and renal tissues. CaSR also can be found in thyroidal C cells, brain cel ls, and in the gastrointestinal tract. The CaSR allows Ca to act as a first mess enger on target tissues and then act by way of other secondmessenger systems (eg , phospholipase enzymes and cyclic adenosine monophosphate). Within parathyroid cells, hypercalcemia increases CaSR-Ca binding, which activates the G-protein. The Gprotein then acti vates the phospholipase C- -1phosphatidylinositol-4,5-biphosphate pathway to incr ease intracellular Ca, which then decreases translation of parathyroid hormone ( PTH), decreases PTH secretion, and increases PTH degradation. The CaSR also is a n integral part of Ca homeostasis within the kidney. The gene for CaSR is locate d on human chromosome 3q13 [3,4,7,1416]. PKCprotein kinase C; HShydrophobic segment ; NH2amino terminal. (From Hebert and Brown [4]; with permission.)

Divalent Cation Metabolism: Calcium 5.7 Gastrointestinal Absorption of Calcium FIGURE 5-11 Gastrointestinal absorption of dietary calcium (Ca). The normal reco mmended dietary intake of Ca for an adult is 800 to 1200 mg/d (2030 mmol/d). Food s high in Ca content include milk, dairy products, meat, fish with bones, oyster s, and many leafy green vegetables (eg, spinach and collard greens). Although se rum Ca levels can be maintained in the normal range by bone resorption, dietary intake is the only source by which the body can replenish stores of Ca in bone. Ca is absorbed almost exclusively within the duodenum, jejunum, and ileum. Each of these intestinal segments has a high absorptive capacity for Ca, with their r elative Ca absorption being dependent on the length of each respective intestina l segment and the transit time of the food bolus. Approximately 400 mg of the us ual 1000 mg dietary Ca intake is absorbed by the intestine, and Ca loss by way o f intestinal secretions is approximately 200 mg/d. Therefore, a net absorption o f Ca is approximately 200 mg/d (20%). Biliary and pancreatic secretions are extr emely rich in Ca. 1,25-dihydroxyvitamin D3 is an extremely important regulatory hormone for intestinal absorption of Ca [1,2,17,18]. Gastrointestinal absorption of dietary calcium (Ca) Net Ca absorption mmol/d mg/ d 0 0.75 1.0 3.25 0 5 0 30 40 130 0 200 % of intake absorbed 0 3 4 13 0 20 Site Stomach Duodenum Jejunum Ileum Colon Total* *Normal dietary Ca intake =1000 mg (25 mmol) per day Lumen Ca2+ Microvilli 1 2 Ca2+ 3 Ca2+ 4 Ca2+ Actin Myosin-I Calmodulin Ca2+ Ca2+ Calbindin-Ca2+ complex Calbindinsynthesis Free Ca2+ Micro- diffusion vesicular transport Calcitriol Ca2+ Nucleus Exocytosis Na Na/Ca exchange Ca2+ ~ Ca2+ Lamina propria Ca2+-ATPase Ca2+ FIGURE 5-12 Proposed pathways for calcium (Ca) absorption across the intestinal epithelium. Two routes exist for the absorption of Ca across the intestinal epit helium: the paracellular pathway and the transcellular route. The paracellular p athway is passive, and it is the predominant means of Ca absorption when the lum inal concentration of Ca is high. This is a nonsaturable pathway and can account for one half to two thirds of total intestinal Ca absorption. The paracellular absorptive route may be indirectly influenced by 1,25-dihydroxy-vitamin D3 (1,25 (OH)2D3) because it may be capable of altering the structure of intercellular ti

ght junctions by way of activation of protein kinase C, making the tight junctio n more permeable to the movement of Ca. However, 1,25(OH)2D3 primarily controls the active absorption of Ca. (1) Ca moves down its concentration gradient throug h a Ca channel or Ca transporter into the apical section of the microvillae. Bec ause the intestinal concentration of Ca usually is 10-3 mol and the intracellula r Ca concentration is 10-6 mol, a large concentration gradient favors the passiv e movement of Ca. Ca is rapidly and reversibly bound to the calmodulin-actin-myo sin I complex. Ca may then move to the basolateral area of the cell by way of mi crovesicular transport, or ionized Ca may diffuse to this area of the cell. (2) As the calmodulin complex becomes saturated with Ca, the concentration gradient for the movement of Ca into the microvillae is not as favorable, which slows Ca absorption. (3) Under the influence of calcitriol, intestinal epithelial cells i ncrease their synthesis of calbindin. (4) Ca binds to calbindin, thereby unloadi ng the Ca-calmodulin complexes, which then remove Ca from the microvillae region . This decrease in Ca concentration again favors the movement of Ca into the mic rovillae. As the calbindin-Ca complex dissociates, the free intracellular Ca is actively extruded from the cell by either the Ca-adenosine triphosphatase (ATPas e) or Na-Ca exchanger. Calcitriol may also increase the synthesis of the plasma membrane Ca-ATPase, thereby aiding in the active extrusion of Ca into the lamina propria [2,7,9,17,18].

5.8 Disorders of Water, Electrolytes, and Acid-Base Renal Handling of Calcium Afferent arteriole Efferent arteriole Glomerular capillary Ca2+-Protein Ca2+ ionized Ca2+ complexed Bowman's space FIGURE 5-13 Glomerular filtration of calcium (Ca). Total serum Ca consists of io nized, protein bound, and complexed fractions (47.5%, 46.0%, and 6.5%, respectiv ely). The complexed Ca is bound to molecules such as phosphate and citrate. The ultrafilterable Ca equals the total of the ionized and complexed fractions. Norm al total serum Ca is approximately 8.9 to 10.1 mg/dL (about 2.22.5 mmol/L). Ca ca n be bound to albumin and globulins. For each 1.0 gm/dL decrease in serum albumi n, total serum Ca decreases by 0.8 mg/dL; for each 1.0 gm/dL decrease in serum g lobulin fraction, total serum Ca decreases by 0.12 mg/dL. Ionized Ca is also aff ected by pH. For every 0.1 change in pH, ionized Ca changes by 0.12 mg/dL. Alkal osis decreases the ionized Ca [1,6,7]. Ca2+-ultrafilterable Proximal tubule Parathyroid hormone and 1,25(OH)2D3 Calcitonin Thiazides Ca2+ ATPase, VDR, CaBP-D, Na+/Ca2+ exchanger colocalized here CNT DCT PCT Cortex CTAL Medulla MAL Papilla 100 Ca remaining in tubular fluid, % 100 80 60 40 20 0 PT DT Urine (40) (20) (10) (2) FIGURE 5-14 Renal handling of calcium (Ca). Ca is filtered at the glomerulus, wi th the ultrafilterable fraction (UFCa) of plasma Ca entering the proximal tubule (PT). Within the proximal convoluted tubule (PCT) and the proximal straight tub ule (PST), isosmotic reabsorption of Ca occurs such that at the end of the PST t he UFCa to TFCa ratio is about 1.1 and 60% to 70% of the filtered Ca has been re absorbed. Passive paracellular pathways account for about 80% of Ca reabsorption in this segment of the nephron, with the remaining 20% dependent on active tran scellular Ca movement. No reabsorption of Ca occurs within the thin segment of t he loop of Henle. Ca is reabsorbed in small amounts within the medullary segment of the thick ascending limb (MAL) of the loop of Henle and calcitonin (CT) stim ulates Ca reabsorption here. However, the cortical segments (cTAL) reabsorb abou t 20% of the initially filtered load of Ca. Under normal conditions, most of the

Ca reabsorption in the cTAL is passive and paracellular, owing to the favorable electrochemical gradient. Active transcellular Ca transport can be stimulated b y both parathyroid hormone (PTH) and 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3) in the cTAL. In the early distal convoluted tubule (DCT), thiazide-activated Ca tra nsport occurs. The DCT is the primary site in the nephron at which Ca reabsorpti on is regulated by PTH and 1,25(OH)2D3. Active transcellular Ca transport must a ccount for Ca reabsorption in the DCT, because the transepithelial voltage becom es negative, which would not favor passive movement of Ca out of the tubular lum en. About 10% of the filtered Ca is reabsorbed in the DCT, with another 3% to 10 % of filtered Ca reabsorbed in the connecting tubule (CNT) by way of mechanisms similar to those in the DCT [1,2,6, 7,18]. ATPaseadenosine triphosphatase; CaBP-DC abinding protein D; DTdistal tubule; VDRvitamin D receptor. (Adapted from Kumar [1 ].)

Divalent Cation Metabolism: Calcium Cortical thick ascending limb + + 5.9 5 Ca2+, Mg2+ Na 2Cl K Urinary space + 2 PK-C PLA2 3 AA P-450 system 4 20-HETE K+ cAMP -Ca2+ IP3 G-protein Ca2+ 1 CaSR ATP Hormone recptor 5 Ca2+, Mg2+ + Hormone FIGURE 5-15 Effects of hypercalcemia on calcium (Ca) reabsorption in the cortica l thick ascending limb (cTAL) of the loop of Henle and urinary concentration. (1 ) Hypercalcemia stimulates the Ca-sensing receptor (CaSR) of cells in the cTAL. (2) Activation of the G-protein increases intracellular free ionized Ca (Ca2+) b y way of the inositol 1,4,5-trisphosphate (IP3) pathway, which increases the act ivity of the P450 enzyme system. The G-protein also increases activity of phosph olipase A2 (PLAA), which increases the concentration of arachidonic acid (AA). ( 3) The P450 enzyme system increases production of 20-hydroxy-eicosatetraenoic ac id (20HETE) from AA. (4) 20-HETE inhibits hormone-stimulated production of cycli c adenosine monophosphate (cAMP), blocks sodium reabsorption by the sodium-potas sium-chloride (Na-K-2Cl) cotransporter, and inhibits movement of K out of K-chan nels. (5) These changes alter the electrochemical forces that would normally fav or the paracellular movement of Ca (and Mg) such that Ca (and Mg) is not passive ly reabsorbed. Both the lack of movement of Na into the renal interstitium and i nhibition of hormonal (eg, vasopressin) effects impair the ability of the nephro n to generate maximally concentrated urine [3,4,14]. ATPadenosine triphosphate; P K-Cprotein kinase C. FIGURE 5-16 Postulated mechanism of the Ca transport pathway shared by PTH and 1,25(OH)2D3. Cyclic adenosine monophosphate (cAMP) generated by PTH stimulation leads to increased influx of Ca into the apical dihydropyridi ne-sensitive Ca channel. There also is increased activity of the basolateral NaCa exchanger and, perhaps, of the plasma membraneassociated Ca-adenosine triphosp hatase (PMCA), which can rapidly extrude the increased intracellular free Ca (Ca 2+). Calcitriol (1,25(OH)2D3), by way of the vitamin D receptor (VDR), stimulate s transcription of calbindin D28k (CaBP28) and calbindin D9k (CaBP9). CaBP28 inc reases apical uptake of Ca by both the dihydropyridine- and thiazide-sensitive C a channels by decreasing the concentration of unbound free Ca2+ and facilitates Ca movement to the basolateral membrane. CaBP9 stimulates PMCA activity, which i ncreases extrusion of Ca by the cell. Similar hormonally induced mechanisms of C a transport are believed to exist throughout the cortical thick ascending limb, the DCT, and the connecting tubule (CNT) [6]. ATPadenosine triphosphate; Na+ionize d sodium. DHP sensitive channel Ca2+ Thiazide sensitive channel Ca2+

Tubular lumen + Ca2+ Ca2+ Distal convoluted tubule cell CaBP28 CaBP9 cAMP ATP PTH + Ca2+ ?+ + Nucleus VDR Na+ ~ PMCA Ca2+ Ca2+ Calcitriol

5.10 Disorders of Water, Electrolytes, and Acid-Base Disturbances of Serum Calcium Hypocalcemia Parathyroid glands Kidney + + + PTH Gastrointestinal tract PTH- + PT DCT Parathyroid cell Nucleus FIGURE 5-17 Physiologic response to hypocalcemia. Hypocalcemia stimulates both p arathyroid hormone (PTH) release and PTH synthesis. Both hypocalcemia and PTH in crease the activity of the 1- -hydroxylase enzyme in the proximal tubular (PT) c ells of the nephron, which increases the synthesis of 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3). PTH increases bone resorption by osteoclasts. PTH and 1,25(OH)2D3 stimulate Ca reabsorption in the distal convoluted tubule (DCT). 1,25(OH)2D3 in creases the fractional absorption of dietary Ca by the gastrointestinal (GI) tra ct. All these mechanisms aid in returning the serum Ca to normal levels [1]. + + 1,25(OH)2D3Bone -Intestinal Ca2+ absorption Renal Ca2+ excretion -Bone resorption Normocalcemia CAUSES OF HYPOCALCEMIA Lack of parathyroid hormone (PTH) After thyroidectomy or parathyroidectomy Hereditary (congenital) hypoparathyroid ism Pseudohypoparathyroidism (lack of effective PTH) Hypomagnesemia (blocks PTH secretion) FIGURE 5-18 Causes of hypocalcemia (decrease in ionized plasma calcium). Increased calcium complexation Bone hunger after parathyroidectomy Rhabdomyolysis Acute pancreatitis Tumor lysis syndrome (hyperphosphatemia) Malignancy (increased osteoblastic activity) Lack of Vitamin D Dietary deficiency or malabsorption (osteomalacia) Inadequate sunlight Defective metabolism Anticonvulsant therapy Liver disease Renal disease Vitamin Dresistant rickets

Divalent Cation Metabolism: Calcium 5.11 Hypercalcemia + Thyroid and parathyroid glands Kidney -CT PTHC-cells + Gastrointestinal tract DCT PTH PT Parathyroid cell Nucleus 1,25(OH)2D3 Bone FIGURE 5-19 Physiologic response to hypercalcemia. Hypercalcemia directly inhibi ts both parathyroid hormone (PTH) release and synthesis. The decrease in PTH and hypercalcemia decrease the activity of the 1- -hydroxylase enzyme located in th e proximal tubular (PT) cells of the nephron, which in turn, decreases the synth esis of 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3). Hypercalcemia stimulates the C cells in the thyroid gland to increase synthesis of calcitonin (CT). Bone resorp tion by osteoclasts is blocked by the increased CT and decreased PTH. Decreased levels of PTH and 1,25(OH)2D3 inhibit Ca reabsorption in the distal convoluted t ubules (DCT) of the nephrons and overwhelm the effects of CT, which augment Ca r eabsorption in the medullary thick ascending limb leading to an increase in rena l Ca excretion. The decrease in 1,25(OH)2D3 decreases gastrointestinal (GI) trac t absorption of dietary Ca. All of these effects tend to return serum Ca to norm al levels [1]. Intestinal Ca2+ absorption -Renal Ca2+ excretion Bone resorption Normocalcemia CAUSES OF HYPERCALCEMIA Excess parathyroid hormone (PTH) production

Primary hyperparathyroidism Tertiary hyperparathyroidism* FIGURE 5-20 Causes of hypercalcemia (increase in ionized plasma calcium). Increa sed intestinal absorption of calcium Vitamin D intoxication Milk-alkali syndrome* Excess 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3) Vitamin D intoxication Sarcoidosis and granulomatous diseases Severe hypophospha temia Neoplastic production of 1,25(OH)2D3 (lymphoma) Decreased renal excretion of calcium Familial hypocalciuric hypercalcemia Thiazides Impaired bone formation and incorporation of calcium Aluminum intoxication* Adynamic (low-turnover) bone disease* Corticosteroids Increased bone resorption Metastatic (osteolytic) tumors (eg, breast, colon, prostate) Humoral hypercalcem ia PTH-related protein (eg, squamous cell lung, renal cell cancer) Osteoclastic activating factor (myeloma) 1,25 (OH)2D3 (lymphoma) Prostaglandins Hyperthyroidi sm Immobilization Paget disease Vitamin A intoxication *Occurs in renal failure.

5.12 Disorders of Water, Electrolytes, and Acid-Base FIGURE 5-21 Therapy available for the treatment of hypercalcemia. AVAILABLE THERAPY FOR HYPERCALCEMIA* Agent Saline and loop diuretics Corticosteroids Ketoconazole Oral or intravenous phosp hate Calcitonin Mithramycin Bisphosphonates Mechanism of action Increase renal excretion of calcium Block 1,25-dihydroxy-vitamin D3 synthesis an d bone resorption Blocks P450 system, decreases 1, 25-dihydroxy-vitamin D3 Compl exes calcium Inhibits bone resorption Inhibits bone resorption Inhibit bone reso rption *Always identify and treat the primary cause of hypercalcemia. Secondary Hyperparathyroidism Renal failure Number of nephrons PT H+ excretion P excretion 1,25(OH)2D3 Ca absorption Gastrointestinal tract Hyperphosp hatemia Activity Hypocalcemia Activity VDR CaSR Increased transcription Degradation of PTH -PTH Release PTH FIGURE 5-22 Pathogenesis of secondary hyperparathyroidism (HPT) in chronic renal failure (CRF). Decreased numbers of proximal tubular (PT) cells, owing to loss of renal mass, cause a quantitative decrease in synthesis of 1,25-dihydroxy-vita min D3 (1,25(OH)2D3). Loss of renal mass also impairs renal phosphate (P) and ac id (H+) excretion. These impairments further decrease the activity of the 1- -hy droxylase enzyme in the remaining PT cells, further contributing to the decrease in levels of 1,25(OH)2D3. 1,25(OH)2D3 deficiency decreases intestinal absorptio n of calcium (Ca), leading to hypocalcemia, which is augmented by the direct eff ect of hyperphosphatemia. Hypocalcemia and hyperphosphatemia stimulate PTH relea se and synthesis and can recruit inactive parathyroid cells into activity and PT H production. Hypocalcemia also may decrease intracellular degradation of PTH. T he lack of 1,25(OH)2D3, which would ordinarily feed back to inhibit the transcri ption of prepro-PTH and exert an antiproliferative effect on parathyroid cells, allows the increased PTH production to continue. In CRF there may be decreased e xpression of the Ca-sensing receptor (CaSR) in parathyroid cells, making them le ss sensitive to levels of plasma Ca. Patients with the b allele or the bb genoty pe vitamin D receptor (VDR) may be more susceptible to HPT, because the VDR1,25( OH)2D3 complex is less effective at suppressing PTH production and cell prolifer ation. The deficiency of 1,25(OH)2D3 may also decrease VDR synthesis, making par athyroid cells less sensitive to 1,25(OH)2D3. Although the PTH receptor in bone

cells is downregulated in CRF (ie, for any level of PTH, bone cell activity is l ower in CRF patients than in normal persons), the increased plasma levels of PTH may have harmful effects on other systems (eg, cardiovascular system, nervous s ystem, and integument) by way of alterations of intracellular Ca. Current therap eutic methods used to decrease PTH release in CRF include correction of hyperpho sphatemia, maintenance of normal to high-normal levels of plasma Ca, administrat ion of 1,25(OH)2D3 orally or intravenously, and administration of a Ca-ion sensi ng receptor (CaSR) agonist [1416,1922]. Hyperparathyroidism ProPTH Pre-proPTH Parathyroid cell -Proliferation Nucleus

Divalent Cation Metabolism: Calcium 5.13 Calcium and Vitamin D Preparations CALCIUM CONTENT OF ORAL CALCIUM PREPARATIONS FIGURE 5-23 Calcium (Ca) content of oral Ca preparations. Calcium (Ca) salt Carbonate Acetate Citrate Lactate Gluconate Tablet size, mg 1250 667 950 325 500 Elemental Ca, mg, % 500 (40) 169 (25) 200 (21) 42 (13) 4.5 (9) Fractional intestinal absorption of Ca may differ between Ca salts. Data from Mc Carthy and Kumar [19] and Physicians' Desk Reference [23]. VITAMIN D PREPARATIONS AVAILABLE IN THE UNITED STATES Ergocalciferol (Vitamin D2) Commercial name Calciferol Calcifediol (25-hydroxy-vitamin D3) Calderol (Organon, Inc, West Orange, NJ) Dihydrotachysterol DHT Intensol (Roxane Laboratories, Columbus, OH) Calcitriol (1,25-dihydroxy-vitamin D3) Rocaltrol (Roche Laboratories, Nutley, NJ) Calcijex (Abbott Laboratories, Abbott P ark, NJ) 0.25- and 0.50-g capsules Oral preparations Usual daily dose Hypoparathyroidism Renal failure Time until i ncrease in serum calcium Time for reversal of toxic effects 50,000 IU tablets 20- and 50-g capsules 0.125-, 0.2-, 0.4-mg tablets 50,000500,000 IU Not used 48 wk 1760 d 20200 g 2040 g* 24 wk 730 d 0.21.0 mg 0.2-0.4 mg* 12 wk 314 d 0.255.0 g 0.250.50 g 47 d 210 d *Not currently advised in patients with chronic renal failure. In patients with hypoparathyroidism who have normal renal function. Data from McCarthy and Kumar [19] and Physicians' Desk Reference [23]. FIGURE 5-24 Vitamin D preparations.

5.14 Disorders of Water, Electrolytes, and Acid-Base References 1. Kumar R: Calcium metabolism. In The Principles and Practice of Nephrology. Ed ited by Jacobson HR, Striker GE, Klahr S. St. Louis: Mosby-Year Book; 1995, 96497 1. 2. Johnson JA, Kumar R: Renal and intestinal calcium transport: roles of vita min D and vitamin D-dependent calcium binding proteins. Semin Nephrol 1994, 14:1 19128. 3. Hebert SC, Brown EM, Harris HW: Role of the Ca2+-sensing receptor in di valent mineral ion homeostasis. J Exp Biol 1997, 200:295302. 4. Hebert SC, Brown EM: The scent of an ion: calcium-sensing and its roles in health and disease. Cu rr Opinion Nephrol Hypertens 1996, 5:4553. 5. Berridge MJ: Elementary and global aspects of calcium signalling. J Exp Biol 1997, 200:315319. 6. Friedman PA, Gesek FA: Cellular calcium transport in renal epithelia: measurement, mechanisms, and regulation. Physiol Rev 1995, 75:429471. 7. Root AW: Recent advances in the gene tics of disorders of calcium homeostasis. Adv Pediatr 1996, 43:77125. 8. Holick M F: Defects in the synthesis and metabolism of vitamin D. Exp Clin Endocrinol 199 5, 103:219227. 9. Kumar R: Calcium transport in epithelial cells of the intestine and kidney. J Cell Biochem 1995, 57:392398. 10. White CP, Morrison NA, Gardiner EM, Eisman JA: Vitamin D receptor alleles and bone physiology. J Cell Biochem 19 94, 56:307314. 11. Fernandez E, Fibla J, Betriu A, et al.: Association between vi tamin D receptor gene polymorphism and relative hypoparathyroidism in patients w ith chronic renal failure. J Am Soc Nephrol 1997, 8:15461552. 12. Tanaka Y, Funah ashi J, Imai T, et al.: Parathyroid function and bone metabolic markers in prima ry and secondary hyperparathyroidism. Sem Surg Oncol 1997, 13:125133. 13. Philbri ck WM, Wysolmerski JJ, Galbraith S, et al.: Defining the roles of parathyroid ho rmone-related protein in normal physiology. Physiol Rev 1996, 76:127173. 14. Good man WG, Belin TR, Salusky IB: In vivo> assessments of calcium-regulated parathyr oid hormone release in secondary hyperparathyroidism [editorial review]. Kidney Int 1996, 50:18341844. 15. Chattopadhyay N, Mithal A, Brown EM: The calcium-sensi ng receptor: a window into the physiology and pathophysiology of mineral ion met abolism. Endocrine Rev 1996, 17:289307. 16. Nemeth EF, Steffey ME, Fox J: The par athyroid calcium receptor: a novel therapeutic target for treating hyperparathyr oidism. Pediatr Nephrol 1996, 10:275279. 17. Wasserman RH, Fullmer CS: Vitamin D and intestinal calcium transport: facts, speculations and hypotheses. J Nutr 199 5, 125:1971S1979S. 18. Johnson JA, Kumar R: Vitamin D and renal calcium transport . Curr Opinion Nephrol Hypertens 1994, 3:424429. 19. McCarthy JT, Kumar R: Renal osteodystrophy. In The Principles and Practice of Nephrology. Edited by Jacobson HR, Striker GE, Klahr S. St. Louis: Mosby-Year Book; 1995, 10321045. 20. Felsenf eld AJ: Considerations for the treatment of secondary hyperparathyroidism in ren al failure. J Am Soc Nephrol 1997, 8:9931004. 21. Parfitt AM. The hyperparathyroi dism of chronic renal failure: a disorder of growth. Kidney Int 1997, 52:39. 22. Salusky IB, Goodman WG: Parathyroid gland function in secondary hyperparathyroid ism. Pediatr Nephrol 1996, 10:359363. 23. Physicians' Desk Reference (PDR). Montval e NJ: Medical Economics Company; 1996.

Disorders of Acid-Base Balance Horacio J. Adrogu Nicolaos E. Madias M aintenance of acid-base homeostasis is a vital function of the living organism. Deviations of systemic acidity in either direction can impose adverse consequenc es and when severe can threaten life itself. Acid-base disorders frequently are encountered in the outpatient and especially in the inpatient setting. Effective management of acid-base disturbances, commonly a challenging task, rests with a ccurate diagnosis, sound understanding of the underlying pathophysiology and imp act on organ function, and familiarity with treatment and attendant complication s [1]. Clinical acid-base disorders are conventionally defined from the vantage point of their impact on the carbonic acid-bicarbonate buffer system. This appro ach is justified by the abundance of this buffer pair in body fluids; its physio logic preeminence; and the validity of the isohydric principle in the living org anism, which specifies that all the other buffer systems are in equilibrium with the carbonic acid-bicarbonate buffer pair. Thus, as indicated by the Henderson equation, [H+] = 24 PaCO2/[HCO3] (the equilibrium relationship of the carbonic a cid-bicarbonate system), the hydrogen ion concentration of blood ([H+], expresse d in nEq/L) at any moment is a function of the prevailing ratio of the arterial carbon dioxide tension (PaCO2, expressed in mm Hg) and the plasma bicarbonate co ncentration ([HCO3], expressed in mEq/L). As a corollary, changes in systemic ac idity can occur only through changes in the values of its two determinants, PaCO 2 and the plasma bicarbonate concentration. Those acid-base disorders initiated by a change in PaCO2 are referred to as respiratory disorders; those initiated b y a change in plasma bicarbonate concentration are known as metabolic disorders. There are four cardinal acid-base disturbances: respiratory acidosis, respirato ry alkalosis, metabolic acidosis, and metabolic alkalosis. Each can be encounter ed alone, as a simple disorder, or can be a part of a mixeddisorder, defined as the simultaneous presence of two or more simple CHAPTER 6

6.2 Disorders of Water, Electrolytes, and Acid-Base illustrated: the underlying pathophysiology, secondary adjustments in acid-base equilibrium in response to the initiating disturbance, clinical manifestations, causes, and therapeutic principles. acid-base disturbances. Mixed acid-base disorders are frequently observed in hos pitalized patients, especially in the critically ill. The clinical aspects of th e four cardinal acid-base disorders are depicted. For each disorder the followin g are Respiratory Acidosis Arterial blood [H+], nEq/L 150 125 100 80 70 60 50 40 30 60 50 40 20 PaCO2 mm Hg 120 100 90 80 70 50 iratory ic resp Chron acidosis 40 30 30 Acute respira tory acidosis Normal 20 20 10 10 6.8 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7

Arterial blood pH Steady-state relationships in respiratory acidosis: average in crease per mm Hg rise in PaCO2 [HCO] mEq/L 3 Acute adaptation Chronic adaptation 0.1 0.3 [H+] nEq/L 0.75 0.3 FIGURE 6-1 Quantitative aspects of adaptation to respiratory acidosis. Respirato ry acidosis, or primary hypercapnia, is the acid-base disturbance initiated by a n increase in arterial carbon dioxide tension (PaCO2) and entails acidification of body fluids. Hypercapnia elicits adaptive increments in plasma bicarbonate co ncentration that should be viewed as an integral part of respiratory acidosis. A n immediate increment in plasma bicarbonate occurs in response to hypercapnia. T his acute adaptation is complete within 5 to 10 minutes from the onset of hyperc apnia and originates exclusively from acidic titration of the nonbicarbonate buf fers of the body (hemoglobin, intracellular proteins and phosphates, and to a le sser extent plasma proteins). When hypercapnia is sustained, renal adjustments m arkedly amplify the secondary increase in plasma bicarbonate, further ameliorati ng the resulting acidemia. This chronic adaptation requires 3 to 5 days for comp letion and reflects generation of new bicarbonate by the kidneys as a result of upregulation of renal acidification [2]. Average increases in plasma bicarbonate and hydrogen ion concentrations per mm Hg increase in PaCO2 after completion of the acute or chronic adaptation to respiratory acidosis are shown. Empiric obse rvations on these adaptations have been used for construction of 95% confidence intervals for graded degrees of acute or chronic respiratory acidosis represente d by the areas in color in the acid-base template. The black ellipse near the ce nter of the figure indicates the normal range for the acid-base parameters [3]. Note that for the same level of PaCO2, the degree of acidemia is considerably lo wer in chronic respiratory acidosis than it is in acute respiratory acidosis. As suming a steady state is present, values falling within the areas in color are c onsistent with but not diagnostic of the corresponding simple disorders. Acid-ba se values falling outside the areas in color denote the presence of a mixed acid -base disturbance [4]. Arterial plasma [HCO], mEq/L 3

Disorders of Acid-Base Balance 6.3 Bicarbonate reabsorption Chloride excretion Net acid excretion Eucapnia Stable Hypercapnia 0 1 2 Days 3 4 5 FIGURE 6-2 Renal acidification response to chronic hypercapnia. Sustained hyperc apnia entails a persistent increase in the secretory rate of the renal tubule fo r hydrogen ions (H+) and a persistent decrease in the reabsorption rate of chlor ide ions (Cl-). Consequently, net acid excretion (largely in the form of ammoniu m) transiently exceeds endogenous acid production, leading to generation of new bicarbonate ions (HCO3) for the bo dy fluids. Conservation of these new bicarbonate ions is ensured by the gradual augmentation in the rate of renal bicarbonate reabsorption, itself a reflection of the hypercapnia-induced increase in the hydrogen ion secretory rate. A new st eady state emerges when two things occur: the augmented filtered load of bicarbo nate is precisely balanced by the accelerated rate of bicarbonate reabsorption a nd net acid excretion returns to the level required to offset daily endogenous a cid production. The transient increase in net acid excretion is accompanied by a transient increase in chloride excretion. Thus, the resultant ammonium chloride (NH4Cl) loss generates the hypochloremic hyperbicarbonatemia characteristic of chronic respiratory acidosis. Hypochloremia is sustained by the persistently dep ressed chloride reabsorption rate. The specific cellular mechanisms mediating th e renal acidification response to chronic hypercapnia are under active investiga tion. Available evidence supports a parallel increase in the rates of the lumina l sodium ion hydrogen ion (Na+-H+) exchanger and the basolateral Na+-3HCO3 cotran sporter in the proximal tubule. However, the nature of these adaptations remains unknown [5]. The quantity of the H+-adenosine triphosphatase (ATPase) pumps doe s not change in either cortex or medulla. However, hypercapnia induces exocytoti c insertion of H+ATPasecontaining subapical vesicles to the luminal membrane of p roximal tubule cells as well as type A intercalated cells of the cortical and me dullary collecting ducts. New H+-ATPase pumps thereby are recruited to the lumin al membrane for augmented acidification [6,7]. Furthermore, chronic hypercapnia increases the steady-state abundance of mRNA coding for the basolateral ClHCO3 ex changer (band 3 protein) of type A intercalated cells in rat renal cortex and me dulla, likely indicating increased band 3 protein levels and therefore augmented basolateral anion exchanger activity [8]. its development include the magnitude and time course of the hypercapnia, severity of the acidemia, and degree of att endant hypoxemia. Progressive narcosis and coma may occur in patients receiving

uncontrolled oxygen therapy in whom levels of arterial carbon dioxide tension (P aCO2) may reach or exceed 100 mm Hg. The hemodynamic consequences of carbon diox ide retention reflect several mechanisms, including direct impairment of myocard ial contractility, systemic vasodilation caused by direct relaxation of vascular smooth muscle, sympathetic stimulation, and acidosis-induced blunting of recept or responsiveness to catecholamines. The net effect is dilation of systemic vess els, including the cerebral circulation; whereas vasoconstriction might develop in the pulmonary and renal circulations. Salt and water retention commonly occur in chronic hypercapnia, especially in the presence of cor pulmonale. Mechanisms at play include hypercapnia-induced stimulation of the renin-angiotensin-aldost erone axis and the sympathetic nervous system, elevated levels of cortisol and a ntidiuretic hormone, and increased renal vascular resistance. Of course, coexist ing heart failure amplifies most of these mechanisms [1,2]. SIGNS AND SYMPTOMS OF RESPIRATORY ACIDOSIS Central Nervous System Mild to moderate hypercapnia Cerebral vasodilation Increased intracranial pressu re Headache Confusion Combativeness Hallucinations Transient psychosis Myoclonic jerks Flapping tremor Severe hypercapnia Manifestations of pseudotumor cerebri Stupor Coma Constricted pupils Depressed tendon reflexes Extensor plantar respon se Seizures Papilledema Respiratory System Breathlessness Central and peripheral cyanosis (especially when breathing room a ir) Pulmonary hypertension Cardiovascular System Mild to moderate hypercapnia Warm and flushed skin Bounding pulse Well maintaine d cardiac output and blood pressure Diaphoresis Severe hypercapnia Cor pulmonale Decreased cardiac output Systemic hypotension Cardiac arrhythmias Prerenal azot emia Peripheral edema FIGURE 6-3 Signs and symptoms of respiratory acidosis. The effects of respirator y acidosis on the central nervous system are collectively known as hypercapnic e ncephalopathy. Factors responsible for

6.4 Disorders of Water, Electrolytes, and Acid-Base Pump Cerebrum Voluntary control Controller Brain stem Automatic control Spinal c ord Load Ventilatory requirement (CO2 production, O2 consumption) Airway resistance Phrenic and intercostal nerves Effectors Muscles of respiratio n V Ppl Pabd V Lung elastic recoil Chest wall elastic recoil Diaphragm Abdominal cavity FIGURE 6-4 Main components of the ventilatory system. The ventilatory system is responsible for maintaining the arterial carbon dioxide tension (PaCO2) within n ormal limits by adjusting minute ventilation (V) to match the rate of carbon dio xide production. The main elements of ventilation are the respiratory pump, whic h generates a pressure gradient responsible for air flow, and the loads that opp ose such action. The machinery of the respiratory pump includes the cerebrum, br ain stem, spinal cord, phrenic and intercostal nerves, and the muscles of respir ation. Inspiratory muscle contraction lowers pleural pressure (Ppl) thereby infl ating the lungs ( V). The diaphragm, the most important inspiratory muscle, move s downward as a piston at the floor of the thorax, raising abdominal pressure (P abd). The inspiratory decrease in Ppl by the respiratory pump must be sufficient to counterbalance the opposing effect of the combined loads, including the airw ay flow resistance, and the elastic recoil of the lungs and chest wall. The vent ilatory requirement influences the load by altering the frequency and depth of t he ventilatory cycle. The strength of the respiratory pump is evaluated by the p ressure generated ( P = Ppl - Pabd).

Disorders of Acid-Base Balance 6.5 DETERMINANTS AND CAUSES OF CARBON DIOXIDE RETENTION Respiratory Pump Depressed Central Drive Acute General anesthesia Sedative overdose Head trauma C erebrovascular accident Central sleep apnea Cerebral edema Brain tumor Encephali tis Brainstem lesion Chronic Sedative overdose Methadone or heroin addiction Sle ep disordered breathing Brain tumor Bulbar poliomyelitis Hypothyroidism Abnormal Neuromuscular Transmission Acute High spinal cord injury Guillain-Barr syndrome Status epilepticus Botulism Tetanus Crisis in myasthenia gravis Hypokalemic myop athy Familial periodic paralysis Drugs or toxic agents eg, curare, succinylcholi ne, aminoglycosides, organophosphorus Chronic Poliomyelitis Multiple sclerosis M uscular dystrophy Amyotrophic lateral sclerosis Diaphragmatic paralysis Myopathi c disease eg, polymyositis Muscle Dysfunction Acute Fatigue Hyperkalemia Hypokal emia Hypoperfusion state Hypoxemia Malnutrition Chronic Myopathic disease eg, po lymyositis Increased Ventilatory Demand High carbohydrate diet Sorbent-regenerat ive hemodialysis Pulmonary thromboembolism Fat, air pulmonary embolism Sepsis Hy povolemia Augmented Airway Flow Resistance Acute Upper airway obstruction Coma-i nduced hypopharyngeal obstruction Aspiration of foreign body or vomitus Laryngos pasm Angioedema Obstructive sleep apnea Inadequate laryngeal intubation Laryngea l obstruction after intubation Lower airway obstruction Generalized bronchospasm Airway edema and secretions Severe episode of spasmodic asthma Bronchiolitis of infants and adults Chronic Upper airway obstruction Tonsillar and peritonsillar hypertrophy Paralysis of vocal cords Tumor of the cords or larynx Airway stenos is after prolonged intubation Thymoma, aortic aneurysm Lower airway obstruction Airway scarring Chronic obstructive lung disease eg, bronchitis, bronchiolitis, bronchiectasis, emphysema Load Lung Stiffness Acute Severe bilateral pneumonia or bronchopneumonia Acute respir atory distress syndrome Severe pulmonary edema Atelectasis Chronic Severe chroni c pneumonitis Diffuse infiltrative disease eg, alveolar proteinosis Interstitial fibrosis Chest Wall Stiffness Acute Rib fractures with flail chest Pneumothorax Hemothorax Abdominal distention Ascites Peritoneal dialysis Chronic Kyphoscolio sis, spinal arthritis Obesity Fibrothorax Hydrothorax Chest wall tumor FIGURE 6-5 Determinants and causes of carbon dioxide retention. When the respira tory pump is unable to balance the opposing load, respiratory acidosis develops. Decreases in respiratory pump strength, increases in load, or a combination of the two, can result in carbon dioxide retention. Respiratory pump failure can oc cur because of depressed central drive, abnormal neuromuscular transmission, or respiratory muscle dysfunction. A higher load can be caused by increased ventilatory demand, augmented airway flow resistance, and stiffness of the lungs or chest wall. In most cases, causes of the various determinants of carbon dioxide retention, and thus respiratory acidosis, are categorized into acute and chronic subgroups, tak ing into consideration their usual mode of onset and duration [2].

6.6 Spontaneous breathing Disorders of Water, Electrolytes, and Acid-Base FIGURE 6-6 Posthypercapnic metabolic alkalosis. Development of posthypercapnic m etabolic alkalosis is shown after abrupt normalization of the arterial carbon di oxide tension (PaCO2) by way of mechanical ventilation in a 70-year-old man with respiratory decompensation who has chronic obstructive pulmonary disease and ch ronic hypercapnia. The acute decrease in plasma bicarbonate concentration ([HCO3 ]) over the first few minutes after the decrease in PaCO2 originates from alkali ne titration of the nonbicarbonate buffers of the body. When a diet rich in chlo ride (Cl-) is provided, the excess bicarbonate is excreted by the kidneys over t he next 2 to 3 days, and acidbase equilibrium is normalized. In contrast, a lowchloride diet sustains the hyperbicarbonatemia and perpetuates the posthypercapn ic metabolic alkalosis. Abrupt correction of severe hypercapnia by way of mechan ical ventilation generally is not recommended. Rather, gradual return toward the patient's baseline PaCO2 level should be pursued [1,2]. [H+]hydrogen ion concentra tion. Mechanical ventilation 80 PaCO2, mm Hg [HCO ], mEq/L 3 60 40 40 Low-Cl diet 30 Cl - rich diet 20 Cl- rich diet 7.60 7.50 pH 7.40 7.30 7.20 0 2 4 Days 6 8 30 40 50 60 [H+], nEq/L Airway patency secured? Yes Oxygen-rich mixture delivered No Remove dentures, foreign bodies, or food particles; Heimlich maneuver (subdiaphr agmatic abdominal thrust); tracheal intubation; tracheotomy nt ate ay p w Air Mental status and blood gases evaluated Alert, blood pH > 7.10, or PaCO2 <60 mm Hg Administer O2 via nasal mask or prongs to maintain PaO2 > 60 mm Hg. Correct reve rsible causes of pulmonary dysfunction with antibiotics, bronchodilators, and co rticosteroids as needed. Monitor patient with arterial blood gases initially at intervals of 20 to 30 minutes and less frequently thereafter. If PaO2 does not i ncrease to > 60 mm Hg or PaCO2 rises to > 60 mm Hg proceed to steps described in

the box below. Consider intubation and initiation of mechanical ventilation. If blood pH is below 7.10 during mechanical ventilation, consider administration o f sodium bicarbonate, to maintain blood pH between 7.10 and 7.20, while monitori ng arterial blood gases closely. Correct reversible causes of pulmonary dysfunct ion as in box above. FIGURE 6-7 Acute respiratory acidosis management. Securing airway patency and de livering an oxygen-rich mixture are critical initial steps in management. Subseq uent measures must be directed at identifying and correcting the underlying caus e, whenever possible [1,9]. PaCO2arterial carbon dioxide tension. Obtunded, blood pH < 7.10, or PaCO2 > 60 mm Hg

Disorders of Acid-Base Balance 6.7 Severe hypercapnic encephalopathy or hemodynamic instability No PaO2 > 60 mm Hg on room air No Yes Observation, routine care. Administer O2 via nasal cannula or Venti mask Correct reversible causes of pulmo nary dysfuntion with antibiotics, bronchodilators, and corticosteroids as needed . Mental status deteriorates Hemodynamic instability CO2 retention worsens PaO2 < 55 mm Hg Consider intubation and use of standard ventilator support. Correct reversible c auses of pulmonary dysfunction with antibiotics, bronchodilators, and corticoste roids as needed. PaO2 55 mm Hg, patient stable Yes Consider use of noninvasive nasal mask ventilation (NMV) or intubation and stand ard ventilator support. FIGURE 6-8 Chronic respiratory acidosis management. Therapeutic measures are gui ded by the presence or absence of severe hypercapnic encephalopathy or hemodynam ic instability. An aggressive approach that favors the early use of ventilator a ssistance is most appropriate for patients with acute respiratory acidosis. In c ontrast, a more conservative approach is advisable in patients with chronic hype rcapnia because of the great difficulty often encountered in weaning these patie nts from ventilators. As a rule, the lowest possible inspired fraction of oxygen that achieves adequate oxygenation (PaO2 on the order of 60 mm Hg) is used. Con trary to acute respiratory acidosis, the underlying cause of chronic respiratory acidosis only rarely can be resolved [1,9]. Continue same measures. Respiratory Alkalosis Arterial blood [H+], nEq/L 150 125 100 80 70 60 50 40 30 60 50 40 20 PaCO2 mm Hg 120 100 90 80 70 50 Arterial plasma [HCO], mEq/L 3 40 30 30

Normal 20 Acut e resp alkalo iratory sis 10 20 10 6.8 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 Arterial blood pH Steady-state relationships in respiratory alkalosis: average d ecrease per mm Hg fall in PaCO2 Acute adaptation Chronic adaptation [HCO] mEq/L 3 0.2 0.4 [H+] nEq/L 0.75 0.4 FIGURE 6-9 Adaptation to respiratory alkalosis. Respiratory alkalosis, or primar y hypocapnia, is the acid-base disturbance initiated by a decrease in arterial c arbon dioxide tension (PaCO2) and entails alkalinization of body fluids. Hypocap nia elicits adaptive decrements in plasma bicarbonate concentration that should be viewed as an integral part of respiratory alkalosis. An immediate decrement i n plasma bicarbonate occurs in response to hypocapnia. This acute adaptation is complete within 5 to 10 minutes from the onset of hypocapnia and is accounted fo r principally by alkaline titration of the nonbicarbonate buffers of the body. T o a lesser extent, this acute adaptation reflects increased production of organi c acids, notably lactic acid. When hypocapnia is sustained, renal adjustments ca use an additional decrease in plasma bicarbonate, further ameliorating the resul ting alkalemia. This chronic adaptation requires 2 to 3 days for completion and reflects retention of hydrogen ions by the kidneys as a result of downregulation of renal acidification [2,10]. Shown are the average decreases in plasma bicarb onate and hydrogen ion concentrations per mm Hg decrease in PaCO2after completio n of the acute or chronic adaptation to respiratory alkalosis. Empiric observati ons on these adaptations have been used for constructing 95% confidence interval s for graded degrees of acute or chronic respiratory alkalosis, which are repres ented by the areas in color in the acid-base template. The black ellipse near th e center of the figure indicates the normal range for the acid-base parameters. Note that for the same level of PaCO2, the degree of alkalemia is considerably l ower in chronic than it is in acute respiratory alkalosis. Assuming that a stead y state is present, values falling within the areas in color are consistent with but not diagnostic of the corresponding simple disorders. Acid-base values fall ing outside the areas in color denote the presence of a mixed acid-base disturba nce [4]. Ch ato pir res osis nic al ro alk

ry

6.8 Eucapnia Disorders of Water, Electrolytes, and Acid-Base FIGURE 6-10 Renal acidification response to chronic hypocapnia. A, Sustained hyp ocapnia entails a persistent decrease in the renal tubular secretory rate of hyd rogen ions and a persistent increase in the chloride reabsorption rate. As a res ult, transient suppression of net acid excretion occurs. This suppression is lar gely manifested by a decrease in ammonium excretion and, early on, by an increas e in bicarbonate excretion. The transient discrepancy between net acid excretion and endogenous acid production, in turn, leads to positive hydrogen ion balance and a reduction in the bicarbonate stores of the body. Maintenance of the resul ting hypobicarbonatemia is ensured by the gradual suppression in the rate of ren al bicarbonate reabsorption. This suppression itself is a reflection of the hypo capnia-induced decrease in the hydrogen ion secretory rate. A new steady state e merges when two things occur: the reduced filtered load of bicarbonate is precis ely balanced by the dampened rate of bicarbonate reabsorption and net acid excre tion returns to the level required to offset daily endogenous acid production. T he transient retention of acid during sustained hypocapnia is normally accompani ed by a loss of sodium in the urine (and not by a retention of chloride as analo gy with chronic respiratory acidosis would dictate). The resulting extracellular fluid loss is responsible for the hyperchloremia that typically accompanies chr onic respiratory alkalosis. Hyperchloremia is sustained by the persistently enha nced chloride reabsorption rate. If dietary sodium is restricted, acid retention is achieved in the company of increased potassium excretion. The specific cellu lar mechanisms mediating the renal acidification response to chronic hypocapnia are under investigation. Available evidence indicates a parallel decrease in the rates of the luminal sodium ionhydrogen ion (Na+-H+) exchanger and the basolater al sodium ion3 bicarbonate ion (Na+-3HCO3) cotransporter in the proximal tubule. This parallel decrease reflects a decrease in the maximum velocity (Vmax) of eac h transporter but no change in the substrate concentration at halfmaximal veloci ty (Km) for sodium (as shown in B for the Na+-H+ exchanger in rabbit renal corti cal brush-border membrane vesicles) [11]. Moreover, hypocapnia induces endocytot ic retrieval of H+adenosine triphosphatase (ATPase) pumps from the luminal membr ane of the proximal tubule cells as well as type A intercalated cells of the cor tical and medullary collecting ducts. It remains unknown whether chronic hypocap nia alters the quantity of the H+-ATPase pumps as well as the kinetics or quanti ty of other acidification transporters in the renal cortex or medulla [6]. NSnot significant. (B, From Hilden and coworkers [11]; with permission.) FIGURE 6-11 S igns and symptoms of respiratory alkalosis. The manifestations of primary hypoca pnia frequently occur in the acute phase, but seldom are evident in chronic resp iratory alkalosis. Several mechanisms mediate these clinical manifestations, inc luding cerebral hypoperfusion, alkalemia, hypocalcemia, hypokalemia, and decreas ed release of oxygen to the tissues by hemoglobin. The cardiovascular effects of respiratory alkalosis are more prominent in patients undergoing mechanical vent ilation and those with ischemic heart disease [2]. Bicarbonate reabsorption Sodium excretion Net acid excretion Stable Hypocapnia 0 1 Days Km NS

2 3 Vmax P<0.01 10 1000 nmol/mg protein min Control Chronic hypocapnia (9% O2) mmol/L 5 500 Control Chronic hypocapnia (9% O2) SIGNS AND SYMPTOMS OF RESPIRATORY ALKALOSIS Central Nervous System Cerebral vasoconstriction Reduction in intracranial pressure Light-headedness Co nfusion Increased deep tendon reflexes Generalized seizures Cardiovascular System Chest oppression Angina pectoris Ischemic electrocardiographic changes Normal or decreased blood pressure Cardiac arrhythmias Peripheral vasoconstriction Neuromuscular System Numbness and paresthesias of the extremities Circumoral numbness Laryngeal spasm Manifestations of tetany Muscle cramps Carpopedal spasm Trousseau's sign Chvostek's sign

Disorders of Acid-Base Balance 6.9 CAUSES OF RESPIRATORY ALKALOSIS Central Nervous System Stimulation Voluntary Pain Anxiety syndromehyperventilation syndrome Psychosis Fever Subarac hnoid hemorrhage Cerebrovascular accident Meningoencephalitis Tumor Trauma Hypoxemia or Tissue Hypoxia Decreased inspired oxygen tension High altitude Bacterial or viral pneumonia Asp iration of food, foreign object, or vomitus Laryngospasm Drowning Cyanotic heart disease Severe anemia Left shift deviation of oxyhemoglobin curve Hypotension S evere circulatory failure Pulmonary edema Drugs or Hormones Nikethamide, ethamivan Doxapram Xanthines Salicylates Catecholamines Angiotensin II Vasopressor agents Progesterone Medroxyprogesterone Dinitrophenol Nicotine Stimulation of Chest Receptors Pneumonia Asthma Pneumothorax Hemothorax Flail chest Acute respiratory distress syndrome Cardiogenic and noncardiogenic pulmonary edema Pulmonary embolism Pulmo nary fibrosis Miscellaneous Pregnancy Gram-positive septicemia Gram-negative septicemia Hepatic failure Mech anical hyperventilation Heat exposure Recovery from metabolic acidosis FIGURE 6-12 Respiratory alkalosis is the most frequent acid-base disorder encoun tered because it occurs in normal pregnancy and highaltitude residence. Patholog ic causes of respiratory alkalosis include various hypoxemic conditions, pulmona ry disorders, central nervous system diseases, pharmacologic or hormonal stimula tion of ventilation, hepatic failure, sepsis, the anxiety-hyperventilation syndr ome, and other entities. Most of these causes are associated with the abrupt occ urrence of hypocapnia; however, in many instances, the process might be sufficie ntly prolonged to permit full chronic adaptation to occur. Consequently, no attempt has been ma de to separate these conditions into acute and chronic categories. Some of the m ajor causes of respiratory alkalosis are benign, whereas others are life-threate ning. Primary hypocapnia is particularly common among the critically ill, occurr ing either as the simple disorder or as a component of mixed disturbances. Its p resence constitutes an ominous prognostic sign, with mortality increasing in dir ect proportion to the severity of the hypocapnia [2]. FIGURE 6-13 Respiratory al kalosis management. Because chronic respiratory alkalosis poses a low risk to he alth and produces few or no symptoms, measures for treating the acid-base disord er itself are not required. In contrast, severe alkalemia caused by acute primar y hypocapnia requires corrective measures that depend on whether serious clinica l manifestations are present. Such measures can be directed at reducing plasma b icarbonate concentration ([HCO3]), increasing the arterial carbon dioxide tensio n (PaCO2), or both. Even if the baseline plasma bicarbonate is moderately decrea sed, reducing it further can be particularly rewarding in this setting. In addit ion, this maneuver combines effectiveness with relatively little risk [1,2]. Respiratory alkalosis Acute No Chronic

Blood pH 7.55 Yes Manage underlying disorder. No specific measures indicated. Hemodynamic instability, altered mental status, or cardiac arrhythmias Yes No Consider having patient rebreathe into a closed system. Manage underlying disord er. Consider measures to correct blood pH 7.50 by: Reducing [HCO3]: acetazolamide, ul trafiltration and normal saline replacement, hemodialysis using a low bicarbonat e bath. Increasing PaCO2: rebreathing into a closed system, controlled hypoventi lation by ventilator with or without skeletal muscle paralysis.

6.10 Disorders of Water, Electrolytes, and Acid-Base FIGURE 6-14 Pseudorespiratory alkalosis. This entity develops in patients with p rofound depression of cardiac function and pulmonary perfusion but relative pres ervation of alveolar ventilation. Patients include those with advanced circulato ry failure and those undergoing cardiopulmonary resuscitation. The severely redu ced pulmonary blood flow limits the amount of carbon dioxide delivered to the lu ngs for excretion, thereby increasing the venous carbon dioxide tension (PCO2). In contrast, the increased ventilation-to-perfusion ratio causes a larger than n ormal removal of carbon dioxide per unit of blood traversing the pulmonary circu lation, thereby giving rise to arterial hypocapnia [12,13]. Note a progressive w idening of the arteriovenous difference in pH and PCO2 in the two settings of ca rdiac dysfunction. The hypobicarbonatemia in the setting of cardiac arrest repre sents a complicating element of lactic acidosis. Despite the presence of arteria l hypocapnia, pseudorespiratory alkalosis represents a special case of respirato ry acidosis, as absolute carbon dioxide excretion is decreased and body carbon d ioxide balance is positive. Furthermore, the extreme oxygen deprivation prevaili ng in the tissues might be completely disguised by the reasonably preserved arte rial oxygen values. Appropriate monitoring of acid-base composition and oxygenat ion in patients with advanced cardiac dysfunction requires mixed (or central) ve nous blood sampling in addition to arterial blood sampling. Management of pseudo respiratory alkalosis must be directed at optimizing systemic hemodynamics [1,13 ]. Lungs Normal pH 7.40 PCO2 40 ] 24 [HCO3 95 PO2 0.21 FiO2 LV RV pH 7.38 PCO2 46 [HCO3 ] 26 PO2 40 Peripheral tissues Arterial compartment Venous compartment Circulatory Failure 7.42 pH 35 PCO2 22 [HCO3 ] 80 PO2 0.35 FiO2 LV RV 7.29 pH 60 PCO2 28 [HCO3 ] 30 PO2 Cardiac Arrest 7.37 pH 27 PCO2 15 [HCO3 ] 116 PO2 1.00 FiO2

LV RV pH 7.00 PCO2 75 [HCO ] 18 3 PO2 17

Disorders of Acid-Base Balance 6.11 Metabolic Acidosis Arterial blood [H+], nEq/L 150 125 100 80 70 60 50 40 30 60 50 40 20 PaCO2 mm Hg 120 100 90 80 70 50 Arterial plasma [HCO], mEq/L 3 40 30 30 Normal 20 M e ac tab ido oli sis c 20 10 10 6.8 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 FIGURE 6-15 Ninety-five percent confidence intervals for metabolic acidosis. Met abolic acidosis is the acid-base disturbance initiated by a decrease in plasma b icarbonate concentration ([HCO3]). The resultant acidemia stimulates alveolar ve ntilation and leads to the secondary hypocapnia characteristic of the disorder. Extensive observations in humans encompassing a wide range of stable metabolic a cidosis indicate a roughly linear relationship between the steadystate decrease in plasma bicarbonate concentration and the associated decrement in arterial car

bon dioxide tension (PaCO2). The slope of the steady state PaCO2 versus [HCO3] r elationship has been estimated as approximately 1.2 mm Hg per mEq/L decrease in plasma bicarbonate concentration. Such empiric observations have been used for c onstruction of 95% confidence intervals for graded degrees of metabolic acidosis , represented by the area in color in the acid-base template. The black ellipse near the center of the figure indicates the normal range for the acid-base param eters [3]. Assuming a steady state is present, values falling within the area in color are consistent with but not diagnostic of simple metabolic acidosis. Acid -base values falling outside the area in color denote the presence of a mixed ac id-base disturbance [4]. [H+] hydrogen ion concentration. Arterial blood pH SIGNS AND SYMPTOMS OF METABOLIC ACIDOSIS Respiratory System Hyperventilation Respiratory distress and dyspnea Decreased strength of respirat ory muscles and promotion of muscle fatigue Cardiovascular System Impairment of cardiac contractility, arteriolar dilation, venoconstriction, and centralization of blood volume Reductions in cardiac output, arterial blood pres sure, and hepatic and renal blood flow Sensitization to reentrant arrhythmias an d reduction in threshold for ventricular fibrillation Increased sympathetic disc harge but attenuation of cardiovascular responsiveness to catecholamines Metabolism Increased metabolic demands Insulin resistance Inhibition of anaerobic glycolysi s Reduction in adenosine triphosphate synthesis Hyperkalemia Increased protein d egradation Central Nervous System Skeleton Impaired metabolism Osteomalacia Inhibition of cell Fractures volume regulation Progressive obtundation Coma FIGURE 6-16 Signs and symptoms of metabolic acidosis. Among the various clinical manifestations, particularly pernicious are the effects of severe acidemia (blo od pH < 7.20) on the cardiovascular system. Reductions in cardiac output, arteri al blood pressure, and hepatic and renal blood flow can occur and lifethreatenin g arrhythmias can develop. Chronic acidemia, as it occurs in untreated renal tub ular acidosis and uremic acidosis, can cause calcium dissolution from the bone m ineral and consequent skeletal abnormalities.

6.12 Normal A 10 HCO3 24 Na+ 140 Cl 106 Disorders of Water, Electrolytes, and Acid-Base Metabolic acidosis Normal anion gap High anion gap (hyperchloremic) (normochlore mic) A 10 A 30 HCO3 4 HCO3 4 Na+ 140 Cl 126 Na+ 140 Cl 106 Causes Causes Renal acidification defects Endogenous acid load Proximal renal tu bular acidosis Ketoacidosis Classic distal tubular acidosis Diabetes mellitus Hy perkalemic distal tubular acidosis Alcoholism Early renal failure Starvation Gas trointestinal loss of bicarbonate Uremia Diarrhea Lactic acidosis Small bowel lo sses Exogenous toxins Ureteral diversions Osmolar gap present Anion exchange res ins Methanol Ingestion of CaCl2 Ethylene glycol Osmolar gap absent Acid infusion Salicylates HCl Paraldehyde Arginine HCl Lysine HCl FIGURE 6-17 Causes of metabolic acidosis tabulated according to the prevailing p attern of plasma electrolyte composition. Assessment of the plasma unmeasured an ion concentration (anion gap) is a very useful first step in approaching the dif ferential diagnosis of unexplained metabolic acidosis. The plasma anion gap is c alculated as the difference between the sodium concentration and the sum of chlo ride and bicarbonate concentrations. Under normal circumstances, the plasma anio n gap is primarily composed of the net negative charges of plasma proteins, pred ominantly albumin, with a smaller contribution from many other organic and inorg anic anions. The normal value of the plasma anion gap is 12 4 (mean 2 SD) mEq/L, where SD is the standard deviation. However, recent introduction of ion-specifi c electrodes has shifted the normal anion gap to the range of about 6 3 mEq/L. I n one pattern of metabolic acidosis, the decrease in bicarbonate concentration i s offset by an increase in the concentration of chloride, with the plasma anion gap remaining normal. In the other pattern, the decrease in bicarbonate is balan ced by an increase in the concentration of unmeasured anions (ie, anions not mea sured routinely), with the plasma chloride concentration remaining normal. Lactic acidosis Glucose Gluconeogenesis Cori cycle Muscle Brain Skin RBC H+ + Lactate Liver Kidney cortex Anaerobic glycolysis Overproduction Lactic acidosis Underutilization FIGURE 6-18 Lactate-producing and lactate-consuming tissues under basal conditio ns and pathogenesis of lactic acidosis. Although all tissues pro-

duce lactate during the course of glycolysis, those listed contribute substantia l quantities of lactate to the extracellular fluid under normal aerobic conditio ns. In turn, lactate is extracted by the liver and to a lesser degree by the ren al cortex and primarily is reconverted to glucose by way of gluconeogenesis (a s maller portion of lactate is oxidized to carbon dioxide and water). This cyclica l relationship between glucose and lactate is known as the Cori cycle. The basal turnover rate of lactate in humans is enormous, on the order of 15 to 25 mEq/kg /d. Precise equivalence between lactate production and its use ensures the stabi lity of plasma lactate concentration, normally ranging from 1 to 2 mEq/L. Hydrog en ions (H+) released during lactate generation are quantitatively consumed duri ng the use of lactate such that acid-base balance remains undisturbed. Accumulat ion of lactate in the circulation, and consequent lactic acidosis, is generated whenever the rate of production of lactate is higher than the rate of utilizatio n. The pathogenesis of this imbalance reflects overproduction of lactate, underu tilization, or both. Most cases of persistent lactic acidosis actually involve b oth overproduction and underutilization of lactate. During hypoxia, almost all t issues can release lactate into the circulation; indeed, even the liver can be c onverted from the premier consumer of lactate to a net producer [1,14].

Disorders of Acid-Base Balance Glucose PFK Glycolysis + low ATP ADP NAD+ 6.13 NADH Pyruvate Gluconeogenesis LDH Lactate + NADH high Cytosol NAD+ Mitochondrial membrane Mitochondria low ATP ADP Oxaloacetate PC PD H NAD+ NADH high NADH NAD+ Acetyl-CoA TCA cycle FIGURE 6-19 Hypoxia-induced lactic acidosis. Accumulation of lactate during hypo xia, by far the most common clinical setting of the disorder, originates from im paired mitochondrial oxidative function that reduces the availability of adenosine triphosphate (ATP) and NAD+ (oxidized nico tinamide adenine dinucleotide) within the cytosol. In turn, these changes cause cytosolic accumulation of pyruvate as a consequence of both increased production and decreased utilization. Increased production of pyruvate occurs because the reduced cytosolic supply of ATP stimulates the activity of 6-phosphofructokinase (PFK), thereby accelerating glycolysis. Decreased utilization of pyruvate refle cts the fact that both pathways of its consumption depend on mitochondrial oxida tive reactions: oxidative decarboxylation to acetyl coenzyme A (acetyl-CoA), a r eaction catalyzed by pyruvate dehydrogenase (PDH), requires a continuous supply of NAD+; and carboxylation of pyruvate to oxaloacetate, a reaction catalyzed by pyruvate carboxylase (PC), requires ATP. The increased [NADH]/[NAD+] ratio (NADH refers to the reduced form of the dinucleotide) shifts the equilibrium of the l actate dehydrogenase (LDH) reaction (that catalyzes the interconversion of pyruv ate and lactate) to the right. In turn, this change coupled with the accumulatio n of pyruvate in the cytosol results in increased accumulation of lactate. Despi te the prevailing mitochondrial dysfunction, continuation of glycolysis is assur ed by the cytosolic regeneration of NAD+ during the conversion of pyruvate to la ctate. Provision of NAD+ is required for the oxidation of glyceraldehyde 3-phosp hate, a key step in glycolysis. Thus, lactate accumulation can be viewed as the toll paid by the organism to maintain energy production during anaerobiosis (hyp oxia) [14]. ADPadenosine diphosphate; TCA cycletricarboxylic acid cycle. FIGURE 620 Conventionally, two broad types of lactic acidosis are recognized. In type A, clinical evidence exists of impaired tissue oxygenation. In type B, no such evi dence is apparent. Occasionally, the distinction between the two types may be le ss than obvious. Thus, inadequate tissue oxygenation can at times defy clinical detection, and tissue hypoxia can be a part of the pathogenesis of certain cause s of type B lactic acidosis. Most cases of lactic acidosis are caused by tissue hypoxia arising from circulatory failure [14,15]. CAUSES OF LACTIC ACIDOSIS Type A: Impaired Tissue Oxygenation Shock Severe hypoxemia Generalized convulsions Vigorous exercise Exertional heat stroke Hypothermic shivering Massive pulmonary emboli Severe heart failure Prof ound anemia Mesenteric ischemia Carbon monoxide poisoning Cyanide poisoning Type B: Preserved Tissue Oxygenation

Diseases and conditions Diabetes mellitus Hypoglycemia Renal failure Hepatic fai lure Severe infections Alkaloses Malignancies (lymphoma, leukemia, sarcoma) Thia mine deficiency Acquired immunodeficiency syndrome Pheochromocytoma Iron deficie ncy D-Lactic acidosis Congenital enzymatic defects Drugs and toxins Epinephrine, norepinephrine, vasoconstrictor agents Salicylates Ethanol Methanol Ethylene gl ycol Biguanides Acetaminophen Zidovudine Fructose, sorbitol, and xylitol Strepto zotocin Isoniazid Nitroprusside Papaverine Nalidixic acid

6.14 Disorders of Water, Electrolytes, and Acid-Base FIGURE 6-21 Lactic acidosis management. Management of lactic acidosis should foc us primarily on securing adequate tissue oxygenation and on aggressively identif ying and treating the underlying cause or predisposing condition. Monitoring of the patient's hemodynamics, oxygenation, and acid-base status should be used to gu ide therapy. In the presence of severe or worsening metabolic acidemia, these me asures should be supplemented by judicious administration of sodium bicarbonate, given as an infusion rather than a bolus. Alkali administration should be regar ded as a temporizing maneuver adjunctive to cause-specific measures. Given the o minous prognosis of lactic acidosis, clinicians should strive to prevent its dev elopment by maintaining adequate fluid balance, optimizing cardiorespiratory fun ction, managing infection, and using drugs that predispose to the disorder cauti ously. Preventing the development of lactic acidosis is all the more important i n patients at special risk for developing it, such as those with diabetes mellit us or advanced cardiac, respiratory, renal, or hepatic disease [1,1416]. Inadequate tissue oxygenation? Yes Oxygen-rich mixture and ventilator support, i f needed No Cause-specific measures No Circulatory failure? Yes Volume repletion Preload and afterload reducing agen ts Myocardial stimulants (dobutamine, dopamine) Avoid vasoconstrictors Antibiotics (sepsis) Dialysis (toxins) Discontinuation of incriminated drugs Ins ulin (diabetes) Glucose (hypoglycemia, alcoholism) Operative intervention (traum a, tissue ischemia) Thiamine (thiamine deficiency) Low carbohydrate diet and ant ibiotics (D-lactic acidosis) Severe/Worsening metabolic acidemia? Yes No Continue therapy Manage predisposing conditions Alkali administration to maintain blood pH 7.20 Diabetic ketoacidosis and nonketotic hyperglycemia A Increased hepatic glucose production Glucagon Insulin deficiency Increased hepat ic ketogenesis Increased lipolysis in adipocytes Decreased glucose utilization i n skeletal muscle Growth hormone Norepinephrine Cortisol Counterregulation Epine phrine B Triglycerides Increased lipolysis Increased ketogenesis Ketonemia (metabolic acidosis) Increased gluconeogenesis I ncreased glycogenolysis Decreased glucose uptake Decreased ketone uptake Decreased glucose excretion Hyperglycemia (hyperosmolality) Increased protein breakdown Decreased amino acid uptake FIGURE 6-22 Role of insulin deficiency and the counterregulatory hormones, and t heir respective sites of action, in the pathogenesis of hyperglycemia and ketosi

s in diabetic ketoacidosis (DKA).A, Metabolic processes affected by insulin defi ciency, on the one hand, and excess of glucagon, cortisol, epinephrine, norepine phrine, and growth hormone, on the other. B, The roles of the adipose tissue, li ver, skeletal muscle, and kidney in the pathogenesis of hyperglycemia and ketone mia. Impairment of glucose oxidation in most tissues and excessive hepatic produ ction of glucose are the main determinants of hyperglycemia. Excessive counterre gulation and the prevailing hypertonicity, metabolic acidosis, and electrolyte i mbalance superimpose a state of insulin resistance. Prerenal azotemia caused by volume depletion can contribute significantly to severe hyperglycemia. Increased hepatic production of ketones and their reduced utilization by peripheral tissu es account for the ketonemia typically observed in DKA. Decreased glucose uptake

Disorders of Acid-Base Balance 6.15 Insulin deficiency/resistance Severe Mild Pure DKA profound ketosis Mixed forms DKA + NKH Pure NKH profound hyperglycemia Mild Excessive counterregulation Feature Incidence Mortality Onset Age of patient Type I diabetes Type II diabetes First indication of diabetes Volume depletion Renal failure (most commonly of prerenal nature) Severe neurologic abnormalities Subsequent therapy with insulin Glucose Ketone bodies Effective osmolality pH [HCO3] [Na+] [K+] Severe Pure DKA 510 times higher 510% Rapid (<2 days) Usually < 40 years Common Rare Often Mild/mo derate Mild, inconstant Rare Always Mixed forms Pure NKH 510 times lower 1060% Slow (> 5 days) Usually > 40 years Rare Common Often Severe Always present Frequent (coma in 2550%) Not always > 800 mg/dL < 2+ in 1:1 diluti on > 340 mOsm/kg Normal Normal Normal or high Variable FIGURE 6-23 Clinical features of diabetic ketoacidosis (DKA) and nonketotic hype rglycemia (NKH). DKA and NKH are the most important acute metabolic complication s of patients with uncontrolled diabetes mellitus. These disorders share the sam e overall pathogenesis that includes insulin deficiency and resistance and exces sive counterregulation; however, the importance of each of these endocrine abnor malities differs significantly in DKA and NKH. As depicted here, pure NKH is cha racterized by profound hyperglycemia, the result of mild insulin deficiency and severe counterregulation (eg, high glucagon levels). In contrast, pure DKA is ch aracterized by profound ketosis that largely is due to severe insulin deficiency , with counterregulation being generally of lesser importance. These pure forms define a continuum that includes mixed forms incorporating clinical and biochemi cal features of both DKA and NKH. Dyspnea and Kussmaul's respiration result from t he metabolic acidosis of DKA, which is generally absent in NKH. Sodium and water deficits and secondary renal dysfunction are more severe in NKH than in DKA. Th ese deficits also play a pathogenetic role in the profound hypertonicity charact eristic of NKH. The severe hyperglycemia of NKH, often coupled with hypernatremi a, increases serum osmolality, thereby causing the characteristic functional abn ormalities of the central nervous system. Depression of the sensorium, somnolenc e, obtundation, and coma, are prominent manifestations of NKH. The degree of obt undation correlates with the severity of serum hypertonicity [17]. < 800 mg/dL 2 + in 1:1 dilution < 340 mOsm/kg Decreased Decreased Normal or low Variable MANAGEMENT OF DIABETIC KETOACIDOSIS AND NONKETOTIC HYPERGLYCEMIA Insulin 1. Give initial IV bolus of 0.2 U/kg actual body weight. 2. Add 100 U of regular insulin to 1 L of normal saline (0.1 U/mL), and follow with continuous IV drip of 0.1 U/kg actual body weight per h until correction of ketosis. 3. Give double rate of infusion if the blood glucose level does not decrease in a 2-h interval

(expected decrease is 4080 mg/dL/h or 10% of the initial value.) 4. Give SQ (1030 U) of regular insulin when ketosis is corrected and the blood glucose l decreases to 300 mg/dL, and continue with SQ insulin injection every 4 h on sliding scale (ie, 5 U if below 150, 10 U if 150200, 15 U if 200250, and 20 50300 mg/dL).

dose leve a U if 2

Fluid Administration Shock absent: Normal saline (0.9% NaCl) at 7 mL/kg/h for 4 h, and half this rate thereafter Shock present: Normal saline and plasma expanders (ie,albumin, low m olecular weight dextran) at maximal possible rate Start a glucose-containing sol ution (eg, 5% dextrose in water) when blood glucose level decreases to 250 mg/dL . Potassium repletion Potassium chloride should be added to the third liter of IV infusion and subsequ ently if urinary output is at least 3060 mL/h and plasma [K+] < 5 mEq/L. Add K+ t o the initial 2 L of IV fluids if initial plasma [K+] < 4 mEq/L and adequate diu resis is secured. Alkali Half-normal saline (0.45% NaCl) plus 12 ampules (44-88 mEq) NaHCO3 per liter when blood pH < 7.0 or total CO2 < 5 mmol/L; in hyperchloremic acidosis, add NaHCO3 when pH < 7.20; discontinue NaHCO3 in IV infusion when total CO2>810 mmol/L. CO2carbon dioxide; IVintravenous; K+potassium ion; NaClsodium chloride; NaHCO3sodium bicarbonate; SQsubcutaneous. FIGURE 6-24 Diabetic ketoacidosis (DKA) and nonketotic hyperglycemia (NKH) manag ement. Administration of insulin is the cornerstone of management for both DKA a nd NKH. Replacement of the prevailing water, sodium, and potassium deficits is a lso required. Alkali are administered only under certain circumstances in DKA an d virtually never in NKH, in which ketoacidosis is generally absent. Because the fluid deficit is gen erally severe in patients with NKH, many of whom have preexisting heart disease and are relatively old, safe fluid replacement may require monitoring of central venous pressure, pulmonary capillary wedge pressure, or both [1,17,18].

6.16 Disorders of Water, Electrolytes, and Acid-Base Renal tubular acidosis FEATURES OF THE RENAL TUBULAR ACIDOSIS (RTA) SYNDROMES Feature Plasma bicarbonate ion concentration Plasma chloride ion concentration Plasma po tassium ion concentration Plasma anion gap Glomerular filtration rate Urine pH d uring acidosis Urine pH after acid loading U-B PCO2 in alkaline urine Fractional excretion of HCO3 at normal [HCO3]p Tm HCO3 Nephrolithiasis Nephrocalcinosis Os teomalacia Fanconi's syndrome* Alkali therapy Proximal RTA 1418 mEq/L Increased Mildly decreased Normal Normal or slightly decreased 5.5 5.5 N ormal >15% Decreased Absent Absent Present Usually present High dose Classic Distal RTA Variable, may be < 10 mEq/L Increased Mildly to severely decreased Normal Normal or slightly decreased >6.0 >6.0 Decreased <5% Normal Present Present Present Ab sent Low dose Hyperkalemic Distal RTA 1520 mEq/L Increased Mildly to severely increased Normal Normal to moderately dec reased 5.5 5.5 Decreased <5% Normal Absent Absent Absent Absent Low dose FIGURE 6-25 Renal tubular acidosis (RTA) defines a group of disorders in which t ubular hydrogen ion secretion is impaired out of proportion to any reduction in the glomerular filtration rate. These disorders are characterized by normal anio n gap (hyperchloremic) metabolic acidosis. The defects responsible for impaired acidification give rise to three distinct syndromes known as proximal RTA (type 2), classic distal RTA (type 1), and hyperkalemic distal RTA (type 4). Tm HCO3maximum reabsorption of bicarbonate; U-B PCO2difference between partial pre ssure of carbon dioxide values in urine and arterial blood. *This syndrome signi fies generalized proximal tubule dysfunction and is characterized by impaired re absorption of glucose, amino acids, phosphate, and urate.

Disorders of Acid-Base Balance 6.17 Lumen Proximal tubule cell Blood B. CAUSES OF PROXIMAL RENAL TUBULAR ACIDOSIS Selective defect (isolated bicarbonate wasting) Primary (no obvious associated d isease) Genetically transmitted Transient (infants) Due to altered carbonic anhy drase activity Acetazolamide Sulfanilamide Mafenide acetate Genetically transmit ted Idiopathic Osteopetrosis with carbonic anhydrase II deficiency York-Yendt sy ndrome Generalized defect (associated with multiple dysfunctions of the proximal tubule) Primary (no obvious associated disease) Sporadic Genetically transmitte d Genetically transmitted systemic disease Tyrosinemia Wilson's disease Lowe syndr ome Hereditary fructose intolerance (during administration of fructose) Cystinos is Pyruvate carboxylate deficiency Metachromatic leukodystrophy Methylmalonic ac idemia Conditions associated with chronic hypocalcemia and secondary hyperparath yroidism Vitamin D deficiency or resistance Vitamin D dependence Dysproteinemic states Multiple myeloma Monoclonal gammopathy Drug- or toxin-induced Outdated te tracycline 3-Methylchromone Streptozotocin Lead Mercury Arginine Valproic acid G entamicin Ifosfamide Tubulointerstitial diseases Renal transplantation Sjgren's syn drome Medullary cystic disease Other renal diseases Nephrotic syndrome Amyloidos is Miscellaneous Paroxysmal nocturnal hemoglobinuria Hyperparathyroidism CO2 H2CO3 CA CA CO2 + OH H 2O H+ Na+ Na+ 3Na 2K+ + HCO 3 3HCO 3 1Na+ HCO + H+ 3 + Na Glucose Amino acids Phosphate Indicates possible cellular mechanisms responsible for Type 2 proximal RTA A FIGURE 6-26 A and B, Potential defects and causes of proximal renal tubular acid osis (RTA) (type 2). Excluding the case of carbonic anhydrase inhibitors, the na ture of the acidification defect responsible for bicarbonate (HCO3) wastage rema ins unknown. It might represent defects in the luminal sodium ion hydrogen ion (N a+-H+) exchanger, basolateral Na+-3HCO3 cotransporter, or carbonic anhydrase act ivity. Most patients with proximal RTA have additional defects in proximal tubul e function (Fanconi's syndrome); this generalized proximal tubule dysfunction migh t reflect a defect in the basolateral Na+-K+ adenosine triphosphatase. K+potassiu m ion; CAcarbonic anhydrase. Causes of proximal renal tubular acidosis (RTA) (typ e 2). An idiopathic form and cystinosis are the most common causes of proximal R TA in children. In adults, multiple myeloma and carbonic anhydrase inhibitors (e g, acetazolamide) are the major causes. Ifosfamide is an increasingly common cau se of the disorder in both age groups.

6.18 Disorders of Water, Electrolytes, and Acid-Base B. CAUSES OF CLASSIC DISTAL RENAL TUBULAR ACIDOSIS Lumen a Intercalated cell (CCT & MCT) Blood Primary (no obvious associated disease ) Sporadic Genetically transmitted Autoimmune disorders Hypergammaglobulinemia H yperglobulinemic purpura Cryoglobulinemia Familial Sjgren's syndrome Thyroiditis Pu lmonary fibrosis Chronic active hepatitis Primary biliary cirrhosis Systemic lup us erythematosus Vasculitis Genetically transmitted systemic disease Ehlers-Danl os syndrome Hereditary elliptocytosis Sickle cell anemia Marfan syndrome Carboni c anhydrase I deficiency or alteration Osteopetrosis with carbonic anhydrase II deficiency Medullary cystic disease Neuroaxonal dystrophy Disorders associated w ith nephrocalcinosis Primary or familial hyperparathyroidism Vitamin D intoxicat ion Milk-alkali syndrome Hyperthyroidism Idiopathic hypercalciuria Genetically t ransmitted Sporadic Hereditary fructose intolerance (after chronic fructose inge stion) Medullary sponge kidney Fabry's disease Wilson's disease Drug- or toxin-induc ed Amphotericin B Toluene Analgesics Lithium Cyclamate Balkan nephropathy Tubulo interstitial diseases Chronic pyelonephritis Obstructive uropathy Renal transpla ntation Leprosy Hyperoxaluria CO2 H + HCO 3 CA Cl H2 O Cl OH H+ K+ Cl A Indicates possible cellular mechanisms responsible for Type 1 distal RTA FIGURE 6-27 A and B, Potential defects and causes of classic distal renal tubula r acidosis (RTA) (type 1). Potential cellular defects underlying classic distal RTA include a faulty luminal hydrogen ionadenosine triphosphatase (H+ pump failur e or secretory defect), an abnormality in the basolateral bicarbonate ionchloride ion exchanger, inadequacy of carbonic anhydrase activity, or an increase in the luminal membrane permeability for hydrogen ions (backleak of protons or permeab ility defect). Most of the causes of classic distal RTA likely reflect a secreto ry defect, whereas amphotericin B is the only established cause of a permeabilit y defect. The hereditary form is the most common cause of this disorder in child ren. Major causes in adults include autoimmune disorders (eg, Sjgren's syndrome) an d hypercalciuria [19]. CAcarbonic anhydrase.

Disorders of Acid-Base Balance 6.19 Lumen Na+ Principal cell Blood B. CAUSES OF HYPERKALEMIC DISTAL RENAL TUBULAR ACIDOSIS Deficiency of aldosterone Associated with glucocorticoid deficiency Addison's dise ase Bilateral adrenalectomy Enzymatic defects 21-Hydroxylase deficiency 3- -ol-D ehydrogenase deficiency Desmolase deficiency Acquired immunodeficiency syndrome Isolated aldosterone deficiency Genetically transmitted Corticosterone methyl ox idase deficiency Transient (infants) Sporadic Heparin Deficient renin secretion Diabetic nephropathy Tubulointerstitial renal disease Nonsteroidal antiinflammat ory drugs -adrenergic blockers Acquired immunodeficiency syndrome Renal transpla ntation Angiotensin I-converting enzyme inhibition Endogenous Captopril and rela ted drugs Angiotensin AT, receptor blockers Resistance to aldosterone action Pse udohypoaldosteronism type I (with salt wasting) Childhood forms with obstructive uropathy Adult forms with renal insufficiency Spironolactone Pseudohypoaldoster onism type II (without salt wasting) Combined aldosterone deficiency and resista nce Deficient renin secretion Cyclosporine nephrotoxicity Uncertain renin status Voltage-mediated defects Obstructive uropathy Sickle cell anemia Lithium Triamt erene Amiloride Trimethoprim, pentamidine Renal transplantation 3Na+ Potential difference Aldosterone receptor 2K+ K+ Cl a Intercalated cell Aldosterone receptor CO2 H+ OH H+ K+ Cl H2 O Cl CA HCO 3 Cl A Indicates possible cellular mechanisms in aldosterone deficiency Indicates defec ts related to aldosterone resistance FIGURE 6-28 A and B, Potential defects and causes of hyperkalemic distal renal t ubular acidosis (RTA) (type 4). This syndrome represents the most common type of RTA encountered in adults. The characteristic hyperchloremic metabolic acidosis in the company of hyperkalemia emerges as a consequence of generalized dysfunct ion of the collecting tubule, including diminished sodium reabsorption and impai red hydrogen ion and potassium secretion. The resultant hyperkalemia causes impa ired ammonium excretion that is an important contribution to the generation of t he metabolic acidosis. The causes of this syndrome are broadly classified into d isorders resulting in aldosterone deficiency and those that impose resistance to the action of aldosterone. Aldosterone deficiency can arise from hyporeninemia, impaired conversion of angiotensin I to angiotensin II, or abnorm al aldosterone synthesis. Aldosterone resistance can reflect the following: bloc kade of the mineralocorticoid receptor; destruction of the target cells in the c ollecting tubule (tubulointerstitial nephropathies); interference with the sodiu m channel of the principal cell, thereby decreasing the lumen-negative potential difference and thus the secretion of potassium and hydrogen ions (voltage-media ted defect); inhibition of the basolateral sodium ion, potassium ionadenosine tri phosphatase; and enhanced chloride ion permeability in the collecting tubule, wi th consequent shunting of the transepithelial potential difference. Some disorde rs cause combined aldosterone deficiency and resistance [20].

6.20 Disorders of Water, Electrolytes, and Acid-Base FIGURE 6-29 Treatment of acute metabolic acidosis. Whenever possible, causespeci fic measures should be at the center of treatment of metabolic acidosis. In the presence of severe acidemia, such measures should be supplemented by judicious a dministration of sodium bicarbonate. The goal of alkali therapy is to return the blood pH to a safer level of about 7.20. Anticipated benefits and potential ris ks of alkali therapy are depicted here [1]. Management of acute metabolic acidosis Cause-specific measures Alkali therapy for severe acidemia (blood pH<7.20) Benefits Prevents or reverses acidemiarelated hemodynamic compromise. Reinstates cardiovascular responsiveness to catecholamines. "Buys time," thus allowing cau sespecific measures and endogenous reparatory processes to take effect. Provides a measure of safety against additional acidifying stresses. Risks Hypernatremia/ hyperosmolality Volume overload "Overshoot" alkalosis Hypok alemia Decreased plasma ionized calcium concentration Stimulation of organic aci d production Hypercapnia Metabolic Alkalosis Arterial blood [H+], nEq/L 150 125 100 80 70 60 50 40 30 60 50 40 20 PaCO2 mm Hg 120 100 90 80 70 50 Arterial plasma [HCO], mEq/L 3 40 30 30 Normal 20 20 10 10 6.8 6.9 7.0 7.1 7.2

7.3 7.4 7.5 7.6 7.7 Arterial blood pH FIGURE 6-30 Ninety-five percent confidence intervals for metabolic alkalosis. Me tabolic alkalosis is the acid-base disturbance initiated by an increase in plasm a bicarbonate concentration ([HCO3]). The resultant alkalemia dampens alveolar v entilation and leads to the secondary hypercapnia characteristic of the disorder . Available observations in humans suggest a roughly linear relationship between the steady-state increase in bicarbonate concentration and the associated incre ment in the arterial carbon dioxide tension (PaCO2). Although data are limited, the slope of the steadystate PaCO2 versus [HCO3] relationship has been estimated as about a 0.7 mm Hg per mEq/L increase in plasma bicarbonate concentration. Th e value of this slope is virtually identical to that in dogs that has been deriv ed from rigorously controlled observations [21]. Empiric observations in humans have been used for construction of 95% confidence intervals for graded degrees o f metabolic alkalosis represented by the area in color in the acid-base template . The black ellipse near the center of the figure indicates the normal range for the acid-base parameters [3]. Assuming a steady state is present, values fallin g within the area in color are consistent with but not diagnostic of simple meta bolic alkalosis. Acid-base values falling outside the area in color denote the p resence of a mixed acid-base disturbance [4]. [H+]hydrogen ion concentration.

Disorders of Acid-Base Balance 6.21 Excess alkali Alkali gain Enteral Milk alkali syndrome Calcium supplements Absorbable alkali Nonabsorbable alkali plus K+ exchange resins Ringer's solution Bicarbonate Blood products Nutrition D ialysis Vomiting Suction Villous adenoma Congenital chloridorrhea Chloruretic di uretics Inherited transport defects Mineralocorticoid excess Posthypercapnia Source? Parenteral H+ loss Gastric Intestinal FIGURE 6-31 Pathogenesis of metabolic alkalosis. Two crucial questions must be a nswered when evaluating the pathogenesis of a case of metabolic alkalosis. 1) Wh at is the source of the excess alkali? Answering this question addresses the pri mary event responsible for generating the hyperbicarbonatemia. 2) What factors p erpetuate the hyperbicarbonatemia? Answering this question addresses the pathoph ysiologic events that maintain the metabolic alkalosis. Renal H+ shift K+ depletion Reduced GFR Mode of perpetuation? Increased renal acidification Cl responsive def ect Cl resistant defect Baseline 45 [HCO3 ], mEq/L 40 35 30 25 Vomiting Maintenance Low NaCl and KCl intake Correction High NaCl and KCl intake 105 [Cl ], mEq/L 100 95 FIGURE 6-32 Changes in plasma anionic pattern and body electrolyte balance durin g development, maintenance, and correction of metabolic alkalosis induced by vom iting. Loss of hydrochloric acid from the stomach as a result of vomiting (or ga stric drainage) generates the hypochloremic hyperbicarbonatemia characteristic o f this disorder. During the generation phase, renal sodium and potassium excreti on increases, yielding the deficits depicted here. Renal potassium losses contin ue in the early days of the maintenance phase. Subsequently, and as long as the low-chloride diet is continued, a new steady state is achieved in which plasma b icarbonate concentration ([HCO3]) stabilizes at an elevated level, and renal exc retion of electrolytes matches intake. Addition of sodium chloride (NaCl) and po tassium chloride (KCl) in the correction phase repairs the electrolyte deficits incurred and normalizes the plasma bicarbonate and chloride concentration ([Cl-] ) levels [22,23]. 0 Cl Cumulative balance, mEq Na+ K+ 200 400 0

100 0 200 400 2 0 2 4 6 8 Days 10 12 14 16 18

6.22 Baseline Disorders of Water, Electrolytes, and Acid-Base 8.0 Urine pH 7.0 6.0 5.0 Vomiting Maintenance Low NaCl and KCl intake Correction High NaCl and KCl intake Baseline Diuresis Maintenance Low NaCl intake Correction High KCl intake Low KCl intake [HCO3 ], mEq/L [Cl ], mEq/L Urine net acid excretion, mEq/d Cumulative balance, mE q K+ Na+ Cl 2 0 2 4 6 8 Days 10 12 14 16 18 40 35 30 25 Urine HCO excretion, 3 mEq/d 75 105 50 25 0 125 100 75 50 100 95 100 Urine net acid excretion, mEq/d 75 50 25 0 0 200 400 25 50 0 100 0 FIGURE 6-33 Changes in urine acid-base composition during development, maintenan ce, and correction of vomiting-induced metabolic alkalosis. During acid removal from the stomach as well as early in the phase after vomiting (maintenance), an alkaline urine is excreted as acid excretion is suppressed, and bicarbonate excr etion (in the company of sodium and, especially potassium; see Fig. 6-32) is inc reased, with the net acid excretion being negative (net alkali excretion). This acid-base profile moderates the steady-state level of the resulting alkalosis. I n the steady state (late maintenance phase), as all filtered bicarbonate is recl aimed the pH of urine becomes acidic, and the net acid excretion returns to base line. Provision of sodium chloride (NaCl) and potassium chloride (KCl) in the co rrection phase alkalinizes the urine and suppresses the net acid excretion, as b icarbonaturia in the company of exogenous cations (sodium and potassium) superve nes [22,23]. HCO3bicarbonate ion. 100 2 0 2 4 6 Days 8 10 12 FIGURE 6-34 Changes in plasma anionic pattern, net acid excretion, and body elec trolyte balance during development, maintenance, and correction of diuretic-indu ced metabolic alkalosis. Administration of a loop diuretic, such as furosemide, increases urine net acid excretion (largely in the form of ammonium) as well as

the renal losses of chloride (Cl-), sodium (Na+), and potassium (K+). The result ing hyperbicarbonatemia reflects both loss of excess ammonium chloride in the ur ine and an element of contraction (consequent to diuretic-induced sodium chlorid e [NaCl] losses) that limits the space of distribution of bicarbonate. During th e phase after diuresis (maintenance), and as long as the low-chloride diet is co ntinued, a new steady state is attained in which the plasma bicarbonate concentr ation ([HCO3]) remains elevated, urine net acid excretion returns to baseline, a nd renal excretion of electrolytes matches intake. Addition of potassium chlorid e (KCl) in the correction phase repairs the chloride and potassium deficits, sup presses net acid excretion, and normalizes the plasma bicarbonate and chloride c oncentration ([Cl-]) levels [23,24]. If extracellular fluid volume has become su bnormal folllowing diuresis, administration of NaCl is also required for repair of the metabolic alkalosis.

Disorders of Acid-Base Balance Maintenance of Cl-responsive metabolic alkalosis Basic mechanisms Mediating facto rs GFR Cl depletion ECF volume depletion -HCO3 reabsorption 6.23 K+ depletion Hypercapnia Na+ 3HCO 3 HCO 3 Cl Na+ Na+ Cl K+ P-cell + K + K K Na + -Na+ reabsorption and consequent -H+ and K+ secretion GFR Na+ H+, NH+ 4 Cl a-cell -HCO3 reabsorption NH4 K+ NH4 , K Na+ 2Cl + + + H+ H + -NH4+ synthesis and luminal entry H 2O NH3 NH3 Na+ HCO 3 + K Cl Cl H+ K+ HCO3 Cl -H+ secretion -H+ secretion coupled to K+ reabsorption -cell

NH4+ NH3 Cl H+ HCO3 Cl HCO3 secretion NH3 -NH4+ entry in medulla and secretion in medullary collecting duct NH4+ Net acid excretion maintained at control FIGURE 6-35 Maintenance of chloride-responsive metabolic alkalosis. Increased re nal bicarbonate reabsorption frequently coupled with a reduced glomerular filtra tion rate are the basic mechanisms that maintain chloride-responsive metabolic a lkalosis. These mechanisms have been ascribed to three mediating factors: chlori de depletion itself, extracellular fluid (ECF) volume depletion, and potassium d epletion. Assigning particular roles to each of these factors is a vexing task. Notwithstanding, here depicted is our cu rrent understanding of the participation of each of these factors in the nephron al processes that maintain chloride-responsive metabolic alkalosis [2224]. In add ition to these factors, the secondary hypercapnia of metabolic alkalosis contrib utes importantly to the maintenance of the prevailing hyperbicarbonatemia [25].

6.24 Disorders of Water, Electrolytes, and Acid-Base Maintenance of Cl-resistant metabolic alkalosis Basic mechanism Mediating factors Na+ 3HCO 3 HCO 3 Cl -HCO3 reabsorption Mineralocorticoid excess K+ depletion P-cell Na+ K Na+ Cl K + K Na + -Na+ reabsorption and consequent -H+ and K+ secretion Na+ H+, NH+ 4 Cl a-cell HCO3 Cl H+ K+ -cell HCO Cl 3 -HCO3 reabsorption NH+4 K+ NH+4, K Na+ 2Cl + H + -H+ secretion coupled to K+ reabsorption -H+ secretion H + -NH4+ synthesis and luminal entry H 2O NH3 NH3 Na+ HCO 3 + K Cl Cl NH+4 NH3 Cl H+ NH3 -NH4+entry in medulla and secretion in medullary collecting duct NH+4 FIGURE 6-36 Maintenance of chloride-resistant metabolic alkalosis. Increased ren

al bicarbonate reabsorption is the sole basic mechanism that maintains chlorideresistant metabolic alkalosis. As its name implies, factors independent of chlor ide intake mediate the heightened bicarbonate reabsorption and include mineralocorticoid excess and potassium depletion. The participation of these factors in the nephronal processes that m aintain chloride-resistant metabolic alkalosis is depicted [2224, 26]. FIGURE 6-3 7 Urinary composition in the diagnostic evaluation of metabolic alkalosis. Asses sing the urinary composition can be an important aid in the diagnostic evaluatio n of metabolic alkalosis. Measurement of urinary chloride ion concentration ([Cl -]) can help distinguish between chloride-responsive and chloride-resistant meta bolic alkalosis. The virtual absence of chloride (urine [Cl-] < 10 mEq/L) indica tes significant chloride depletion. Note, however, that this test loses its diag nostic significance if performed within several hours of administration of chlor uretic diuretics, because these agents promote urinary chloride excretion. Measu rement of urinary potassium ion concentration ([K+]) provides further diagnostic differentiation. With the exception of the diuretic phase of chloruretic agents , abundance of both urinary chloride and potassium signifies a state of mineralo corticoid excess [22]. Urinary [Cl] Virtually absent (< 10 mEq/L) Abundant (> 20 mEq/L) Vomiting, gastric suction Postdiuretic phase of loop and distal agents Posthyper capnic state Villous adenoma of the colon Congenital chloridorrhea Post alkali l oading Urinary [K+] Low (< 20 mEq/L) Laxative abuse Other causes of profound K+ depleti on Abundant (> 30 mEq/L) Diuretic phase of loop and distal agents Bartter's and Gitelman's syndromes Prim ary aldosteronism Cushing's syndrome Exogenous mineralocorticoid agents Secondar y aldosteronism malignant hypertension renovascular hypertension primary reninis m Liddle's syndrome

Disorders of Acid-Base Balance 6.25 SIGNS AND SYMPTOMS OF METABOLIC ALKALOSIS Central Nervous System Headache Lethargy Stupor Delirium Tetany Seizures Potentiation of hepatic enceph alopathy Cardiovascular System Supraventricular and ventricular arrhythmias Potentiation of digitalis toxicity Positive inotropic ventricular effect Respiratory System Hypoventilation with attendant hypercapnia and hypoxemia Neuromuscular System Chvostek's sign Trousseau's sign Weakness (severity depends on degree of potassium d epletion) Metabolic Effects Increased organic acid and ammonia production Hypokalemia Hypocalcemia Hypomagne semia Hypophosphatemia Renal (Associated Potassium Depletion) Polyuria Polydipsia Urinary concentration defect Cortical and medullary renal cy sts FIGURE 6-38 Signs and symptoms of metabolic alkalosis. Mild to moderate metaboli c alkalosis usually is accompanied by few if any symptoms, unless potassium depl etion is substantial. In contrast, severe metabolic alkalosis ([HCO3] > 40 mEq/L ) is usually a symptomatic disorder. Alkalemia, hypokalemia, hypoxemia, hypercap nia, and decreased plasma ionized calcium concentration all contribute to these clinical manifestations. The arrhythmogenic potential of alkalemia is more pronounced in patients with underlying heart disease and is heightened by the a lmost constant presence of hypokalemia, especially in those patients taking digi talis. Even mild alkalemia can frustrate efforts to wean patients from mechanica l ventilation [23,24]. of hypercalcemia after primary hyperparathyroidism and ma lignancy. Another common presentation of the syndrome originates from the curren t use of calcium carbonate in preference to aluminum as a phosphate binder in pa tients with chronic renal insufficiency. The critical element in the pathogenesi s of the syndrome is the development of hypercalcemia that, in turn, results in renal dysfunction. Generation and maintenance of metabolic alkalosis reflect the combined effects of the large bicarbonate load, renal insufficiency, and hyperc alcemia. Metabolic alkalosis contributes to the maintenance of hypercalcemia by increasing tubular calcium reabsorption. Superimposition of an element of volume contraction caused by vomiting, diuretics, or hypercalcemia-induced natriuresis can worsen each one of the three main components of the syndrome. Discontinuati on of calcium carbonate coupled with a diet high in sodium chloride or the use o f normal saline and furosemide therapy (depending on the severity of the syndrom e) results in rapid resolution of hypercalcemia and metabolic alkalosis. Althoug h renal function also improves, in a considerable fraction of patients with the chronic form of the syndrome serum creatinine fails to return to baseline as a r esult of irreversible structural changes in the kidneys [27]. Ingestion of large amounts of calcium Ingestion of large amounts of absorbable alkali

Augmented body content of calcium Increased urine calcium excretion (early phase) Urine alkalinization Augmented body bicarbonate stores Nephrocalcinosis Reduced renal bicarbonate excretion Hypercalcemia Renal vasoconstriction Renal insufficiency Metabolic alkalosis Decreased urine calcium excretion Increased renal H+ secretion Increased renal reabsorption of calcium FIGURE 6-39 Pathophysiology of the milk-alkali syndrome. The milk-alkali syndrom e comprises the triad of hypercalcemia, renal insufficiency, and metabolic alkal osis and is caused by the ingestion of large amounts of calcium and absorbable a lkali. Although large amounts of milk and absorbable alkali were the culprits in the classic form of the syndrome, its modern version is usually the result of l arge doses of calcium carbonate alone. Because of recent emphasis on prevention and treatment of osteoporosis with calcium carbonate and the availability of thi s preparation over the counter, milk-alkali syndrome is currently the third lead ing cause

6.26 Clinical syndrome Bartter's syndrome Type 1 Disorders of Water, Electrolytes, and Acid-Base and hypercalciuria and nephrocalcinosis are present. In contrast, Gitelman's syndr ome is a milder disease presenting later in life. Patients often are asymptomati c, or they might have intermittent muscle spasms, cramps, or tetany. Urinary con centrating ability is maintained; hypocalciuria, renal magnesium wasting, and hy pomagnesemia are almost constant features. On the basis of certain of these clin ical features, it had been hypothesized that the primary tubular defects in Bart ter's and Gitelman's syndromes reflect impairment in sodium reabsorption in the thic k ascending limb (TAL) of the loop of Henle and the distal tubule, respectively. This hypothesis has been validated by recent genetic studies [28-31]. As illust rated here, Bartter's syndrome now has been shown to be caused by loss-of-function mutations in the loop diureticsensitive sodium-potassium-2chloride cotransporter (NKCC2) of the TAL (type 1 Bartter's syndrome) [28] or the apical potassium chann el ROMK of the TAL (where it recycles reabsorbed potassium into the lumen for co ntinued operation of the NKCC2 cotransporter) and the cortical collecting duct ( where it mediates secretion of potassium by the principal cell) (type 2 Bartter's syndrome) [29,30]. On the other hand, Gitelman's syndrome is caused by mutations i n the thiazide-sensitive Na-Cl cotransporter (TSC) of the distal tubule [31]. No te that the distal tubule is the major site of active calcium reabsorption. Stim ulation of calcium reabsorption at this site is responsible for the hypocalciuri c effect of thiazide diuretics. Affected gene Affected chromosome Localization of tubular defect TAL NKCC2 15q15-q21 TAL CCD Type 2 Gitelman's syndrome ROMK 11q24 DCT TSC 16q13 Tubular lumen Na+ K+,NH+ 4 Cl Loop diuretics H+ Cell + Peritubular space 2K+ ATPase Tubular lumen Na + Cell 3Na+ + K Cl Cl Peritubular space 2K+ ATPase Tubular lumen Na+ Cell

Peritubular space Cl 3Na 3Na K+ K + + K 3HCO 3 Na+ + Cl Thiazides ATPase + 2K K+ 3Na+ Ca 2+ Ca 2+ Ca2+ Mg2+ Thick ascending limb (TAL) Distal convoluted tuble (DCT) Cortical coll ecting duct (CCD) FIGURE 6-40 Clinical features and molecular basis of tubular defects of Bartter's and Gitelman's syndromes. These rare disorders are characterized by chloride-resis tant metabolic alkalosis, renal potassium wasting and hypokalemia, hyperreninemi a and hyperplasia of the juxtaglomerular apparatus, hyperaldosteronism, and norm otension. Regarding differentiating features, Bartter's syndrome presents early in life, frequently in association with growth and mental retardation. In this syn drome, urinary concentrating ability is usually decreased, polyuria and polydips ia are present, the serum magnesium level is normal,

Disorders of Acid-Base Balance 6.27 Management of metabolic alkalosis For alkali gain For H+ loss Eliminate source of excess alkali For H+ shift Discontinue administrationof bicarbonate or its precursors. via gastric route Ad minister antiemetics; discontinue gastric suction; administer H2 blockers or H+K+ ATPase inhibitors. via renal route Discontinue or decrease loop and distal di uretics; substitute with amiloride, triamterene, or spironolactone; discontinue or limit drugs with mineralocorticoid activity. Potassium repletion ECF volume r epletion; renal replacement therapy For decreased GFR FIGURE 6-41 Metabolic alkalosis management. Effective management of metabolic al kalosis requires sound understanding of the underlying pathophysiology. Therapeu tic efforts should focus on eliminating or moderating the processes that generat e the alkali excess and on interrupting the mechanisms that perpetuate the hyper bicarbonatemia. Rarely, when the pace of correction of metabolic alkalosis must be accelerated, acetazolamide or an infusion of hydrochloric acid can be used. T reatment of severe metabolic alkalosis can be particularly challenging in patien ts with advanced cardiac or renal dysfunction. In such patients, hemodialysis or continuous hemofiltration might be required [1]. Interrupt perpetuating mechanisms For Cl responsive acidification defect Administer NaCl and KCl For Cl resistant acidification defect Adrenalectomy or other surgery, potassiuim repletion, administration of amilorid e, triamterene, or spironolactone. References 1. Adrogu HJ, Madias NE: Management of life-threatening acid-base disorders. N En gl J Med, 1998, 338:2634, 107111. 2. Madias NE, Adrogu HJ: Acid-base disturbances i n pulmonary medicine. In Fluid, Electrolyte, and Acid-Base Disorders. Edited by Arieff Al, DeFronzo RA. New York: Churchill Livingstone; 1995:223253. 3. Madias N E, Adrogu HJ, Horowitz GL, et al.: A redefinition of normal acid-base equilibrium in man: carbon dioxide tension as a key determinant of plasma bicarbonate conce ntration. Kidney Int 1979, 16:612618. 4. Adrogu HJ, Madias NE: Mixed acid-base dis orders. In The Principles and Practice of Nephrology. Edited by Jacobson HR, Str iker GE, Klahr S. St. Louis: Mosby-Year Book; 1995:953962. 5. Krapf R: Mechanisms of adaptation to chronic respiratory acidosis in the rabbit proximal tubule. J Clin Invest 1989, 83:890896. 6. Al-Awqati Q: The cellular renal response to respi ratory acid-base disorders. Kidney Int 1985, 28:845855. 7. Bastani B: Immunocytoc hemical localization of the vacuolar H+ATPase pump in the kidney. Histol Histopa thol 1997, 12:769779. 8. Teixeira da Silva JC Jr, Perrone RD, Johns CA, Madias NE : Rat kidney band 3 mRNA modulation in chronic respiratory acidosis. Am J Physio l 1991, 260:F204F209. 9. Respiratory pump failure: primary hypercapnia (respirato ry acidosis). In Respiratory Failure. Edited by Adrogu HJ, Tobin MJ. Cambridge, M

A: Blackwell Science; 1997:125134. 10. Krapf R, Beeler I, Hertner D, Hulter HN: C hronic respiratory alkalosis: the effect of sustained hyperventilation on renal regulation of acidbase equilibrium. N Engl J Med 1991, 324:13941401. 11. Hilden S A, Johns CA, Madias NE: Adaptation of rabbit renal cortical Na+-H+-exchange acti vity in chronic hypocapnia. Am J Physiol 1989, 257:F615F622. 12. Adrogu HJ, Rashad MN, Gorin AB, et al.: Arteriovenous acid-base disparity in circulatory failure: studies on mechanism. Am J Physiol 1989, 257:F1087F1093. 13. Adrogu HJ, Rashad MN , Gorin AB, et al.: Assessing acid-base status in circulatory failure: differenc es between arterial and central venous blood. N Engl J Med 1989, 320:13121316. 14 . Madias NE: Lactic acidosis. Kidney Int 1986, 29:752774. 15. Kraut JA, Madias NE : Lactic acidosis. In Textbook of Nephrology. Edited by Massry SG, Glassock RJ. Baltimore: Williams and Wilkins; 1995:449457. 16. Hindman BJ: Sodium bicarbonate in the treatment of subtypes of acute lactic acidosis: physiologic consideration s. Anesthesiology 1990, 72:10641076. 17. Adrogu HJ: Diabetic ketoacidosis and hype rosmolar nonketotic syndrome. In Therapy of Renal Diseases and Related Disorders . Edited by Suki WN, Massry SG. Boston: Kluwer Academic Publishers; 1997:233251. 18. Adrogu HJ, Barrero J, Eknoyan G: Salutary effects of modest fluid replacement in the treatment of adults with diabetic ketoacidosis. JAMA 1989, 262:21082113. 19. Bastani B, Gluck SL: New insights into the pathogenesis of distal renal tubu lar acidosis. Miner Electrolyte Metab 1996, 22:396409. 20. DuBose TD Jr: Hyperkal emic hyperchloremic metabolic acidosis: pathophysiologic insights. Kidney Int 19 97, 51:591602. 21. Madias NE, Bossert WH, Adrogu HJ: Ventilatory response to chron ic metabolic acidosis and alkalosis in the dog. J Appl Physiol 1984, 56:16401646. 22. Gennari FJ: Metabolic alkalosis. In The Principles and Practice of Nephrolo gy. Edited by Jacobson HR, Striker GE, Klahr S. St Louis: Mosby-Year Book; 1995: 932942.

6.28 Disorders of Water, Electrolytes, and Acid-Base 28. Simon DB, Karet FE, Hamdan JM, et al.: Bartter's syndrome, hypokalaemic alkalo sis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NK CC2. Nat Genet 1996, 13:183188. 29. Simon DB, Karet FE, Rodriguez-Soriano J, et a l.: Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ ch annel, ROMK. Nat Genet 1996, 14:152156. 30. International Collaborative Study Gro up for Bartter-like Syndromes. Mutations in the gene encoding the inwardly-recti fying renal potassium channel, ROMK, cause the antenatal variant of Bartter synd rome: evidence for genetic heterogeneity. Hum Mol Genet 1997, 6:1726. 31. Simon D B, Nelson-Williams C, et al.: Gitelman's variant of Bartter's syndrome, inherited hy pokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cot ransporter. Nat Genet 1996, 12:2430. 23. Sabatini S, Kurtzman NA: Metabolic alkalosis: biochemical mechanisms, pathop hysiology, and treatment. In Therapy of Renal Diseases and Related Disorders Edi ted by Suki WN, Massry SG. Boston: Kluwer Academic Publishers; 1997:189210. 24. G alla JH, Luke RG: Metabolic alkalosis. In Textbook of Nephrology. Edited by Mass ry SG, Glassock RJ. Baltimore: Williams & Wilkins; 1995:469477. 25. Madias NE, Ad rogu HJ, Cohen JJ: Maladaptive renal response to secondary hypercapnia in chronic metabolic alkalosis. Am J Physiol 1980, 238:F283289. 26. Harrington JT, Hulter H N, Cohen JJ, Madias NE: Mineralocorticoidstimulated renal acidification in the d og: the critical role of dietary sodium. Kidney Int 1986, 30:4348. 27. Beall DP, Scofield RH: Milk-alkali syndrome associated with calcium carbonate consumption. Medicine 1995, 74:8996.

Disorders of Phosphate Balance Moshe Levi Mordecai Popovtzer T he physiologic concentration of serum phosphorus (phosphate) in normal adults ra nges from 2.5 to 4.5 mg/dL (0.801.44 mmol/L). A diurnal variation occurs in serum phosphorus of 0.6 to 1.0 mg/dL, the lowest concentration occurring between 8 AM and 11 AM. A seasonal variation also occurs; the highest serum phosphorus conce ntration is in the summer and the lowest in the winter. Serum phosphorus concent ration is markedly higher in growing children and adolescents than in adults, an d it is also increased during pregnancy [1,2]. Of the phosphorus in the body, 80 % to 85% is found in the skeleton. The rest is widely distributed throughout the body in the form of organic phosphate compounds. In the extracellular fluid, in cluding in serum, phosphorous is present mostly in the inorganic form. In serum, more than 85% of phosphorus is present as the free ion and less than 15% is pro tein-bound. Phosphorus plays an important role in several aspects of cellular me tabolism, including adenosine triphosphate synthesis, which is the source of ene rgy for many cellular reactions, and 2,3-diphosphoglycerate concentration, which regulates the dissociation of oxygen from hemoglobin. Phosphorus also is an imp ortant component of phospholipids in cell membranes. Changes in phosphorus conte nt, concentration, or both, modulate the activity of a number of metabolic pathw ays. Major determinants of serum phosphorus concentration are dietary intake and gastrointestinal absorption of phosphorus, urinary excretion of phosphorus, and shifts between the intracellular and extracellular spaces. Abnormalities in any of these steps can result either in hypophosphatemia or hyperphosphatemia [37]. The kidney plays a major role in the regulation of phosphorus homeostasis. Most of the inorganic phosphorus in serum is ultrafilterable at the level of the glom erulus. At physiologic levels of serum phosphorus and during a normal dietary ph osphorus intake, approximately 6 to 7 g/d of phosphorous is filtered by the kidn ey. Of that CHAPTER 7

7.2 Disorders of Water, Electrolytes, and Acid-Base (type I and type II Na-Pi cotransport proteins). Most of the hormonal and metabo lic factors that regulate renal tubular phosphate reabsorption, including altera tions in dietary phosphate content and parathyroid hormone, have been shown to m odulate the proximal tubular apical membrane expression of the type II Na-Pi cot ransport protein [1116]. FIGURE 7-1 Summary of phosphate metabolism for a normal adult in neutral phospha te balance. Approximately 1400 mg of phosphate is ingested daily, of which 490 m g is excreted in the stool and 910 mg in the urine. The kidney, gastrointestinal (GI) tract, and bone are the major organs involved in phosphorus homeostasis. amount, 80% to 90% is reabsorbed by the renal tubules and the rest is excreted i n the urine. Most of the filtered phosphorus is reabsorbed in the proximal tubul e by way of a sodium gradient-dependent process (Na-Pi cotransport) located on t he apical brush border membrane [810]. Recently two distinct Na-Pi cotransport pr oteins have been cloned from the kidney Bone GI intake 1400 mg/d Digestive juice phosphorus 210 mg/d Formation 210 mg/d Resorption 210 mg/d Extracellular fluid Total absorbed intestinal phosphorus 1120 mg/d Urine 910 mg/d Stool 490 mg/d Major determinants of ECF or serum inorganic phosphate (Pi) concentration Dietar y intake Intestinal absorption FIGURE 7-2 Major determinants of extracellular fluid or serum inorganic phosphat e (Pi) concentration include dietary Pi intake, intestinal Pi absorption, urinar y Pi excretion and shift into the cells. Serum Pi Urinary excretion Cells

Disorders of Phosphate Balance 7.3 Renal Tubular Phosphate Reabsorption 100% PCT 55-75% DCT 5-10% FIGURE 7-3 Renal tubular reabsorption of phosphorus. Most of the inorganic phosp horus in serum is ultrafilterable at the level of the glomerulus. At physiologic levels of serum phosphorus and during a normal dietary phosphorus intake, most of the filtered phosphorous is reabsorbed in the proximal convoluted tubule (PCT ) and proximal straight tubule (PST). A significant amount of filtered phosphoru s is also reabsorbed in distal segments of the nephron [7,9,10]. CCTcortical coll ecting tubule; IMCDinner medullary collecting duct or tubule; PSTproximal straight tubule. PST 10-20% CCT 2-5% IMCD <1% 0.2%-20% Urine Lumen Na+ Na + Blood Pi 3 Na+ ?An Na+ Pi Gluconeogenesis [HPO4= Pi Glycolysis H2PO4 ] Pi FIGURE 7-4 Cellular model for renal tubular reabsorption of phosphorus in the pr oximal tubule. Phosphate reabsorption from the tubular fluid is sodium gradientde pendent and is mediated by the sodium gradient dependent phosphate transport (NaPi cotransport) protein located on the apical brush border membrane. The sodium gradient for phosphate reabsorption is generated by then sodium-potassium adenos ine triphosphatase (Na-K ATPase) pump located on the basolateral membrane. Recen t studies indicate that the Na-Pi cotransport system is electrogenic [8,11]. ADPa denosine diphosphate; Ananion. Pi+ADP ATP P +ADP ATP Respiratory chain Oxidative phosphorylation i Na-K ATPase 65mV 65mV

7.4 Disorders of Water, Electrolytes, and Acid-Base Cellular model of proximal tubule Pi-reabsorption Lumen Blood FACTORS REGULATING RENAL PROXIMAL TUBULAR PHOSPHATE REABSORPTION Decreased transport Increased transport Low phosphate diet Growth hormone Insulin Thyroid hormone 1,25-dihydroxy-vitamin D3 Chronic metabolic alkalosis High calcium diet High potassium diet Stanniocal cin Parathyroid hormone dietary Pi content HPO42 3Na + HPO42 Na+ A FIGURE 7-5 Celluar model of proximal tubular phosphate reabsorption. Major physi ologic determinants of renal tubular phosphate reabsorption are alterations in p arathyroid hormone activity and alterations in dietary phosphate content. The re gulation of renal tubular phosphate reabsorption occurs by way of alterations in apical membrane sodiumphosphate (Na-Pi) cotransport 3Na+-HPO2 4 activity [1114]. High phosphate diet Parathyroid hormone and parathyroidhormonerelated protein Glu cocorticoids Chronic metabolic acidosis Acute respiratory acidosis Aging Calcito nin Atrial natriuretic peptide Fasting Hypokalemia Hypercalcemia Diuretics Phosp hatonin FIGURE 7-6 Factors regulating renal proximal tubular phosphate reabsorption. FIG URE 7-7 (see Color Plate) Effects of a diet low in phosphate on renal tubular ph osphate reabsorption in rats. A, Chronic high Pi diet. B, Acute low Pi diet. C, Colchicine and high Pi diet. D, Colchicine and low Pi diet. In response to a low phosphate diet, a rapid adaptive increase occurs in the sodium-phosphate (Na-Pi ) cotransport activity of the proximal tubular apical membrane (A, B). The incre ase in Na-Pi cotransport activity is mediated by rapid upregulation of the type II Na-Pi cotransport protein, in the absence of changes in Na-Pi messenger RNA ( mRNA) levels. This rapid upregulation is dependent on an intact microtubular net work because pretreatment with colchicine prevents the upregulation of Na-Pi cot ransport activity and Na-Pi protein expression (C, D). In this immunofluorescenc e micrograph, the Na-Pi protein is stained green (fluorescein) and the actin cyt oskeleton is stained red (rhodamine). Colocalization of green and red at the lev el of the apical membrane results in yellow color [14]. A B C D

Disorders of Phosphate Balance 7.5 FIGURE 7-8 (see Color Plate) Effects of parathyroid hormone (PTH) on renal tubul ar phosphate reabsorption in rats. In response to PTH administration to parathyr oidectomized rats, a rapid decrease occurs in the sodium-phosphate (Na-Pi) cotra nsport activity of the proximal tubular apical membrane. The decrease in Na-Pi c otransport activity is mediated by rapid downregulation of the type II Na-Pi cot ransport protein. In this immunofluorescence micrograph, the Na-Pi protein is st ained green (fluorescein) and the actin cytoskeleton is stained red (rhodamine). Colocalization of green and red at the level of the apical membrane results in yellow color [13]. A, parathyroidectomized (PTX) effects. B, effects of PTX and PTH. A 490 Cholesterol, nmol/mg B 600 440 A 390 1600 GlcCer, ng/mg Na-Pi, pmol/5s/mg A 1100 Na-Pi, pmol/5s/mg 0 PDMP 1600 Control DEX 600 B Low Pi diet and/or young Control High Pi diet and/or aged FIGURE 7-9 Renal cholesterol content modulates renal tubular phosphate reabsorpt ion. In aged rats versus young rats and rats fed a diet high in phosphate versus a diet low in phosphate, an inverse correlation exists between the brush border membrane (BBM) cholesterol content (A) and Na-Pi cotransport activity (B). Stud ies in isolated BBM vesicles and recent studies in opossum kidney cells grown in culture indicate that direct alterations in cholesterol content per se modulate Na-Pi cotransport activity [15]. CONcontrols. B 0 PDMP

Control DEX FIGURE 7-10 Renal glycosphingolipid content modulates renal tubular phosphate re absorption. In rats treated with dexamethasone (DEX) and in rats fed a potassium -deficient diet, an inverse correlation exists between brush border membrane (BB M) glucosylceramide (GluCer)and ganglioside GM3, content and Na-Pi cotransport ac tivity. Treatment of rats with a glucosylceramide synthase inhibitor PDMP lowers BBM glucosylceramide content (A) and increases Na-Pi cotransport activity (B) [ 16].

7.6 Disorders of Water, Electrolytes, and Acid-Base Hypophosphatemia/Hyperphosphatemia MAJOR CAUSES OF HYPOPHOSPHATEMIA Internal redistribution Increased insulin, particularly during refeeding Acute respiratory alkalosis Hun gry bone syndrome FIGURE 7-11 Major causes of hypophosphatemia. (From Angus [1]; with permission.) Increased urinary excretion Primary and secondary hyperparathyroidism Vitamin D deficiency or resistance Fan coni's syndrome Miscellaneous: osmotic diuresis, proximally acting diuretics, acut e volume expansion Decreased intestinal absorption Inadequate intake Antacids containing aluminum or magnesium Steatorrhea and chro nic diarrhea CAUSES OF MODERATE HYPOPHOSPHATEMIA Pseudohypophosphatemia Mannitol Bilirubin Acute leukemia Decreased dietary intak e Decreased intestinal absorption Vitamin D deficiency Malabsorption Steatorrhea Secretory diarrhea Vomiting PO34-binding antacids Shift from serum into cells R espiratory alkalosis Sepsis Heat stroke Neuroleptic malignant syndrome Hepatic c oma Salicylate poisoning Gout Panic attacks Psychiatric depression Hormonal effe cts Insulin Glucagon Epinephrine Androgens Cortisol Anovulatory hormones Nutrien t effects Glucose Fructose Glycerol Lactate Amino acids Xylitol Cellular uptake syndromes Recovery from hypothermia Burkitt's lymphoma Histiocytic lymphoma Acute myelomonocytic leukemia Acute myelogenous leukemia Chronic myelogenous leukemia in blast crisis Treatment of pernicious anemia Erythropoietin therapy Erythroder mic psoriasis Hungry bone syndrome After parathyroidectomy Acute leukemia Increa sed excretion into urine Hyperparathyroidism Renal tubule defects Fanconi's syndro me X-linked hypophosphatemic rickets Hereditary hypophosphatemic rickets with hy percalciuria Polyostotic fibrous dysphasia Panostotic fibrous dysphasia Neurofib romatosis Kidney transplantation Oncogenic osteomalacia Recovery from hemolyticuremic syndrome Aldosteronism Licorice ingestion Volume expansion Inappropriate secretion of antidiuretic hormone Mineralocorticoid administration Corticosteroi d therapy Diuretics Aminophylline therapy FIGURE 7-12 Causes of moderate hypophosphatemia. (From Popovtzer, et al. [6]; wi th permission.)

Disorders of Phosphate Balance 7.7 CAUSES OF SEVERE HYPOPHOSPHATEMIA Acute renal failure: excessive P binders Chronic alcoholism and alcohol withdraw al Dietary deficiency and PO34-binding antacids Hyperalimentation Neuroleptic ma lignant syndrome Recovery from diabetic ketoacidosis Recovery from exhaustive ex ercise Kidney transplantation Respiratory alkalosis Severe thermal burns Therape utic hypothermia Reye's syndrome After major surgery Periodic paralysis Acute mala ria Drug therapy Ifosfamide Cisplatin Acetaminophen intoxication Cytokine infusi ons Tumor necrosis factor Interleukin-2 CAUSES OF HYPOPHOSPHATEMIA IN PATIENTS WITH NONKETOTIC HYPERGLYCEMIA OR DIABETIC KETOACIDOSIS Decreased net intestinal phosphate absorption Decreased phosphate intake Increased urinary phosphate excretion Glucosuria-induced osmotic diuresis Acidosis Acute movement of extracellular phosphate into the cells Insulin therapy FIGURE 7-14 Causes of hypophosphatemia in patients with nonketotic hyperglycemia or diabetic ketoacidosis. FIGURE 7-13 Causes of severe hypophosphatemia. (From Popovtzer, et al. [6]; with permission.) CAUSES OF HYPOPHOSPHATEMIA IN PATIENTS WITH ALCOHOLISM Decreased net intestinal phosphate absorption Poor dietary intake of phosphate and vitamin D Use of phosphate binders to treat recurring gastritis Chronic diarrhea CAUSES OF HYPOPHOSPHATEMIA IN PATIENTS WITH RENAL TRANSPLANTATION Acute movement of extracellular phosphate into the cells Insulin release induced by intravenous solutions containing dextrose Acute respi ratory alkalosis caused by alcohol withdrawal, sepsis, or hepatic cirrhosis Refe eding of the patient who is malnourished Increased urinary phosphate excretion Persistent hyperparathyroidism (hyperplasia or adenoma) Proximal tubular defect (possibly induced by glucocorticoids, cyclosporine, or both) Increased urinary phosphate excretion Alcohol-induced reversible proximal tubular defect Secondary hyperparathyroidism induced by vitamin D deficiency FIGURE 7-16 Causes of hypophosphatemia in patients with renal transplantation. FIGURE 7-15 Causes of hypophosphatemia in patients with alcoholism. FIGURE 7-17 Major consequences of hypophosphatemia. MAJOR CONSEQUENCES OF HYPOPHOSPHATEMIA Decreased erythrocyte 2,3-diphosphoglycerate levels, which result in increased a ffinity of hemoglobin for oxygen and reduced oxygen release at the tissue level Decreased intracellular adenosine triphosphate levels, which result in impairmen t of cell functions dependent on energy-rich phosphate compounds

7.8 Disorders of Water, Electrolytes, and Acid-Base SIGNS AND SYMPTOMS OF HYPOPHOSPHATEMIA Central nervous system dysfunction Metabolic encephalopathy owing to tissue ischemia Irritability Paresthesias Conf usion Delirium Coma Cardiac dysfunction Impaired myocardial contractility Congestive heart failure Pulmonary dysfunction Weakness of the diaphragm Respiratory failure Skeletal and smooth muscle dysfunction Proximal myopathy Dysphagia and ileus Rhabdomyolysis Hematologic dysfunction Bone disease Renal effects Decreased glomerular filtration rate Decreased tubular transport maximum for bic arbonate Decreased renal gluconeogenesis Decreased titratable acid excretion Hyp ercalciuria Hypermagnesuria Metabolic effects Low parathyroid hormone levels Increased 1,25-dihydroxy-vitamin D3 levels Increa sed creatinine phosphokinase levels Increased aldolase levels Erythrocytes Increased bone resorption Increased erythrocyte Rickets and osteori gidity malacia caused by decreased bone Hemolysis mineralization Leukocytes Impa ired phagocytosis Decreased granulocyte chemotaxis Platelets Defective clot retr action Thrombocytopenia FIGURE 7-18 Signs and symptoms of hypophosphatemia. (Adapted from Hruska and Sla topolsky [2] and Hruska and Gupta [7].) FIGURE 7-19 Pseudofractures (Looser's tran sformation zones) at the margins of the scapula in a patient with oncogenic oste omalacia. Similar to the genetic X-linked hypophosphatemic rickets, a circulatin g phosphaturic factor is believed to be released by the tumor, causing phosphate wasting and reduced calcitriol formation by the kidney. Note the radiolucent ri bbonlike decalcification extending into bone at a right angle to its axillary ma rgin. Pseudofractures are pathognomonic of osteomalacia with a low remodeling ra te. FIGURE 7-20 (see Color Plate) Histologic appearance of trabecular bone from a pa tient with oncogenic osteomalacia. Undecalcified bone section with impaired mine ralization and a wide osteoid (organic matrix) seam stained with von Kossa's stain is illustrated. Note the wide bands of osteoid around the mineralized bone. Abs ence of osteoblasts on the circumference of the trabecular bone portion indicate s a low remodeling rate.

Disorders of Phosphate Balance 7.9 FIGURE 7-21(see Color Plate) Microscopic appearance of bone section from a patie nt with vitamin D deficiency caused by malabsorption. The bone section was stain ed with Masson trichrome stain. Hypophosphatemia and hypocalcemia were present. Note the trabecular bone consisting of very wide osteoid areas (red) characteris tic of osteomalacia. USUAL DOSAGES FOR PHOSPHORUS REPLETION Severe symptomatic hypophosphatemia (plasma phosphate concentration < 1 mg/dL) 10 mg/kg/d, intravenously, until the plasma phosphate concentration reaches 2 mg /dL FIGURE 7-22 Usual dosages for phosphorus repletion. Phosphate depletion 24 g/d (64 to 128 mmol/d), orally, in 3 to 4 divided doses Hypophosphatemic rickets 14 g/d (32 to 128 mmol/d), orally, in 3 to 4 divided doses PHOSPHATE PREPARATIONS FOR ORAL USE Preparation K-Phos Neutral, tablet (Beach Pharmaceuticals, Conestee, SC) Neutra-Phos, capsule or 75-mL solution (Baker Norton Pharmaceuticals, Miami, FL) Neutra-Phos K, capsul e or 75-mL solution (Baker Norton Pharmaceuticals, Miami, FL) FIGURE 7-23 Phosphate preparations for oral use. Phosphate, mg 250 250 250 Sodium, mEq 13 7.1 0 Potassium, mEq 1.1 7.1 14.2 PHOSPHATE PREPARATIONS FOR INTRAVENOUS USE Phosphate, mmol/mL 3.0 3.0 0.09 1.10 FIGURE 7-24 Phosphate preparations for intravenous use. (From Popovtzer, et al. [6]; with permission.) Sodium, mEq/mL 0 4.0 0.2 0.2 Phosphate preparation Potassium Sodium Neutral sodium Neutral sodium, potassium Composition, mg/mL 236 mg K2HPO4 224 mg KH2PO4 142 mg Na2HPO4 276 mg NaH2HPO4.H2O 10.0 mg Na2HPO 2. 7 mg NaH2PO4.H2O 11.5 mg Na2HPO4 2.6 mg KH2PO4 Potassium, mEq/mL 4.4 0 0 0.02 3 mmol/mL of phosphate corresponds to 93 mg of phosphorus.

7.10 Disorders of Water, Electrolytes, and Acid-Base CAUSES OF HYPERPHOSPHATEMIA Pseudohyperphosphatemia Multiple myeloma Extreme hypertriglyceridemia In vitro hemolysis Increased endogenous loads Tumor lysis syndrome Rhabdomyolysis Bowel infarction Malignant hyperthermia Heat stroke Acid-base disorders Organic acidosis Lactic acidosis Ketoacidosis Respir atory acidosis Chronic respiratory alkalosis Reduced urinary excretion Renal failure Hypoparathyroidism Hereditary Acquired Pseudohypoparathyroidism Vi tamin D intoxication Growth hormone Insulin-like growth factor-1 Glucocorticoid withdrawal Mg2+ deficiency Tumoral calcinosis Diphosphonate therapy Hyopophospha tasia Miscellaneous Fluoride poisoning -Blocker therapy Verapamil Hemorrhagic shock Sleep deprivatio n Increased exogenous phosphorus load or absorption Phosphorus-rich cow's milk in premature neonates Vitamin D intoxication PO34-conta ining enemas Intravenous phosphorus supplements White phosphorus burns Acute pho sphorus poisoning FIGURE 7-25 Causes of hyperphosphatemia. (From Knochel and Agarwal [5]; with per mission.) CLINICAL MANIFESTATIONS OF HYPERPHOSPHATEMIA Consequences of secondary changes in calcium, parathyroid hormone, vitamin D met abolism and hypocalcemia: Neuromuscular irritability Tetany Hypotension Increased QT interval TREATMENT OF HYPERPHOSPHATEMIA Acute hyperphosphatemia in patients with adequate renal function Chronic hyperph osphatemia in patients with end-stage renal disease Dietary phosphate restriction Phosphate binders to decrease gastrointestinal pho sphate reabsorption Consequences of ectopic calcification: Periarticular and soft tissue calcification Vascular calcification Ocular calcif ication Conduction abnormalities Pruritus Saline diuresis that causes phosphaturia FIGURE 7-27 Treatment of hyperphosphatemia. FIGURE 7-26 Clinical manifestations of hyperphosphatemia.

Disorders of Phosphate Balance 7.11 A FIGURE 7-28 Periarticular calcium phosphate deposits in a patient with endstage renal disease who has severe hyperphosphatemia and a high level of the product o f calcium and phosphorus. Note the partial B resolution of calcific masses after dietary phosphate restriction and oral phosp hate binders. Left shoulder joint before (A) and after (B) treatment. (From Ping gera and Popovtzer [17]; with permission.) A FIGURE 7-29 Resolution of soft tissue calcifications. The palms of the hands of the patient in Figure 7-28 with end-stage renal disease are shown before (A) and after (B) treatment of hyperphosphatemia. The B patient has a high level of the product of calcium and phosphorus. (From Pingger a and Popovtzer [17]; with permission.)

7.12 Disorders of Water, Electrolytes, and Acid-Base A B FIGURE 7-30 A, B, Bone sections from the same patient as in Figures 7-28 and 7-2 9, illustrating osteitis fibrosa cystica caused by renal secondary hyperparathyr oidism with hyperphosphatemia. FIGURE 7-31 Roentgenographic appearance of femoral arterial vascular calcificati on in a patient on dialysis who has severe hyperphosphatemia. The patient has a high level of the product of calcium and phosphorus. FIGURE 7-32 (see Color Plate) Microscopic appearance of a cross section of a cal cified artery in a patient with end-stage renal disease undergoing chronic dialy sis. The patient has severe hyperphosphatemia and a high level of the product of calcium and phosphorus. Note the intimal calcium phosphate deposit with a secon dary occlusion of the arterial lumen. FIGURE 7-33 Massive periarticular calcium phosphate deposit (around the hip join t) in a patient with genetic tumoral calcinosis. The patient exhibits hyperphosp hatemia and increased renal tubular phosphate reabsorption. Normal parathyroid h ormone levels and elevated calcitriol levels are present. The same disease affec ts two of the patient's brothers.

Disorders of Phosphate Balance 7.13 FIGURE 7-34 Massive periarticular calcium phosphate deposit in the plantar joint s in the same patient in Figure 7-33 who has genetic tumoral calcinosis. FIGURE 7-35 (see Color Plate) Complications of the use of aluminum-based phospha te binders to control hyperphosphatemia. Appearance of bone section from a patie nt with end-stage renal disease who was treated with oral aluminum gels to contr ol severe hyperphosphatemia. A bone biopsy was obtained 6 months after a parathy roidectomy was performed. Note the wide areas of osteoid filling previously reso rbed bone. FIGURE 7-36 (see Color Plate) The same bone section as in Figure 7-35 but under polarizing lenses, illustrating the partially woven appearance of osteoid typica l of chronic renal failure. FIGURE 7-37 (see Color Plate) The same bone section as in Figure 7-35 with posit ive aluminum stain of the trabecular surface. These findings are consistent with aluminum-related osteomalacia. Acknowledgments The authors thank Sandra Nickerson and Teresa Autrey for secretarial assistance and the Medical Media Department at the Dallas VA Medical Center for the illustr ations.

7.14 Disorders of Water, Electrolytes, and Acid-Base References 1. 2. Agus ZS: Phosphate metabolism. In UpToDate, Inc.. Edited by Burton D. Rose , 1998. Hruska KA, Slatopolsky E: Disorders of phosphorus, calcium, and magnesiu m metabolism. In Diseases of the Kidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little and Brown; 1997. Levi M, Knochel JP: The management of disor ders of phosphate metabolism. In Therapy of Renal Diseases and Related Disorders . Edited by Massry SG, Suki WN. Boston, Martinus Nijhoff; 1990. Levi M, Cronin R E, Knochel JP: Disorders of phosphate and magnesium metabolism. In Disorders of Bone and Mineral Metabolism. Edited by Coe FL, Favus MJ. New York: Raven Press; 1992. Knochel JP, Agarwal R: Hypophosphatemia and hyperphosphatemia. In The Kidn ey, edn 5. Edited by Brenner BM. Philadelphia: WB Saunders; 1996. Popovtzer M, K nochel JP, Kumar R: Disorders of calcium, phosphorus, vitamin D, and parathyroid hormone activity. In Renal Electrolyte Disorders, edn 5. Edited by Schrier RW. Philadelphia: LippincottRaven; 1997. Hruska K, Gupta A: Disorders of phosphate h omeostasis. In Metabolic Bone Disease, edn 3. Edited by Avioli LV, SM Krane. New York: Academic Press; 1998. Murer H, Biber J: Renal tubular phosphate transport : cellular mechanisms. In The Kidney: Physiology and Pathophysiology, edn 2. Edi ted by Seldin DW, Giebisch G. New York: Raven Press; 1997. Berndt TJ, Knox FG: R enal regulation of phosphate excretion. In The Kidney: Physiology and Pathophysi ology, edn 2. Edited by Seldin DW, Giebisch G. New York: Raven Press; 1992. 10. Suki WN, Rouse D: Renal Transport of calcium, magnesium, and phosphate. In The K idney, edn 5. Edited by Brenner BM. Philadelphia: WB Saunders; 1996. 11. Levi M, Kempson, SA, Ltscher M, et al.: Molecular regulation of renal phosphate transpor t. J Membrane Biol 1996, 154:19. 12. Levi M, Ltscher M, Sorribas V, et al.: Cellul ar mechanisms of acute and chronic adaptation of rat renal phosphate transporter to alterations in dietary phosphate. Am J Physiol 1994, 267:F900F908. 13. Kempso n SA, Ltscher M, Kaissling B, et al.: Effect of parathyroid hormone on phosphate transporter mRNA and protein in rat renal proximal tubules. Am J Physiol 1995, 2 68:F784F791. 14. Ltscher M, Biber J, Murer H, et al.: Role of microtubules in the rapid upregulation of rat renal proximal tubular Na-Pi cotransport following die tary P restriction. J Clin Invest 1997, 99:13021312. 15. Levi M, Baird B, Wilson P: Cholesterol modulates rat renal brush border membrane phosphate transport. J Clin Invest 1990, 85:231237. 16. Levi M, Shayman J, Abe A, et al.: Dexamethasone modulates rat renal brush border membrane phosphate transporter mRNA and protein abundance and glycosphingolipid composition. J Clin Invest 1995, 96:207216. 17. Pinggera WF, Popovtzer MM: Uremic osteodystrophy: the therapeutic consequences o f effective control of serum phosphorus. JAMA 1972, 222:16401642. 3. 4. 5. 6. 7. 8. 9.

Acute Renal Failure: Causes and Prognosis Fernando Liao Julio Pascual T here are many causesmore than fifty are given within this present chapterthat can trigger pathophysiological mechanisms leading to acute renal failure (ARF). This syndrome is characterized by a sudden decrease in kidney function, with a conse quence of loss of the hemostatic equilibrium of the internal medium. The primary marker is an increase in the concentration of the nitrogenous components of blo od. A second marker, oliguria, is seen in 50% to 70% of cases. In general, the c auses of ARF have a dynamic behavior as they change as a function of the economi cal and medical development of the community. Economic differences justify the d ifferent spectrum in the causes of ARF in developed and developing countries. Th e setting where ARF appears (community versus hospital), or the place where ARF is treated (intensive care units [ICU] versus other hospital areas) also show di fferences in the causes of ARF. While functional outcome after ARF is usually go od among the surviving patients, mortality rate is high: around 45% in general s eries and close to 70% in ICU series. Although it is unfortunate that these mort ality rates have remained fairly constant over the past decades, it should be no ted that today's patients are generally much older and display a generally much mo re severe condition than was true in the past. These age and severity factors, t ogether with the more aggressive therapeutical possibilities presently available , could account for this apparent paradox. As is true for any severe clinical co ndition, a prognostic estimation of ARF is of great utility for both the patient s and their families, the medical specialists (for analysis of therapeutical man euvers and options), and for society in general (demonstrating the monetary cost s of treatment). This chapter also contains a brief review of the prognostic too ls available for application to ARF. CHAPTER 8

8.2 Acute Renal Failure Causes of Acute Renal Failure Sudden causes affecting Renal perfusion Induce Called A c u t e r e n a l f a i l u r e CAUSES OF PARENCHYMATOUS ACUTE RENAL FAILURE Acute tubular necrosis Hemodynamic: cardiovascular surgery,* sepsis,* prerenal c auses* Toxic: antimicrobials,* iodide contrast agents,* anesthesics, immunosuppr essive or antineoplastic agents,* Chinese herbs, Opiaceous, Extasis, mercurials, organic solvents, venoms, heavy metals, mannitol, radiation Intratubular deposi ts: acute uric acid nephropathy, myeloma, severe hypercalcemia, primary oxalosis , sulfadiazine, fluoride anesthesics Organic pigments (endogenous nephrotoxins): Myoglobin rhabdomyolisis: muscle trauma; infections; dermatopolymyositis; metab olic alterations; hyperosmolar coma; diabetic ketoacidosis; severe hypokalemia; hyper- or hyponatremia; hypophosphatemia; severe hypothyroidism; malignant hyper thermia; toxins such as ethylene glycol, carbon monoxide, mercurial chloride, st ings; drugs such as fibrates, statins, opioids and amphetamines; hereditary dise ases such as muscular dystrophy, metabolopathies, McArdle disease and carnitine deficit Hemoglobinuria: malaria; mechanical destruction of erythrocytes with ext racorporeal circulation or metallic prosthesis, transfusion reactions, or other hemolysis; heat stroke; burns; glucose-6-phosphate dehydrogenase; nocturnal paro xystic hemoglobinuria; chemicals such as aniline, quinine, glycerol, benzene, ph enol, hydralazine; insect venoms Acute tubulointerstitial nephritis (see Fig. 84) Vascular occlusion Principal vessels: bilateral (unilateral in solitary funct ioning kidney) renal artery thrombosis or embolism, bilateral renal vein thrombo sis Small vessels: atheroembolic disease, thrombotic microangiopathy, hemolyticuremic syndrome or thrombotic thrombocytopenic purpura, postpartum acute renal f ailure, antiphospholipid syndrome, disseminated intravascular coagulation, scler oderma, malignant arterial hypertension, radiation nephritis, vasculitis Acute g lomerulonephritis Postinfectious: streptococcal or other pathogen associated wit h visceral abscess, endocarditis, or shunt Henoch-Schonlein purpura Essential mi xed cryoglobulinemia Systemic lupus erythematosus ImmunoglobulinA nephropathy Me sangiocapillary With antiglomerular basement membrane antibodies with lung disea se (Goodpasture is syndrome) or without it Idiopathic, rapidly progressive, with out immune deposits Cortical necrosis, abruptio placentae, septic abortion, diss eminated intravascular coagulation Prerenal Parenchymal structures GFR Parenchymatous Urine output Obstructive FIGURE 8-1 Characteristics of acute renal failure. Acute renal failure is a synd rome characterized by a sudden decrease of the glomerular filtration rate (GFR) and consequently an increase in blood nitrogen products (blood urea nitrogen and creatinine). It is associated with oliguria in about two thirds of cases. Depen ding on the localization or the nature of the renal insult, ARF is classified as prerenal, parenchymatous, or obstructive (postrenal). CAUSES OF PRERENAL ACUTE RENAL FAILURE

Decreased effective extracellular volume Renal losses: hemorrhage, vomiting, dia rrhea, burns, diuretics Redistribution: hepatopathy, nephrotic syndrome, intesti nal obstruction, pancreatitis, peritonitis, malnutrition Decreased cardiac outpu t: cardiogenic shock, valvulopathy, myocarditis, myocardial infarction, arrhythm ia, congestive heart failure, pulmonary emboli, cardiac tamponade Peripheral vas odilation: hypotension, sepsis, hypoxemia, anaphylactic shock, treatment with in terleukin L2 or interferons, ovarian hyperstimulation syndrome Renal vasoconstri ction: prostaglandin synthesis inhibition, -adrenergics, sepsis, hepatorenal syn drome, hypercalcemia Efferent arteriole vasodilation: converting-enzyme inhibito rs FIGURE 8-2 Causes of prerenal acute renal failure (ARF). Prerenal ARF, also know n as prerenal uremia, supervenes when glomerular filtration rate falls as a cons equence of decreased effective renal blood supply. The condition is reversible i f the underlying disease is resolved. FIGURE 8-3 Causes of parenchymal acute renal failure (ARF). When the sudden decr ease in glomerular filtration rate that characterizes ARF is secondary to intrin sic renal damage mainly affecting tubules, interstitium, glomeruli and/or vessel s, we are facing a parenchymatous ARF. Multiple causes have been described, some of them constituting the most frequent ones are marked with an asterisk.

Acute Renal Failure: Causes and Prognosis 8.3 MOST FREQUENT CAUSES OF ACUTE TUBULOINTERSTITIAL NEPHRITIS CAUSES OF OBSTRUCTIVE ACUTE RENAL FAILURE Antimicrobials Penicillin Ampicillin Rifampicin Sulfonamides Analgesics, anti-in flammatories Fenoprofen Ibuprofen Naproxen Amidopyrine Glafenine Other drugs Cim etidine Allopurinol Immunological Systemic lupus erythematosus Rejection Infections (at present quit e rare) Neoplasia Myeloma Lymphoma Acute leukemia Idiopathic Isolated Associated with uveitis Congenital anomalies Ureterocele Bladder diverticula Posterior urethral valves N eurogenic bladder Acquired uropathies Benign prostatic hypertrophy Urolithiasis Papillary necrosis Iatrogenic ureteral ligation Malignant diseases Prostate Blad der Urethra Cervix Colon Breast (metastasis) Retroperitoneal fibrosis Idiopathic Associated with aortic aneurysm Trauma Iatro genic Drug-induced Gynecologic non-neoplastic Pregnancy-related Uterine prolapse Endometriosis Acute uric acid nephropathy Drugs -Aminocaproic acid Sulfonamides Infections Schistosomiasis Tuberculosis Candidiasis Aspergillosis Actinomycosis Other Accidental urethral catheter occlusion FIGURE 8-4 Most common causes of tubulointerstitial nephritis. During the last y ears, acute tubulointerstitial nephritis is increasing in importance as a cause of acute renal failure. For decades infections were the most important cause. At present, antimicrobials and other drugs are the most common causes. FIGURE 8-5 Causes of obstructive acute renal failure. Obstruction at any level o f the urinary tract frequently leads to acute renal failure. These are the most frequent causes. FIGURE 8-6 This figure shows a comparison of the percentages of the different types of acute renal failure (ARF) in a western European country in 19771980 and 1991: A, distribution in a typical Madrid hospital; B, the Madrid ARF Study [1]. There are two main differences: 1) the appearance of a new group in 1991, acute on chronic ARF, in which only mild forms (serum creatinine concent rations between 1.5 and 3.0 mg/dL) were considered, for methodological reasons; 2) the decrease in prerenal ARF suggests improved medical care. This low rate of prerenal ARF has been observed by other workers in an intensive care setting [2 ]. The other types of ARF remain unchanged. FIGURE 8-7 Incidences of different f orms of acute renal failure (ARF) in the Madrid ARF Study [1]. Figures express c ases per million persons per year with 95% confidence intervals (CI). Arterial disease 2.5% ATN 43.1% Other parenchymal 6.4% Obstructive 3.4% ATN 45% Other parenchymal 4.5% ATIN 1.6% Arterial disease 1% Obstructive 10% Prerenal 40.6% Prerenal 21% Acute-on-chronic 13% A n = 202 19771980

B n = 748 1991 FINDINGS OF THE MADRID STUDY Condition Acute tubular necrosis Prerenal acute renal failure Acute on chronic renal failu re Obstructive acute renal failure Glomerulonephritis (primary or secondary) Acu te tubulointerstitial nephritis Vasculitis Other vascular acute renal failure To tal Incidence (per million persons per year) 88 46 29 23 6.3 3.5 3.5 2.1 209 95% CI 7997 4052 2434 1927 4.88.3 1.75.3 1.75.3 0.83.4 195223

8.4 Acute Renal Failure FIGURE 8-8 The most frequent causes of acute renal failure (ARF) in patients wit h preexisting chronic renal failure are acute tubular necrosis (ATN) and prerena l failure. The distribution of causes of ARF in these patients is similar to tha t observed in patients without previous kidney diseases. (Data from Liao et al. [ 1]) ATN 43% Other 15% Prerenal 27% Not recorded 15% Sclerodermal crisis 1 Tumoral obstruction 1 Secondary glomerulonephritis 1 Vascu litis 1 Malignant hypertension 2.1 Myeloma 2.1 Acute tubulointerstitial nephriti s 2.1 Atheroembolic disease 4.2 Bun/SCr increase Small kidneys and/or and/or Normal or big kidneys (excluding am iloidosis and polycystic kidney disease - SCr > 0.5 mg/dL/d Previous SCr normal FIGURE 8-9 Discovering the cause of acute renal failure (ARF). This is a great c hallenge for clinicians. This algorithm could help to determine the cause of the increase in blood urea nitrogen (BUN) or serum creatinine (SCr) in a given pati ent. - SCr < 0.5 mg/dL/d Previous SCr increased and/or and/or CRF ARF + Echography - SCr < 0.5 mg/dL/d Normal Flare of previous disease Acute-on-chronic r enal failure Urinary tract dilatation Repeat echograph after 24 h Normal No Parenchymatous glomerular or systemic ARF Vascular ARF Acute tubuloint erstitial nephritis Tumor lysis Sulfonamides Amyloidosis Other Data indicating g lomerular or systemic disease? Great or small vessel disease? Data indicating in terstitial disease? Crystals or tubular deposits? Prerenal factors? No Yes Obstr uctive ARF Yes Improvement with specific treatment? Yes Prerenal ARF Yes No Yes No Acute tubular necrosis Yes No No

Acute Renal Failure: Causes and Prognosis 8.5 BIOPSY RESULTS IN THE MADRID STUDY Disease Primary GN Extracapillary Acute proliferative Endocapillary and extracapillary F ocal sclerosing Secondary GN Antiglomerular basement membrane Acute postinfectio us Diffuse proliferative (systemic lupus erythematosus) Vasculitis Necrotizing W egener's granulomatosis Not specified Acute tubular necrosis Acute tubulointerstit ial nephritis Atheroembolic disease Kidney myeloma Cortical necrosis Malignant h ypertension ImmunoglobulinA GN + ATN Hemolytic-uremic syndrome Not recorded * On e patient with acute-on-chronic renal failure. Patients, n 12 6 3 2 1 6 3 2 1* 10 5* 3 2 4* 4 2 2* 1 1 1 1 2 FIGURE 8-10 Biopsy results in the Madrid acute renal failure (ARF) study. Kidney biopsy has had fluctuating roles in the diagnostic work-up of ARF. After extrar enal causes of ARF are excluded, the most common cause is acute tubular necrosis (ATN). Patients with well-established clinical and laboratory features of ATN r eceive no benefit from renal biopsy. This histologic tool should be reserved for parenchymatous ARF cases when there is no improvement of renal function after 3 weeks' evolution of ARF. By that time, most cases of ATN have resolved, so other causes could be influencing the poor evolution. Biopsy is mandatory when a poten tially treatable cause is suspected, such as vasculitis, systemic disease, or gl omerulonephritis (GN) in adults. Some types of parenchymatous non-ATN ARF might have histologic confirmation; however kidney biopsy is not strictly necessary in cases with an adequate clinical diagnosis such as myeloma, uric acid nephropath y, or some types of acute tubulointerstitial nephritis . Other parenchymatous fo rms of ARF can be accurately diagnosed without a kidney biopsy. This is true of acute post-streptococcal GN and of hemolytic-uremic syndrome in children. Kidney biopsy was performed in only one of every 16 ARF cases in the Madrid ARF Study [1]. All patients with primary GN, 90% with vasculitis and 50% with secondary GN were diagnosed by biopsy at the time of ARF. As many as 15 patients were diagno sed as having acute tubulointerstitial nephritis, but only four (27%) were biops ied. Only four of 337 patients with ATN (1.2%) underwent biopsy. (Data from Liao et al. [1].) Predisposing Factors for Acute Renal Failure Renal insult Advanced age Proteinuria 20% Volume depletion Myeloma Diuretic use 39% Diabetes mellitus Previous cardiac or renal insufficiency 48% 56% Very elder ly 11% Elderly 12% 11% 29% 30% Young 17% 7% 21% Other Obstructive Prerenal Acute tubular necrosis (n=103) (n=256) (n=389) Higher probability for ARF FIGURE 8-11 Factors that predispose to acute renal failure (ARF). Some of them a ct synergistically when they occur in the same patient. Advanced age and volume depletion are particularly important. FIGURE 8-12 Causes of acute renal failure (ARF) relative to age. Although the ca use of ARF is usually multifactorial, one can define the cause of each case as t he most likely contributor to impairment of renal function. One interesting appr

oach is to distribute the causes of ARF according to age. This figure shows the main causes of ARF, dividing a population diagnosed with ARF in to the very elderly (at least 80 years), elderly (65 to 79), and young (younger than 65). Essentially, acute tubular necrosis (ATN) is less frequent (P=0.004) a nd obstructive ARF more frequent (P<0.001) in the very old than in the youngest patients. Prerenal diseases appear with similar frequency in the three age group s. (Data from Pascual et al. [3].)

8.6 Acute Renal Failure Epidemiology EPIDEMIOLOGY Study Period 19651966 (2 19911992 (9 of Acute Renal Failure OF ACUTE RENAL FAILURE (Study Length) yrs) 19841986 (2 yrs) 19861988 (2 yrs) 19881989 (2 yrs) 19861987 (2 yrs) mo)

Investigator, Year Eliahou et al., 1973 [4] Abraham et al., 1989 [5] McGregor et al., 1992 [6] Sanc hez et al., 1992 [7] Feest et al., 1993 [8] Madrid ARF Study Group, 1996 [1] Country (City) Israel Kuwait United Kingdom (Glasgow) Spain (Cuenca) United Kingdom (Bristol an d Devon) Spain (Madrid) Study Population (millions) 2.2 0.4 0.94 0.21 0.44 4.23 Incidence (pmp/y) 52 95 185 254 175 209 FIGURE 8-13 Prospective studies. Prospective epidemiologic studies of acute rena l failure (ARF) in large populations have not often been published . The first s tudy reported by Eliahou and colleagues [4] was developed in Israel in the 1960s and included only Jewish patients. This summary of available data suggests a pr ogressive increase in ARF incidence that at present seems to have stabilized aro und 200 cases per million population per year (pmp/y). No data about ARF inciden ce are available from undeveloped countries. EPIDEMIOLOGY OF ACUTE RENAL FAILURE: NEED OF DIALYSIS Investigator, Year Lunding et al., 1964 [9] Eliahou et al., 1973 [4] Lachhein et al., 1978 [10] Win g et al., 1983 [11] Wing et al., 1983 [11] Abraham et al., 1989 [5] Sanchez et a l., 1992 [7] McGregor et al., 1992 [6] Gerrard et al., 1992 [12] Feest et al., 1 993 [8] Madrid ARF Study Group [1] * Very restrictive criteria. Only secondary care facilities. Country Scandinavia Israel West Germany European Dialysis and Transplant Association Spa in Kuwait Spain United Kingdom United Kingdom United Kingdom Spain Cases (pmp/y) 28 17* 30 29 59 31 21 31 71 22 57 FIGURE 8-14 Number of patients needing dialysis for acute renal failure (ARF), e xpressed as cases per million population per year (pmp/y). This has been another way of assessing the incidence of the most severe cases of ARF. Local situation s, mainly economics, have an effect on dialysis facilities for ARF management. I n 1973 Israeli figures showed a lower rate of dialysis than other countries at t he same time. The very limited access to dialysis in developing countries suppor ts this hypothesis. At present, the need for dialysis in a given area depends on the level of health care offered there. In two different countries (eg, the Uni ted Kingdom and Spain) the need for dialysis for ARF was very much lower when on ly secondary care facilities were available. At this level of health care, both countries had the same rate of dialysis. The Spanish data of the EDTA-ERA Regist ry in 1982 gave a rate of dialysis for ARF of 59 pmp/y. This rate was similar to

that found in the Madrid ARF Study 10 years later. These data suggest that, whe n a certain economical level is achieved, the need of ARF patients for dialysis tends to stabilize. HISTORICAL PATTERNS OF ACUTE RENAL FAILURE Proportion of Cases, % France 1973 Surgical Medical Obstetric 46 30 24 India 19651974 11 67 22 France 19811986 30 70 2 India 19811986 30 61 9 South Africa 19861988 8 77 15 FIGURE 8-15 Historical perspective of acute renal failure (ARF) patterns in Fran ce, India, and South Africa. In the 1960s and 1970s, obstetrical causes were a g reat problem in both France and India and overall incidences of ARF were similar . Surgical cases were almost negligible in India at that time, probably because of the relative unavailability of hospital facilities. During the 1980s surgical and medical causes were similar in both countries. In India, the increase in su rgical cases may be explained by advances in health care, so that more surgical procedures could be done. The decrease in surgical cases in France, despite the fact that surgery had become very sophisticated, could be explained by better ma nagement of surgical patients. (Legend continued on next page)

Acute Renal Failure: Causes and Prognosis FIGURE 8-15 (Continued) Changes in classification criteriainclusion of a larger p ercentage of medical cases than a decade beforecould be an alternative explanatio n. In addition, obstetric cases had almost disappeared in France in the 1980s, b ut they were still an important cause of ARF in India. In a South African study that excluded the white population the distribution of ARF causes was almost ide ntical to that observed in India 20 years earlier. In conclusion, 1) the economi c 8.7 level of a country determines the spectrum of ARF causes observed; 2) when a dev eloping country improves its economic situation, the spectrum moves toward that observed in developed countries; and 3) great differences can be detected in ARF causes among developing countries, depending on their individual economic power . (Data from Kleinknecht [13]; Chugh et al. [14]; Seedat et al. [15].) 25 Percentage of total ARF cases 20 15 10 5 0 19651974 19751980 Years 19811986 Diarrhea HD 68% Hemolysis HD 60% UF 1% PD 5% Obstetric CRRT 1% PD 31% EDTA (1982) CRRT 33% Madrid study (1992) A 2221 patients B 270 patients FIGURE 8-16 Changing trends in the causes of acute renal failure (ARF) in the Th ird-World countries. Trends can be identified from the analysis of medical and o bstetric causes by the Chandigarh Study [14]. Chugh and colleagues showed how ob stetric (septic abortion) and hemolytic (mainly herbicide toxicity) causes tende d to decrease as economic power and availability of hospitalization improved wit h time. These causes of ARF, however, did not completely disappear. By contrast, diarrheal causes of ARF, such as cholera and other gastrointestinal diseases, r emained constant. In conclusion, gastrointestinal causes of ARF will remain impo rtant in ARF until structural and sanitary measures (eg, water treatment) are im plemented. Educational programs and changes in gynecological attention, focused on controlled medical abortion and contraceptive measures, should be promoted to eradicate other forms of ARF that constitute a plague in Third World countries. FIGURE 8-17 Evolution of dialysis techniques for acute renal failure (ARF) in Sp ain. A, The percentages of different modalities of dialysis performed in Spain i n the early 1980s. B, The same information obtained a decade. At this latter tim e, 90% of conventional hemodialysis (HD) was performed using bicarbonate as a bu

ffer. These rates are those of a developed country. In developing countries, dia lysis should be performed according to the available facilities and each individ ual doctor's experience in the different techniques. PDperitoneal dialysis; CRRTcont inuous renal replacement technique; UFisolated ultrafiltration. (A, Data from the EDTA-ERA Registry [11]; B data from the Madrid ARF Study [1].) Hospital-Related Epidemiologic Data 60 50 40 30 20 10 0 % P<0.001 FIGURE 8-18 Serum creatinine (SCr) at hospital admission has diagnostic and prog nostic implications for acute renal failure (ARF). A, Of the patients included i n an ARF epidemiologic study 39% had a normal SCr concentration (less than 1.5 m g/dL) at hospital admission. It is worth noting that only 22% of the patients ha d clearly established ARF (SCr greater than 3 mg/dL) when admitted (no acute-onchronic case was included). Mortality was significantly higher in patients with normal SCr at admission. (Continued on next page) Mortality A SCr<1.5 mg/dL Mortality SCr>3.0 mg/dL

8.8 Acute Renal Failure FIGURE 8-18 (Continued) B, With the same two groups, acute tubular necrosis (ATN ) predominated among the hospital-induced ARF group, whereas the obstructive for m was the main cause of community-acquired ARF. In conclusion, the hospital coul d be considered an ARF generator, particularly of the most severe forms. Nonethe less, these iatrogenic ARF cases are usually innocent, and are an unavoidable cons equence of diagnostic and therapeutic maneuvers. (Data from Liao et al. [1].) ARF ATN Prerenal Obstructive Total Community-acquired (SCr at admission>3 mg/dL) 41.8 47.5 77.3 49.7 Hospital-acquired (SCr at admission<1.5 mg/dL) 58.2 52.5 22.7 50.3 B ICUs 27% Trauma 2% Nephrology 13% Surgical dept. 23% Mortality, % Medical dept. 34% 80 70 60 50 40 30 20 10 0 All cases ICUs Medical Surgical *P<0.001 respect to al l cases * Nephrol A Gynecology 1% B FIGURE 8-19 Acute renal failure: initial hospital location and mortality. A, Ini tial departmental location of ARF patients in a hospital in a Western country. T he majority of the cases initially were seen in medical, surgical, and intensive care units (ICUs). The cases initially treated in nephrology departments were c ommunity acquired, whereas the ARF patients in the other settings generally acqu ired ARF in those settings. Obstetric-gynecologic ARF cases have almost disappea red. ARF of traumatic origin is also rare, for two reasons: 1) polytrauma patients are now treated in the ICU and 2) early and effective treatments applied today to trauma patients at the accident scene, and quick transfer to hospital, have decreased this cause of ARF. B, Mortality was greater for patients initially treated in the ICU and lower in the nephrology se tting than rates observed in other departments. These figures were obtained from 748 ARF patients admitted to 13 different adult hospitals. (Data from Liao et al . [1].) FIGURE 8-20 Epidemiologic variable. The incidence of hospital-acquired a cute renal failure (ARF) depends on what epidemiologic method is used. In case-c ontrol studies the incidence varied between 49 and 19 per thousand. When the rea l occurrence was measured in large populations over longer intervals, the incide nce of hospital-acquired ARF decreased to 1.5 per thousand admissions. (Data fro m [1,5,16,17,18].) EPIDEMIOLOGIC VARIABLES

Acute Renal Failure in Hospitalized Patients (per 1000 admissions) 49.0 19.0 16.0 6.5 1.3 1.5 Investigator, Year Hou et al., 1983* Shusterman et al., 1987* Lauzurica et al., 1989* First period Second period Abraham et al., 1989 Madrid Study, 1992 * Case-control studies.

Acute Renal Failure: Causes and Prognosis 8.9 Prognosis HISTORICAL PERSPECTIVE OF MEDICAL PROGNOSIS APPLIED IN ACUTE RENAL FAILURE Criteria Classical Traditional Present Derivation Doctor's experience Univariate statistical analysis Multivariate statistical analy sis Computing facilities Multivariate analysis Computing facilities Applications Individual prognosis Risk stratification Risk stratification Individual prognosi s? Risk stratification Individual prognosis Patient's quality of life evaluation F unctional prediction Advantages Easy Easy Measurable Theoretically, all factors influencing outcome are considered Measurable All factors considered Drawbacks Doctor's inexperience Unmeasurable Only one determinant of prognosis is considered Complexity (variable, depending on model) Future Ideally, none FIGURE 8-21 Estimating prognosis. The criteria for estimating prognosis in acute renal failure can be classified into four periods. The Classical or heuristic w ay is similar to that used since the Hippocratic aphorisms. The Traditional one based on simple statistical procedures, is not useful for individual prognosis. The Present form is more or less complex, depending on what method is used, and it is possible, thanks to computing facilities and the development of multivariable analysis. Theoretically, few of these methods can g ive an individual prognosis [19]. They have not been used for triage. The next s tep will need a great deal of work to design and implement adequate tools to str atify risks and individual prognosis. In addition, the estimate of residual rena l function and survivors' quality of life, mainly for older people, are future cha llenges. Renal insult 100 80 Mortality, % 60 40 20 0 Prognosis Cumulative trend Mean ARF Outcome 11 10 2 3 3 1 6 34 5 2 7 11

16 57 8 5 9 20 13 11 131110 10 8 Number 9 6 55 478 6 5 64 5 of 3 2 publications 75 80 85 199 0 1951 55 60 65 70 Year FIGURE 8-22 Ideally, prognosis should be established as the problem, the episode of acute renal failure (ARF), starts. Correct prognostic estimation gives the r eal outcome for a patient or group of patients as precisely as possible. In this ideal scenario, this fact is illustrated by giving the same surface area for th e concepts of outcome and prognosis. FIGURE 8-23 Mortality trends in acute renal failure (ARF). This figure shows the evolution of mortality during a 40-year period, starting in 1951. The graphic w as elaborated after reviewing the outcome of 32,996 ARF patients reported in 258 published papers. As can be appreciated, mortality rate increases slowly but co nstantly during this follow-up, despite theoretically better availability of the rapeutic armamentarium (mainly antibiotics and vasoactive drugs), deeper knowled ge of dialysis techniques, and wider access to intensive care facilities. This i mprovement in supporting measures allows the physician to keep alive, for longer periods of time patients who otherwise would have died. A complementary explana tion could be that the patients treated now are usually older, sicker, and more likely to be treated more aggressively. (From Kierdorf et al. [20]; with permiss ion.)

8.10 Acute Renal Failure Prognostic systems used in ARF ICU methods Specific ARF methods Apache system SAPS MPM OSF Liano APACHE II APACHE III SAPS I SAPS II MPM I MPM II OSF MODS SOFA Rasmussen Lohr Schaefer Brivet FIGURE 8-24 Ways of estimating prognosis in acute renal failure (ARF). This can be done using either general intensive care unit (ICU) score systems or methods developed specifically for ARF patients. ICU systems include Acute Physiological and Chronic Health Evaluation (APACHE) [21,22], Simplified Physiologic Score (S APS)[23,24], Mortality Prediction Model (MPM) [25,26], and Organ System Failure scores (OSF) [27]. Multiple Organ Dysfunction Score (MODS) [28] and Sepsis-Related Organ Failure Assessment Score (SOFA) [29] are those that seem mo st suitable for this purpose. APACHE II used to be most used. Other systems (whi te boxes) have been used in ARF. On the other hand, at least 17 specific ARF pro gnostic methods have been developed [20,30]. The figure shows only those that ha ve been used after their publication [31], plus one recently published system wh ich is not yet in general use [2]. prognostic methods usually employed in the IC U setting. The best curve comes from the APACHE III method, which has an area un

der the ROC curve of 0.74 0.04 (SE). B, Four ROC curves corresponding to prognos tic methods specifically developed for ARF patients are depicted. The best curve in this panel comes from the Liao method for ARF prognosis. Its area under the c urve is 0.78 0.03 (SE). APACHEAcute Physiology and Chronic Health Evaluation, (II second version [21]; III third version [22]); SAPSSimplified Acute Physiology Sc ore [23]; SAPS-R SAPS-reduced [33]; SAPS-ESAPSExtended [32]; SSSickness Score [33]; MPMMortality Prediction Model [25]; ROC curveReceiving Operating Characteristic c urve; SEStandard Error. (From Douma [31]; with permission.) 100 80 Sensitivity, % 60 40 20 APACHE II APACHE III SAPS SAPS-R SAPS-E SS MPM 100 80 60 40 20 Rasmussen Liao Lohr Schaefer 0 0 20 0 40 60 1- Specificity, % 80 100 0 20 A B 40 60 80 1- Specificity, % 100 FIGURE 8-25 Comparison of prognostic methods for acute renal failure (ARF) by RO C curve analysis [31]. A method is better when its ROC-curve moves to the upper left square determined by the sensitivity and the reciprocal of the specificity. A, ROC curves of seven

Acute Renal Failure: Causes and Prognosis 8.11 Cumulative frequencies of resolved cases, % ACUTE RENAL FAILURE: VARIABLES STUDIED WITH UNIVARIATE ANALYSIS Age Jaundice Sepsis Burns Trauma NSAIDs BUN increments Coma Oliguria Obstetric o rigin Malignancies Cardiovascular disease X-ray contrast agents Acidosis Hypoten sion Catabolism Hemolysis Hepatic disease Kind of surgery Hyperkalemia Need for dialysis Assisted respiration Site of war injuries Disseminated intravascular co agulopathy Pancreatitis Antibiotics Timing of treatment 100 Nonsurvivors 8 patients to chronic hemodialysis 80 60 40 20 0 1 Survivors 5 10 15 20 25 30 35 40 Days of ARF evolution 45 50 55 60 FIGURE 8-26 Individual factors that have been associated with acute renal failur e (ARF) outcome. Most of these innumerable variables have been related to an adv erse outcome, whereas few (nephrotoxicity as a cause of ARF and early treatment) have been associated with more favorable prognosis. For a deep review of variab les studied with univariate statistical analysis [34, 35]. NSAIDnonsteroidal anti inflammatory drugs; BUNblood urea nitrogen. FIGURE 8-27 Duration and resolution of acute renal failure (ARF). Most of the ep isodes of ARF resolved in the first month of evolution. Mean duration of ARF was 14 days. Seventy-eight percent of the patients with ARF who died did so within 2 weeks after the renal insult. Similarly, 60% of survivors had recovered renal function at that time. After 30 days, 90% of the patients had had a final resolu tion of the ARF episode, one way or the other. Patients who finally lost renal f unction and needed to be included in a chronic periodic dialysis program usually had severe forms of glomerulonephritis, vasculitis, or systemic disease. (From Liao et al. [1]; with permission.) 80 Mortality, % ARF patients, % 60 40 20 0 100 80 60 40 20 0 Persistent hypotension 100 Mortality, % 80 60

Assisted repiration 80 69 P<0.001 33 P<0.001 40 20 0 32 Yes No Yes No n A res ssis pir ted ati on Jau nd ice co No nsc rm iou al sne ss Sed ati on Co ma ten sio Ol igu 100 Mortality, % 80 60 40 20 0 Yes 67 Jaundice 100 Mortality, % 80 60 40 20 0 No Yes 52 Oliguria ria Hy po P<0.001 40 FIGURE 8-28 Precipitating condition of acute renal failure (ARF). The initial cl inical condition observed in ARF patients is shown. Oliguria: urine output of le ss than 400 mL per day; hypotension: systolic blood pressure lower than 100 mm H g for at least 10 hours per day independent of the use of vasoactive drugs; jaun dice: serum bilirubin level higher than 2 mg/dL; coma: Glasgow coma score of 5 o r less. The presence of these factors is associated with poorer outcome (see Fig . 8-29). (Data from Liao et al. [1].) P<0.02 36

No FIGURE 8-29 Mortality associated with the presence or absence of oliguria, persi stent hypotension, assisted respiration and jaundice (as defined in Fig. 8-28). The presence of an unfavorable factor was significantly associated with higher m ortality. (Data from Liao et al. [1].)

8.12 100 80 Mortality rate, % 60 Acute Renal Failure FIGURE 8-30 Consciousness level and mortality. Coma patients had a Glasgow coma score of 5 or lower. Sedation refers to the use of this kind of treatment, prima rily in patients with assisted respiration. Both situations are associated with significantly higher mortality (P<0.001) than that observed in either patients w ith a normal consciousness level or the total population. (Data from Liao et al. [1].) 92 77 45 40 20 0 30 Normal Sedation Coma All cases 2 Original disease 1 Previous health condition 3 Kind and severity of kidney insult FIGURE 8-31 Outcome of acute renal failure (ARF). Two groups of factors play a r ole on ARF outcome. The first includes factors that affect the patient: 1) previ ous health condition; 2) initial diseaseusually, the direct or indirect (eg, trea tments) cause of kidney failure; 3) the kind and severity of kidney injury. Whil e 1 is a conditioning element, 2 and 3 trigger the second group of factors: the response of the patient to the insult. If this response includes a systemic infl ammatory response syndrome (SIRS) like that usually seen in intensive care patie nts (eg, sepsis, pancreatitis, burns), a multiple organ dysfunction syndrome (MO DS) frequently appears and consequently outcome is associated with a higher fata lity rate (thick line). On the contrary, if SIRS does not develop and isolated A RF predominates, death (thin line, right) is less frequent than survival (thick line). SIR S Depending on 2 and 3 No SIR S Isolated ARF ARF in a MODS complex Death Depending on: *2,3, & 1 *No. of failing organs *Recovery process Recovery

Recovery

Acute Renal Failure: Causes and Prognosis 8.13 INDIVIDUAL SEVERITY INDEX ISI=0.032 (age-decade) 0.086 (male) 0.109 (nephrotoxic) 0.109 (oliguria) 0.116 ( hypotension) 0.122 (jaundice) 0.150 (coma) 0.154 (consciousness) 0.182 (assisted respiration) 0.210 Case example A 55-year-old man was seen because of oliguria following pancreatic surgery. At that moment he was hypotensive and connected to a respirator, and jaundice was evident. He was diagnosed with acute tubular nec rosis. His ISI was calculated as follows: ISI=0.032(6) 0.086 0.109 0.116 0.122 0 .182 0.210 = 0.845 FIGURE 8-32 Individual severity index (ISI). The ISI was published in its second version in 1993 [36]. The ISI estimates the probability of death. Nephrotoxic i ndicates an ARF of that origin; the other variables have been defined in precedi ng figures. The numbers preceding these keys denote the contribution of each one to the prognosis and are the factor for multiplying the clinical variables; 0.2 10 is the equation constant. Each clinical variable takes a value of 1 or 0, dep ending, respectively, on its presence or absence (with the exception of the age, which takes the value of the patient's decade). The parameters are recorded when the nephrologist sees the patient the first time. Calculation is easy: only a ca rd with the equation values, a pen, and paper are necessary. A real example is g iven. ATN 6 6 Acute GN 11 11 32 32 35 Partial recovery 24 No recovery 47 No recovery Partial recovery 31 31 63 63 24 29 5 yr Total recovery 57 57 41 5 yr 1 yr HUS/ACN 8 25 63 No recovery 91 Total recovery 1 yr Acute TIN 25 No recovery Partial recovery 75 FIGURE 8-33 Outcome of acute renal failure (ARF). Long-term outcome of ARF has b een studied only in some series of intrinsic or parenchymatous ARF. The figure s hows the different long-term prognoses for intrinsic ARF of various causes. Left , The percentages of recovery rate of renal function 1 year after the acute epis ode of renal failure. Right, The situation of renal function 5 years after the A RF episode. Acute tubulointerstitial nephritis (TIN) carries the better prognosi s: the vast majority of patients had recovered renal function after 1 and 5 year s. Two thirds of the patients with acute tubule necrosis (ATN) recovered normal renal function, 31% showed partial recovery, and 6% experienced no functional re covery. Some patients with ATN lost renal function over the years. Patients with ARF due to glomerular lesions have a poorer prognosis; 24% at 1 year and 47% at 5 years show terminal renal failure. The poorest evolution is observed with sev ere forms of acute cortical necrosis or hemolytic-uremic syndrome. GNglomerulonep

hritis; HUS hemolytic-uremic syndrome; ACNacute cortical necrosis. (Data from Bono mini et al. [37].) Total recovery 67 27 Partial recovery 9 5 yr 1 yr 5 yr 1 yr Dead 174 Alive 225 < 65 yr (n = 399) Dead 113 Alive 143 6579 yr (n = 256) Dead 50 Alive 53 > 80 yr (n = 103) FIGURE 8-34 Age as a prognostic factor in acute renal failure (ARF). There is a tendency to treat elders with ARF less aggressively because of the presumed wors e outcomes; however, prognosis may be similar to that found in the younger popul ation. In the multicenter prospective longitudinal study in Madrid, relative ris k for mortality in patients older than 80 years was not significantly different (1.09 as compared with 1 for the group younger than 65 years). Age probably is n ot a poor prognostic sign, and outcome seems to be within acceptable limits for elderly patients with ARF. Dialysis should not be withheld from patients purely because of their age.

8.14 Acute Renal Failure VARIABLES ASSOCIATED WITH PROGNOSIS: MULTIVARIATE ANALYSIS (16 STUDIES) Assisted respiration Hypotension or inotropic support Age Cardiac failure/compli cations Jaundice Diuresis volume Coma Male sex Sepsis Chronic disease Neoplastic disease Other organ failures Serum creatinine Other conditions Summary Clinical variables Laboratory variables 11 10 8 6 6 5 5 4 3 3 2 2 2 12 20 6 PROGNOSIS IN ACUTE RENAL FAILURE 19601969 No. Mortality (%) Mean age (y) Median APACHE II score Range 119 51 50.9 32 (2245) P NS < 0.0001 < 0.0001 19801989 124 63 63 35 (2549) FIGURE 8-36 Prognosis in acute renal failure (ARF). This figure shows the utilit y of a prognostic system for evaluating the severity of ARF over time, using the experience of Turney [38]. He compared the age, mortality, and APACHE II score of ARF patients treated at one hospital between 1960 and 1969 and 1980 and 1989. In the latter period there were significant increases in both the severity of t he illness as measured by APACHE II and age. Although there was a tendency to a higher mortality rate in the second period, this tendency was not great enough t o be statistically significant. FIGURE 8-35 Outcome of acute renal failure (ARF). A great number of variables ha ve been associated with outcome in ARF by multivariate analysis. This figure giv es the frequency with which these variables appear in 16 ARF studies performed w ith multivariable analysis (all cited in [30]). 70 60 50 Mortality, % 40 30 20 10 0 68 Time 42 Nonsurvivors 24 22 25 24 Survivors 22 22 22 22 Admission in ICU Before dialysis 24 h after dialysis 48 h after dialysis 22 6 Dialysis patients Apache II score 22 6 Nondialysis patients A B FIGURE 8-37 APACHE score. The APACHE II score is not a good method for estimatin g prognosis in acute renal failure (ARF) patients. A, Data from Verde and cowork ers show how mortality was higher in their ICU patients with ARF needing dialysi

s than in those without need of dialysis, despite the fact that the APACHE II sc ore before dialysis was equal in both groups [39]. B, Similar data were observed by Schaefer's group [40], who found that the median APACHE II score was similar in both the surviving or nonsurviving ARF pat ients treated in an intensive care unit. Recently Brivet and associates have fou nd that APACHE II score influences ARF prognosis when included as a factor in a more complex logistic equation [2]. Although not useful for prognostic estimatio ns, APACHE II score has been used in ARF for risk stratification.

Acute Renal Failure: Causes and Prognosis 8.15 P<0.001 Mortality, % Severity index 80 66 P<0.001 0.57 0.35 0.8 0.6 33 60 % 40 20 0 0.4 0.2 0 FIGURE 8-38 Analysis of the severity and mortality in acute renal failure (ARF) patients needing dialysis. This figure is an example of the uses of a severity i ndex for analyzing the effect of treatment on the outcome of ARF. Looking at the mortality rate, it is clear that it is higher in patients who need dialysis tha n in those who do not. It could lead to the sophism that dialysis is not a good treatment; however, it is also clear that the severity index score for ARF was h igher in patients who needed dialysis. Severity index is the mean of the individ ual severity index of each of the patients in each group [36]. (Data from Liao et al. [1].) Dialysis No dialysis Severity index 200 Number of cases 150 100 50 0 FIGURE 8-39 Causes of death. The causes of death from acute renal failure (ARF) were analyzed in 337 patients in the Madrid ARF Study [1]. In this work all the potential causes of death were recorded; thus, more than one cause could be pres ent in a given patient. In fact, each dead patient averaged two causes, suggesti ng multifactorial origin. This could be the expression of a high presence of mul tiple organ dysfunction syndrome (MODS) among the nonsurviving patients. The mai n cause of death was the original disease, which was present in 55% of nonsurviv ing patients. Infection and shock were the next most common causes of death, usu ally concurrent in septic patients. It is worth noting that, if we exclude from the mortality analysis patients who died as a result of the original disease, th e corrected mortality due to the ARF episode itself and its complications, drops to 27%. GIgastrointestinal; DICdisseminated intravascular coagulation. Or igin al d ise a se Inf ec t ion Re spi rat dis eas ory Ca e rdi ac dis eas Ga e str oin ble te ed s ti ing na l oc k References 1. Liao F, Pascual J the Madrid ARF Study Group: Epidemiology of acute renal fail

ure: A prospective, multicenter, community-based study. Kidney Int 1996, 50:81181 8. 2. Brivet FG, Kleinknecht DJ, Loirat P, et al.: Acute renal failure in intens ive care unitscauses, outcome and prognostic factors of hospital mortality: A pro spective, multicenter study. Crit Care Med 1995, 24:192197. 3. Pascual J, Liao F, the Madrid ARF Study Group: Causes and prognosis of acute renal failure in the v ery old. J Am Geriatr Soc 1998, 46:15. 4. Eliahou HE, Modan B, Leslau V, et al.: Acute renal failure in the community: An epidemiological study. Acute Renal Fail ure Conference, Proceedings. New York 1973. 5. Abraham G, Gupta RK, Senthilselva n A, et al.: Cause and prognosis of acute renal failure in Kuwait: A 2-year pros pective study. J Trop Med Hyg 1989, 92:325329. 6. McGregor E, Brown I, Campbell H , et al.: Acute renal failure. A prospective study on incidence and outcome (Abs tract). XXIX Congress of EDTA-ERA, Paris, 1992, p 54. 7. Sanchez Rodrguez L, Martn Escobar E, Lozano L, et al.: Aspectos epidemiolgicos del fracaso renal agudo en el rea sanitaria de Cuenca. Nefrologa 1992, 12(Suppl 4):8791. 8. Feest TG, Round A, Hamad S: Incidence of severe acute renal failure in adults: Results of a commun ity based study. Br Med J 1993, 306:481483. 9. Lunding M, Steiness I, Thaysen JH: Acute renal failure due to tubular necrosis. Immediate prognosis and complicati ons. Acta Med Scand 1964, 176:103119. 10. Lachhein L, Kielstein R, Sauer K, et al .: Evaluation of 433 cases of acute renal failure. Proc EDTA 1978, 14:628629. 11. Wing AJ, Broyer M, Brunner FP, et al.: Combined report on regular dialysis and transplantation in Europe XIII-1982. Proc EDTA 1983, 20:578. 12. Gerrard JM, Catt o GRD, Jones MC: Acute renal failure: An iceberg revisited (Abstract). Nephrol D ial Transplant 1992, 7:458. 13. Kleinknecht D: Epidemiology of acute renal failu re in France today. In Acute Renal Failure in the Intensive Therapy Unit. Edited by Bihari D, Neild G. London:Springer-Verlag; 1990:1321. 14. Chugh S, Sakhuja V, Malhotra HS, Pereira BJG: Changing trends in acute renal failure in Third-World countriesChandigarh study. Q J Med 1989, 272:11171123. 15. Seedat YK, Nathoo BC: Acute renal failure in blacks and Indians in South AfricaComparison after 10 year s. Nephron 1993, 64:198201. 16. Hou SH, Bushinsky DA, Wish JB, et al.: Hospital-a cquired renal insufficiency: A prospective study. Am J Med 1983, 74:243248. 17. S husterman N, Strom BL, Murray TG, et al.: Risk factors and outcome of hospital-a cquired acute renal failure. Am J Med 1987, 83:6571. ICT Ot he r C DI Sh US

8.16 Acute Renal Failure 29. Vincent JL, Moreno R, Takala J, et al.: The SOFA (sepsis-related organ failu re assessment) score to describe organ dysfunction/failure. Intensive Care Med 1 996, 22:707710. 30. Liao F, Pascual J: Acute renal failure, critical illness and t he artificial kidney: Can we predict outcome? Blood Purif 1997, 15:346353. 31. Do uma CE, Redekop WK, Van der Meulen JHP, et al.: Predicting mortality in intensiv e care patients with acute renal failure treated with dialysis. J Am Soc Nephrol 1997, 8:111117. 32. Viviand X, Gouvernet J, Granthil C, Francois G: Simplificati on of the SAPS by selecting independent variables. Intensive Care Med 1991, 17:1 64168. 33. Bion JF, Aitchison TC, Edlin SA, Ledingham IM: Sickness scoring and re sponse to treatment as predictors of outcome from critical illness. Intensive Ca re Med 1988, 14:167172. 34. Chew SL, Lins RL, Daelemans R, De Broe ME: Outcome in acute renal failure. Nephrol Dial Transplant 1993, 8:101107. 35. Liao F: Severity of acute renal failure: The need of measurement. Nephrol Dial Transplant 1994, 9(Suppl. 4):229238. 36. Liao F, Gallego A, Pascual J, et al.: Prognosis of acute t ubular necrosis: An extended prospectively contrasted study. Nephron 1993, 63:212 3. 37. Bonomini V, Stefoni S, Vangelista A: Long-term patient and renal prognosi s in acute renal failure. Nephron 1984, 36:169172. 38. Turney JH: Why is mortalit y persistently high in acute renal failure? Lancet 1990, 335:971. 39. Verde E, R uiz F, Vozmediano MC, et al.: Valor predictivo del APACHE II en el fracaso renal agudo de las unidades de cuidados intensivos (Abstract). Nefrologa 1996, 16(Supp l. 19):32. 40. Schaefer JH, Jochimsen F, Keller F, et al.: Outcome prediction of acute renal failure in medical intensive care. Intensive Care Med 1991, 17:1924. 18. Lauzurica R, Caralps A: Insuficiencia renal aguda producida en el hospital: Estudio prospectivo y prevencin de la misma. Med Cln (Barc) 1989, 92:331334. 19. Li ao F, Solez K, Kleinknecht D: Scoring the patient with ARF. In Critical Care Neph rology. Edited by Ronco C, Bellomo R. Dordrecht:Kluwer Academic; 1998; Section 2 3.1: 15351545. 20. Kierdorf H, Sieberth HG: Continuous treatment modalities in ac ute renal failure. Nephrol Dial Transplant 1995; 10:20012008. 21. Knaus WA, Drape r EA, Wagner DP, Zimmerman JE: APACHE II: A severity of disease classification s ystem. Crit Care Med 1985, 13:818829. 22. Knaus WA, Wagner DP, Draper EA, et al.: The APACHE III prognostic system: Risk prediction of hospital mortality for cri tically ill hospitalized adults. Chest 1991, 100:16191636. 23. Le Gall JR, Loirat P, Alperovitch A, et al.: A simplified acute physiology score for ICU patients. Crit Care Med 1984, 12:975977. 24. Le Gall, Lemeshow S, Saulnier F: A new Simpli fied Acute Phisiology Score (SAPS II) based on a European/North American multice nter study. JAMA 1993, 270:29572963. 25. Lemeshow S, Teres D, Pastides H, et al.: A method for predicting survival and mortality of ICU patients using objectivel y derived weights. Crit Care Med 1985, 13:519525. 26. Lemeshow S, Teres D, Klar J , et al.: Mortality probability models (MPM II) based on an international cohort of intensive care unit patients. JAMA 1993, 270:24782486. 27. Knaus WA, Draper E A, Wagner DP, Zimmerman JE: Prognosis in acute organ-system failure. Ann Surg 19 85, 202:685693. 28. Marshall JC, Cook DJ, Christou NV, et al.: Multiple organ dys function score: A reliable descriptor of a complex clinical outcome. Crit Care M ed 1995, 23:16381652.

Renal Histopathology, Urine Cytology, and Cytopathology of Acute Renal Failure Lorraine C. Racusen Cynthia C. Nast C auses of acute renal failure can be divided into three categories: 1) prerenal, due to inadequate perfusion; 2) postrenal, due to obstruction of outflow; and 3) intrinsic, due to injury to renal parenchyma. Among the latter, diseases of, or injury to, glomeruli, vessels, interstitium, or tubules may lead to a decrease in glomerular filtration rate (GFR). Glomerular diseases that lead to acute rena l failure are the proliferative glomerulonephritides, including postinfectious a nd membranoproliferative glomerulonephritis secondary to glomerular deposition o f immune complexes. If glomerular injury is severe enough to damage the glomerul ar basement membrane, leakage of fibrin and other plasma proteins stimulates for mation of cellular extracapillary crescents composed of epithelial cells and monoc ytes and macrophages. Crescents may form as a result of an inflammatory reaction to immune complexes formed to nonglomerular antigens; antibody reaction to intr insic glomerular antigens, as in antiglomerular basement membrane disease; and, i n the absence of immune complexes, the pauci-immune processes, which include the small vessel vasculitides, including Wegener's granulomatosis and microscopic pol yarteritis. Immunohistologic examination and electron microscopy play important roles in the diagnosis of these processes. Extensive crescent formation is accom panied by rapidly progressive acute renal failure. The urine sediment in these d iseases often contains red blood cells and red cell casts. Vascular diseases (in volving veins, arteries, or arterioles and capillaries) can lead to hypoperfusio n and acute renal failure. Venous thrombosis, most often due to trauma or a neph rotic state, and arterial thrombosis due to trauma or vasculitis, cause parenchy mal ischemia and CHAPTER 9

9.2 Acute Renal Failure process or associated with immune glomerular injury. Tubulitis is seen when the inflammatory reaction extends into the tubular epithelium. Epithelial cell injur y is often produced by such inflammatory processes. The urine sediment reveals w hite blood cells and white cell casts, which may include numerous polymorphonucl ear leukocytes or eosinophils. The most common cause of acute renal failure is i njury to tubule epithelium. Primary tubule cell injury typically results from is chemia, toxic injury, or both. Cell injury results in disruption of the epitheli um and its normal reabsorptive functions, and may lead to obstruction of tubule lumens. Cell exfoliation often occurs, and intact cells and cell fragments and d ebris can be seen in the urine sediment; these may be in the form of casts. Necr otic cells may be seen in situ along the tubule epithelium or in the tubule lume n, but often overt cell necrosis is not prominent. Apoptosis of tubule cells is seen after injury as well. infarction. Small vessel vasculitides involve small arteries, arterioles, and gl omerular capillaries, causing injury and necrosis in the glomerular tuft, which may result in crescent formation. Thrombotic microangiopathies result from endot helial injury damage in small arteries and arterioles, producing thrombosis, obs truction to blood flow, and glomerular hypoperfusion. Urine sediment in these di seases often shows hematuria or cellular casts, reflecting ischemia. Interstitia l inflammatory processes lead to acute renal failure via compression of peritubu lar capillaries or injury to tubules. Causes of acute interstitial nephritis inc lude infection, and immune-mediated reactions. With infection, polymorphonuclear leukocytes may be seen in tubules as well as in interstitium. Inflammatory infi ltrates in hypersensitivity reactions, often due to drug exposure, feature eosin ophils. Immunohistologic studies may reveal the presence of immune complexes; im mune complex deposition around tubules occurs as a primary Glomerular Diseases FIGURE 9-1 (see Color Plate) Early postinfectious glomerulonephritis. Numerous p olymorphonuclear leukocytes in glomerular capillary loops contribute to the hype rcellular appearance of the glomerulus. There is also a segmental increase in me sangial cells (hematoxylin and eosin, original magnification 400). This reactive inflammatory process occurs in response to glomerular deposition of immune comp lexes, including the large subepithelial hump-like deposits which are typical of p ost-infectious glomerulonephritis. The glomerulonephritis is usually selflimited and reversible, and especially with appropriate treatment of the underlying inf ection, long-term prognosis is excellent [1]. FIGURE 9-2 (see Color Plate) A large epithelial crescent fills Bowman's space and compresses the capillary loops in the glomerular tuft. This silver stain highlig hts the glomerular mesangium and the basement membrane of the glomerular capilla ries (silver stain, original magnification 400). The patient presented with hema turia and acute renal failure. Immunostains were negative in this case, a findin g consistent with a pauci-immune process. The differential diagnosis includes sm all vessel vasculitis, and anti-neutrophil cytoplasmic antibody may be positive. Crescentic glomerulonephritis may also occur with anti-glomerular basement memb rane antibody disease, or as a complication of immune complex glomerulonephritis [2].

Renal Histopathology, Urine Cytology, and Cytopathology of Acute Renal Failure 9.3 FIGURE 9-3 (see Color Plate) Urine sediment of a patient with acute renal failur e revealing red blood cells and some red blood cell casts (original magnificatio n 600). Biopsy in this case revealed crescentic glomerulonephritis. However, hem aturia may be seen in any proliferative glomerulonephritis or with parenchymal i nfarcts. The casts assume the cylindrical shape of the renal tubules, and confirm an intrarenal source of the blood in the urine. Fragmented or dysmorphic red blo od cells may be seen when the red cells have traversed through damaged glomerula r capillaries. Vascular Diseases FIGURE 9-4 (see Color Plate) An early thrombus is seen in a small renal artery i n a patient with patchy cortical infarction (original magnification 250). The pa tient presented with acute renal failure. The thrombosis may be due to a hyperco aggulable state (eg, disseminated intravascular coaggulation) or endothelial inj ury (eg, hemolytic uremic syndrome). If the cortical necrosis is patchy, recover y of adequate renal function may occur [3]. FIGURE 9-5 (see Color Plate) A parenchymal infarct in a patient with renal vein thrombosis (hematoxylin and eosin, original magnification 200). A few surviving tubules and a rim of inflammatory cells are seen at the periphery of the infarct . Infarcts may also be seen with arterial thromboses, and with severe injury to the microvasculature, as occurs in thrombotic microangiopathies [3]. If the proc ess is extensive, acute cortical necrosis may occur, often leading to irreversib le renal failure.

9.4 Acute Renal Failure A FIGURE 9-6 (see Color Plate) A fine-needle aspirate in renal infarction. A, Low magnification shows many degenerating cells with a dirty background containing cel lular debris and scattered neutrophils. Compare to acute tubular necrosis, which has only scattered degenerated or necrotic cells without the extensive necrosis and cell debris. Neutrophils may be numerous if the B edge of an infarct is aspirated (May-Grunwald Giemsa, original magnification 40) . B, Diffusely degenerated and necrotic cells with condensed and disrupted cytop lasm and pyknotic nuclei, and an adjacent neutrophil. No significant numbers of viable tubule epithelial cells remain (May-Grunwald Giemsa, original magnificati on 160). FIGURE 9-7 (see Color Plate) A small artery with severe inflammation in a patient with a small vessel vasculitis. The wall of the vessel is infiltrated by lymphocytes, plasma cells, and eosinophils (hematoxylin and eosin, original magnification 250). The patient was p-ANCA positive. ANCA may play a pathogenic role in the vasculitis process [4]. Vasculitis in the kidney is often part of a systemic syndrome, but may occur as an apparently renal-limited process. FIGURE 9-8 (see Color Plate) Microangiopathic changes in a small artery, with en dothelial activation, evidenced by the large endothelial cells with hyperchromat ic nuclei and vacuolization. There is intimal edema with some cell proliferation , and a prominent band of fibrinoid necrosis is seen; the latter appears dark re d-pink on this hematoxylin-eosin stain, and represents insudation of fibrin and plasma proteins into the wall of the injured vessel (original magnification 250) . The differential diagnosis includes hemolytic uremic syndrome, thrombotic thro mbocytopenic purpura, malignant hypertension, scleroderma, and drug toxicity, th e latter due most commonly to mitomycin C or cyclosporine/FK506 [5].

Renal Histopathology, Urine Cytology, and Cytopathology of Acute Renal Failure 9.5 FIGURE 9-9 (see Color Plate) A cast of necrotic tubular cells in urine sediment (Papanicolaou stain, original magnification 400). The most likely causes of dama ge to the renal tubules with such findings in the urinary sediment are severe is chemia/infarction, or tubular necrosis due to exposure to toxins which injure th e renal tubules. The latter include antibiotics, including aminoglycosides and c ephalosporins, and chemotherapeutic agents. Interstitial Disease FIGURE 9-10 (see Color Plate) Interstitial nephritis with edema and a mononuclea r inflammatory infiltrate. Eosinophils in the infiltrate suggest a possible hype rsensitivity reaction (hematoxylin and eosin, original magnification 400). Drugs are the most common cause of such a reaction, which often presents with acute r enal failure [6]. Inflammatory cells and cell casts may be seen in the urine sed iment in these cases, as inflammatory cells infiltrate the tubular epithelium. FIGURE 9-11 (see Color Plate) Tubulitis, with infiltration of mononuclear cells into the tubular epithelium (hematoxylin and eosin, original magnification 400). There is a mononuclear infiltrate and edema in the surrounding interstitium. Tu bule cells may show evidence of lethal or sublethal injury as the inflammatory c ells release damaging enzymes. Tubulitis is often seen in interstitial nephritis especially if the targets of the inflammatory reaction are tubular cell antigen s or antigens deposited around the tubules. Immunofluorescence may reveal granul ar or linear deposits of immunoglobulin and complement around the tubules.

9.6 Acute Renal Failure FIGURE 9-12 (see Color Plate) Polymorphonuclear leukocytes forming a cast in a c ortical tubule (hematoxylin and eosin, original magnification 400). Note edema a nd inflammation in adjacent interstitium. These intratubular cells are highly su ggestive of acute infection, and may be seen in distal as well as proximal nephr on as part of an ascending infection. Intratubular PML may also be seen in vascu litis and other necrotizing glomerular processes, in which these cells escape ac ross damaged areas of the inflamed glomerular tuft. A FIGURE 9-13 (see Color Plate) Fine-needle aspirate of acute infectious interstit ial nephritis (acute pyelonephritis). A 25-gauge needle attached to a 10-cc syri nge was utilized to withdraw the aspirate into 4 cc of RPMI-based medium. The sp ecimen was then cytocentrifuged and stained with May-Grunwald Giemsa. A, The ren al aspirate contains large numbers of intrarenal neutrophils, which are focally undergoing degenerative changes with cytoplasmic vacuolization and nuclear B breakdown. In bacterial infection there are many infiltrating neutrophils and th ere may be associated necrosis of tubule epithelial cells (original magnificatio n 80). B, A neutrophil contains phagocytosed bacteria within the cytoplasm; bact eria stain with Giemsa, so are readily detectable in this setting. Adjacent tubu le epithelial cells have cytoplasmic granules but do not phagocytize bacteria (o riginal magnification 160). FIGURE 9-14 (see Color Plate) Numerous polymorphonuc lear leukocytes (PML) in the urine sediment of a patient with acute pyelonephrit is (hematoxylin and eosin, original magnification 400). Some red blood cells and tubular cells are seen in the background of this cytospin preparation. PML may be found in the urine with acute infection of the lower urinary tract as well, o r as a contaminant from vaginal secretions in females. PML casts, on the other h and, are evidence that the cells are from the kidney.

Renal Histopathology, Urine Cytology, and Cytopathology of Acute Renal Failure 9.7 A FIGURE 9-15 (see Color Plate) Fine-needle aspirate from patient with intrarenal cytomegalovirus (CMV) infection. A, There are activated and transformed lymphocy tes with immature nuclear chromatin and abundant blue cytoplasm that infiltrate the kidney in response to the infection; large granular lymphocytes (NK cells) m ay be seen as well, but few neutrophils. Similar activated lymphocytes, NK cells , and atypical monocytes can be observed within the peripheral blood. The tubule epithelial cells are virtually never seen to contain CMV inclusions in aspirate material, in contrast to core biopsy specimens. All intrarenal B viral infections have a similar appearance, and immunostaining or in situ hybrid ization is required to identify specific viruses (MayGrunwald Giemsa, original m agnification 80). B, Tubular epithelial cells stained with antibody to CMV immed iate and early nuclear proteins in active intrarenal CMV infection. With an immu noalkaline phosphatase method, cytoplasmic and prominent nuclear staining for th ese early proteins are observed in the tubular epithelium. In very early infecti on, neutrophils also may have cytoplasmic staining for these proteins (original magnification 240). FIGURE 9-16 (see Color Plate) Numerous eosinophils in an int erstitial inflammatory infiltrate. Eosinophils may be diffuse within the infiltr ate, but may also be clustered, forming eosinophilic abscesses, as in this area (h ematoxylin and eosin, original magnification 400). Eosinophils may also be demon strated in the urine sediment. Drugs most commonly producing acute interstitial nephritis as part of a hypersensitivity reaction include: penicillins, sulfonami des, and nonsteroidal antiinflammatory drugs [6]. The patient had recently under gone a course of therapy with methicillin. The interstitial nephritis may be par t of a systemic reaction which includes fever, rash, and eosinophilia.

9.8 Acute Renal Failure A FIGURE 9-17 (see Color Plate) Fine-needle aspirate of acute allergic interstitia l nephritis. A, The aspirate contains numerous lymphocytes, occasional activated lymphocytes, and eosinophils without fully transformed lymphocytes, correspondi ng to the inflammatory component within the tubulointerstitium observed on routi ne renal biopsy. Monocytes often are B present (May-Grunwald Giemsa, original magnification 80). B, Higher magnificatio n showing the typical infiltrating cells, including a monocyte, activated lympho cyte, and an eosinophil. A neutrophil is present, likely owing to blood contamin ation (May-Grunwald Giemsa, original magnification 160). Tubular Diseases FIGURE 9-18 (see Color Plate) Severe vacuolization of tubular cells in injured t ubular epithelium (hematoxylin and eosin, original magnification 400). The vacuo les reflect cell injury and derangement of homeostatic mechanisms that maintain the normal intracellular milieu. In this case, the vacuoles developed on exposur e to intravenous immunoglobulin in a sucrose vehicle; the morphology is reminisc ent of the severe changes produced by osmotic agents. While generally a nonspeci fic marker of cell injury, a distinctive pattern of isometric vacuolization, in wh ich there are numerous intracellular vacuoles of uniform size (not shown here) i s very typical of cyclosporine/FK506 effect [6]. FIGURE 9-19 (see Color Plate) Necrotic tubular cells and cell debris in tubular lumina. One tubule shows extensive cell loss, with tubular epithelium lined only by a very flattened layer of cytoplasm. The dilated lumen contains numerous nec rotic tubular cells with pyknotic nuclei. Several tubules contain cell debris an d one contains red blood cells (hematoxylin and eosin, original magnification 25 0). Such changes are more often seen with toxic than with ischemic injury [6], u nless the latter is very severe.

Renal Histopathology, Urine Cytology, and Cytopathology of Acute Renal Failure 9.9 FIGURE 9-20 (see Color Plate) This micrograph shows sites of cell exfoliation, a ttenuation of remaining cells, and reactive and regenerative changes (hematoxyli n and eosin, original magnification 400). Exfoliation occurs with disruption of cell-cell and cell-substrate adhesion, and may involve viable as well as non-via ble cells [7]. Reactive and regenerative changes may include basophilia of cell cytoplasm, increased nuclear:cytoplasmic ratio, heterogeneity of nuclear size an d appearance, hyperchromatic nuclei and mitotic figures. FIGURE 9-21 (see Color Plate) Outer medulla shows in situ cell necrosis and loss in medullary thick ascending limb (hematoxylin and eosin, original magnificatio n 250). Tubules contain cells and cell debris. Changes reflect ischemic injury. Impaction of cells and cast material may lead to tubular obstruction, especially in narrow regions of the nephron. Adhesion molecules on the surface of exfoliat ed cells may contribute to aggregation of cells within the tubule and adhesion o f detached cells to in situ tubular cells [8]. A FIGURE 9-22 (see Color Plate) Fine-needle aspirate showing acute tubular cell in jury and necrosis. A, The aspirate shows scattered tubular epithelial cells with swelling and focal degenerative changes, and a minimal associated inflammatory infiltrate. There is no significant background cell debris (MayGrunwald Giemsa, original magnification 40). B, One tubular cell is degenerated with reduction in cell size, condensed gray-blue B cytoplasm, and a pyknotic nucleus. Another cell has more advanced necrosis with additional cytoplasmic disruption and a very small pyknotic nucleus. Compare the adjacent swollen damaged tubular cell which has not yet undergone necrosis (May -Grunwald Giemsa, original magnification 160).

9.10 Acute Renal Failure FIGURE 9-23 (see Color Plate) Urine sediment from a patient with acute tubular i njury showing tubular cells and cell casts (Papanicolaou stain, original magnifi cation 250). Many of these cells are morphologically intact, even by electron mi croscopy. Studies have shown that a significant percentage of the cells shed int o the urine may exclude vital dyes, and may even grow when placed in culture, in dicating that they remain viable. Such cells clearly detached from tubular basem ent membrane as a manifestation of sub-lethal injury [7]. A FIGURE 9-24 (see Color Plate) Myoglobin casts in the tubules of a patient who ab used cocaine. A, Hematoxylin and eosin stained casts have a dark red, coarsely g ranular appearance (original magnification 250). B, Immunoperoxidase stain for m yoglobin confirms positive staining in the casts B (original magnification 250). These casts may obstruct the nephron, especially w ith dehydration and low tubular fluid flow rates. Rhabdomyolysis with formation of intrarenal myoglobin casts may also occur with severe trauma, crush injury, o r extreme exercise.

Renal Histopathology, Urine Cytology, and Cytopathology of Acute Renal Failure 9.11 FIGURE 9-25 (see Color Plate) Apoptosis of tubular cells following tubular cell injury. Note the shrunken cells with condensed nuclei and cytoplasm in the centr al tubule. The patient had presumed ischemic injury (hematoxylin and eosin, orig inal magnification 400). The role of apoptosis in injury to the renal tubule rem ains to be defined. The process may be difficult to quantitate, since apoptotic cells may rapidly disintegrate. In experimental models, the degree of apoptosis versus coaggulative necrosis occurring following injury is related to the severi ty and duration of injury, with milder injury showing more apoptosis [9]. Disintegrating fragments Shrunken cell with peripheral condensed nuclear chromat in and intact organelles FIGURE 9-26 Apoptosis-schematic of histologic changes in tubular epithelium. The process begins with condensation of the cytoplasm and of the nucleus, a process which involves endonucleases, which digest the DNA into ladder-like fragments c haracteristic of this process. The cell disintegrates into discrete membrane-bou nd fragments, so-called apoptotic bodies. These fragments may be rapidly extruded into the tubular lumen or phagocytosed by neighboring epithelial cells or inflam matory cells. (Modified from Arends, et al. [10]; with permission.) Phagocytosed apoptic cell fragments

9.12 Acute Renal Failure Ischemia Toxins Altered permeability Vascular endothelial injury Inflammatory infiltrate Sublethal Tubular cell injury Apoptosis Lethal Upregulation of adhesion molecules Interstitial edema Tubular cell swelling Comp ression of peritubular capillaries Loss of normal transport function Loss of surface area and cell polarity Altered adhesion Changes of repair and regeneration In situ necrosis Increased epithelial permeability Loss of tubular integrity Exfoliation Impaction in the tubules Vacuolization of smooth muscle cells Arteriolar vasoconstriction Loss of distal flow Glomerular collapse "Backleak" of filtrate Obstruction Increased intratubular pressure Cast formation Tubular dilatation Increased renal vascular resistance Aggregation of erythrocytes,fibrin and/or le ukocytes in peritubular capillaries Decrease in glomerular filtration rate Reduc ed renal blood flow FIGURE 9-27 A schematic showing the relationship between morphologic and functio nal changes with injury to the renal tubule due to ischemia or nephrotoxins. Mor phologic changes are shown in italics. Histology reflects the altered hemodynamics, epithelial derangements, and obstru ction which contribute to loss of renal function. (Modified from Racusen [11]; w ith permission.) References 1. 2. Popovic-Rolovic M, Kostic M, Antic-Peco A, et al.: Medium and long-term pr ognosis of patients with acute post-streptococcal glomerulonephritis. Nephron 19 91, 58:393399. Jennette JC: Crescentic glomerulonephritis. In Heptinstall's Patholo gy of the Kidney, edn. 5. Edited by Jennette JC, JL Olson, M Schwarz, FG Silva.

New York:Lippincott-Raven, 1998. Racusen LC, Solez K: Renal cortical necrosis, i nfarction and atheroembolic disease. In Renal Pathology. Edited by Tisher C, B B renner. Philadelphia:Lippincott-Raven, 1993:811. Evert BH, Jennette JC, Falk RJ: The pathogenic role of antineutrophil cytoplasmic autoantibodies. Am J Kidney D is 1991, 8:188195. Remuzzi G, Ruggenenti P: The hemolytic uremic syndrome. Kidney Int 1995, 47:219. Nadasdy T, Racusen LC: Renal injury caused by therapeutic and diagnostic agents, and abuse of analgesics and narcotics. In Heptinstalls Pathol ogy of the Kidney, edn. 5. Edited by Jennette JC, JL Olson, MM Schwartz, FG Silv a. New York:Lippincott-Raven, 1998. 7. Racusen LC, Fivush BA, Li Y-L, et al.: Di ssociation of tubular detachment and tubular cell death in clinical and experime ntal acute tubular necrosis. Lab Invest 1991, 64:546556. 8. Goligorsky MS, Lieberth al W, Racusen L, Simon EE: Integrin receptors in renal tubular epithelium: New i nsights into pathophysiology of acute renal failure. Am J Physiol 1993, 264:F1F8. 9. Schumer KM, Olsson CA, Wise GJ, Buttyan R: Morphologic, biochemical and mole cular evidence of apoptosis during the reperfusion phase after brief periods of renal ischemia. Am J Pathol 1992, 140:831838. 10. Arends MJ, Wyllie AH: Apoptosis : Mechanisms and role in pathology. Int Rev Exp Pathol 1991, 32:225254. 11. Racus en LC: Pathology of acute renal failure: Structure/function correlations. Advanc es in Renal Replacement Therapy, 1997 4(Suppl. 2): 316. 3. 4. 5. 6.

Acute Renal Failure in the Transplanted Kidney Kim Solez Lorraine C. Racusen A cute renal failure (ARF) in the transplanted kidney represents a high-stakes are a of nephrology and of transplantation practice. A correct diagnosis can lead to rapid return of renal function; an incorrect diagnosis can lead to loss of the graft and severe sequelae for the patient. The diagnostic possibilities are many (Fig. 10-1) and treatments quite different, although the clinical presentations of newonset functional renal impairment and of persistent nonfunctioning after transplant may be identical. In transplant-related ARF percutaneous kidney allog raft biopsy is crucial in differentiating such diverse entities as acute rejecti on (Figs. 10-2 to 10-9), acute tubular necrosis (Figs. 10-10 to 10-14), cyclospo rine toxicity (Figs. 10-15 and 10-16), posttransplant lymphoproliferative disord er (Fig. 10-17), and other, rarer, conditions. In the case of acute rejection, s tandardization of transplant biopsy interpretation and reporting is necessary to guide therapy and to establish an objective endpoint for clinical trials of new immunosuppressive agents. The Banff Classification of Renal Allograft Pathology [1] is an internationally accepted standard for the assessment of renal allogra ft biopsies sponsored by the International Society of Nephrology Commission of A cute Renal Failure. The classification had its origins in a meeting held in Banf f, Alberta, in the Canadian Rockies, in August, 1991, where subsequent meetings have been held every 2 years. Hot topics likely to influence the Banff Classific ation of Renal Allograft Pathology in 1999 and beyond are shown in Figs. 10-17 t o 10-19. CHAPTER 10

10.2 Acute Renal Failure Acute Rejection DIAGNOSTIC POSSIBILITIES IN TRANSPLANTRELATED ACUTE RENAL FAILURE 1. Acute (cell-mediated) rejection 2. Delayed-appearing antibody-mediated reject ion 3. Acute tubular necrosis 4. Cyclosporine or FK506 toxicity 5. Urine leak 6. Obstruction 7. Viral infection 8. Post-transplant lymphoproliferative disorder 9. Vascular thrombosis 10. Prerenal azotemia FIGURE 10-1 Diagnostic possibilities in transplant-related acute renal failure. Lesions-tubulitis, intimal arteritis None Borderline M ild tu bu lit is Mild Moderate Severe Rejection FIGURE 10-2 Diagnosis of rejection in the Banff classification makes use of two basic lesions, tubulitis and intimal arteritis. The 19931995 Banff classification depicted in this figure is the standard in use in virtually all current clinica l trials and in many individual transplant units. In this construct, rejection i s regarded as a continuum of mild, moderate, and severe forms. The 1997 Banff cl assification is similar, having the same threshold for rejection diagnosis, but it recognizes three different histologic types of acute rejection: tubulointersi titial, vascular, and transmural. The quotation marks emphasize the possible ove rlap of features of the various types (eg, the finding of tubulitis should not d issuade the pathologist from conducting a thorough search for intimal arteritis) . No tubulitis M tu ode bu ra lit te is M ild i m (w ntim od it a er of h an l ar ate, tu y ter se bu de it ve lit gr is re is) ee re ve itis Se bul tu FIGURE 10-3 Tubulitis is not absolutely specific for acute rejection. It can be found in mild forms in acute tubular necrosis, normally functioning kidneys, and in cyclosporine toxicity and in conditions not related to rejection. Therefore, quantitation is necessary. The number of lymphocytes situated between and benea th tubular epithelial cells is compared with the number of tubular cells to dete rmine the severity of tubulitis. Four lymphocytes per most inflamed tubule cross section or per ten tubular cells is required to reach the threshold for diagnos ing rejection. In this figure, the two tubule cross sections in the center have eight mononuclear cells each. Rejection with intimal arteritis or transmural art eritis can occur without any tubulitis whatsoever, although usually in well-esta blished rejection both tubulitis and intimal arteritis are observed.

Acute Renal Failure in the Transplanted Kidney 10.3 FIGURE 10-4 (see Color Plate) In this figure the tubules with lymphocytic invasi on are atrophic with thickened tubular basement membranes. There are 13 or 14 ly mphocytes per tubular cross section. This is an example of how a properly perfor med periodic acid-Schiff (PAS) stain should look. The Banff classification is cr itically dependent on proper performance of PAS staining. The invading lymphocyt es are readily apparent and countable in the tubules. In the Banff 1997 classifi cation one avoids counting lymphocytes in atrophic tubules, as tubulitis there i s more nonspecific than in nonatrophed tubules. (From Solez et al. [1]; with permi ssion.) FIGURE 10-5 Intimal arteritis in a case of acute rejection. Note that more than 20 lymphocytes are present in the thickened intima. With this lesion, however, e ven a single lymphocyte in this site is sufficient to make the diagnosis. Thus, the pathologist must search for subtle intimal arteritis lesions, which are high ly reliable and specific for rejection. (From Solez et al. [1]; with permission. ) FIGURE 10-6 Artery in longitudinal section shows a more florid intimal arteritis than that in Figure 10-5. Aggregation of lymphocytes is also seen in the lumen, but this is a nonspecific change. The reporting for some clinical trials has in volved counting lymphocytes in the most inflamed artery, but this has not been s hown to correlate with clinical severity or outcome, whereas the presence or abs ence of the lesion has been shown to have such a correlation. (From Solez et al. [1]; with permission.) FIGURE 10-7 Transmural arteritis with fibrinoid change. In addition to the influ x of inflammatory cells there has been proliferation of modified smooth muscle c ells migrated from the media to the greatly thickened intima. Note the fibrinoid change at lower left and the penetration of the media by inflammatory cells at the upper right. Patients with these types of lesions have a less favorable prog nosis, greater graft loss, and poorer long-term function as compared with patien ts with intimal arteritis alone. These sorts of lesions are also common in antib odymediated rejection (see Fig. 10-9).

10.4 Acute Renal Failure FIGURE 10-8 Diagram of arterial lesions of acute rejection. The initial changes (15) before intimal arteritis (6) occurs are completely nonspecific. These early changes are probably mechanistically related to the diagnostic lesions but can o ccur as a completely self-limiting phenomenon unrelated to clinical rejection. L esions 7 to 10 are those characteristic of transmural rejection. Lesion 1 is periv ascular inflammation; lesion 2, myocyte vacuolization; lesion 3, apoptosis; lesi on 4, endothelial activation and prominence; lesion 5, leukocyte adherence to th e endothelium; lesion 6 (specific), penetration of inflammatory cells under the endothelium (intimal arteritis); lesion 7, inflammatory cell penetration of the media; lesion 8, necrosis of medial smooth muscle cells; lesion 9, platelet aggr egation; lesion 10, fibrinoid change; and lesion 11 is thrombosis. Arterial lesions in acute rejection 1 Adventitia 3 10 8 7 Media 2 Endothelium Lumen 4 5 6 9 11 FIGURE 10-9 (see Color Plate) Antibody-mediated rejection with aggregates of pol ymorphonuclear leukocytes (polymorphs) in peritubular capillaries. This lesion i s a feature of both classic hyperacute rejection and of later appearing antibody -mediated rejection, which is by far the more common entity. Antibody- and cellmediated rejection can coexist, so one may find both tubulitis and intimal arter itis along with this lesion; however many cases of antibody-mediated rejection h ave a paucity of tubulitis [2]. The polymorph aggregates can be subtle, another reason for looking with care at the biopsy that appears to show nothing. Acute Tubular Necrosis FIGURE 10-10 (see Color Plate) Acute tubular necrosis in the allograft. Unlike ac ute tubule necrosis in native kidney, in this condition actual necrosis appears i n the transplanted kidney but in a very small proportion of tubules, often less than one in 300 tubule cross sections. Where the necrosis does occur it tends to affect the entire tubule cross section, as in the center of this field [3].

Acute Renal Failure in the Transplanted Kidney 10.5 FIGURE 10-11 (see Color Plate) A completely necrotic tubule in the center of the picture in a case of acute tubular necrosis (ATN) in an allograft. The tubule i s difficult to identify because, in contrast to the appearance in native kidney ATN, no residual tubular cells survive; the epithelium is 100% necrotic. FIGURE 10-12 (see Color Plate) Calcium oxalate crystals seen under polarized lig ht. These are very characteristic of transplant acute tubular necrosis (ATN), pr obably because they relate to some degree to the duration of uremia, which is of ten much longer in transplant ATN (counting the period of uremia before transpla ntation) than in native ATN. With prolonged uremia elevation of plasma oxalate i s greater and more persistent and consequently tissue deposition is greater [4]. FEATURES OF TRANSPLANT ACUTE TUBULAR NECROSIS (ATN) WHICH DIFFERENTIATE IT FROM NATIVE KIDNEY ATN 1. Apparently intact proximal tubular brush border 2. Occasional foci of necrosi s of entire tubular cross sections 3. More extensive calcium oxalate deposition 4. Significantly fewer tubular casts 5. Significantly more interstitial inflamma tion 6. Less cell-to-cell variation in size and shape (tubular cell unrest) FIGURE 10-13 Calcium oxalate crystals seen by electron microscopy in transplant acute tubular necrosis. FIGURE 10-14 Features of transplant acute tubular necrosis that differentiate it from the same condition in native kidney [3].

10.6 Acute Renal Failure Cyclosporine Toxicity FIGURE 10-15 Cyclosporine nephrotoxicity with new-onset hyaline arteriolar thick ening in the renin-producing portion of the afferent arteriole [5]. This lesion can be highly variable in extent and severity from section to section of the bio psy specimen, and it represents one of the strong arguments for examining multip le sections. The lesion is reversible if cyclosporine levels are reduced. Tacrol imus (FK506) produces an identical picture. FIGURE 10-16 (see Color Plate) Bland hyaline arteriolar thickening of donor orig in in a renal allograft recipient never treated with cyclosporine. This phenomen on provides a strong argument for doing implantation biopsies; otherwise, donor changes can be mistaken for cyclosporine toxicity. Posttransplant Lymphoproliferative Disorder FIGURE 10-17 Posttransplant lymphoproliferative disorder (PTLD). The least satis fying facet of the 1997 Fourth Banff Conference on Allograft Pathology was the c ontinued lack of good tools for the renal pathologist trying to distinguish the more subtle forms of PTLD from rejection. PTLD is rare, but, if misdiagnosed and treated with increased (rather than decreased) immunosuppression, it can quickl y lead to death. The fact that both rejection and PTLD can occur simultaneously makes the challenge even greater [6]. It is hoped that newer techniques will mak e the diagnosis of this important condition more accurate in the future [79]. Thi s figure shows an expansile plasmacytic infiltrate in a case of PTLD. However, m ost cases of PTLD are the result of Epstein-Barr virusinduced lymphoid proliferat ion.

Acute Renal Failure in the Transplanted Kidney 10.7 Subclinical Rejection FIGURE 10-18 (see Color Plate) Subclinical rejection. Subclinical rejection char acterized by moderate to severe tubulitis may be found in as many as 35% of norm ally functioning grafts. Far from representing false-positive readings, such fin dings now appear to represent bona fide smoldering rejection that, if left untre ated, is associated with increased incidence of chronic renal functional impairm ent and graft loss [10,11]. The important debate for the future is when to perfo rm protocol biopsies to identify subclinical rejection and how best to treat it. This picture shows severe tubulitis in a normally functioning graft 15 months a fter transplantation. In the tubule in the center are 30 lymphocytes (versus 14 tubule cells). A year and a half later the patient developed renal functional im pairment. Thrombotic Microangiopathy FIGURE 10-19 Thrombotic microangiopathy in renal allografts. A host of different conditions and influences can lead to arteriolar and capillary thrombosis in re nal allografts and these are as various as the first dose reaction to OKT3, HIV infection, episodes of cyclosporine toxicity, and antibody-mediated rejection [2 , 12, 13]. It is hoped that further study will allow for more accurate diagnosis in patients manifesting this lesion. The figure shows arteriolar thrombosis and ischemic capillary collapse in a case of transplant thrombotic microangiopathy.

10.8 Acute Renal Failure Peritubular Capillary Basement Membrane Changes in Chronic Rejection A FIGURE 10-20 (see Color Plate) Peritubular capillary basement membrane ultrastru ctural changes, A, and staining for VCAM-1 as specific markers for chronic rejec tion, B [1416]. Splitting and multilayering of peritubular capillary basement mem branes by electron microscopy holds promise as a relatively specific marker for chronic rejection [14,15]. VCAM-1 staining by immunohistology in these same stru ctures may also be B of diagnostic utility [16]. Ongoing studies of large numbers of patients using t hese parameters will test the value of these parameters which may eventually be added to the Banff classification. A, Multilayering of peritubular capillary bas ement membrane in a case of chronic rejection; B, shows staining of peritubular capillaries for VCAM-1 by immunoperoxidase in chronic rejection. References 1. Solez K, Axelsen RA, Benediktsson H, et al.: International standardization of criteria for the histologic diagnosis of renal allograft rejection: The Banff w orking classification of kidney transplant pathology. Kidney Int 1993, 44:411422. 2. Trpkov K, Campbell P, Pazderka F, et al.: Pathologic features of acute renal allograft rejection associated with donor-specific antibody, analysis using the Banff grading schema. Transplantation 1996, 61(11):15861592. 3. Solez K, Racusen LC, Marcussen N, et al.: Morphology of ischemic acute renal failure, normal fun ction, and cyclosporine toxicity in cyclosporine-treated renal allograft recipie nts. Kidney Int 1993, 43(5):10581067. 4. Salyer WR, Keren D:Oxalosis as a complic ation of chronic renal failure. Kidney Int 1973, 4(1):6166. 5. Strom EH, Epper R, Mihatsch MJ: Cyclosporin-associated arteriolopathy: The renin producing vascula r smooth muscle cells are more sensitive to cyclosporin toxicity. Clin Nephrol 1 995, 43(4):226231. 6. Trpkov K, Marcussen N, Rayner D, et al.: Kidney allograft w ith a lymphocytic infiltrate: Acute rejection, post-transplantation lymphoprolif erative disorder, neither, or both entities? Am J Kidney Dis 1997, 30(3):449454. 7. Sasaki TM, Pirsch JD, D'Alessndro AM, et al.: Increased 2-microglobulin (B2M) is useful in the detection of post-transplant lymphoproliferative disease (PTLD) . Clin Transplant 1997, 11(1):2933. 8. Chetty R, Biddolph S, Kaklamanis L, et al. : bcl-2 protein is strongly expressed in post-transplant lymphoproliferative dis orders. J Pathol 1996, 180(3):254258. 9. Wood A, Angus B, Kestevan P, et al.: Alp ha interferon gene deletions in post-transplant lymphoma. Br J Haematol 1997, 98 (4):10021003. 10. Nickerson P, Jeffrey J, McKenna R, et al.: Do renal allograft f unction and histology at 6 months posttransplant predict graft function at 2 yea rs? Transplant Proc 1997, 29(6):25892590. 11. Rush D: Subclinical rejection. Pres entation at Fourth Banff Conference on Allograft Pathology, March 712, 1997. 12. Wiener Y, Nakhleh RE, Lee MW, et al.: Prognostic factors and early resumption of cyclosporin A in renal allograft recipients with thrombotic microangiopathy and hemolytic uremic syndrome. Clin Transplant 1997, 11(3):157162. 13. Frem GJ, Renn ke HG, Sayegh MH: Late renal allograft failure secondary to thrombotic microangi opathyhuman immunodeficiency virus nephropathy. J Am Soc Nephrol 1994, 4(9):164316 48. 14. Monga G, Mazzucco G, Messina M, et al.: Intertubular capillary changes i n kidney allografts: A morphologic investigation on 61 renal specimens. Mod Path ol 1992, 5(2):125130. 15. Mazzucco G, Motta M, Segoloni G, Monga G: Intertubular capillary changes in the cortex and medulla of transplanted kidneys and their re lationship with transplant glomerulopathy: An ultrastructural study of 12 transp lantectomies. Ultrastruct Pathol 1994, 18(6):533537. 16. Solez K, Racusen LC, Abd ulkareem F, et al.: Adhesion molecules and rejection of renal allografts. Kidney Int 1997, 51(5):14761480.

Renal Injury Due To Environmental Toxins, Drugs, and Contrast Agents Marc E. De Broe T he kidneys are susceptible to toxic or ischemic injury for several reasons. Thus , it is not surprising that an impressive list of exogenous drugs and chemicals can cause clinical acute renal failure (ARF) [1]. On the contrary, the contribut ion of environmental toxins to ARF is rather limited. In this chapter, some of t he most common drugs and exogenous toxins encountered by the nephrologist in cli nical practice are discussed in detail. The clinical expression of the nephrotox icity of drugs and chemicals is highly variable and is influenced by several fac tors. Among these is the direct toxic effect of drugs and chemicals on a particu lar type of nephron cell, the pharmacologic activity of some substances and thei r effects on renal function, the high metabolic activity (ie, vulnerability) of particular segments of the nephron, the multiple transport systems, which can re sult in intracellular accumulation of drugs and chemicals, and the high intratub ule concentrations with possible precipitation and crystallization of particular drugs. CHAPTER 11

11.2 Acute Renal Failure General Nephrotoxic Factors The nephron FIGURE 11-1 Sites of renal damage, including factors that contribute to the kidney's susceptibility to damage. ACEangiotensin-converting enzyme; NSAIDno nsteroidal anti-inflammatory drugs; HgCl2mercuric chloride. Sites of renal damage Cortex S1 S2 Medullary ray ACE inhibitors NSAIDs Aminoglycosides Acyclovir Cisplatinum HgCl2 Lithium S1 S2 Outer stripe Outer medulla S3 S3 Ischemia Inner stripe Vulnerability of the kidney Important blood flow (1/4 cardiac output) High metab olic activity Largest endothelial surface by weight Multiple enzyme systems Tran scellular transport Concentration of substances Protein unbinding High O2 consum ption/delivery ratio in outer medulla Inner medula

Renal Injury Due To Environmental Toxins, Drugs, and Contrast Agents 11.3 DRUGS AND CHEMICALS ASSOCIATED WITH ACUTE RENAL FAILURE Mechanisms M1 Reduction in renal perfusion through alteration of intrarenal hemo dynamics M2 Direct tubular toxicity M3 Heme pigmentinduced toxicity (rhabdomyolys is) M4 Intratubular obstruction by precipitation of the agents or its metabolites or byproducts M5 Allergic interstitial nephritis M6 Hemolytic-uremic syndrome M1 M2 M3 M4 M5* M6 Drugs Cyclosporine, tacrolimus Amphotericin B, radiocontrast agents Nonsteroidal antiinflammatory drugs Angiotensin-converting enzyme inhibitors, interleukin-2 Methot rexate Aminoglycosides, cisplatin, foscarnet, heavy metals, intravenous immunoglo bulin, organic solvents, pentamidine Cocaine Ethanol, lovastatin** Sulfonamides A cyclovir, Indinavir, chemotherapeutic agents, ethylene glycol*** Allopurinol, ce phalosporins, cimetidine, ciprofloxacin, furosemide, penicillins, phenytoin, rif ampin, thiazide diuretics Conjugated estrogens, mitomycin, quinine

* Many other drugs in addition to the ones listed can cause renal failure by thi s mechanism. Interleukin-2 produces a capillary leak syndrome with volume contra ctions. Uric acid crystals form as a result of tumor lysis. The mechanism of thi s agent is unclear but may be due to additives. ** Acute renal failure is most l ikely to occur when lovastatin is given in combination with cyclosporine. *** Et hylene glycolinduced toxicity can cause calcium oxalate crystals. FIGURE 11-2 Drugs and chemicals associated with acute renal failure. (Apapted fr om Thadhani, et al. [2].)

11.4 Acute Renal Failure Aminoglycosides 1. Filtration 2. Binding Glomerulus + + Lysosomal phospholipidosis ABOVE threshold: lysosomal swelling, disruption or le akage * * BELOW threshold: exocytosis shuttle 3. Adsorptive pinocytosis Proximal tubule 4. Lysosomal trapping and storage * * * Cell necrosis regeneration Regression of drug-induced changes Aminoglycoside * * Hydrolase Toxins FIGURE 11-3 Renal handling of aminoglycosides: 1) glomerular filtration; 2) bind ing to the brush border membranes of the proximal tubule; 3) pinocytosis; and 4) storage in the lysosomes [3]. Nephrotoxicity and otovestibular toxicity remain frequent side effects that seriously limit the use of aminoglycosides, a still i mportant class of antibiotics. Aminoglycosides are highly charged, polycationic, hydrophilic drugs that cross biologic membranes little, if at all [4,5]. They a re not metabolized but are eliminated unchanged almost entirely by the kidneys. Aminoglycosides are filtered by the glomerulus at a rate almost equal to that of water. After entering the luminal fluid of proximal renal tubule, a small but t oxicologically important portion of the filtered drug is reabsorbed and stored i n the proximal tubule cells. The major transport of aminoglycosides into proxima l tubule cells involves interaction with acidic, negatively charged phospholipid -binding sites at the level of the brush border membrane. After charge-mediated binding, the drug is taken up into the cell in small invag inations of the cell membrane, a process in which megalin seems to play a role [ 6]. Within 1 hour of injection, the drug is located at the apical cytoplasmic va cuoles, called endocytotic vesicles. These vesicles fuse with lysosomes, sequest ering the unchanged aminoglycosides inside those organelles. Once trapped in the lysosomes of proximal tubule cells, aminoglycosides electrostatically attached to anionic membrane phospholipids interfere with the normal action of some enzym es (ie, phospholipases and sphingomyelinase). In parallel with enzyme inhibition , undigested phospholipids originating from the turnover of cell membranes accum ulate in lysosomes, where they are normally digested. The overall result is lyso somal phospholipidosis due to nonspecific accumulation of polar phospholipids as myeloid bodies, so called for their typical electron microscopic appearance. (Ada

pted from De Broe [3].) B FIGURE 11-4 Ultrastructural appearance of proximal tubule cells in aminoglycosid e-treated patients (4 days of therapeutic doses). Lysosomes (large arrow) contai n dense lamellar and concentric structures. Brush border, mitochondria (small ar rows) and peroxisomes are unaltered. At higher magnification the structures in l ysosomes show a periodic pattern. The bar in A represents 1 m, in part B, 0.1 m [7 ]. A

Renal Injury Due To Environmental Toxins, Drugs, and Contrast Agents 11.5 A B FIGURE 11-5 (see Color Plate) Administration of aminoglycosides for days induces progression of lysosomal phospholipidosis. The overloaded lysosomes continue to swell, even if the drug is then withdrawn. In vivo this overload may result in loss of integrity of the membranes of lysosomes and release of large amounts of lysosomal enzymes, phospholipids, and aminoglycosides into the cytosol, but this has not been proven. Thus, these aminoglycosides can gain access to and injure other organelles, such as mitochondria, and disturb their functional integrity, which leads rapidly to cell death. As a consequence of cell necrosis, A, intratu bular obstruction by cell debris increased intratubule pressure, a decrease in t he glomerular filtration rate and cellular infiltration, B, may ensue. In parall el with these lethal processes in the kidney, a striking regeneration process is observed that is characterized by a dramatic increase in tubule cell turnover a nd proliferation, C, in the cortical interstitial compartment. C 200 Vmax= 149.83 + 9.08 g/g/h Km= 15.01+1.55 g/ml Renal cortical gentamicin accumulation rate, g/g/h 150 FIGURE 11-6 A, Relationship between constant serum levels and concomitant renal cortical accumulation of gentamicin after a 6 hour intravenous infusion in rats. The rate of accumulation is expressed in micrograms of aminoglycoside per gram of wet kidney cortex per hour, due to the linear accumulation in function of tim e. Each point represents one rat whose aminoglycosides were measured in both kid neys at the end of the infusion and the serum levels assayed twice during the in fusion [8]. (Continued on next page) 100 Renal cortical gentamicin accumulation rate, g/g/h 60 40 20 0 V= 6.44 + 4.88 C r = 0.96 50 0 5 10 15 Serum gentamicin concentration, g/ml 0 0 10 20 A 30 40 50 60 70 80 Serum gentamicin concentration, g/ml 90 100

11.6 Acute Renal Failure FIGURE 11-6 (Continued) B, Kidney cortical concentrations of gentamicin in rats given equal daily amounts of aminoglycoside in single injections, three injectio ns, or by continuous infusion over 8 days. Each block represents the mean of sev en rats SD. Significance is shown only between cortical levels achieved after con tinuous infusion and single injections (asteriskP < 0.05; double asteriskP < 0.01) [9]. In rats, nephrotoxicity of gentamicin is more pronounced when the total da ily dose is administered by continuous infusion rather than as a single injectio n. Thus, a given daily drug does not produce the same degree of toxicity when it is given by different routes. Indeed, renal cortical uptake is less efficient at high serum concentration than at low ones. A single injection results in high pe ak serum levels that overcome the saturation limits of the renal uptake mechanis m. The high plasma concentrations are followed by fast elimination and, finally, absence of the drug for a while. This contrasts with the continuous low serum l evels obtained with more frequent dosing when the uptake at the level of the ren al cortex is not only more efficient but remains available throughout the treatm ent period. Vmaxmaximum velocity. 1000 Renal cortical gentamicin accumulation, g/g 800 One injection a day Three injections a day Continuous infusion Total daily dose: 10 mg/kg i.p. ** ** ** 600 400 ** ** 200 0 1 B 2 4 Days of administration 6 8 Renal cortical concentration after one day, g/g 40 35 30 Serum levels, g/ml 25 20 15 10 5 0 0 40 35 30 Serum levels, g/ml 25 20 Tobramycin 4.5 mg/kg/d Continuous infusion Single injection Gentamicin 4.5 mg/kg /d 40 35 30 25 20 15 10 5 0 4 8 12 16 20 24 90 80 70 60 50 40 Amikacin 15 mg/kg/d Continuous infusion Netilmicin 5 mg/kg/d One injection a day

Continuous infusion (n6) N.S. P< 0.05 250 200 150 100 50 0 P< 0.025 P< 0.025 Single injection B 0 4 8 12 16 20 24 Gentamicin 4.5 mg/kg Netilmicin 5 mg/kg Tobramycin 4.5 mg/kg/d Amikacin 15 mg/kg/d 15 10 5 0 0 Single injection Single injection 30 20 Continuous infusion Continuous infusion 10 0 0 24 Time, hrs 4 8 12 16 20 4 8 12 16 20 24 A FIGURE 11-7 Course of serum concentrations, A, and of renal cortical concentrati ons, B, of gentamicin, netilmicin, tobramycin, and amikacin after dosing by a 30 -minute intravenous injection or continuous infusion over 24 hours [10,11]. Two trials in humans found that the dosage schedule had a critical effect on renal u ptake of gentamicin, netilmicin [10], amikacin, and tobramycin [11]. Subjects we re patients with normal renal function (serum creatinine concentration between 0 .9 and 1.2 mg/dL, proteinuria lower than 300 mg/24 h) who had renal cancer and s ubmitted to nephrectomy. Before surgery, patients received gentamicin (4.5 mg/kg /d), netilmicin (5 mg/kg/d), amikacin (15 mg/kg/d), or tobramycin (4.5 mg/kg/d) as a single injection or as a continuous intravenous infusion over 24 hours. The single-injection schedule resulted in 30% to 50% lower cortical drug concentrat ions of netilmicin, gentamicin, and amikacin as compared with continuous infusio

n. For tobramycin, no difference in renal accumulation could be found, indicatin g the linear cortical uptake of this particular aminoglycoside [8]. These data, which supported decreased nephrotoxic potential of single-dose regimens, coincid ed with new insights in the antibacterial action of aminoglycosides (concentrati on-dependent killing of gram-negative bacteria and prolonged postantibiotic effe ct) [12]. N.S.not significant.

Renal Injury Due To Environmental Toxins, Drugs, and Contrast Agents 11.7 RISK FACTORS FOR AMINOGLYCOSIDE NEPHROTOXICITY Patient-Related Factors Older age* Preexisting renal disease Female gender Magnesium, potassium, or calc ium deficiency* Intravascular volume depletion* Hypotension* Hepatorenal syndrom e Sepsis syndrome Aminoglycoside-Related Factors Recent aminoglycoside therapy Larger doses* Treatment for 3 days or more* Other Drugs Amphotericin B Cephalosporins Cisplatin Clindamycin Cyclosporine Foscarnet Furos emide Piperacillin Radiocontrast agents Thyroid hormone Dose regimen* * Similar to experimental data. FIGURE 11-8 Risk factors for aminoglycoside nephrotoxicity. Several risk factors have been identified and classified as patient related, aminoglycoside related, or related to concurrent administration of certain drugs. The usual recommended aminoglycoside dose may be excessive for older patients because of decreased re nal function and decreased regenerative capacity of a damaged kidney. Preexistin g renal disease clearly can expose patients to inadvertent overdosing if careful dose adjustment is not performed. Hypomagnesemia, hypokalemia, and calcium defi ciency may be predisposing risk factors for consequences of aminoglycoside-induc ed damage [13]. Liver disease is an important clinical risk factor for aminoglyc oside nephrotoxicity, particularly in patients with cholestasis [13]. Acute or c hronic endotoxemia amplifies the nephrotoxic potential of the aminoglycosides [1 4]. PREVENTION OF AMINOGLYCOSIDE NEPHROTOXICITY Identify risk factor Patient related Drug related Other drugs Give single daily dose of gentamicin, netilmicin, or amikacin Reduce the treatment course as much as possible Avoid giving nephrotoxic drugs concurrently Make interval between am inoglycoside courses as long as possible Calculate glomerular filtration rate ou t of serum creatinine concentration FIGURE 11-9 Prevention of aminoglycoside nephrotoxicity. Coadministration of oth er potentially nephrotoxic drugs enhances or accelerates the nephrotoxicity of a minoglycosides. Comprehension of the pharmacokinetics and renal cell biologic ef fects of aminoglycosides, allows identification of aminoglycoside-related nephro toxicity risk factors and makes possible secondary prevention of this important clinical nephrotoxicity.

11.8 Acute Renal Failure Amphotericin B Water Phospholipid Lipid Cholesterol FIGURE 11-10 Proposed partial model for the amphotericin B (AmB)induced pore in t he cell membrane. AmB is an amphipathic molecule: its structure enhances the dru g's binding to sterols in the cell membranes and induces formation of aqueous pore s that result in weakening of barrier function and loss of protons and cations f rom the cell. The drug acts as a counterfeit phospholipid, with the C15 hydroxyl , C16 carboxyl, and C19 mycosamine groups situated at the membrane-water interfa ce, and the C1 to C14 and C20 to C33 chains aligned in parallel within the membr ane. The heptaene chain seeks a hydrophobic environment, and the hydroxyl groups seek a hydrophilic environment. Thus, a cylindrical pore is formed, the inner w all of which consists of the hydroxyl-substituted carbon chains of the AmB molec ules and the outer wall of which is formed by the heptaene chains of the molecul es and by sterol nuclei [15]. C20-C33 heptaene segment Amphotericin B Pore C O N H

Renal Injury Due To Environmental Toxins, Drugs, and Contrast Agents 11.9 RISK FACTORS IN THE DEVELOPMENT OF AMPHOTERICIN NEPHROTOXICITY Age Concurrent use of diuretics Abnormal baseline renal function Larger daily do ses Hypokalemia Hypomagnesemia Other nephrotoxic drugs (aminoglycosides, cyclosp orine) FIGURE 11-11 Risk factors for development of amphotericin B (AmB) nephrotoxicity . Nephrotoxicity of AmB is a major problem associated with clinical use of this important drug. Disturbances in both glomerular and tubule function are well des cribed. The nephrotoxic effect of AmB is initially a distal tubule phenomenon, c haracterized by a loss of urine concentration, distal renal tubule acidosis, and wasting of potassium and magnesium, but it also causes renal vasoconstriction l eading to renal ischemia. Initially, the drug binds to membrane sterols in the r enal vasculature and epithelial cells, altering its membrane permeability. AmB-i nduced vasoconstriction and ischemia to very vulnerable sections of the nephron, such as medullary thick ascending limb, enhance the cell death produced by dire ct toxic action of AmB on those cells. This explains the salutary effect on AmB nephrotoxicity of salt loading, furosemide, theophylline, or calcium channel blo ckers, all of which improve renal blood flow or inhibit transport in the medulla ry thick ascending limb. FIGURE 11-12 Proposed approach for management of amphot ericin B (AmB) therapy. Several new formulations of amphotericin have been devel oped either by incorporating amphotericin into liposomes or by forming complexes to phospholipid. In early studies, nephrotoxicity was reduced, allowing an incr ease of the cumulative dose. Few studies have established a therapeutic index be tween antifungal and nephrotoxic effects of amphotericin. To date, the only clin ically proven intervention that reduces the incidence and severity of nephrotoxi city is salt supplementation, which should probably be given prophylactically to all patients who can tolerate it. (From Bernardo JF, et al. [16]; with permissi on.) Indication for amphotericin B therapy Clinical evaluation: Is patient salt depleted? yes Correction: Correct salt depletion Avoid diuretics Liberalize dietary sodium Wei gh risk-benefit ratio Seek alternatives Select drug with high salt content Corre ct abnormalities Begin amphotericin B therapy Will salt loading exacerbate underlying disease? Does patient require concommita nt antibiotics? Is potassium (K) or magnesium (Mg) depleted? No yes yes yes Begin amphotericin B with sodium supplement, 150 mEq/d Routine Monitoring: Clinical evaluation (cardiovascular/respiratory status; body weight; fluid intak e and excretion) Laboratory tests (renal function; serum electrolyte levels; 24 -hours urinary electrolyte excretion) Clinical evaluation: Is patient vomiting? No yes Increase salt load Correction: Laboratory evaluation: Is serum creatinine >3 mg/dL or is renal deterioration ra pid? creratinine >3 mg/dL or is renal deterioration rapid? Is K level ,3.5 mEq/L or Mg level <1.6 mEq/L? No yes

Interrupt amphotericin B therapy, resume on improvement Use oral or intravenous supplementation yes Continue amphotericin B therapy and routine monitoring Close follow-up of serum electrolytes

11.10 Acute Renal Failure Cyclosporine release of vasoconstrictor prostaglandins such as thromboxane A2, and activation of the sympathetic nervous system, are among the candidates for cyclosporine-in duced vasoconstriction [18]. The diagnosis of cyclosporine-induced acute renal d ysfunction is not difficult when the patient has no other reason for reduced ren al function (eg, psoriasis, rheumatoid arthritis). In renal transplant recipient s, however, the situation is completely different. In this clinical setting, the clinician must differentiate between cyclosporine injury and acute rejection. T he incidence of this acute cyclosporine renal injury can be enhanced by extended graft preservation, preexisting histologic lesions, donor hypotension, or preop erative complications. The gold standard for this important distinction remains renal biopsy. In addition, cyclosporine has been associated with hemolytic-uremi c syndrome with thrombocytopenia, red blood cell fragmentation, and intravascula r (intraglomerular) coagulation. Again, this drug-related intravascular coagulat ion has to be differentiated from that of acute rejection. The absence of clinic al signs and of rejection-related interstitial edema and cellular infiltrates ca n be helpful. Vanrenterghem and coworkers [19] found a high incidence of venous thromboembolism shortly after (several of them within days) cadaveric kidney tra nsplantation in patients treated with cyclosporine, in contrast to those treated with azathioprine. Recent studies [20] have shown that impaired fibrinolysis, d ue mainly to excess plasminogen activator inhibitor (PAI-1), may also contribute to this imbalance in coagulation and anticoagulation during cyclosporine treatm ent. FIGURE 11-13 (see Color Plate) Intravascular coagulation in a cyclosporine-treat ed renal transplant recipient. Cyclosporine produces a dose-related decrease in renal function in experimental animals and humans [17] that is attributed to the drug's hemodynamic action to produce vasoconstriction of the afferent arteriole e ntering the glomerulus. When severe enough, this can decrease glomerular filtrat ion rate. Although the precise pathogenesis of the renal hemodynamic effects of cyclosporine are unclear, endothelin, inhibition of nitric oxide, Lithium-Induced Acute Renal Failure SIGNS AND SYMPTOMS OF TOXIC EFFECTS OF LITHIUM Toxic Effect Mild Plasma Lithium Level 11.5 mmol/L Signs and Symptoms Impaired concentration, lethargy, irritability, muscle weakness, tremor, slurred speech, nausea Disorientation, confusion, drowsiness, restlessness, unsteady ga it, coarse tremor, dysarthria, muscle fasciculation, vomiting Impaired conscious ness (with progression to coma), delirium, ataxia, generalized fasciculations, e xtrapyramidal symptoms, convulsions, impaired renal function Moderate 1.62.5 mmol/L Severe >2.5 mmol/L FIGURE 11-14 Symptoms and signs of toxic effects of lithium. Lithium can cause a

cute functional and histologic (usually reversible) renal injury. Within 24 hour s of administration of lithium to humans or animals, sodium diuresis occurs and impairment in the renal concentrating capacity becomes apparent. The defective c oncentrating capacity is caused by vasopressin-resistant (exogenous and endogeno us) diabetes insipidus. This is in part related to lithium's inhibition of adenyla te cyclase and impairment of vasopressin-induced generation of cyclic adenosine monophosphatase. Lithium-induced impairment of distal urinary acidification has also been defined. Acute lithium intoxication in humans and animals can cause ac ute renal failure. The clinical picture features nonspecific signs of degenerati ve changes and necrosis of tubule cells [21]. The most distinctive and specific acute lesions lie at the level of the distal tubule [22]. They consist of swelli ng and vacuolization of the cytoplasm of the distal nephron cells plus periodic acid-Schiffpositive granular material in the cytoplasm (shown to be glycogen) [23 ]. Most patients receiving lithium have side effects, reflecting the drug's narrow therapeutic index.

Renal Injury Due To Environmental Toxins, Drugs, and Contrast Agents 11.11 DRUG INTERACTIONS WITH LITHIUM Salt depletion strongly impairs renal elimination of lithium. Salt loading incre ases absolute and fractional lithium clearance. Diuretics Acetazolamide Thiazide s Loop diuretics Amiloride Increased lithium clearance Increased plasma lithium level due to decreased lithium clearance Acute increased lithium clearance Usual ly no change in plasma lithium level; may be used to treat lithium-induced polyu ria Increased plasma lithium level due to decreased renal lithium clearance (exc eptions are aspirin and sulindac) Decreased plasma lithium level due to increase d renal lithium clearance May increase plasma lithium level Decreased lithium cl earance Nonsteroidal anti-inflammatory drugs Bronchodilators (aminophylline, theophyllin e) Angiotensin-converting enzyme inhibitors Cyclosporine FIGURE 11-15 Drug interactions with lithium [24]. Acute renal failure, with or w ithout oliguria, can be associated with lithium treatment, and with severe dehyd ration. In this case, acute renal failure can be considered a prerenal type; con sequently, it resolves rapidly with appropriate fluid therapy. Indeed, the histo logic appearance in such cases is remarkable for its lack of significant abnorma lities. Conditions that stimulate sodium retention and consequently lithium reab sorption, such as low salt intake and loss of body fluid by way of vomiting, dia rrhea, or diuretics, decreasing lithium clearance should be avoided. With any ac ute illness, particularly one associated with gastrointestinal symptoms such as diarrhea, lithium blood levels should be closely monitored and the dose adjusted when necessary. Indeed, most episodes of acute lithium intoxication are largely predictable, and thus avoidable, provided that precautions are taken [25]. Remo ving lithium from the body as soon as possible the is the mainstay of treating l ithium intoxication. With preserved renal function, excretion can be increased b y use of furosemide, up to 40 mg/h, obviously under close monitoring for excessi ve losses of sodium and water induced by this loop diuretic. When renal function is impaired in association with severe toxicity, extracorporeal extraction is t he most efficient way to decrease serum lithium levels. One should, however, rem ember that lithium leaves the cells slowly and that plasma levels rebound after hemodialysis is stopped, so that longer dialysis treatment or treatment at more frequent intervals is required. Inhibitors of the Renin-Angiotensin System Pre-kallikrein Angiotensinogen Renin + Angiotensin I + Angiotensin II Angiotensi n converting enzyme Kininase II Kininogen Activated factor XII + Kallikrenin Bra dykinin + Inactive peptide + Arachidonic acid + : stimulation Increased aldosterone release Potentiation of sympathetic activity Increased Ca2 + current Prostaglandins A Vasoconstriction Vasodilation Cough? FIGURE 11-16 Soon after the release of this useful class of antihypertensive dru

gs, the syndrome of functional acute renal insufficiency was described as a clas s effect. This phenomenon was first observed in patients with renal artery steno sis, particularly when the entire renal mass was affected, as in bilateral renal artery stenosis or in renal transplants with stenosis to a solitary kidney [26] . Acute renal dysfunction appears to be related to loss of postglomerular efferent arteriolar vascular tone and in general is reversible after withdrawing the angiotensin-converting enzyme (ACE) inhibitor [27]. Inhibition of the ACE k inase II results in at least two important effects: depletion of angiotensin II and accumulation of bradykinin [28]. The role of the latter effect on renal perf usion pressure is not clear, A. To understand the angiotensin I converting enzym e inhibitorinduced drop in glomerular filtration rate, it is important to underst and the physiologic role of the renin-angiotensin system in the regulation of re nal hemodynamics, B. When renal perfusion drops, renin is released into the plas ma and lymph by the juxtaglomerular cells of the kidneys. Renin cleaves angioten sinogen to form angiotensin I, which is cleaved further by converting enzyme to form angiotensin II, the principal effector molecule in this system. Angiotensin II participates in glomerular filtration rate regulation in a least two ways. F irst, angiotensin II increases arterial pressuredirectly and acutely by causing v asoconstriction and more chronically by increasing body fluid volumes through stim ulation of renal sodium retention; directly through an effect on the tubules, as well as by stimulating thirst (Continued on next page)

11.12 Acute Renal Failure : vasodilation Autoregulation + Afferent arteriole Myogenic reflex (Laplace) Tubu loglomerular feedback Glomerulus +: vasoconstriction B1. Normal condition + Efferent arteriole Tubule B2. Perfusion pressure reduced but still within autoregulatory range (congestive heart failure, renal artery stenosis, diuretic therapy, nephrotic syndrome cirr hosis, sodium restriction depletion, advanced age [age >80]) PGE2 + Local angiotensin II PGE2 Intraglomerular pressure B3. Perfusion pressure seriously reduced (prerenal azotemia) + + Local angiotensin II B Sympathetic activity angiotensin II FIGURE 11-16 (Continued) and indirectly via aldosterone. Second, angiotensin II preferentially constricts the efferent arteriole, thus helping to preserve glome rular capillary hydrostatic pressure and, consequently, glomerular filtration ra te. When arterial pressure or body fluid volumes are sensed as subnormal, the re ninangiotensin system is activated and plasma renin activity and angiotensin II levels increase. This may occur in the context of clinical settings such as rena l artery stenosis, dietary sodium restriction or sodium depletion as during diuretic therapy, conge stive heart failure, cirrhosis, and nephrotic syndrome. When activated, this ren inangiotensin system plays an important role in the maintenance of glomerular pr essure and filtration through preferential angiotensin IImediated constriction of the efferent arteriole. Thus, under such conditions the kidney becomes sensitiv e to the effects of blockade of the reninangiotensin system by angiotensin Iconve rting enzyme inhibitor or angiotensin II receptor antagonist. The highest incide nce of renal failure in patients treated with ACE inhibitors was associated with bilateral renovascular disease [27]. In patients with already compromised renal function and congestive heart failure, the incidence of serious changes in seru m creatinine during ACE inhibition depends on the severity of the pretreatment h eart failure and renal failure. Volume management, dose reduction, use of relati vely short-acting ACE inhibitors, diuretic holiday for some days before initiati ng treatment, and avoidance of concurrent use of nonsteroidal antiinflammatory d rug (hyperkalemia) are among the appropriate measures for patients at risk. Acut e interstitial nephritis associated with angiotensin Iconverting enzyme inhibitio n has been described [29]. (Adapted from Opie [30]; with permission.) Nonsteroidal Anti-inflammatory Drugs Patients at risk for NSAID-induced acute renal failure -Renin-angiotensin axis -Angi

otensin II -Adrenergic nervous system -Catecholamines Renal vasoconstriction Renal function "Normalized" renal function Inhibition by NSAID FIGURE 11-17 Mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) di srupt the compensatory vasodilatation response of renal prostaglandins to vasoco nstrictor hormones in patients with prerenal conditions. Most of the renal abnor malities encountered clinically as a result of NSAIDs can be attributed to the a ction of these compounds on prostaglandin production in the kidney [31]. Sodium chloride and water retention are the most common side effects of NSAIDs. This sh ould not be considered drug toxicity because it represents a modification of a p hysiologic control mechanism without the production of a true functional disorde r in the kidney. Compensatory vasodilation induced by renal prostaglandin synthesis

Renal Injury Due To Environmental Toxins, Drugs, and Contrast Agents 11.13 PREDISPOSING FACTORS FOR NSAIDINDUCED ACUTE RENAL FAILURE Severe heart disease (congestive heart failure) Severe liver disease (cirrhosis) Nephrotic syndrome (low oncotic pressure) Chronic renal disease Age 80 years or older Protracted dehydration (several days) FIGURE 11-18 Conditions associated with risk for nonsteroidal anti-inflammatory drugs (NSAID)-induced acute renal failure. NSAIDs can induce acute renal decompe nsation in patients with various renal and extrarenal clinical conditions that c ause a decrease in blood perfusion to the kidney [32]. Renal prostaglandins play an important role in the maintenance of homeostasis in these patients, so disru ption of counter-regulatory mechanisms can produce clinically important, and eve n severe, deterioration in renal function. Physiologic stimulus Inflammatory stimuli COX-1 constitutive Stomach Kidney Intestine Platelets Endothelium PGE2 TxA2 PGI2 Inhibition by NSAID COX-2 inducible Inflammatory sites (macrophages, synoviocytes) Inflammatory PGs Proteases O2 Physiologic functions Inflammation FIGURE11-19 Inhibition by nonsteroidal anti-inflammatory drugs (NSAIDs) on pathw ays of cyclo-oxygenase (COX) and prostaglandin synthesis [33]. The recent demons tration of the existence of functionally distinct isoforms of the cox enzyme has major clinical significance, as it now appears that one form of cox is operativ e in the gastric mucosa and kidney for prostaglandin generation (COX-1) whereas an inducible and functionally distinct form of cox is operative in the productio n of prostaglandins in the sites of inflammation and pain (COX-2) [33]. The clin ical therapeutic consequence is that an NSAID with inhibitory effects dominantly or exclusively upon the cox isoenzyme induced at a site of inflammation may pro duce the desired therapeutic effects without the hazards of deleterious effects on the kidneys or gastrointestinal tract. PGprostaglandin; TxA2thromboxane A2.

11.14 Acute Renal Failure unusual combination of findings and in the setting of protracted NSAID use is vi rtually pathognomic of NSAID-related nephrotic syndrome. A focal diffuse inflamm atory infiltrate can be found around the proximal and distal tubules. The infilt rate consists primarily of cytotoxic T lymphocytes but also contains other T cel ls, some B cells, and plasma cells. Changes in the glomeruli are minimal and res emble those of classic minimalchange glomerulonephritis with marked epithelial f oot process fusion. Hyperkalemia, an unusual complication of NSAIDs, is more lik ely to occur in patients with pre-existing renal impairment, cardiac failure, di abetes, or multiple myeloma or in those taking potassium supplements, potassiumsparing diuretic therapy, or intercurrent use of an angiotensin-converting enzym e inhibitor. The mechanism of NSAID hyperkalemiasuppression of prostaglandin-medi ated renin releaseleads to a state of hyporeninemic hypoaldosteronism. In additio n, NSAIDs, particularly indomethacin, may have a direct effect on cellular uptak e of potassium. The renal saluretic response to loop diuretics is partially a co nsequence of intrarenal prostaglandin production. This component of the response to loop diuretics is mediated by an increase in renal medullary blood flow and an attendant reduction in renal concentrating capacity. Thus, concurrent use of an NSAID may blunt the diuresis induced by loop diuretics. EFFECTS OF NSAIDS ON RENAL FUNCTION Renal Syndrome Sodium retension and edema Hyperkalemia Mechanism Prostaglandin Prostaglandin Potassium to distal tubule Aldosterone/reninangioten sin Risk Factors NSAID therapy (most common side effect) Renal disease Heart failure Diabetes Mul tiple myeloma Potassium therapy Potassium-sparing diuretic Liver disease Renal d isease Heart failure Dehydration Old age Fenoprofen Combination aspirin and acet aminophen abuse Prevention/Treatment [34] Stop NSAID Stop NSAID Avoid use in high-risk patients Acute deterioration of renal function Prostaglandin and disruption of hemodynamic balance - Lymphocyte recruitment and a ctivation Direct toxicity Stop NSAID Avoid use in high-risk patients Nephrotic syndrome with: Interstitial nephritis Papillary necrosis Stop NSAID Dialysis and steroids (?) Stop NSAID Avoid long-term analgesic use FIGURE 11-20 Summary of effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on renal function [31]. All NSAIDs can cause another type of renal dysfunction that is associated with various levels of functional impairment and characterize d by the nephrotic syndrome together with interstitial nephritis. Characteristic ally, the histology of this form of NSAIDinduced nephrotic syndrome consists of m inimal-change glomerulonephritis with tubulointerstitial nephritis. This is an Contrast MediumAssociated Nephrotoxicity RISK FACTORS THAT PREDISPOSE TO CONTRAST ASSOCIATED NEPHROPATHY Confirmed

Chronic renal failure Diabetic nephropathy Severe congestive heart failure Amoun t and frequency of contrast media Volume depletion or hypotension Suspected Hypertension Generalized atherosclerosis Abnormal liver function tests Hyperuric emia Proteinuria Disproved Myeloma Diabetes without nephropathy FIGURE 11-21 Risk factors that predispose to contrast-associated nephropathy. In random populations undergoing radiocontrast imaging the incidence of contrasts associated nephropathy defined by a change in serum creatinine of more than 0.5 mg/dL or a greater than 50% increase over baseline, is between 2% and 7%. For co nfirmed high-risk patients (baseline serum creatinine values greater than 1.5 mg /dL) it rises to 10% to 35%. In addition, there are suspected risk factors that should be taken into consideration when considering the value of contrast-enhanc ed imaging.

Renal Injury Due To Environmental Toxins, Drugs, and Contrast Agents 11.15 Hypersomolar radiocontrast medium Systemic -Endothelin ATPase hypoxemia -Vasopressin -A denosine -Blood viscosity Osmotic load to distal tubule PGI2 -PGE2 -ANF -RBF RBF Calcium antagonists Theophylline Net O2 delivery Net -O2 consumption Cell injury -TH protein -Intrarenal number of macrophages, T cells Stimulation of me sangium Superoxidase dismutase Tubular obstruction RBF GFR Reactive O2 species lipid peroxidase Contrast associated nephropathy FIGURE 11-22 A proposed model of the mechanisms involved in radiocontrast mediumi nduced renal dysfunction. Based on experimental models, a consensus is developing to the effect that contrast-associated nephropath y involves combined toxic and hypoxic insults to the kidney [35]. The initial gl omerular vasoconstriction that follows the injection of radiocontrast medium ind uces the liberation of both vasoconstrictor (endothelin, vasopressin) and vasodi lator (prostaglandin E2 [PGE2], adenosine, atrionatiuretic factor {ANP}) substan ces. The net effect is reduced oxygen delivery to tubule cells, especially those in the thick ascending limb of Henle. Because of the systemic hypoxemia, raised blood viscosity, inhibition of sodium-potassiumactivated ATPase and the increase d osmotic load to the distal tubule at a time of reduced oxygen delivery, the de mand for oxygen increases, resulting in cellular hypoxia and, eventually cell de ath. Additional factors that contribute to the acute renal dysfunction of contra st-associated nephropathy are the tubule obstruction that results from increased secretion of Tamm-Horsfall proteins and the liberation of reactive oxygen speci es and lipid peroxidation that accompany cell death. As noted in the figure, cal cium antagonists and theophylline (adenosine receptor antagonist) are thought to act to diminish the degree of vasoconstriction induced by contrast medium. The clinical presentation of contrast-associated nephropathy involves an asymptomati c increase in serum creatinine within 24 hours of a radiographic imaging study u sing contrast medium, with or without oliguria [36]. We have recently reviewed t he clinical outcome of 281 patients with contrast-associated nephropathy accordi ng to the presence or absence of oliguric acute renal failure at the time of dia gnosis. Of oliguric acute renal failure patients, 32% have persistent elevations of serum creatinine at recovery and half require permanent dialysis. In the abs ence of oliguric acute renal failure the serum creatinine value does not return to baseline in 24% of patients, approximately a third of whom require permanent dialysis. Thus, this is not a benign condition but rather one whose defined risk s are not only permanent dialysis but also death. GFRglomerular filtration rate; RBFrenal blood flow; THTamm Horsfall protein. Thus it is important to select the l east invasive diagnostic procedure that provides the most information, so that t he patient can make an informed choice from the available clinical alternatives. Since radiographic contrast imaging is frequently performed for diabetic nephro

pathy, congestive heart failure, or chronic renal failure, concurrent administra tion of renoprotective agents has become an important aspect of imaging. A list of maneuvers that minimize the risk of contrast-associated nephropathy is contai ned in this table. The correction of prestudy volume depletion and the use of ac tive hydration before and during the procedure are crucial to minimizing the ris k of contrast-associated nephropathy. Limiting the total volume of contrast medi um and using nonionic, isoosmolar media have proven to be protective for high-ri sk patients. Pretreatment with calcium antagonists is an intriguing but unsubsta ntiated approach. PREVENTION OF CONTRAST ASSOCIATED NEPHROPATHY Hydrate patient before the study (1.5 mL/kg/h) 12 h before and after. Hemodynami cally stabilize hemodynamics. Minimize amount of contrast medium administered. U se nonionic, iso-osmolar contrast media for patients at high risk (see Figure 11 -21). FIGURE 11-23 Prevention of contrast-associated nephropathy. The goal of manageme nt is the prevention of contrast-associated nephropathy.

11.16 Acute Renal Failure References 1. Bennett WM, Porter GA: Overview of clinical nephrotoxicity. In Toxicology of the Kidney, edn 2. Edited by Hook JB, Goldstein RS. Raven Press, 1993:6197. 2. Th adhani R, Pascual M, Bonventre JV: Acute renal failure. N Engl J Med 1996, 334:1 4481460. 3. De Broe ME: Prevention of aminoglycoside nephrotoxicity. In Proc EDTA -ERA. Edited by Davison AM, Guillou PJ. London:Baillire Tindal, 1985:959973. 4. Li etman PS: Aminoglycosides and spectinoycin: aminocylitols. In Principles and Pra ctice of Infectious Diseases, edn 2, Part I. Edited by Mandel GL, Doublas RG Jr, Bennett JE. New York: John Wiley & Sons, 1985:192206. 5. Kaloyanides GJ, Pastori za-Munoz E: Aminoglycoside nephrotoxicity. Kidney Int 1980, 18:571582. 6. Molitor is BA. Cell biology of aminoglycoside nephrotoxicity: newer aspects. Curr Opin N ephrol Hypertens 1997, 6:384388. 7. De Broe ME, Paulus GJ, Verpooten GA, et al.: Early effects of gentamicin, tobramycin, and amikacin on the human kidney. Kidne y Int 1984, 25:643652. 8. Giuliano RA, Verpooten GA, Verbist L, et al.: In vivo u ptake kinetics of aminoglycosides in the kidney cortex of rats. J Pharmacol Exp Ther 1986, 236:470475. 9. Giuliano RA, Verpooten GA, De Broe ME: The effect of do sing strategy on kidney cortical accumulation of aminoglycosides in rats. Am J K idney Dis 1986, 8:297303. 10. Verpooten GA, Giuliano RA, Verbist L, et al.: A onc e-daily dosage schedule decreases the accumulation of gentamicin and netilmicin in the renal cortex of humans. Clin Pharmacol Ther 1989, 44:15. 11. De Broe ME, V erbist L, Verpooten GA: Influence of dosage schedule on renal cortical accumulat ion of amikacin and tobramycin in man. J Antimicrob Chemother 1991, 27 (suppl C) :4147. 12. Bennett WM, Plamp CE, Gilbert DN, et al.: The influence of dosage regi men on experimental gentamicin nephrotoxicity: dissociation of peak serum levels from renal failure. J Infect Dis 1979, 140:576580. 13. Moore RD, Smith CR, Lipsk y JJ, et al.: Risk factors for nephrotoxicity in patients treated with aminoglyc osides. Ann Intern Med 1984, 100:352357. 14. Zager RA: A focus of tissue necrosis increases renal susceptibility to gentamicin administration. Kidney Int 1988; 3 3:8490. 15. Andreoli TE: On the anatomy of amphotericin B-cholesterol pores in li pid bilayer membranes. Kidney Int 1973, 4:33745. 16. Bernardo J, Sabra R, Branch RA: Amphotericin B. In Clinical NephrotoxinsRenal Injury From Drugs and Chemicals . Edited by De Broe ME, Porter GA, Bennett WM, Verpooten GA. Dordrecht: Kluwer A cademic, 1998:135151. 17. Bennett WM: Mechanisms of acute and chronic nephrotoxic ity from immunosuppressive drugs. Renal Failure 1996, 18:453460. 18. de Mattos AM , Olyaei AJ, Bennett WM: Pharmacology of immunosuppressive medications used in r enal diseases and transplantation. Am J Kidney Dis 1996, 28:631667. 19. Vanrenter ghem Y, Lerut T, Roels L, et al.: Thromboembolic complications and haemostatic c hanges in cyclosporin-treated cadaveric kidney allograft recipients. Lancet 1985 , 1:9991002. 20. Verpooten GA, Cools FJ, Van der Planken MG, et al.: Elevated pla sminogen activator inhibitor levels in cyclosporin-treated renal allograft recip ients. Nephrol Dial Transplant 1996, 11:347351. 21. Vestergaard P, Amdisen A, Han sen AE, Schou M: Lithium treatment and kidney function. Acta Psychiatry Scand 19 79; 60:504520. 22. Johnson GF, Hunt G, Duggin GG, et al.: Renal function and lith ium treatment: initial and follow-up tests in manic-depressive patients. J Affec tive Disord 1984; 6:249263. 23. Coppen A, Bishop ME, Bailey JE, et al.: Renal fun ction in lithium and nonlithium-treated patients with affective disorders. Acta P sychiatry Scand 1980; 62:343355. 24. Battle DC, Dorhout-Mees EJ: Lithium and the kidney. In Clinical nephrotoxinsrenal injury from drugs and chemicals. Edited by De Broe ME, Porter GA, Bennett WM, Verpooten GA. Dordrecht: Kluwer Academic, 199 8:383395. 25. Jorgensen F, Larsen S, Spanager E, et al.: Kidney function and quan titative histological changes in patients on long-term lithium therapy. Acta Psy chiatry Scand 1984, 70:455462. 26. Hricik DE, Browning PJ, Kopelman R, et al.: Ca ptopril-induced functional renal insufficiency in patients with bilateral renal artery stenosis or renal artery stenosis in a solitary kidney. N Engl J Med 1983 , 308:373376. 27. Textor SC: ACE inhibitors in renovascular hypertension. Cardiov asc Drugs Ther 1990; 4:229235. 28. de Jong PE, Woods LL: Renal injury from angiot

ensin I converting enzyme inhibitors. In Clinical nephrotoxinsrenal injury from d rugs and chemicals. Edited by De Broe ME, Porter GA, Bennett WM, Verpooten GA. D ordrecht: Kluwer Academic, 1998:239250. 29. Smith WR, Neil J, Cusham WC, Butkus D E: Captopril associated acute interstitial nephritis. Am J Nephrol 1989, 9:230235 . 30. Opie LH: Angiotensin-converting enzyme inhibitors. New York: Willy-Liss, 1 992; 3. 31. Whelton A, Watson J: Nonsteroidal anti-inflammatory drugs: effects o n kidney function. In Clinical NephrotoxinsRenal Injury From drugs and Chemicals. Edited by De Broe ME, Porter GA, Bennett WM, Verpooten GA. Dordrecht: Kluwer Ac ademic, 1998:203216. 32. De Broe ME, Elseviers MM: Analgesic nephropathy. N Engl J Med 1998, 338:446452. 33. Mitchell JA, Akarasereenont P, Thiemermann C, et al.: Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutiv e and inducible cyclooxygenase. Proc Natl Acad Sci USA 1993, 90(24):1169311697. 3 4. Bennett WM, Henrich WL, Stoff JS: The renal effects of nonsteroidal anti-infl ammatory drugs: summary and recommendations. Am J Kidney Dis 1996, 28(1 Suppl 1) :S56S62. 35. Heyman SN, Rosen S, Brezis M: Radiocontrast nephropathy: a paradigm for the synergism between toxic and hypoxic insults in the kidney. Exp Nephrol 1 994, 2:153. 36. Porter GA, Kremer D: Contrast associated nephropathy: presentati on, pathophysiology and management. In Clinical nephrotoxinsRenal Injury From Dru gs and Chemicals. Edited by De Broe ME, Porter GA, Bennett WM, Verpooten GA. Dor drecht: Kluwer Academic, 1998:317331.

Diagnostic Evaluation of the Patient with Acute Renal Failure Brian G. Dwinnell Robert J. Anderson A cute renal failure (ARF) is abrupt deterioration of renal function sufficient to result in failure of urinary elimination of nitrogenous waste products (urea ni trogen and creatinine). This deterioration of renal function results in elevatio ns of blood urea nitrogen and serum creatinine concentrations. While there is no disagreement about the general definition of ARF, there are substantial differe nces in diagnostic criteria various clinicians use to define ARF (eg, magnitude of rise of serum creatinine concentration). From a clinical perspective, for per sons with normal renal function and serum creatinine concentration, glomerular f iltration rate must be dramatically reduced to result in even modest increments (eg, 0.1 to 0.3 mg/dL) in serum creatinine concentration. Moreover, several stud ies demonstrate a direct relationship between the magnitude of serum creatinine increase and mortality from ARF. Thus, the clinician must carefully evaluate all cases of rising serum creatinine. The process of urine formation begins with de livery of blood to the glomerulus, filtration of the blood at the glomerulus, fu rther processing of the filtrate by the renal tubules, and elimination of the fo rmed urine by the renal collecting system. A derangement of any of these process es can result in the clinical picture of rapidly deteriorating renal function an d ARF. As the causes of ARF are multiple and since subsequent treatment of ARF d epends on a clear delineation of the cause, prompt diagnostic evaluation of each case of ARF is necessary. CHAPTER 12

12.2 Acute Renal Failure RATIONALE FOR ORGANIZED APPROACH TO ACUTE RENAL FAILURE PRESENTING FEATURES OF ACUTE RENAL FAILURE Common Present in 1%2% of hospital admissions Develops after admission in 1%5% of noncritically ill patients Develops in 5%20% after admission to an intensive care unit Multiple causes Prerenal Postrenal Renal Therapy dependent upon diagnosing cause Prerenal: improve renal perfusion Postrenal: relieve obstruction Renal: i dentify and treat specific cause Poor outcomes Twofold increased length of stay Two- to eightfold increased mortality Substantial morbidity Common Rising BUN or creatinine Oligoanuria Less common Symptoms of uremia Chara cteristic laboratory abnormalities FIGURE 12-1 Rationale for an organized approach to acute renal failure (ARF). An organized approach to the patient with ARF is necessary, as this disorder is co mmon and is caused by several insults that operate via numerous mechanisms. Succ essful amelioration of the renal failure state depends on early identification a nd treatment of the cause of the disorder [17]. If not diagnosed and treated and reversed quickly, it can lead to substantial morbidity and mortality. FIGURE 12-2 Presenting features of acute renal failure (ARF). ARF usually comes to clinical attention by the finding of either elevated (or rising) blood urea n itrogen (BUN) or serum creatinine concentration. Less commonly, decreased urine output ( less than 20 mL per hour) heralds the presence of ARF. It is important to acknowledge, however, that at least half of all cases of ARF are nonoliguric [26]. Thus, healthy urine output does not ensure normal renal function. Rarely, A RF comes to the attention of the clinician because of symptoms of uremia (eg, an orexia, nausea, vomiting, confusion, pruritus) or laboratory findings compatible with renal failure (metabolic acidosis, hyperkalemia, hyperphosphatemia, hypoca lcemia, hyperuricemia, hypermagnesemia, anemia). Blood Urea Nitrogen, Creatinine, and Renal Failure OVERVIEW OF BLOOD UREA NITROGEN AND SERUM CREATININE Blood Urea Nitrogen Source Constancy of production Renal handling Value as marker for glomerular fil tration rate Correlation with uremic symptoms Protein that can be of exogenous o r endogenous origin Variable Completely filtered; significant tubular reabsorpti on Modest Good Serum Creatinine Nonenzymatic hydrolysis of creatine released from skeletal muscle More stable Co mpletely filtered; some tubular secretion Good in steady state Poor FIGURE 12-3 Overview of blood urea nitrogen (BUN) and serum creatinine. Given th e central role of BUN and serum creatinine in determining the presence of renal failure, an understanding of the metabolism of these substances is needed. Urea nitrogen derives from the breakdown of proteins that are delivered to the liver. Thus, the urea nitrogen production rate can vary with exogenous protein intake and endogenous protein catabolism. Urea n itrogen is a small, uncharged molecule that is not protein bound, and as such, i t is readily filtered at the renal glomerulus. Urea nitrogen undergoes renal tub ular reabsorption by specific transporters. This tubular reabsorption limits the value of BUN as a marker for glomerular filtration. However, the BUN usually co rrelates with the symptoms of uremia. By contrast, the production of creatinine

is usually more constant unless there has been a marked reduction of skeletal mu scle mass (eg, loss of a limb, prolonged starvation) or diffuse muscle injury. A lthough creatinine undergoes secretion into renal tubular fluid, this is very mo dest in degree. Thus, a steady-stable serum creatinine concentration is usually a relatively good marker of glomerular filtration rate as noted in Figure 12-5.

Diagnostic Evaluation of the Patient with Acute Renal Failure 12.3 BLOOD UREA NITROGEN (BUN)-CREATININE RATIO > 10 Increased protein intake Catabolic state Fever Sepsis Trauma Corticosteroids Tis sue necrosis Tetracyclines Diminished urine flow Prerenal state Postrenal state < 10 Starvation Advanced liver disease Postdialysis state Drugs that impair tubular s ecretion Cimetidine Trimethoprim Rhabdomyolysis FIGURE 12-4 The blood urea nitrogen (BUN)-creatinine ratio. Based on the informa tion in Figure 12-3, the BUN-creatinine ratio often deviates from the usual valu e of about 10:1. These deviations may have modest diagnostic implications. As an example, for reasons as yet unclear, tubular reabsorption of urea nitrogen is e nhanced in low-urine flow states. Thus, a high BUN-creatinine ratio often occurs in prerenal and postrenal (see Fig. 12-6) forms of renal failure. Similarly, en hanced delivery of amino acids to the liver (as with catabolism, corticosteroids , etc.) can enhance urea nitrogen formation and increase the BUN-creatinine rati o. A BUN-creatinine ratio lower than 10:1 can occur because of decreased urea ni trogen formation (eg, in protein malnutrition, advanced liver disease), enhanced creatinine formation (eg, with rhabdomyolysis), impaired tubular secretion of c reatinine (eg, secondary to trimethoprim, cimetidine), or relatively enhanced re moval of the small substance urea nitrogen by dialysis. CORRELATION OF STEADY-STATE SERUM CREATININE CONCENTRATION AND GLOMERULAR FILTRA TION RATE (GFR) FIGURE 12-5 Correlation of steady-state serum creatinine concentration and glome rular filtration rate (GFR). Creatinine (mg/dL) 1 2 4 8 16 GFR (mL/min) 100 50 25 12.5 6.25 Renal Failure Favors acute Normal Normal Absent Kidney size Carbamylated hemoglobin Broad cast s on urinalysis History of kidney disease, hypertension, abnormal urinalysis Ane mia, metabolic acidosis, hyperkalemia, hyperphosphatemia Favors chronic Small High Present Absent Present FIGURE 12-6 Categories of renal failure. Once the presence of renal failure is a scertained by elevated blood urea nitrogen (BUN) or serum creatinine value, the clinician must decide whether it is acute or chronic. When previous values are a vailable for review, this judgment is made relatively easily. In the absence of such values, the factors depicted here may be helpful. Hemoglobin potentially un dergoes nonenzymatic carbamylation of its terminal valine [8]. Thus, similar to the hemoglobin A1C value as an index of blood sugar control, the level of carbam ylated hemoglobin is an indicator of the degree and duration of elevated BUN, bu t, this test is not yet widely available. The presence of small kidneys strongly

suggests that renal failure is at least in part chronic. From a practical stand point, because even chronic renal failure often is partially reversible, the cli nician should assume and evaluate for the presence of acute reversible factors i n all cases of acute renal failure. Often present Usually complete Usually present Sometimes, partial Reversibility with time

12.4 Acute Renal Failure Categorization of Causes of Acute Renal Failure Acute renal failure Prerenal causes Renal causes Postrenal causes Vascular disorders Glomerulonephritis Interstitial nephritis Tubular necrosis Ischemia Toxins Pigments FIGURE 12-7 Acute renal failure (ARF). This figure depicts the most commonly use d schema to classify and diagnostically approach the patient with ARF [1, 6, 9]. The most common general cause of ARF (60% to 70% of cases) is prerenal factors. Prerenal causes include those secondary to renal hypoperfusion, which occurs in the setting of extracellular fluid loss (eg, with vomiting, nasogastric suction ing, gastrointestinal hemorrhage, diarrhea, burns, heat stroke, diuretics, gluco suria), sequestration of extracellular fluid (eg, with pancreatitis, abdominal surgery, muscle crush injury, early sepsis), or impaired cardiac outpu t. In most prerenal forms of ARF, one or more of the vasomotor mechanisms noted in Figure 12-8 is operative. The diagnostic criteria for prerenal ARF are deline ated in Figure 12-9. Once prerenal forms of ARF have been ruled out, postrenal f orms (ie, obstruction to urine flow) should be considered. Obstruction to urine flow is a less common (5% to 15% of cases) cause of ARF but is nearly always ame nable to therapy. The site of obstruction can be intrarenal (eg, crystals or pro teins obstructing the terminal collecting tubules) or extrarenal (eg, blockade o f the renal pelvis, ureters, bladder, or urethra). The diagnosis of postrenal fo rms of ARF is supported by data outlined in Figure 12-10. After preand postrenal forms of ARF have been considered, attention should focus on the kidney. When c onsidering renal forms of ARF, it is helpful to think in terms of renal anatomic compartments (vasculature, glomeruli, interstitium, and tubules). Acute disorde rs involving any of these compartments can lead to ARF. FIGURE 12-8 Vasomotor me chanisms contributing to acute renal failure (ARF). Most prerenal forms of ARF h ave operational one or more of the vasomotor mechanisms depicted here [6]. Colle ctively, these factors lead to diminished glomerular filtration and ARF. NSAIDs n onsteroidal anti-inflammatory drugs. VASOMOTOR MECHANISMS CONTRIBUTING TO ACUTE RENAL FAILURE Decreased Renal Perfusion Pressure Extracellular fluid volume loss or sequestration Impaired cardiac output Antihyp ertensive medications Sepsis Afferent Arteriolar Constriction

Sepsis Medications (NSAIDs, cyclosporine, contrast medium, amphotericin, alpha-a drenergic agonists) Hypercalcemia Postoperative state Hepatorenal syndrome Efferent Arteriolar Dilation Converting enzyme inhibitors Angiotensin II receptor antagonists

Diagnostic Evaluation of the Patient with Acute Renal Failure 12.5 DIAGNOSIS OF POSSIBLE PRERENAL CAUSES OF ACUTE RENAL FAILURE History Extracellular fluid loss or sequestration from skin, gastrointestinal and/or ren al source (see Fig. 12-15) Orthostatic lightheadedness Thirst Oliguria Symptoms of heart failure Edema Examination Orthostatic hypotension and tachycardia Dry mucous membranes No axillary moistur e Decreased skin turgor Evidence of congestive heart failure Presence of edema Laboratory/Other Normal urinalysis Urinary indices compatible with normal tubular function (see F ig. 12-14) Elevated BUN-creatinine ratio Improved renal function with correction of the underlying cause Rarely, chest radiography, cardiac ultrasound, gated bl ood pool scan, central venous and/or Swan-Ganz wedge pressure recordings FIGURE 12-9 Diagnosis of possible prerenal causes of acute renal failure (ARF). Prerenal events are the most common factors that lead to contemporary ARF. The h istorical, physical examination, and laboratory and other investigations involve d in identifying a prerenal form of ARF are outlined here [1]. BUNblood urea nitr ogen. DIAGNOSIS OF POSSIBLE POSTRENAL CAUSES OF ACUTE RENAL FAILURE History Very young or very old age Nocturia Decreased size or force of urine stream Anti cholinergic or alpha-adrenergic agonist medications Bladder, prostate, pelvic, o r intra-abdominal cancer Fluctuating urine volume Oligoanuria Suprapubic pain Ur olithiasis Medication known to produce crystalluria (sulfonamides, acyclovir, me thotrexate, protease inhibitors) Examination Distended bladder Enlarged prostate Abnormal pelvic examination Laboratory/Other Abnormal urinalysis Elevated BUN-creatinine ratio Elevated postvoiding residual volume Abnormal renal ultrasound, CT or MRI findings Improvement after drainage FIGURE 12-10 Diagnosis of possible postrenal causes of acute renal failure (ARF) . Postrenal causes of ARF are less common (5% to 15% of ARF population) but are nearly always amenable to therapy. This figure depicts the historical, physical examination and tests that can lead to an intrarenal (crystal deposition) or ext rarenal (blockade of the collecting system) form of obstructive uropathy [1, 6, 9, 10]. BUNblood urea nitrogen; CTcomputed tomography; MRImagnetic resonance imagin g. POSTOPERATIVE ACUTE RENAL FAILURE Frequency Elective surgery 1%5% Emergent or vascular surgery 5%10% Predisposing Factors Comorbidity results in decreased renal reserve The surgical experience decreases renal function (volume shifts, vasoconstriction) A second insult usually occurs (sepsis, reoperation, nephrotoxin, volume/cardiac issue) Preventive Strategies Avoid nephrotoxins Minimize hospital-acquired infections (invasive equipment) Se

lective use of volume expansion, vasodilators, inotropes Preoperative hemodynami c optimization in selected cases Increase tissue oxygenation delivery to suprano rmal levels in selected cases FIGURE 12-11 Postoperative acute renal failure (ARF). The postoperative setting of ARF is very common. This figure depicts data on the frequency, predisposing f actors, and potential strategies for preventing postoperative ARF [11, 12].

12.6 Acute Renal Failure Diagnostic Steps in Evaluating STEPWISE APPROACH TO DIAGNOSIS Step 1 History Record review Physical goanuric) Urinalysis (see Fig. Step 2 Step 3 Step 4 Consider renal biopsy Consider empiric therapy for suspected diagnosis Consider urinary diagnostic Consider selected indices (see Fig. 12-16) therapeut ic trials Consider need for further evaluation to exclude urinary tract obstruct ion Consider need for more data to assess intravascular volume or cardiac output status Consider need for additional blood tests Consider need for evaluation of renal vascular status FIGURE 12-12 Stepwise approach to diagnosis of acute renal failure (ARF). The mu ltiple causes, predisposing factors, and clinical settings demand a logical, seq uential approach to each case of ARF. This figure presents a four-step approach to assessing ARF patients in an effort to delineate the cause in a timely and co st-effective manner. Step 1 involves a focused history, record review, and exami nation. The salient features of these analyses are noted in more detail in Figur e 12-13. In many cases, a single bladder catheterization is needed to assess the degree of residual volume, which should be less than 30 to 50 mL. Urinalysis is a critical part of the initial evaluation of all patients with ARF. Generally, a relatively normal urinalysis suggests either a prerenal or postrenal cause, wh ereas a urinalysis containing cells and casts is most compatible with a renal ca use. A detailed schema of urinalysis interpretation in the setting of ARF is dep icted in Figure 12-15. Usually, after Step 1 the clinician has a reasonably good idea of the likely cause of the ARF. Sometimes, the information noted under Ste p 2 is needed to ascertain definitively the cause of the ARF. More details of St ep 2 are depicted in Figure 12-14. Oftentimes, urinary diagnostic indices (see F ig. 12-16), are helpful in differentiating between prerenal (intact tubular function) and ac ute tubular necrosis (impaired tubular function) as the cause of renal failure. Sometimes, further evaluation (usually ultrasonography, less commonly computed t omography or magnetic resonance imaging) is needed to exclude the possibility of bilateral ureteric obstruction (or single ureteric obstruction in patients with a single kidney). Occasionally, additional studies such as central venous press ure or left ventricular filling pressure determinations are needed to better ass ess whether prerenal factors are contributing to the ARF. When the cause of the ARF continues to be difficult to ascertain and renal vascular disorders (see Fig . 12-17 and 12-18), glomerulonephritis (see Fig. 12-19) or acute interstitial ne phritis (see Fig. 12-20) remain possibilities, additional blood analyses and oth er tests described in Figures 12-18 through 12-20 may be indicated. Sometimes, s elected therapeutic trials (eg, volume expansion, maneuvers to increase cardiac index, ureteric stent or nephrostomy tube relief of obstruction) are necessary t o document the cause of ARF definitively. Empiric therapy (eg, corticosteroids f or suspected acute allergic interstitial nephritis) is given as both a diagnosti c and a therapeutic maneuver in selected cases. Rarely, despite all efforts, the cause of the ARF remains unknown and renal biopsy is necessary to establish a d efinitive diagnosis. Acute Renal Failure OF ACUTE RENAL FAILURE examination Urinary bladder catherization (if oli 12-15)

Diagnostic Evaluation of the Patient with Acute Renal Failure 12.7 FIRST STEP IN EVALUATION OF ACUTE RENAL FAILURE History Disorders that suggest or predispose to renal failure: hypertension, dia betes mellitus, human immunodeficiency virus, vascular disease, abnormal urinaly ses, family history of renal disease, medication use, toxin or environmental exp osure, infection, heart failure, vasculitis, cancer Disorders that suggest or pr edispose to volume depletion: vomiting, diarrhea, pancreatitis, gastrointestinal bleeding, burns, heat stroke, fever, uncontrolled diabetes mellitus, diuretic u se, orthostatic hypotension, nothing-by-mouth status, nasogastric suctioning Dis orders that suggest or predispose to obstruction: stream abnormalities, nocturia , anticholingeric medications, stones, urinary tract infections, bladder or pros tate disease, intra-abnominal malignancy, suprapubic or flank pain, anuria, fluc tuating urine volumes Symptoms of renal failure: anorexia, vomiting, reversed sl eep pattern, puritus Record review Recent events (procedures, surgery) Medicatio ns (see Fig. 12-22) Vital signs Intake and output Body weights Blood chemistries and hemogram Physical examination Skin: rash suggestive of allergy, palpable purpura of vascu litis, livedo reticularis and digital infarctions suggesting atheroemboli Eyes: hypertension, diabetes mellitus, Hollenhorst plaques, vasculitis, candidemia Lun gs: rales, rubs Heart: evidence of heart failure, pericardial disease, jugular v enous pressure Vascular system: bruits, pulses, abdominal aortic aneurysm Abdome n: flank or suprapubic masses, ascites, costovertebral angle pain Extremities: e dema, pulses, compartment syndromes Nervous system: focal findings, asterixis, m ini-mental status examination Consider bladder catheterization Urinalysis (see F ig. 12-13) FIGURE 12-13 First step in evaluation of acute renal failure. FIGURE 12-14 Secon d step in evaluation of acute renal failure. SECOND STEP IN EVALUATION OF ACUTE RENAL FAILURE Urine diagnostic indices (see Fig. 12-16) Consider need for further evaluation f or obstruction Ultrasonography, computed tomography, or magnetic resonance imagi ng Consider need for additional blood tests Vasculitis/glomerulopathy: human imm unodeficiency virus infections, antineutrophilic cytoplasmic antibodies, antinuc lear antibodies, serologic tests for hepatitis, systemic bacterial endocarditis and streptococcal infections, rheumatoid factor, complement, cryoglobins Plasma cell disorders: urine for light chains, serum analysis for abnormal proteins Dru g screen/level, additional chemical tests Consider need for evaluation of renal vascular supply Isotope scans, Doppler sonography, angiography Consider need for more data to assess volume and cardiac status Swan-Ganz catheterization

12.8 Acute Renal Failure Urinalysis in acute renal failure Normal Abnormal RBC RBC casts Proteinuria WBC WBC casts Eosinophils RTE cells Pigmented casts Crystalluria Low grade proteinuria Prerenal, postrenal, high oncotic pressure (dextran, mannitol) Glomerulopathy, vasculitis, thrombotic microangiopathy Pyelonephritis, interstitial nephritis Allergic interstitial nephritis, atheroemboli, glomerulopathy ATN, myoglobinuria, hemoglobinuria Uric acid, drugs or toxins Plasma cell dyscrasia FIGURE 12-15 Urinalysis in acute renal failure (ARF). A normal urinalysis sugges ts a prerenal or postrenal form of ARF; however, many patients with ARF of postr enal causes have some cellular elements on urinalysis. Relatively uncommon cause s of ARF that usually present with oligoanuria and a normal urinalysis are manni tol toxicity and large doses of dextran infusion. In these disorders, a hyperonco tic state occurs in which glomerular capillary oncotic pressure, combined with th e intratubular hydrostatic pressure, exceeds the glomerular capillary hydrostati c pressure and stop glomerular filtration. Red blood cells (RBCs) can be seen wi th all renal forms of ARF. When RBC casts are present, glomerulonephritis or vas culitis is most likely. White blood cells (WBCs) can also be present in small numbers in the urine of pa tients with ARF. Large numbers of WBCs and WBC casts strongly suggest the presen ce of either pyelonephritis or acute interstitial nephritis. Eosinolphiluria (Ha nsel's stain) is often present in either allergic interstitial nephritis or athero embolic disease [13, 14]. Renal tubular epithelial (RTE) cells and casts and pig mented granular casts typically are present in pigmenturia-associated ARF (see F ig. 12-21) and in established acute tubular necrosis (ATN). The presence of larg e numbers of crystals on urinalysis, in conjunction with the clinical history, m ay suggest uric acid, sulfonamides, or protease inhibitors as a cause of the ren al failure. FIGURE 12-16 Urinary diagnostic indices in acute renal failure (ARF) . These indices have traditionally been used in the setting of oliguria, to help differentiate between prerenal (intact tubular function) and acute tubular necr osis (ATN, impaired tubular function). Several caveats to interpretation of thes

e indices are in order [1]. First, none of these is completely sensitive or spec ific in differentiating the prerenal from the ATN form of ARF. Second, often a c ontinuum exists between early prerenal conditions and late prerenal conditions t hat lead to ischemic ATN. Most of the data depicted here are derived from patien ts relatively late in the progress of ARF when the serum creatinine concentratio ns were 3 to 5 mg/dL. Third, there is often a relatively large gray area, in which the various indices do not give definitive results. Finally, some of the indice s (eg, fractional excretion of endogenous lithium [FE lithium]) are not readily available in the clinical setting. The fractional excretion (FE) of a substance is determined by the formula: U/P substance U/P creatinine 100. U/Purine-plasma r atio. Urinary diagnostic indices in acute renal failure Prerenal Hyaline casts >1.020 >500 <20 <1 <7 <7 Urinalysis Specific gravity Uosm (mOsm/kg H2O) Una (mEq/L) FE Na (%) FE uric acid (%) FE lithium (%) Renal Abnormal ~1.010 >300 >40 >2 >15 >20

Diagnostic Evaluation of the Patient with Acute Renal Failure 12.9 Vascular Mechanisms Involved in Acute Renal Failure VASCULAR CAUSES OF ACUTE RENAL FAILURE Arterial Large vessels Renal artery stenosis Thrombosis Cross-clamping Emboli Atheroembol i Endocarditis Atrial fibrillation Mural thrombus Tumor Small vessels Cortical n ecrosis malignant hypertension Scleroderma Vasculitis Antiphospholipid syndrome Thrombotic microangiopathies Hemolytic-uremic syndrome Thrombotic thrombocytopen ic purpura Postpartum Medications (mitomycin C, cyclosporine, tacrolimus) Venous Occlusion Clot Tumor FIGURE 12-17 Vascular causes of acute renal failure (ARF). Once prerenal and pos trenal causes of ARF have been excluded, attention should be focused on the kidn ey. One useful means of classifying renal causes of ARF is to consider the anato mic compartments of the kidney. Thus, disorders of the renal vasculature (see Fi g. 12-18), glomerulus (see Fig. 12-19), interstitium (see Fig. 12-20) and tubule s can all result in identical clinical pictures of ARF [1]. This figure depicts the disorders of the renal arterial and venous systems that can result in ARF [1 5]. DIAGNOSIS OF POSSIBLE VASCULAR CAUSE OF ACUTE RENAL FAILURE History Factors that predispose to vascular disease (smoking, hypertension, diabetes mel litus, hyperlipidemia) Claudication, stroke, myocardial infarction Surgical proc edure on aorta Catheterization procedure involving aorta Selected clinical state s (scleroderma, pregnancy) Selected medications, toxins (cyclosporine, mitomycin C, cocaine, tacrolimus) Constitutional symptoms Examination Marked hypertension Atrial fibrillation Scleroderma Palpable purpura Abdominal a ortic aneurysm Diminished pulses Infarcted toes Hollendhorst plaques Vascular br uits Stigmata of bacterial endocarditis Illeus Laboratory/Other Thrombocytopenia Microangiopathic hemolysis Coagulopathy Urinalysis with hematur ia and low-grade proteinuria Abnormal renal isotope scan and/or Doppler ultrason ography Renal angiography Renal or extrarenal tissue analysis FIGURE 12-18 Diagnosis of a possible vascular cause of acute renal failure (ARF) . This figure depicts the historical, physical examination, and testing procedur es that often lead to diagnosis of a vascular cause of ARF [1, 15, 16].

12.10 Acute Renal Failure Acute Glomerulonephritis DIAGNOSIS OF A POSSIBLE ACUTE GLOMERULAR PROCESS AS THE CAUSE OF ACUTE RENAL FAI LURE FIGURE 12-19 Diagnosis of a possible acute glomerular process as the cause of ac ute renal failure (ARF). Acute glomerulonephritis is a relatively rare cause of ARF in adults. In the pediatric age group, acute glomerulonephritis and a disord er of small renal arteries (hemolytic-uremic syndrome) are relatively common cau ses. This figure depicts the historical, examination, and laboratory findings th at collectively may support a diagnosis of acute glomerulonephritis as the cause of ARF [16, 17]. History Recent infection Sudden onset of edema, dyspnea Systemic disorder (eg, lupus ery thematosus, Wegener's granulomatosis, Goodpasture's syndrome) No evidence of other c auses of renal failure Examination Hypertension Edema Rash Arthropathy Prominent pulmonary findings Stigmata of bac terial endocarditis or visceral abscess Laboratory/Other Urinalysis with hematuria, red cell casts, and proteinuria Serologic or culture evidence of recent infection Laboratory evidence of immunemediated process (low complement, cryoglobulinemia, antinuclear antibody, anti-DNA, rheumatoid factor, antiglomerular basement membrane antibody, antineutrophilic cytoplasmic antibody ) Renal tissue examination Interstitial Nephritis DIAGNOSIS OF POSSIBLE ACUTE INTERSTITIAL NEPHRITIS AS THE CAUSE OF ACUTE RENAL F AILURE FIGURE 12-20 Diagnosis of possible acute interstitial nephritis as the cause of acute renal failure (ARF). This figure outlines the historical, physical examina tion and other investigative methods that can lead to identification of acute in terstitial nephritis as the cause of ARF [18]. History Medication exposure Severe pyelonephritis Systemic infection Examination Fever Rash Back or flank pain Laboratory/Other Abnormal urinalysis (white blood cells or cell casts, eosinophils, eosinophilic casts, low-grade proteinuria, sometimes hematuria) Eosinophilia Urinary diagnosi tc indices compatible with a renal cause of renal failure (see Fig. 12-16) Uptak e on gallium or indium scan Renal biopsy

Diagnostic Evaluation of the Patient with Acute Renal Failure 12.11 Acute Tubular Necrosis DIAGNOSIS OF POSSIBLE PIGMENT-ASSOCIATED FORMS OF ACUTE RENAL FAILURE Myoglobinuria History Trauma to muscles Condition known to predispose to nontraumatic rhabdomyolysis M uscle pain or stiffness Dark urine Hemoglobinuria Laboratory Serum creatinine disproportionately elevated related to BUN Elevated (10-fold) e nzymes (CK, SGOT, LDH, adolase) Elevations of plasma potassium, uric acid, phosp horus, and hypocalcemia Urinalysis with pigmented granular casts, ( ) stick reac tion for blood in the absence of hematuria, and myoglobin test if available Clea r plasma Examination Can be normal Muscle edema, weakness, pain Neurovascular entrapment or compartme nt syndromes in severe cases Flank pain History Condition associated with intravascular hemolysis (red cell trauma, antibodymedi ated hemolysis, direct red cell toxicity, sickle cell disease) Examination Can be normal Pallor Flank pain Laboratory Normocytic anemia High red cell LDH fraction Reticulocytosis Low haptoglobin Uri nalysis with pigmented granular casts, ( ) stick reaction for blood in absence o f hemataria and reddish brown or pink plasma FIGURE 12-21 Diagnosis of possible pigment-associated forms of acute renal failu re (ARF). Once prerenal and postrenal forms of ARF have been ruled out and renal vascular, glomerular, and interstitial processes seem unlikely, a diagnosis of acute tubular necrosis (ATN) is probable. A diagnosis of ATN is thus one of excl usion (of other causes of ARF). In the majority of cases when ATN is present, on e or more of the three predisposing conditions have been identified to be operat ional. These conditions include renal ischemia due to a prolonged prerenal state , nephrotoxin exposure, and sometimes pigmenturia. A diagnosis of ATN is supported by the absence of other causes of ARF, the presence of one o r more predisposing factors, and the presence of urinary diagnostic indices and urinalysis suggested of ATN (see Figs. 12-15 and 12-16). A pigmenturic disorder (myloglobinuria or hemoglobinuria) can predispose to ARF. This figure depicts th e historical, physical examination, and supporting diagnostic tests that often l ead to a diagnosis of pigment-associated ARF [19]. BUNblood urea nitrogen; CKcreat inine kinase; SGOTserum glutamic-oxaloacetic transaminase; LDHlactic dehydrogenase . Nephrotoxin Acute Renal Failure NEPHROTOXIC ACUTE RENAL FAILURE Prerenal Diuretics Interleukin 2 CEIs Antihypertensive agents Tubular toxicity A minoglyosides Cisplatin Vancomycin Foscarnet Pentamidine Radiocontrast Amphoterc in Heavy metals Vasoconstriction NSAIDs Radiocontrast agents Cyclosporine Tacrol imus Amphotericin Endothelial injury Cyclosporine Mitomycin C Tacrolimus Cocaine Conjugated estrogens Quinine Crystalluria Sulfonamides Methotrexate Acyclovir T riamterene Ethylene glycol Protease inhibitors Glomerulopathy Gold Penicillamine NSAIDs Interstitial nephritis Multiple

FIGURE 12-22 Nephrotoxin acute renal failure (ARF). A variety of nephrotoxins ha ve been implicated in causing 20% to 30% of all cases of ARF. These potential ne phrotoxins can act through a variety of mechanisms to induce renal dysfunction [ 6, 20, 21]. CEIconverting enzyme inhibitor; NSAIDnonsteroidal anti-inflammatory dr ugs.

12.12 Acute Renal Failure References 1. Anderson RJ, Schrier RW: Acute renal failure. In Diseases of the Kidney. Edit ed by Schrier RW, Gottschalk CW. Boston: Little, Brown; 1997:10691113. 2. Hou SH, Bushinsky D, Wish JB, Harrington JT: Hospital-acquired renal insufficiency: A p rospective study. Am J Med 1983, 74:243248. 3. Shusterman N, Strom BL, Murray TG, et al.: Risk factors and outcome of hospital-acquired acute renal failure. Am J Med 1987, 83:6571. 4. Levy EM, Viscoli CM, Horwitz RI: The effect of acute renal failure on mortality. JAMA 1996, 275:14891494. ~ 5. Liano F, Pascual J: Epidemio logy of acute renal failure: A prospective, multicenter, community-based study. Kid Int 1996, 50:811818. 6. Thadhani R, Pascual M, Bonventre JV: Acute renal fail ure. New Engl J Med 1996, 334:14481460. 7. Feest TG, Round A, Hamad S: Incidence of severe acute renal failure in adults: Results of a community-based study. Br Med J 1993, 306:481483. 8. Davenport A: Differentiation of acute from chronic ren al impairment by detection of carbamylated hemoglobin. Lancet 1993, 341:16141616. 9. Mendell JA, Chertow GM: A practical approach to acute renal failure. Med Cli n North Am 1997, 81:731748. 10. Kopp JB, Miller KD, Mican JM, et al.: Crystalluri a and urinary tract abnormalities associated with indinovir. Ann Intern Med 1997 , 127:119125. 11. Charlson ME, MacKenzie CR, Gold JP, Shires T: Postoperative cha nges in serum creatinine. Ann Surg 1989, 209:328335. 12. Kellerman PS: Perioperat ive care of the renal patient. Arch Intern Med 1994, 154:16741681. 13. Nolan CR, Anger MS, Kelleher SP: Eosinophiluria a new method of detection and definition of the clinical spectrum. N Engl J Med 1986, 315:15161519. 14. Wilson DM, Salager T L, Farkouh ME: Eosinophiluria in atheroembolic renal disease. Am J Med 1991, 91: 186191. 15. Abuelo JG: Diagnosing vascular causes of acute renal failure. Ann Int ern Med 1995, 123:601614. 16. Falk RJ, Jennette JC: ANCA small-vessel vasculitis. J Am Soc Nephrol 1997, 8:314322. 17. Kobrin S, Madacio MP: Acute poststreptococc al glomerulonephritis and other bacterial infection-related glomerulonephritis. In Diseases of the Kidney. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown; 1997:15791594. 18. Eknoyan G: Acute tubulointerstitial nephritis. In Disea ses of the Kidney. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown; 1 997:12491272. 19. Don BR, Rodriguez RA, Humphreys MH: Acute renal failure associa ted with pigmenturia as crystal deposits. In Diseases of the Kidney. Edited by S chrier RW, Gottschalk CW. Boston: Little, Brown; 1997:12731302. 20. Chaudbury O, Ahmed Z: Drug-induced nephrotoxicity. Med Clin North Am 1997, 81:705717. 21. Palm er B, Henrich WL: Nephrotoxicity of nonsteroidal anti-inflammatory agents, analg esics, and angiotensin converting enzyme inhibitors. In Diseases of the Kidney. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown; 1997:11671188.

Pathophysiology of Ischemic Acute Renal Failure: Cytoskeletal Aspects Bruce A. Molitoris Robert Bacallao I schemia remains the major cause of acute renal failure (ARF) in the adult popula tion [1]. Clinically a reduction in glomerular filtration rate (GFR) secondary t o reduced renal blood flow can reflect prerenal azotemia or acute tubular necros is (ATN). More appropriate terms for ATN are acute tubular dysfunction or acute tubular injury, as necrosis only rarely is seen in renal biopsies, and renal tub ular cell injury is the hallmark of this process. Furthermore, the reduction in GFR during acute tubular dysfunction can now, in large part, be related to tubul ar cell injury. Ischemic ARF resulting in acute tubular dysfunction secondary to cell injury is divided into initiation, maintenance, and recovery phases. Recen t studies now allow a direct connection to be drawn between these clinical phase s and the cellular phases of ischemic ARF (Fig. 13-1). Thus, renal function can be directly related to the cycle of cell injury and recovery. Renal proximal tub ule cells are the cells most injured during renal ischemia (Fig. 13-2) [2,3]. Pr oximal tubule cells normally reabsorb 70% to 80% of filtered sodium ions and wat er and also serve to selectively reabsorb other ions and macromolecules. This ve ctorial transport across the cell from lumen to blood is accomplished by having a surface membrane polarized into apical (brush border membrane) and basolateral membrane domains separated by junctional complexes (Fig. 13-3) [4]. Apical and basolateral membrane domains are biochemically and functionally different with r espect to many parameters, including enzymes, ion channels, hormone receptors, e lectrical resistance, membrane transporters, membrane lipids, membrane fluidity, and cytoskeletal associations. This epithelial cell polarity is essential for n ormal cell function, as demonstrated by the vectorial transport of sodium from t he lumen to the blood (see Fig. 13-3). The establishment CHAPTER 13

13.2 Acute Renal Failure induced by ischemia can be mimicked by F-actin disassembly mediated by cytochala sin D [11]. Although these correlations are highly suggestive of a central role for actin alterations in the pathophysiology of ischemia-induced surface membran e damage they fall short in providing mechanistic data that directly relate acti n cytoskeletal changes to cell injury. Proximal tubule cell injury during ischem ia is also known to be principally responsible for the reduction in GFR. Figure 13-5 illustrates the three known pathophysiologic mechanisms that relate proxima l tubule cell injury to a reduction in GFR. Particularly important is the role o f the cytoskeleton in mediating these three mechanisms of reduced GFR. First, lo ss of apical membrane into the lumen and detachment of PTC result in substrate f or cast formation. Both events have been related to actin cytoskeletal and integ rin polarity alterations [1215]. Cell detachment and the loss of integrin polarit y are felt to play a central role in tubular obstruction (Fig. 13-6). Actin cyto skeletalmediated tight junction opening during ischemia occurs and results in ba ck-leak of glomerular filtrate into the blood. This results in ineffective glome rular filtration (Fig. 13-7). Finally, abnormal proximal sodium ion reabsorption results in large distal tubule sodium delivery and a reduction in GFR via tubul oglomerular feedback mechanisms [2,16,17]. In summary, ischemia-induced alterati ons in proximal tubule cell surface membrane structure and function are in large part responsible for cell and organ dysfunction. Actin cytoskeletal dysregulati on during ischemia has been shown to be responsible for much of the surface memb rane structural damage. FIGURE 13-1 Relationship between the clinical and cellular phases of ischemic ac ute renal failure. Prerenal azotemia results from reduced renal blood flow and i s associated with reduced organ function (decreased glomerular filtration rate), but cellular integrity is maintained through vascular and cellular adaptive res ponses. The initiation phase occurs when renal blood flow decreases to a level t hat results in severe cellular ATP depletion that, in turn, leads to acute cell injury. Severe cellular ATP depletion causes a constellation of cellular alterat ions culminating in proximal tubule cell injury, cell death, and organ dysfuncti on [2]. During the clinical phase known as maintenance, cells undergo repair, mi gration, apoptosis, and proliferation in an attempt to re-establish and maintain cell and tubule integrity [3]. This cellular repair and reorganization phase re sults in slowly improving cell and organ function. During the recovery phase, ce ll differentiation continues, cells mature, and normal cell and organ function r eturn [18]. and maintenance of this specialized organization is a dynamic and ATP dependent multistage process involving the formation and maintenance of cell-cell and cell -substratum attachments and the targeted delivery of plasma membrane components to the appropriate domains [5]. These processes are very dependent on the cytosk eleton, in general, and the cytoskeletal membrane interactions mediated through F-actin (see Fig. 13-2, 13-3), in particular. Ischemia in vivo and cellular ATP depletion in cell culture models (chemical ischemia) are known to produce characte ristic surface membrane structural, biochemical, and functional abnormalities in proximal tubule cells. These alterations occur in a duration-dependent fashion and are illustrated in Figures 13-2 and 13-3 and listed in Figure 13-4. Ischemia -induced alterations in the actin cytoskeleton have been postulated to mediate m any of the aforementioned surface membrane changes [2,6,7]. This possible link b etween ischemia-induced actin cytoskeletal alterations and surface membrane stru ctural and functional abnormalities is suggested by several lines. First, the ac tin cytoskeleton is known to play fundamental roles in surface membrane formatio n and stability, junctional complex formation and regulation, Golgi structure an d function, and cellextracellular membrane attachment [2,4,5,8]. Second, proximal tubule cell actin cytoskeleton is extremely sensitive to ischemia and ATP deple tion [9,10]. Third, there is a strong correlation between the time course of act in and surface membrane alterations during ischemia or ATP depletion [2,9,10]. F

inally, many of the characteristic surface membrane changes RELATIONSHIP BETWEEN THE CLINICAL AND CELLULAR PHASES OF ISCHEMIC ACUTE RENAL FA ILURE Clinical Phases Prerenal azotemia Initiation Maintenance Recovery Cellular Phases Vascular and cellular adaptation ATP depletion, cell injury Repair, migration, a poptosis, proliferation Cellular differentiation

Pathophysiology of Ischemic Acute Renal Failure: Cytoskeletal Aspects 13.3 A B C D E F FIGURE 13-2 Ischemic acute renal failure in the rat kidney. Light A, B, transmis sion electron, C, D, and immunofluorescence E, F, microscopy of control renal co rtical sections, A, C, E, and after moderate ischemia induced by 25 minutes of r enal artery occlusion, B, D, F. Note the extensive loss of apical membrane struc ture, B, D, in proximal (PT) but not distal tubule cells. This has been shown to correlate with extensive alterations in F-actin as shown by FITC-phalloidin lab eling, E, F. G, Drawing of a proximal tubule cell under physiologic conditions. Note the orderly arrangement of the actin cytoskeleton and its extensive interac tion with the surface membrane at the zonula occludens (ZO, tight junction) zonu la adherens (ZA, occludens junction), interactions with ankyrin to mediate Na+, K+-ATPase [2] stabilization and cell adhesion molecule attachment [5,8]. The act in cytoskeleton also mediates attachment to the extracellular matrix (ECM) via i ntegrins [12,15]. Microtubules (MT) are involved in the polarized delivery of en docytic and exocytic vesicles to the surface membrane. Finally, F-actin filament s bundle together via actin-bundling proteins [19] to mediate amplification of t he apical surface membrane via microvilli (MV). The actin bundle attaches to the surface membrane by the actin-binding proteins myosin I and ezrin [19,20]. MV ZO ZA MT x N x HD ECM G

13.4 Acute Renal Failure FIGURE 13-3 Fate of an injured proximal tubule cell. The fate of a proximal tubu le cell after an ischemic episode depends on the extent and duration of the isch emia. Cell death can occur immediately via necrosis or in a more programmed fash ion (apoptosis) hours to days after the injury. Fortunately, most cells recover either in a direct fashion or via an intermediate undifferentiated cellular path way. Again, the severity of the injury determines the route taken by a particula r cell. Adjacent cells are often injured to varying degrees, especially during m ild to moderate ischemia. It is believed that the rate of organ functional recov ery relates directly to the severity of cell injury during the initiation phase. ECMextracellular membrane; Na+sodium ion; K+potassium ion; P1phosphate. Proximal tubule cell ADP +P 1 ATP + K Ischemia ted tia ren iffe + Na + ADP K ATP +P 1 Recovery Inj ure d Na+ + K ATP ADP +P 1 Death Necrosis Apoptosis D ECM Na+ d Un ted tia ren iffe ISCHEMIA INDUCED PROXIMAL TUBULE CELL ALTERATIONS Alterations Surface Membrane Alterations 1. Microvilli fusion, internalization, fragmentatio n and luminal shedding resulting in loss of surface membrane area and tubular ob struction 2. Loss of surface membrane polarity for lipids and proteins 3. Juncti onal complex dissociation with unregulated paracellular permeability (backleak) 4. Reduced PTC vectorial transport Actin Cytoskeletal Alterations 1. Polymerizat ion of actin throughout the cell cytosol 2. Disruption and delocalization of F-a ctin structures including stress fibers, cortical actin and the junctional ring 3. Accumulation of intracellular F-actin aggregates containing surface membrane proteinsmyosin I, the tight junction proteins ZO-1, ZO-2, cingulin 4. Disruption and dissociation of the spectrin cytoskeleton 5. Disruption of microtubules duri ng early reflow in vivo 6. The cytoskeleton of proximal tubule cells, as compare

d to distal tubule cells, is more sensitive to ischemia in vivo and ATP depletio n in vitro FIGURE 13-4 Ischemia induced proximal tubule cell alterations. References [21] [2,22,23] [6,2427] [28] [6,16,29] [2,7,16] [20,30] [31,32] [33] [6,16,34]

Pathophysiology of Ischemic Acute Renal Failure: Cytoskeletal Aspects 13.5 A Afferent arteriole Glomerular plasma flow Normal Efferent arteriole Glomerular hydrostatic pressure Intratubular pressure Glomerular filtration B Afferent arteriolar constriction C Obstruction D Backleak Glomerular pressure Obstructing cast Leakage of filtrate FIGURE 13-5 Mechanisms of proximal tubule cellmediated reductions in glomerular f iltration rate (GFR) following ischemic injury. A, GFR depends on four factors: 1) adequate blood flow to the glomerulus; 2) an adequate glomerular capillary pr essure as determined by afferent and efferent arteriolar resistance; 3) glomerul ar permeability; and 4) low intratubular pressure. B, Afferent arteriolar constr iction diminishes GFR by reducing blood flowand, therefore, glomerular capillary pressure. This occurs in response to a high distal sodium delivery and is mediat ed by tubular glomerular feedback. C, Obstruction of the tubular lumen by cast f ormation increases tubular pressure and, when it exceeds glomerular capillary pr essure, a marked decrease or no filtration occurs. D, Back-leak occurs when the paracellular space between cells is open for the flux of glomerular filtrate to leak back into the extracellular space and into the blood stream. This is believ ed to occur through open tight junctions. RG D D RG RGD RGD B FIGURE 13-6 Overview of potential therapeutic effects of cyclic integrin-bindi ng peptides. A, During ischemic injury, tubular obstruction occurs as a result o f loss of apical membrane, cell contents, and detached cells released into the l umen. B, Also, basolateral integrins diffuse to the apical region of the cell. B iotinylated cyclic peptides containing the sequence cRGDDFV bind to desquamated cells in the ascending limb of the loop of Henle and in proximal tubule cells in ischemic rat kidneys. The desquamated cells can adhere to injured cells or aggr egate, causing tubule obstruction. (Continued on next page) A D RG D RG

D RG

13.6 Acute Renal Failure FIGURE 13-6 (Continued) C, When cyclic peptides that contain the RGD canonical b inding site of integrins are perfused intra-arterially, the peptides ameliorate the extent of acute renal failure, as demonstrated by a higher glomerular filtra tion rate (GFR) in rats receiving peptide containing the RGD sequence. B, Propos ed mechanism of renal protection by cyclic RGD peptides. By adhering to the RGD binding sites of the integrins located on the apical plasma membrane or distribu ted randomly on desquamated cells, the cyclic peptide blocks cellular aggregatio n and tubular obstruction [1215]. (Courtesy of MS Goligorski, MD.) 1400 1200 1000 GFR, l/min 800 600 400 200 0 cRGDDFLG x x cRGDDFV cRDADFV Control x * ** x * ** x ** x C 0 Pre-Op Day 1 Day 2 Day 3 80 70 60 50 40 30 20 10 TER vs. Time ATP depleted ATP depleted Control Repletion buffer added A C TER, -cm2 0 0 10 20 30 40 Time,min 60 90 120 150 FIGURE 13-7 Functional and morphologic changes in tight junction integrity assoc iated with ischemic injury or intracellular ATP depletion. A and B, Ruthenium re d paracellular permeability in rat proximal tubules. A, In control kidneys, note the electron-dense staining of the brush border, which cuts off at the tight ju

nctions (tj, arrows). B, Sections from a perfusion-fixed kidney after 20 minutes of renal artery crossclamp [35]. The electron-dense staining can be seen at cel l contact sites beyond the tight junction (arrows). The paracellular pathway is no longer sealed by the tight junction, permitting backleak of the electron-dens e ruthenium red. C, Changes in the transepithelial resistance (TER) versus time during ATP depletion and ATP repletion [36]. Paracellular resistance to electron movement (Continued on next page) B

Pathophysiology of Ischemic Acute Renal Failure: Cytoskeletal Aspects 13.7 D E FIGURE 13-7 (Continued) (the TER falls to zero with ATP depletion). The cellular junctional complex that controls the TER is the tight junction. When the TER fa lls to zero, this suggests that tight junction structural integrity has been com promised. D and E, Staining of renal epithelial cells with antibodies that bind to a component of the tight junction, ZO-1 [37]. D, ZO-1 staining in untreated M ardin-Darby carnine kidney (MDCK) cells. ZO-1 is located at the periphery of cel ls at cell contact sites, forming a continuous linear contour. E, In ATPdepleted cells the staining pattern is discontinuous. F and G, Ultrastructural analysis o f the tight junction in MDCK cells. In untreated MDCK cells, electron micrograph s of the tight junction shows a continuous ridge like structure in freeze fractu re preparations [38]. In ATP depleted cells the strands are disrupted, forming a ggregates (arrows). Note that the continuous strands are no longer present and l arge gaps are observable. F G Acknowledgment These studies were in part supported by the National Institute of Diabetes and D igestive and Kidney Diseases Grants DK 41126 (BAM) and DK4683 (RB) and by an Ame rican Heart Association Established Investigator Award (BAM), a VA Merrit Review Grant (BAM), and a NKF Clinical Scientist Award (RB).

13.8 Acute Renal Failure References 1. ~ Liano F, Pascual J, Madrid Acute Renal Failure Study Group: Epidemiology of acute renal failure: A prospective, multicenter, community-based study. Kidney Int 1996, 50:811818. Molitoris BA, Wagner MC: Surface membrane polarity of proxim al tubular cells: Alterations as a basis for malfunction. Kidney Int 1996, 49:15 921597. Thadhani R, Pascual M, Bonventre JV: Acute renal failure. N Engl J Med 19 96, 334:14481457. Drubin DG, Nelson WJ: Origins of cell polarity. Cell 1996, 84:3 35344. Mays RW, Nelson WJ, Marrs JA: Generation of epithelial cell polarity: Role s for protein trafficking, membrane-cytoskeleton, and E-cadherinmediated cell adh esion. Cold Spring Harbor Symposia on Quantitative Biol 1995, 60:763773. Bacallao R, Garfinkel A, Monke S, et al.: ATP depletion: A novel method to study junctio nal properties in epithelial tissues. I. Rearrangement of the actin cytoskeleton . J Cell Sci 1994, 107:33013313. Kroshian VM, Sheridan AM, Lieberthal W: Function al and cytoskeletal changes induced by sublethal injury in proximal tubular epit helial cells. Am J Physiol 1994, F21F30. Fish EM, Molitoris BA: Alterations in ep ithelial polarity and the pathogenesis of disease states. N Engl J Med 1994, 330 :15801588. 2. 20. Wagner MC, Molitoris BA: ATP depletion alters myosin Ib cellula r location in LLC-PK1 cells. Am J Physiol 1997, 272:C1680C1690. 21. Venkatachalam MA, Jones DB, Rennke HG, et al.: Mechanism of proximal tubule brush border loss and regeneration following mild ischemia. Lab Invest 1981, 45:355365. 22. Ritter D, Dean AD, Guan ZH, et al.: Polarized distribution of renal natriuretic peptid e receptors in normal physiology and ischemia. Am J Physiol 1995, 269:F918F925. 2 3. Alejandro VSJ, Nelson WJ, Huie P, et al.: Postischemic injury, delayed functi on and Na+/K+-ATPase distribution in the transplanted kidney. Kidney Int 1995, 4 8:13081315. 24. Donohoe JF, Venkatachalam MA, Benard DB, et al.: Tubular leakage and obstruction after renal ischemia: Structural-functional correlations. Kidney Int 1978, 13:208222. 25. Molitoris BA, Falk SA, Dahl RH: Ischemic-induced loss o f epithelial polarity. Role of the tight junction. J Clin Invest 1989, 84:1334133 9. 26. Mandel LJ, Bacallao R, Zampighi G: Uncoupling of the molecular fence and paracellular gate functions in epithelial tight junctions. Nature 1993, 361:55255 5. 27. Kwon O, Nelson J, Sibley RK, et al.: Backleak, tight junctions and cell-c ell adhesion in postischemic injury to the renal allograft (Abstract). J Am Soc Nephrol 1996, 7:A2907. 28. Molitoris BA. Na+-K+-ATPase that redistributes to api cal membrane during ATP depletion remains functional. Am J Physiol 1993, 265:F69 3F597. 29. Kellerman PS: Exogenous adenosine triphosphate (ATP) proximal tubule m icrofilament structure and function in vivo in a maleic acid model of ATP deplet ion. J Clin Invest 1993, 92:19401949. 30. Tsukamoto T, Nigam SK: ATP depletion ca uses tight junction proteins to form large, insoluble complexes with cytoskeleta l proteins in renal epithelial cells. J Biol Chem 1997, 273:F463F472. 31. Molitor is BA, Dahl R, Hosford M: Cellular ATP depletion induces disruption of the spect rin cytoskeletal network. Am J Physiol 1996, 271:F790F798. 32. Edelstein CL, Ling H, Schrier RW: The nature of renal cell injury. Kidney Int 1997, 51:13411351. 33 . Abbate M, Bonventre JV, Brown D: The microtubule network of renal epithelial c ells is disrupted by ischemia and reperfusion. Am J Physiol 1994, 267:F971F978. 3 4. Sheridan AM, Schwartz JH, Kroshian VM, et al.: Renal mouse proximal tubular c ells are more susceptible than MDCK cells to chemical anoxia. Am J Physiol 1993, 265:F342F350. 35. Molitoris BA, Falk SA, Dahl RH: Ischemia-induced loss of epith elial polarity. Role of the tight junction. J Clin Invest 1989, 84:13341339. 36. Doctor RB, Bacallao R, Mandel LJ: Method for recovering ATP content and mitochon drial function after chemical anoxia in renal cell cultures. Am J Physiol 1994, 266:C1803C1811. 37. Stevenson BR, Siliciano JD, Mooseker MS, et al.: Identificati on of ZO-1: A high molecular weight polypeptide associated with the tight juncti on (zonula occludens) in a variety of epithelia. J Cell Biol 1986, 103:755766. 38 . Mandel LJ, Bacallao R, Zampighi G: Uncoupling of the molecular `fence' and paracel lular `gate' functions in epithelial tight junctions. Nature 1993, 361:552555.

3. 4. 5. 6. 7. 8. 9. Glaumann B, Glauman H, Berezesky IK, et al.: Studies on the cellular recovery fr om injury II. Ultrastructural studies on the recovery of the pars convoluta of t he proximal tubule of the rat kidney from temporary ischemia. Virchows Arch B 19 77, 24:118. 10. Kellerman PS, Norenberg SL, Jones GM: Early recovery of the actin cytoskeleton during renal ischemic injury in vivo. Am J Kidney Dis 1996, 16:3342 . 11. Kellerman PS, Clark RAF, Hoilien CA, et al.: Role of microfilaments in the m aintenance of proximal tubule structural and functional integrity. Am J Physiol 1990, 259:F279F285. 12. Noiri E, Gailit J, Gurrath M, et al.: Cyclic RGD peptides ameliorate ischemic acute renal failure in rats. Kidney Int 1994, 46:10501058. 1 3. Noiri E, Goligorsky MS, Som P: Radiolabeled RGD peptides as diagnostic tools in acute renal failure and tubular obstruction. J Am Soc Nephrol 1996, 7:26822688 . 14. Romanov V, Noiri E, Czerwinski G, et al.: Two novel probes reveal tubular and vascular RGD binding sites in the ischemic rat kidney. Kidney Int 1997, 52:9 2102. 15. Goligorsky MS, Noiri E, Romanov V, et al.: Therapeutic potential of RGD peptides in acute renal failure. Kidney Int 1997, 51:14871493. 16. Molitoris BA, Dahl R, Geerdes AE: Cytoskeleton disruption and apical redistribution of proxim al tubule Na+,K+-ATPase during ischemia. Am J Physiol 1992, 263:F488F495. 17. Ale jandro V, Scandling JD, Sibley RK, et al.: Mechanisms of filtration failure duri ng postischemic injury of the human kidney: A study of the reperfused renal allo graft. J Clin Invest 1995, 95:820831. 18. Bacallao R, Fine LG: Molecular events i n the organization of renal tubular epithelium: From nephrogenesis to regenerati on. Am J Physiol 1989, 257:F913F924. 19. Molitoris BA: Putting the actin cytoskel eton into perspective: pathophysiology of ischemic alterations. Am J Physiol 199 7, 272:F430F433.

Pathophysiology of Ischemic Acute Renal Failure Michael S. Goligorsky Wilfred Lieberthal A cute renal failure (ARF) is a syndrome characterized by an abrupt and reversible kidney dysfunction. The spectrum of inciting factors is broad: from ischemic an d nephrotoxic agents to a variety of endotoxemic states and syndrome of multiple organ failure. The pathophysiology of ARF includes vascular, glomerular and tub ular dysfunction which, depending on the actual offending stimulus, vary in the severity and time of appearance. Hemodynamic compromise prevails in cases when n oxious stimuli are related to hypotension and septicemia, leading to renal hypop erfusion with secondary tubular changes (described in Chapter 13). Nephrotoxic o ffenders usually result in primary tubular epithelial cell injury, though endoth elial cell dysfunction can also occur, leading to the eventual cessation of glom erular filtration. This latter effect is a consequence of the combined action of tubular obstruction and activation of tubuloglomerular feedback mechanism. In t he following pages we shall review the existing concepts on the phenomenology of ARF including the mechanisms of decreased renal perfusion and failure of glomer ular filtration, vasoconstriction of renal arterioles, how formed elements gain access to the renal parenchyma, and what the sequelae are of such an invasion by primed leukocytes. CHAPTER 14

14.2 Acute Renal Failure Vasoactive Hormones Ischemic or toxic insult Tubular injury and dysfunction Hemodynamic changes Afferent arteriolar vasoconstriction Mesangial contraction Reduced tubular reabsorption of NaCl Backleak of glomerular filtrate Tubular obstruction Reduced GPF and P Reduced glomerular filtration surface area available for filtration and a fall i n Kf Increased delivery of NaCl to distal nephron (macula densa) and activation of TG feedback Backleak of urea, creatinine, and reduction in "effective GFR" Compromises patency of renal tubules and prevents the recovery of renal function FIGURE 14-1 Pathophysiology of ischemic and toxic acute renal failure (ARF). The severe reduction in glomerular filtration rate (GFR) associated with establishe d ischemic or toxic renal injury is due to the combined effects of alterations i n intrarenal hemodynamics and tubular injury. The hemodynamic alterations associ ated with ARF include afferent arteriolar constriction and mesangial contraction , both of which directly reduce GFR. Tubular injury reduces GFR by causing tubular obstruc tion and by allowing backleak of glomerular filtrate. Abnormalities in tubular r eabsorption of solute may contribute to intrarenal vasoconstriction by activatin g the tubuloglomerular (TG) feedback system. GPFglomerular plasmaflow; Pglomerular pressure; Kf glomerular ultrafiltration coefficient. Ischemic or toxic injury to the kidney Increase in vasoconstrictors Angiotensin II Endothelin Thromboxane Adenosine Leukotrienes Platelet-activating factor Defi ciency of vasodilators PGI2 EDNO FIGURE 14-2 Vasoactive hormones that may be responsible for the hemodynamic abno rmalities in acute tubule necrosis (ATN). A persistent reduction in renal blood flow has been demonstrated in both animal models of acute renal failure (ARF) an d in humans with ATN. The mechanisms responsible for the hemodynamic alterations in ARF involve an increase in the intrarenal activity of vasoconstrictors and a deficiency of important vasodilators. A number of vasoconstrictors have been im plicated in the reduction in renal blood flow in ARF. The importance of individu al vasoconstrictor hormones in ARF probably varies to some extent with the cause of the renal injury. A deficiency of vasodilators such as endotheliumderived ni tric oxide (EDNO) and/or prostaglandin I2 (PGI2) also contributes to the renal h

ypoperfusion associated with ARF. This imbalance in intrarenal vasoactive hormon es favoring vasoconstriction causes persistent intrarenal hypoxia, thereby exace rbating tubular injury and protracting the course of ARF. Imbalance in vasoactive hormones causing persistent intrarenal vasoconstriction Persistent medullary hypoxia

Pathophysiology of Ischemic Acute Renal Failure 14.3 Glomerular basement membrane Glomerular capillary endothelial cells M Glomerular epithelial cells M Mesangial cell contraction Angiotensin II Endothelin1 Thromboxane Sympathetic ner ves FIGURE 14-3 The mesangium regulates single-nephron glomerular filtration rate (S NGFR) by altering the glomerular ultrafiltration coefficient (Kf). This schemati c diagram demonstrates the anatomic relationship between glomerular capillary lo ops and the mesangium. The mesangium is surrounded by capillary loops. Mesangial cells (M) are specialized pericytes with contractile elements that can respond to vasoactive hormones. Contraction of mesangium can close and prevent perfusion of anatomically associated glomerular capillary loops. This decreases the surfa ce area available for glomerular filtration and reduces the glomerular ultrafilt ration coefficient. Mesangial cell relaxation Prostacyclin EDNO Afferent arteriole Periportal cell Extraglomerular mesangial cells Macula densa cells FIGURE 14-4 A, The topography of juxtaglomerular apparatus (JGA), including macu la densa cells (MD), extraglomerular mesangial cells (EMC), and afferent arterio lar smooth muscle cells (SMC). Insets schematically illustrate, B, the structure of JGA; C, the flow of information within the JGA; and D, the putative messenge rs of tubuloglomerular feedback responses. AAafferent arteriole; PPCperipolar cell ; EAefferent arteriole; GMCglomerular mesangial cells. (Modified from Goligorsky e t al. [1]; with permission.) Glomerus A AA AA MD PPC EMC G GMC EMC MD AA SMC+GC MD PPC EMC G GMC Chloride Adenosine PGE2 Angiotensin Nitric oxide Osmolarity Unk nown? EA G GMC PPC EA EA B C D

14.4 Acute Renal Failure FIGURE 14-5 The tubuloglomerular (TG) feedback mechanism. A, Normal TG feedback. In the normal kidney, the TG feedback mechanism is a sensitive device for the r egulation of the single nephron glomerular filtration rate (SNGFR). Step 1: An i ncrease in SNGFR increases the amount of sodium chloride (NaCl) delivered to the juxtaglomerular apparatus (JGA) of the nephron. Step 2: The resultant change in the composition of the filtrate is sensed by the macula densa cells and initiat es activation of the JGA. Step 3: The JGA releases renin, which results in the l ocal and systemic generation of angiotensin II. Step 4: Angiotensin II induces v asocontriction of the glomerular arterioles and contraction of the mesangial cel ls. These events return SNGFR back toward basal levels. B, TG feedback in ARF. S tep 1: Ischemic or toxic injury to renal tubules leads to impaired reabsorption of NaCl by injured tubular segments proximal to the JGA. Step 2: The composition of the filtrate passing the macula densa is altered and activates the JGA. Step 3: Angiotensin II is released locally. Step 4: SNGFR is reduced below normal le vels. It is likely that vasoconstrictors other than angiotensin II, as well as v asodilator hormones (such as PGI2 and nitric oxide) are also involved in modulat ing TG feedback. Abnormalities in these vasoactive hormones in ARF may contribut e to alterations in TG feedback in ARF. The normal tubuloglomerular (TG) feedback mechanism 4. Afferent arteriolar and mesangial contraction reduce SNGFR back toward contro l levels. 3. Renin is released from specialized cells of JGA and the intrarenal renin angiotensin system generates release of angiotensin II locally. 1. SNGFR increases causing increase in delivery of solute to the distal nephron. 2. The composition of filtrate passing the macula densa is altered and stimulate s the JGA. A Role of TG feedback in ARF 4. Afferent arteriolar and mesangial contraction reduce SNGFR below normal level s. 3. Local release of angiotensin II is stimulated. 1. Renal epithelial cell injury reduces reabsorption of NaCl by proximal tubules . 2. The composition of filtrate passing the macula densa is altered and stimulate s the JGA. B

Pathophysiology of Ischemic Acute Renal Failure Osswald's Hypothesis Increased ATP hydrolysis (increased distal Na+ load) Increa sed generation of adenosine Activation of JGA 14.5 FIGURE 14-6 Metabolic basis for the adenosine hypothesis. A, Osswald's hypothesis on the role of adenosine in tubuloglomerular feedback. B, Adenosine metabolism: production and disposal via the salvage and degradation pathways. (A, Modified f rom Osswald et al. [2]; with permission.) Afferent arteriolar vasoconstriction Nerve endings [Na+] ATP Adenosine Na+ Adenosine Renincontaining cells Renin secretion ANG II [Cl ] ANG I Signal Transmission Mediator(s) Effects Vascular smooth muscle GFR A Adenosine nucleotide metabolism ATP ADP AMP Adenosine A1 e se AT Pas se A2 AD Pa 5'nu cle ot id a Receptors Transporter Phosphorylation or degradation ATP ADP AMP Salvage pathway Adenosine Inosine Degradation pathway Uric acid Hypoxanthine

B Xanthine

14.6 20 Adenosine, nmoles/mL 15 10 5 0 25 20 15 10 5 0 30 25 20 15 10 5 0 1 2 Acute Renal Failure FIGURE 14-7 Elevated concentration of adenosine, inosine, and hypoxanthine in th e dog kidney and urine after renal artery occlusion. (Modified from Miller et al . [3]; with permission.) Hypoxanthine, nmoles/mL Inosine, nmoles/mL 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Volume collected, mL Post Ischemia Glomerul I SNGFR: 17.41.7 nL/min PFR: 66.65.6 nL/min Glomeruli II SN GFR: 27.03.1 nL/min PFR: 128.714.4 nL/min B Anti-endothelin A FIGURE 14-8 Endothelin (ET) is a potent renal vasoconstrictor. Endothelin (ET) i s a 21 amino acid peptide of which three isoformsET-1, ET-2 and ET-3have been desc ribed, all of which have been shown to be present in renal tissue. However, only the effects of ET-1 on the kidney have been clearly elucidated. ET-1 is the mos t potent vasoconstrictor known. Infusion of ET-1 into the kidney induces profoun

d and long lasting vasoconstriction of the renal circulation. A, The appearance of the rat kidney during the infusion of ET-1 into the inferior branch of the ma in renal artery. The lower pole of the kidney perfused by this vessel is profoun dly vasoconstricted and hypoperfused. B, Schematic illustration of function in s eparate populations of glomeruli within the same kidney. The entire kidney under went 25 minutes of ischemia 48 hours before micropuncture. Glomeruli I are nephr ons not exposed to endothelin antibody; Glomeruli II are nephrons that received infusion with antibody through the inferior branch of the main renal artery. SNG FRsingle nephron glomerular filtration rate; PFRglomerular renal plasma flow rate. (From Kon et al. [4]; with permission.)

Pathophysiology of Ischemic Acute Renal Failure 14.7 Preproendothelin1 NH2 53 LysArg 74 92 ArgArg Dibasic pairspecific endopeptidase(s) CO OH 203 FIGURE 14-9 Biosynthesis of mature endothelin-1 (ET-1). The mature ET-1 peptide is produced by a series of biochemical steps. The precursor of active ET is prepro ET, which is cleaved by dibasic pairspecific endopeptidases and carboxypepti dases to yield a 39amino acid intermediate termed big ET-1. Big ET-1, which has l ittle vasoconstrictor activity, is then converted to the mature 21amino acid ET b y a specific endopeptidase, the endothelinconverting enzyme (ECE). ECE is locali zed to the plasma membrane of endothelial cells. The arrows indicate sites of cl eavage of pre-pro ET and big ET. NH3 Big endothelin COOH Endothelin converting enzyme (ECE) TrpVal Leu Ser Ser Cys Ser Cys Met Asp Lys Glu NH3 Mature endothelin Cys Val Tyr Phe Cys His Leu Asp Ile Ile Trp COOH Plasma Mature ET ET E EC Endothelium ETB receptor NO PGI2 ECE Mature ET ETA receptor Vascular smooth muscle Vasoconstriction ETB receptor Cycl ic GMP Cyclic AMP FIGURE 14-10 Regulation of endothelin (ET) action; the role of the ET receptors. Pre-pro ET is produced and converted to big ET. Big ET is converted to mature, active ET by endothelin-converting enzyme (ECE) present on the endothelial cell membrane. Mature ET secreted onto the basolateral aspect of the endothelial cell binds to two ET receptors (ETA and ETB); both are present on vascular smooth mu scle (VSM) cells. Interaction of ET with predominantly expressed ETA receptors o n VSM cells induces vasoconstriction. ETB receptors are predominantly located on the plasma membrane of endothelial cells. Interaction of ET-1 with these endoth elial ETB receptors stimulates production of nitric oxide (NO) and prostacyclin by endothelial cells. The production of these two vasodilators serves to counter balance the intense vasoconstrictor activity of ET-1. PGI2prostaglandin I2. Vasodilation

14.8 Acute Renal Failure FIGURE 14-11 Endothelin-1 (ET-1) receptor blockade ameliorates severe ischemic a cute renal failure (ARF) in rats. The effect of an ETA receptor antagonist (BQ12 3) on the course of severe postischemic ARF was examined in rats. BQ123 (light b ars) or its vehicle (dark bars) was administered 24 hours after the ischemic ins ult and the rats were followed for 14 days. A, Survival. All rats that received the vehicle were dead by the 3rd day after ischemic injury. In contrast, all rat s that received BQ123 post-ischemia survived for 4 days and 75% recovered fully. B, Glomerular filtration rate (GFR). In both groups of rats GFR was extremely l ow (2% of basal levels) 24 hours after ischemia. In BQ123-treated rats there was a gradual increase in GFR that reached control levels by the 14th day after isc hemia. C, Serum potassium. Serum potassium increased in both groups but reached significantly higher levels in vehicle-treated compared to the BQ123-treated rat s by the second day. The severe hyperkalemia likely contributed to the subsequen t death of the vehicle treated rats. In BQ123-treated animals the potassium fell progressively after the second day and reached normal levels by the fourth day after ischemia. (Adapted from Gellai et al. [5]; with permission.) 10 Number of rats 8 6 4 2 0 Ischemia BQ123(0.1mg/kg min, for 3h) Vehicle BQ123 A 150 GFR, mL/h 120 90 60 30 0 Basal 24h control 1 2 3 4 5 6 14 Ischemia BQ123(0.1mg/kg min, for 3h) B 10 8 6 4 2 0 Basal 24h control 1

2 3 4 5 6 14 Plasma K+, mEq/L Ischemia BQ123(0.1mg/kg min, for 3h) Basal C 24h control 1 2 3 4 5 6 14 Posttreatment days Lipid Membrane Phospholipase A2 Arachidonic acid NSAID PGG2 Prostaglandin intermediates PGH2 Th romboxane TxA2 Cycloxygenase FIGURE 14-12 Production of prostaglandins. Arachidonic acid is released from the plasma membrane by phospholipase A2. The enzyme cycloxygenase catalyses the con version of arachidonate to two prostanoid intermediates (PGH2 and PGG2). These a re converted by specific enzymes into a number of different prostanoids as well as thromboxane (TXA2). The predominant prostaglandin produced varies with the ce ll type. In endothelial cells prostacyclin (PGI2) (in the circle) is the major m etabolite of cycloxygenase activity. Prostacyclin, a potent vasodilator, is invo lved in the regulation of vascular tone. TXA2 is not produced in endothelial cel ls of normal kidneys but may be produced in increased amounts and contribute to the pathophysiology of some forms of acute renal failure (eg, cyclosporine Ainduc ed nephrotoxicity). The production of all prostanoids and TXA2 is blocked by non steroidal anti-inflammatory agents (NSAIDs), which inhibit cycloxygenase activit y. PGF2

PGI2 Prostacyclin PGE2

Pathophysiology of Ischemic Acute Renal Failure 14.9 Aorta Cyclosporine A in circulation Intraarterial infusion of ETA receptor antagonist CSA FIGURE 14-13 Endothelin (ET) receptor blockade ameliorates acute cyclosporineind uced nephrotoxicity. Cyclosporine A (CSA) was administered intravenously to rats . Then, an ET receptor anatgonist was infused directly into the right renal arte ry. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were reduced by the CSA in the left kidney. The ET receptor antagonist protected GFR and RPF fr om the effects of CSA on the right side. Thus, ET contributes to the intrarenal vasoconstriction and reduction in GFR associated with acute CSA nephrotoxicity. (From Fogo et al. [6]; with permission.) Right renal artery GFR and RPF: near normal Right kidney Left renal artery GFR and RPF: Reduced 20-25% below normal Left kidney Normal basal state Circulating levels of vasoconstrictors: Low Afferent arteriol ar tone normal Intrarenal levels of prostacyclin: Low Intraglomerular normal P A Intravascular volume depletion Circulating levels of vasoconstrictors: High Affe rent arteriolar tone normal or mildly reduced Intrarenal levels of prostacyclin: High GFR normal Intraglomerular P normal or mildly reduced B GFR normal or mildly reduced Intravascular volume depletion and NSAID administra tion Circulating levels of vasoconstrictors: High Afferent arteriolar tone sever ely increased Intrarenal levels of prostacyclin: Low Intraglomerular P severely reduced FIGURE 14-14 Prostacyclin is important in maintaining renal blood flow (RBF) and glomerular filtration rate (GFR) in prerenal states. A, When intravascular volume is normal, prostacyclin production in the endothelial cells of the kidney is lo w and prostacyclin plays little or no role in control of vascular tone. B, The r eduction in absolute or effective arterial blood volume associated with all preren al states leads to an increase in the circulating levels of a number of of vasoc onstrictors, including angiotensin II, catecholamines, and vasopressin. The incr ease in vasoconstrictors stimulates phospholipase A2 and prostacyclin production in renal endothelial cells. This increase in prostacyclin production partially counteracts the effects of the circulating vasoconstrictors and plays a critical role in maintaining normal or nearly normal RBF and GFR in prerenal states. C, The effect of cycloxygenase inhibition with nonsteroidal anti-inflammatory drugs (NSAIDs) in prerenal states. Inhibition of prostacyclin production in the prese nce of intravascular volume depletion results in unopposed action of prevailing vasoconstrictors and results in severe intrarenal vascasoconstriction. NSAIDs ca n precipitate severe acute renal failure in these situations. C

GFR severely reduced

14.10 Acute Renal Failure A. VASODILATORS USED IN EXPERIMENTAL ACUTE RENAL FAILURE (ARF) Time Given in Relation to Induction Before, during, after Before, during, after After Before, during Before, after A fter Before, during Before, during, after Before Before Before, during, after Be fore Before, during Before, during, after Before After Vasodilator Propranolol Phenoxybenzamine Clonidine Bradykinin Acetylcholine Prostaglandin E1 Prostaglandin E2 Prostaglandin I2 Saralasin Captopril Verapamil Nifedipine Nitr endipine Diliazem Chlorpromazine Atrial natriuretic peptide ARF Disorder Ischemic Toxic Ischemic Ischemic Ischemic Ischemic Ischemic, toxic Ischemic Toxi c, ischemic Toxic, ischemic Ischemic, toxic Ischemic Toxic Toxic Toxic Ischemic, toxic Observed Effect Scr, BUN if given before, during; no effect if given after Prevented fall in RBF S cr, BUN -RBF, GFR -RBF; no change in GFR -RBF; no change in GFR -GFR -GFR -RBF; no change in Scr, BUN -RBF; no change in Scr, BUN -RBF, GFR in most studies -GFR -GFR -GFR; recovery ti me -GFR; recovery time -RBF, GFR BUNblood urea nitrogen; GFRglomerular filtration rate; RBFrenal blood flow; Scrserum creatinine. B. VASODILATORS USED TO ALTER COURSE OF CLINICAL ACUTE RENAL FAILURE (ARF) Vasodilator Dopamine Phenoxybenzamine Phentolamine Prostaglandin A1 Prostaglandin E1 Dihydra lazine Verapamil Diltiazem Nifedipine Atrial natriuretic peptide ARF Disorder Ischemic, toxic Ischemic, toxic Ischemic, toxic Ischemic Ischemic Ischemic, toxi c Ischemic Transplant, toxic Radiocontrast Ischemic Observed Effect Improved V, Scr if used early No change in V, RBF No change in V, RBF No change in V, Scr -RBF, no change v, Ccr -RBF, no change V, Scr -Ccr or no effect -Ccr or no eff ect No effect -Ccr Remarks Combined with furosemide Used with dopamine Used with NE Prophylactic use Ccrcreatinine clearance; NEnorepinephrine; RBFrenal blood flow; Scrserum creatinine; Vurine flow rate. FIGURE 14-15 Vasodilators used in acute renal failure (ARF). A, Vasodilators use d in experimental acute ARF. B, Vasodilators used to alter the course of clinica l ARF. (From Conger [7]; with permission.)

Pathophysiology of Ischemic Acute Renal Failure NH2 + NH2 NH2 + NOH O2 H 2O NH2 + O Target domain 14.11 NH NADPH NADP+ O2 H 2O + 1/ 1 2 NADPH / NADP 2 Modular structure of nitric oxide synthases H BH4 ARG CaM FMN FAD Oxygenase domain Reductase domain NADPH NH NH + NO nNOS Dimerization site(s) 1314 23 eNOS 1820 2123 1921 2429 2226 BH4 + BH4 + G nitric oxide + 45 6 79 1012 151617 1618 1112 1 23 4 57 M 810 131415 1213 NH3 COO NH3 COO NH3 COO iNOS A L-arginine N -hydroxy-L-arginine L-citrulline FIGURE 14-16 Chemical reactions leading to the generation of nitric oxide (NO), A, and enzymes that catalize them, B. (Modified from Gross [8]; with permission. )

1921 23 45 6 79 1011 13 1418 23 48 912 Mammalian P450 Reductases Bacterial Flavodoxi ant Ferredoxin NADPH Reductases B. mega P450 DHF Reductases Mammalian Syntrophin s (GLGF Motif) B 2226 1316 L-arginine NOS Nitric oxide Smooth muscle L-citrulline GTP GC cGMP Immune cells CNS and PNS Inhibition of iron-containing enzymes Target cell death Neurotransmi ssion Hemoglobin NO3 + NO2 cGMP Vasodilatation NO concentration M mM M ROIs DNA damage Activation of apoptotic signal Thiols Heme- & ironcontaining pro teins Guanylate cyclase Cell death Apoptosis Induction of stress proteins Inacti vation of enzymes Antioxidant cGMP (cellular signal) nM B Time Consequences A Urine excretion Endothelium-dependent vasodilators + Shear stress + L-Arginine NO Nitroglycerin N O Leukocyte migration Platelet aggregation + NOS + GTP sGC + cGMP + ANP pGC FIGURE 14-17 Major organ, A, and cellular, B, targets of nitric oxide (NO). A, S ynthesis and function of NO. B, Intracellular targets for NO and pathophysiologi cal consequences of its action. C, Endotheliumdependent vasodilators, such as ac etylcholine and the calcium ionophore A23187, act by stimulating eNOS activity t hereby increasing endothelium-derived nitric oxide (EDNO) production. In contras t, other vasodilators act independently of the endothelium. Some endothelium-ind ependent vasodilators such as nitroprusside and nitroglycerin induce vasodilatio n by directly releasing nitric oxide in vascular smooth muscle cells. NO release d by these agents, like EDNO, induces vasodilation by stimulating the production of cyclic guanosine monophosphate (cGMP) in vascular smooth muscle (VSM) cells. Atrial natriuretic peptide (ANP) is also an endothelium-independent vasodilator but acts differently from NO. ANP directly stimulates an isoform of guanylyl cy clase (GC) distinct from soluble GC (called particulate GC) in VSM. CNScentral ne rvous system; GTPguanosine triphosphate; NOSnitric oxide synthase; PGCparticulate g uanylyl cyclase; PNSperipheral nervous system; ROIreduced oxygen intermediates; SG Csoluble guanylyl cyclase. (A, From Reyes et al. [9], with permission; B, from Ki m et al. [10], with permission.)

C Relaxation

14.12 Acute Renal Failure FIGURE 14-18 Impaired production of endothelium-dependent nitric oxide (EDNO) co ntributes to the vasoconstriction associated with established acute renal failur e (ARF). Ischemia-reperfusion injury in the isolated erythrocyte-perfused kidney induced persistant intarenal vasoconstriction. The endothelium-independent vaso dilators (atrial natriuretic peptide [ANP] and nitroprusside) administered durin g the reflow period caused vasodilation and restored the elevated intrarenal vas cular resistance (RVR) to normal. In marked contrast, two endothelium-dependent vasodilators (acetylcholine and A23187) had no effect on renal vascular resistan ce after ischemia-reflow. These data suggest that EDNO production is impaired fo llowing ischemic injury and that this loss of EDNO activity contributes to the v asoconstriction associated with ARF. (Adapted from Lieberthal [11]; with permiss ion.) Ischemia (I) alone I + ANP I+ nitroprusside I+ Acetylcholine I + A23187 0 20 40 80 60 Increase in RVR above control, % 60 50 40 30 20 Percent LDH release 10 0 O2 150 BUN mg/dL Hypoxia P<.001 P<.001 Hypoxia + L-NAME Control 100 50 0 3.0 2.5 1.5 Cr * * * 50 40 30 20 10 0 0 10 20 30 Time, min P<.001 Control P<.01 Hypoxia P<.05 mg/dL 60 O2 Hypoxia + L-Arg 1.0 0.5 0 Control * * * P<.001 Ischemia S SCR AS Vehicle

40 50 A B P<.001 50 40 LDH release, % 30 NS 20 10 0 C Normoxia Hypoxia Wild type mice Normoxia Hypoxia iNOS knockout mice FIGURE 14-19 Deleterious effects of nitric oxide (NO) on the viability of renal tubular epithelia. A, Hypoxia and reoxygenation lead to injury of tubular cells (filled circles); inhibition of NO production improves the viability of tubular cells subjected to hypoxia and reoxygenation (triangles in upper graph), whereas addition of L-arginine enhances the injury (triangles in lower graph). B, Ameli oration of ischemic injury in vivo with antisense oligonucleotides to the iNOS: blood urea nitrogen (BUN), and creatinine (CR) in rats subjected to 45 minutes o f renal ischemia after pretreatment with antisense phosphorothioate oligonucleot ides (AS) directed to iNOS or with sense (S) and scrambled (SCR) constructs. C, Resistance of proximal tubule cells isolated from iNOS knockout mice to hypoxiainduced injury. LDHlactic dehydrogenase. (A, From Yu et al. [12], with permission ; B, from Noiri et al. [13], with permission; C, from Ling et al. [14], with per mission.)

Pathophysiology of Ischemic Acute Renal Failure 14.13 Iothalamate Radiocontrast 100 50 0 Iothalamate 100 Cortex Percent of baseline 50 0 200 150 100 50 Iothalamate Normal kidneys Chronic renal insufficiency Compensatory increase in PGI2 and EDNO release Increased endothelin Reduced or absent increase in PGI2 or EDNO Medulla 100 50 0 0 20 40 Minutes No pretreatment (n = 6) Mild vasoconstriction 0 20 40 Minutes Pretreatment with L-NAME (n = 6) Severe vasoconstriction 0 60 60 A B No loss of GFR Acute renal failure FIGURE 14-20 Proposed role of nitric oxide (NO) in radiocontrast-induced acute r enal failure (ARF). A, Administration of iothalamate, a radiocontrast dye, to ra ts increases medullary blood flow. Inhibitors of either prostaglandin production (such as the NSAID, indomethacin) or inhibitors of NO synthesis (such as L-NAME ) abolish the compensatory increase in medullary blood flow that occurs in respo nse to radiocontrast administration. Thus, the stimulation of prostaglandin and NO production after radiocontrast administration is important in maintaining med ullary perfusion and oxygenation after administration of contrast agents. B, Rad iocontrast stimulates the production of vasodilators (such as prostaglandin [PGI 2] and endothelium-dependent nitric oxide [EDNO]) as well as endothelin and othe r vasoconstrictors within the normal kidney. The vasodilators counteract the effects of the vasoconstricto rs so that intrarenal vasoconstriction in response to radiocontrast is usually m odest and is associated with little or no loss of renal function. However, in si tuations when there is preexisting chronic renal insufficiency (CRF) the vasodil

ator response to radiocontrast is impaired, whereas production of endothelin and other vasoconstrictors is not affected or even increased. As a result, radiocon trast administration causes profound intrarenal vasoconstriction and can cause A RF in patients with CRF. This hypothesis would explain the predisposition of pat ients with chronic renal dysfunction, and especially diabetic nephropathy, to co ntrastinduced ARF. (A, Adapted from Agmon and Brezis [15], with permission; B, f rom Agmon et al. [16], with permission.) FIGURE 14-21 Cellular calcium metabolism and potential targets of the elevated c ytosolic calcium. A, Pathways of calcium mobilization. B, Pathophysiologic mecha nisms ignited by the elevation of cytosolic calcium concentration. (A, Adapted f rom Goligorsky [17], with permission; B, from Edelstein and Schrier [18], with p ermission.)

14.14 Acute Renal Failure * 60 100 40 Pre NE NS Post NE Verapamil before NE P<.001 P<.05 400 Estimated [Ca2+]i , nM * * * * * * * 80 60 40 Pl stained nuclei, % 20 CIn, mL/min 0 60 NS 300 200 150 0 * Verapamil after NE * Significant vs. time 0 Hypoxia 20 0 40 20 0 P<.001 P<.02 10 Time, min 20 30 A B Control 1h 24 h FIGURE 14-22 Pathophysiologic sequelae of the elevated cytosolic calcium (C2+). A, The increase in cytosolic calcium concentration in hypoxic rat proximal tubul es precedes the tubular damage as assessed by propidium iodide (PI) staining. B, Administration of calcium channel inhibitor verapamil before injection of norepinephrine (cross-hatched bars) significantly attenuated the drop in inulin clearance induced by norepinephrine alone (open ba rs). (A, Adapted from Kribben et al. [19], with permission; B, adapted from Burk e et al. [20], with permission.) FIGURE 14-23 Dynamics of heat shock proteins (H

SP) in stressed cells. Mechanisms of activation and feedback control of the indu cible heat shock gene. In the normal unstressed cell, heat shock factor (HSF) is rendered inactive by association with the constitutively expressed HSP70. After hypoxia or ATP depletion, partially denatured proteins (DP) become preferential ly associated with HSC73, releasing HSF and allowing trimerization and binding t o the heat shock element (HSE) to initiate the transcription of the heat shock g ene. After translation, excess inducible HSP (HSP72) interacts with the trimeriz ed HSF to convert it back to its monomeric state and release it from the HSE, th us turning off the response. (Adapted from Kashgarian [21]; with permission.)

Pathophysiology of Ischemic Acute Renal Failure 14.15 Free Radical Pathways in the Mitochondrion Catalase/GPx complex? Hydrogen H2O 2 peroxide H 2O 2 Outer membrane Inner membrane Superoxide anion Mn-SOD (tetramer) Matrix 2O2 Hydroperoxyl radical O2 Hydrogen peroxide HO2 HO2 Hepatocyte (and other cells) Golgi complex O2 (From glycolysis/ TCA cycle) e Plasma ECSOD Proteinase? Tissue ECSOD + 2H+ Mitochondrion Manganese superoxide dismatase (Mn-SOD) mRNA chrom 6 Catalas e mRNA Endoplasmic reticulum Secretory vesicle Heparin sulfate proteoglycans 2H+ H 2O 2 + Chromosome (chrom) 4 Extracellular superoxide dismutase (EC-SOD) mRNA chrom 3 chrom 11 chrom 21 GPx subunit Se GPx (tetramer) H2O+O2 +GSSG + O2 Glutathione peroxidase (GPx) mRNA Cu,ZnSOD (dimer) Glutathione (dimer) +2GSH Glutathione (monomer) Plasma membrane damaged (enlarged below) Catalase subunit Peroxisome Copperzinc superoxide dismutase (Cu,ZnSOD) mRNA 2O2 +2H+ +O2 Perxisome reactions Oxidative enzyme (eg, urate oxidase) RH2 + O2 Catalase (tetramer) Heme Hydrogen peroxide 2H2O+O2

Lipid peroxidation of plasma membrane Phospholipid hydroperoxide glutathione peroxidase (PHGPx) Inside cell LH LH 2GSH's + LOOH OH LO LOH+ GSSG+ Lipid peroxide O L LOO LH Free radical R LH LH Lipid LOOH Vitamin E (a-Tocopherol) inhibits lipid peroxidation chain reaction LOOH LH e FIGURE 14-24 Cellular sources of reactive oxygen species (ROS) defense systems f rom free radicals. Superoxide and hydrogen peroxide are produced during normal c ellular metabolism. ROS are constantly being produced by the normal cell during a number of physiologic reactions. Mitochondrial respiration is an important sou rce of superoxide production under normal conditions and can be increased during ischemia-reflow or gentamycininduced renal injury. A number of enzymes generate superoxide and hydrogen peroxide during their catalytic cycling. These include cycloxygenases and lipoxygenes that catalyze prostanoid and leukotriene synthesi s. Some cells (such as leukocytes, endothelial cells, and vascular smooth muscle cells) have NADH/ or NADPH oxidase enzymes in the plasma membrane that are capa ble of generating superoxide. Xanthine oxidase, which converts hypoxathine to xa nthine, has been implicated as an important source of ROS after ischemia-reperfu sion injury. Cytochrome p450, which is bound to the membrane of the endoplasmic reticulum, can be increased by the presence of high concentrations of metabolite s that are oxidized by this cytochrome or by injurious events that uncouple the activity of the p450. Finally, the oxidation of small molecules including free h eme, thiols, hydroquinines, catecholamines, flavins, and tetrahydropterins, also contribute to intracellular superoxide production. (Adapted from [22]; with per mission.) H LO RH Lipid radical O LOO H L Outside cell Lipid chain collpases (now hydrophilic)

14.16 Acute Renal Failure FIGURE 14-25 Evidence suggesting a role for reactive oxygen metabolites in acute renal failure. The increased ROS production results from two major sources: the conversion of hypoxanthine to xanthine by xanthine dehydrogenase and the oxidat ion of NADH by NADH oxidase(s). During the period of ischemia, oxygen deprivatio n results in the massive dephosphorylation of adenine nucleotides to hypoxanthin e. Normally, hypoxanthine is metabolized by xanthine dehydrogenase which uses NA D+ rather than oxygen as the acceptor of electrons and does not generate free ra dicals. However, during ischemia, xanthine dehydrogenase is converted to xanthin e oxidase. When oxygen becomes available during reperfusion, the metabolism of h ypoxanthine by xanthine oxidase generates superoxide. Conversion of NAD+ to its reduced form, NADH, and the accumulation of NADH occurs during ischemia. During the reperfusion period, the conversion of NADH back to NAD+ by NADH oxidase also results in a burst of superoxide production. (From Ueda et al. [23]; with permi ssion.) EVIDENCE SUGGESTING A ROLE FOR REACTIVE OXYGEN METABOLITES IN ISCHEMIC ACUTE REN AL FAILURE Enhanced generation of reactive oxygen metabolites and xanthine oxidase and incr eased conversion of xanthine dehydrogenase to oxidase occur in in vitro and in v ivo models of injury. Lipid peroxidation occurs in in vitro and in vivo models o f injury, and this can be prevented by scavengers of reactive oxygen metabolites , xanthine oxidase inhibitors, or iron chelators. Glutathione redox ratio, a par ameter of oxidant stress decreases during ischemia and markedly increases on reper fusion. Scavengers of reative oxygen metabolites, antioxidants, xanthine oxidase inhibitors, and iron chelators protect against injury. A diet deficient in sele nium and vitamin E increases susceptibility to injury. Inhibition of catalase ex acerbates injury, and transgenic mice with increased superoxide dismutase activi ty are less susceptible to injury. 250 24 3.0 2.5 Creatinine, mg/dL *P < 0.001 16 *P < 0.001 Plasma urea nitrogen, mg/dL 200 150 100 16* 2.0 1.5 1.0 8* 50 26 8* 6* 13* 4* 6* 8* 5* 4* 0.5 0.0

18 0 O HB FO nz U t t Con Gen MT MS +Be +D +D +D +D FIGURE 14-26 Effect of different scavengers of reactive oxygen metabolites and i ron chelators on, A, blood urea nitrogen (BUN) and, B, creatinine in gentamicininduced acute renal failure. The numbers shown above the error bars indicate the number of animals in each group. Benzsodium benzoate; Contcontrol group; DFOdefero xamine; DHB 2,3 dihydroxybenzoic acid; DMSO dimethyl sulfoxide; DMTUdimethylthioure a; Gentgentamicin group. (From Ueda et al. [23]; with permission.) O Con Gen MT MS +Be +D A B Superoxide O2 Iron stores (Ferritin) Release of free iron Fe2+ Fe3+ OH +Fe3+ Hydrogen Peroxide (H2O2) Hydroxyl Radical (OH) FIGURE 14-27 Production of the hydroxyl radical: the Haber-Weiss reaction. Super oxide is converted to hydrogen peroxide by superoxide dismutase. Superoxide and hydrogen peroxide per se are not highly reactive and cytotoxic. However, hydroge n peroxide can be converted to the highly reactive and injurious hydroxyl radica l by an iron-catalyzed reaction that requires the presence of free reduced iron. The availability of free catalytic iron is a critical determinant of hydroxyl rad ical production. In addition to providing a source of hydroxyl radical, superoxi de potentiates hydroxyl radical production in two ways: by releasing free iron f rom iron stores such as ferritin and by reducing ferric iron and recycling the a vailable free iron back to the ferrous form. The heme moiety of hemoglobin, myog lobin, or cytochrome present in normal cells can be oxidized to metheme (Fe3+). The further oxidation of metheme results in the production of an oxyferryl moiet y (Fe4+=O), which is a long-lived, strong oxidant which likely plays a role in t he cellular injury associated with hemoglobinuria and myoglobinuria. Activated l eukocytes produce superoxide and hydrogen peroxide via the activity of a membran e-bound enzyme NADPH oxidase. This superoxide and hydrogen peroxide can be conve rted to hydroxyl radical via the Haber-Weiss reaction. Also, the enzyme myeloper oxidase, which is specific to leukocytes, converts hydrogen peroxide to another highly reactive and injurious oxidant, hypochlorous acid. +D

+D +D HB FO nz U t t

Pathophysiology of Ischemic Acute Renal Failure 14.17 :OO + NO :OONO 22 kcal/mol ...Large Gibbs energy ONOO ...Faster than SOD Initiation LH + OH H2O + L LOO :O2 6.7 x 109 M1s1 [NO] Propagation L + O2 O 2 + H 2O 2 1 x 109 M1s1 [SOD] H O O O O N O N O N O OH ...Peroxynitrous OH A acid i n trans FIGURE 14-28 Cell injury: point of convergence between the reduced oxygen interm ediatesgenerating and reduced nitrogen intermediates generating pathways, A, and m echanisms of lipid peroxidation, B. LOO + LH Termination L + L LOOH + L LL LOONO B LOO + NO ONOO X XO NO2 Tyr NO2 116 KD OH R Nitrotyrosine X: SOD, Cu2+, Fe3+ Cortex Medulla 116 KD A 66 KD 66 KD C CI LN C CI LN

C Free R' radical Free Control Control Ischemia L-Nil + Ischemia R O2 OO R O O R' H NE HNE OH O Ab O OH R' radical R Unsaturated fatty acid O O R OO R' O2 B FIGURE 14-29 Detection of peroxynitrite production and lipid peroxidation in isc hemic acute renal failure. A, Formation of nitrotyrosine as an indicator of ONOO - production. Interactions between reactive oxygen species such as the hydroxyl radical results in injury to the ribose-phosphate backbone of DNA. This results in singleand double-strand breaks. ROS can also cause modification and deletion of individual bases within the DNA molecule. Interaction between reactive oxygen and nitrogen species results in injury to the ribose-phosphate backbone of DNA, nuclear DNA fragmentation (single- and double-strand breaks) and activation of poly(ADP)-ribose synthase. B, Immunohistochemical staining of kidneys with antib odies to nitrotyrosine. C, Western blot analysis of nitrotyrosine. D, Reactions describing lipid peroxidation and formation of hemiacetal products. The interact ion of oxygen radicals with lipid bilayers leads to the removal of hydrogen atom s from the unsaturated fatty acids bound to phospholipid. This R Lipid based peroxyradical (LOO) OH R' O X Protein X Formation of stable hemiacetal adducts D (X: Cys, His, Lys) process is called lipid peroxidation. In addition to impairing the structural an d functional integrity of cell membranes, lipid peroxidation can lead to a selfperpetuating chain reaction in which additional ROS are generated. (Continued on next page)

14.18 Acute Renal Failure Cortex Medulla Control Control Ischemia L-Nil + Ischemia E FIGURE 14-29 (Continued) E, Immunohistochemical staining of kidneys with antibod ies to HNEmodified proteins. F, Western blot analysis of HNE expression. Ccontrol; CIcentral ischemia; LNischemia with L-Nil pretreatment (Courtesy of E. Noiri, MD. ) C CI LN C CI LN F Leukocytes in Acute Renal Failure Inactive leukocyte Leukocyte adhesion molecules b2 integrins (LFA1 or Mac1) Select ions Endothelial adhesion molecules ICAM Ligand for leukocyte selections Activated leukocyte FIGURE 14-30 Role of adhesion molecules in mediating leukocyte attachment to end othelium. A, The normal inflammatory response is mediated by the release of cyto kines that induce leukocyte chemotaxis and activation. The initial interaction o f leukocytes with endothelium is mediated by the selectins and their ligands bot h of which are present on leukocytes and endothelial cells, (Continued on next p age) Selectionmediated rolling of leukocytes Firm adhesion of leukocytes (integrinmediated) Diapedesis Release of oxidants pro teases elastases Tissue injury A

Pathophysiology of Ischemic Acute Renal Failure 14.19 B. LEUKOCYTE ADHESION MOLECULES AND THEIR LIGANDS POTENTIALLY IMPORTANT IN ACUTE RENAL FAILURE Major Families Selectins L-selectin P-selectin E-selectin Carbohydrate ligands for selectins Su lphated polysacharides Oligosaccharides Integrins CD11a/CD18 CD11b/CD18 Immunogl obulin Glike ligands for integrins Intracellular adhesion molecules (ICAM) Cell Distribution Leukocytes Endothelial cells Endothelial cells Endothelium Leukocytes Leukocytes Leukocytes FIGURE 14-29 (Continued) B. Selectin-mediated leukocyte-endothelial interaction results in the rolling of leukocytes along the endothelium and facilitates the f irm adhesion and immobilization of leukocytes. Immobilization of leukocytes to e ndothelium is mediated by the 2-integrin adhesion molecules on leukocytes and th eir ICAM ligands on endothelial cells. Immobilization of leukocytes is necessary for diapedesis of leukocytes between endothelial cells into parenchymal tissue. Leukocytes release proteases, elastases, and reactive oxygen radicals that indu ce tissue injury. Activated leukocytes also elaborate cytokines such as interleu kin 1 and tumor necrosis factor which attract additional leukocytes to the site, causing further injury. Endothelial cells 125 100 Blood urea nitrogen 75 50 25 0 Anti-ICAM antibody Vehicle 2 Plasma creatinine 1.5 1 0.5 0 Anti-ICAM antibody Vehicle A 0 24 48 72 Time following ischemia-reperfusion, d B 0 24 48 72 96 Time following ischemia-reperfusion, d FIGURE 14-31 Neutralizing antiICAM antibody ameliorates the course of ischemic re nal failure with blood urea nitrogen, A, and plasma creatinine, B. Rats subjecte d to 30 minutes of bilateral renal ischemia or a sham-operation were divided int o three groups that received either anti-ICAM antibody or its vehicle. Plasma cr eatinine levels are shown at 24, 48, and 72 hours. ICAM antibody ameliorates the severity of renal failure at all three time points. (Adapted from Kelly et al. [24]; with permission.) 1250 1000 750 500 250 0 0 4 24 48 Time after reperfusion, hrs 72 Vehicle Anti-ICAM antibody Myeloperoxidase activity FIGURE 14-32 Neutralizing anti-ICAM-1 antibody reduces myeloperoxidase activity in rat kidneys exposed to 30 minutes of ischemia. Myeloperoxidase is an enzyme s pecific to leukocytes. Anti-ICAM antibody reduced myeloperoxidase activity (and

by inference the number of leukocytes) in renal tissue after 30 minutes of ische mia. (Adapted from Kelly et al. [24]; with permission.)

14.20 Acute Renal Failure Mechanisms of Cell Death: Necrosis and Apoptosis FIGURE 14-33 Apoptosis and necrosis: two distinct morphologic forms of cell deat h. A, Necrosis. Cells undergoing necrosis become swollen and enlarged. The mitoc hondria become markedly abnormal. The main morphoplogic features of mitochondria l injury include swelling and flattening of the folds of the inner mitochondrial membrane (the christae). The cell plasma membrane loses its integrity and allow s the escape of cytosolic contents including lyzosomal proteases that cause inju ry and inflammation of the surrounding tissues. B, Apoptosis. In contrast to nec rosis, apoptosis is associated with a progressive decrease in cell size and main tenance of a functionally and structurally intact plasma membrane. The decrease in cell size is due to both a loss of cytosolic volume and a decrease in the siz e of the nucleus. The most characteristic and specific morphologic feature of ap optosis is condensation of nuclear chromatin. Initially the chromatin condenses against the nuclear membrane. Then the nuclear membrane disappears, and the cond ensed chromatin fragments into many pieces. The plasma membrane undergoes a proc ess of budding, which progresses to fragmentation of the cell itself. Multiple pla sma membranebound fragments of condensed DNA called apoptotic bodies are formed a s a result of cell fragmentation. The apoptotic cells and apoptotic bodies are r apidly phagocytosed by neighboring epithelial cells as well as professional phag ocytes such as macrophages. The rapid phagocytosis of apoptotic bodies with inta ct plasma membranes ensures that apoptosis does not cause any surrounding inflam matory reaction. A B [Ca2+]i ? Mitochondrion ? Signal transduction pathways Regulation by Hcl-2 and its relatives ? Mitochondrial permeability transition Consequences of permeability transition: Disruption of ym and mitochondrial biogene sis Breakdown of energy metabolism Uncoupling of respiratory chain Calcium relea se frommitochondrial matrix Hyperproduction of superoxide anion Depletion of glu tathione ? ROS effects NAD/NADH Increase in ATP [Ca2+]i depletion depletion Tyro sin kinases G-proteins ? Cytoplasmic effects Disruption of anabolic reactions Dilatation of ER Activation of proteases Disruption of intracellular calcium compartimentalization Disorgan ization of cytoskeleton Nucleus Activation of endonucleases Activation of repair enzymes (ATP depletion) Activation of poly(ADP) ribosly transferase (NAD depletion) Chromatinolysis, nu cleolysis Degradation phase Effector phase Positive feedback loop

? Activation of ICE/ced-3-like proteases ? Induction phase FIGURE 14-34 Hypothetical schema of cellular events triggering apoptotic cell de ath. (From Kroemer et al. [25]; with permission.)

Pathophysiology of Ischemic Acute Renal Failure 14.21 FIGURE 14-35 Phagocytosis of an apoptotic body by a renal tubular epithelial cel l. Epithelial cells dying by apoptosis are not only phagocytosed by macrophages and leukocytes but by neighbouring epithelial cells as well. This electron micro graph shows a normal-looking epithelial cell containing an apoptotic body within a lyzosome. The nucleus of an epithelial cell that has ingested the apoptotic b ody is normal (white arrow). The wall of the lyzosome containing the apoptotic b ody (black arrow) is clearly visible. The apoptotic body consists of condensed c hromatin surrounded by plasma membrane (black arrowheads). Nucleosome ~200 bp Internucleosome "Linker" regions DNA fragmentation Apoptosis Necrosis FIGURE 14-36 DNA fragmentation in apoptosis vs necrosis. DNA is made up of nucle osomal units. Each nucleosome of DNA is about 200 base pairs in size and is surr ounded by histones. Between nucleosomes are small stretches of DNA that are not surrounded by histones and are called linker regions. During apoptosis, early ac tivation of endonuclease(s) causes double-strand breaks in DNA between nucleosom es. No fragmentation occurs in nucleosomes because the DNA is protected by the his tones. Because of the size of nucleosomes, the DNA is fragmented during apoptosi s into multiples of 200 base pair pieces (eg, 200, 400, 600, 800). When the DNA of apoptotic cells is electrophoresed, a characteristic ladder pattern is found. In contrast, necrosis is associated with the early release of lyzosomal proteas es, which cause proteolysis of nuclear histones, leaving naked stretches of DNA no t protected by histones. Activation of endonucleases during necrosis therefore c ause DNA cleavage at multiple sites into double- and single-stranded DNA fragmen ts of varying size. Electrophoresis of DNA from necrotic cells results in a smea r pattern. Loss of histones 800 bp 600 bp 400 bp 200 bp DNA electrophoresis Apoptic "ladder" pattern Necrotic "smear" pattern

14.22 Acute Renal Failure FIGURE 14-37 Potential causes of apoptosis in acute renal failure (ARF). The sam e cytotoxic stimuli that induce necrosis cause apoptosis. The mechanism of cell death induced by a specific injury depends in large part on the severity of the injury. Because most cells require constant external signals, called survival si gnals, to remain viable, the loss of these survival signals can trigger apoptosi s. In ARF, a deficiency of growth factors and loss of cell-substrate adhesion ar e potential causes of apoptosis. The death pathways induced by engagement of tum our necrosis factor (TNF) with the TNF receptor or Fas with its receptor (Fas li gand) are well known causes of apoptosis in immune cells. TNF and Fas can also i nduce apoptosis in epithelial cells and may contribute to cell death in ARF. POTENTIAL CAUSES OF APOPTOSIS IN ACUTE RENAL FAILURE Loss of survival factors Deficiency of renal growth factors (eg, IGF-1, EGF, HGF ) Loss of cell-cell and cell-matrix interactions Receptor-mediated activators of apoptosis Tumor necrosis factor Fas/Fas ligand Cytotoxic events Ischemia; hypox ia; anoxia Oxidant injury Nitric oxide Cisplati Apoptotic Trigger Commitment phase Anti-apoptic factors BclXL Bcl2 Execution phase Crma p35 Caspase activation ? Point of no return? Proteolysis of multiple intracellular substrat es Pro-apoptic factors BAD Bax FIGURE 14-38 Apoptosis is mediated by a highly coordinated and genetically progr ammed pathway. The response to an apoptotic stimulus can be divided into a commi tment and execution phases. During the commitment phase the balance between a nu mber of proapoptotic and antiapoptotic mechanisms determine whether the cell sur vives or dies by apoptosis. The BCL-2 family of proteins consists of at least 12 isoforms, which play important roles in this commitment phase. Some of the BCL2 family of proteins (eg, BCL-2 and BCL-XL) protect cells from apoptosis whereas other members of the same family (eg, BAD and Bax) serve proapoptotic functions . Apoptosis is executed by a final common pathway mediated by a class of cystein e proteases-caspases. Caspases are proteolytic enzymes present in cells in an in active form. Once cells are commited to undergo apoptosis, these caspases are ac tivated. Some caspases activate other caspases in a hierarchical fashion resulti ng in a cascade of caspase activation. Eventually, caspases that target specific substrates within the cell are activated. Some substrates for caspases that hav e been identified include nuclear membrane components (such as lamin), cytoskele tal elements (such as actin and fodrin) and DNA repair enzymes and transcription elements. The proteolysis of this diverse array of substrates in the cell occur s in a predestined fashion and is responsible for the characteristic morphologic features of apoptosis. Apoptosis

Pathophysiology of Ischemic Acute Renal Failure 14.23 Stress Restoration of fluid and electrolyte balance ETR antagonists Kf Ca channel inhib itors ATP-Mg ETR antagonists Ca channel inhibitors Hemodynamic compromise Loss of tubular integrity and function PMN infiltration ICAM-1 antibody RGD Back leak IGF-1l T4 HGF RBF Dopamine ANP IGF-1 Obstruction Mannitol Lasix ANP RGD Avoidance and discontinuation of nephrotoxins Survival factors (HGF, IGF-1) ATPMg T4 NOS inhibitors FIGURE 14-39 Therapeutic approaches, both experimental and in clinical use, to p revent and manage acute renal failure based on its pathogenetic mechanisms. ETRET receptor; GFR glomerular filtration rate; HGFhepatocyte growth factor 1; IGF-1insu lin-like growth factor 1; Kfglomerular ultrafiltration coefficient; NOSnitric oxid e synthase; PMN polymorphonuclear leukocytes; RBFrenal blood flow; T4thyroxine. GFR and maintenance phase Restoration of renal hemodynamics Recovery Reparation of tubular integrity and function References 1. Goligorsky M, Iijima K, Krivenko Y, et al.: Role of mesangial cells in macula densa-to-afferent arteriole information transfer. Clin Exp Pharm Physiol 1997, 24:527531. 2. Osswald H, Hermes H, Nabakowski G: Role of adenosine in signal tran smission of TGF. Kidney Int 1982, 22(Suppl. 12):S136S142. 3. Miller W, Thomas R, Berne R, Rubio R: Adenosine production in the ischemic kidney. Circ Res 1978, 43 (3):390397. 4. Kon V, et al.: Glomerular actions of endothelin in vivo. J Clin In vest 1989, 83:17621767. 5. Gellai M, Jugus M, Fletcher T, et al.: Reversal of pos tischemic acute renal failure with a selective endothelin A receptor antagonist in the rat. J Clin Invest 1994, 93:900906. 6. Fogo, et al.: Endothelin receptor a ntagonism is protective in vivo in acute cyclosporine toxicity. Kidney Int 1992, 42:770774. 7. Conger J: NO in acute renal failure. In: Nitric Oxide and the Kidn ey. Edited by Goligorsky M, Gross S. New York:Chapman and Hall, 1997. 8. Gross S : Nitric oxide synthases and their cofactors. In: Nitric Oxide and the Kidney. E dited by Goligorsky M, Gross S. New York:Chapman and Hall, 1997. 9. Reyes A, Kar l I, Klahr S: Role of arginine in health and in renal disease. Am J Physiol 1994 , 267:F331F346. 10. Kim Y-M, Tseng E, Billiar TR: Role of NO and nitrogen interme diates in regulation of cell functions. In: Nitric Oxide and the Kidney. Edited by Goligorsky M, Gross S. New York:Chapman and Hall, 1997. 11. Lieberthal W:Rena l ischemia and reperfusion impair endotheliumdependent vascular relaxation. Am J Physiol 1989, 256:F894F900. 12. Yu L, Gengaro P, Niederberger M, et al.: Nitric oxide: a mediator in rat tubular hypoxia/reoxygenation injury. Proc Natl Acad Sc i USA 1994, 91:16911695. 13. Noiri E, Peresleni T, Miller F, Goligorsky MS: In vi vo targeting of iNOS with oligodeoxynucleotides protects rat kidney against isch emia. J Clin Invest 1996, 97:23772383. 14. Ling H, Gengaro P, Edelstein C, et al. : Injurious isoform of NOS in mouse proximal tubular injury. Kidney Int, 1998, 5 3:1642 15. Agmon Y, et al.: Nitric oxide and prostanoids protect the renal outer medulla from radiocontrast toxicity in the rat. J Clin Invest 1994, 94:10691075. 16. Agmon Y, Brezis M: NO and the medullary circulation. In: Nitric Oxide and t he Kidney. Edited by Goligorsky M, Gross S. New York:Chapman and Hall, 1997. 17.

Goligorsky MS: Cell biology of signal transduction. In: Hormones, autacoids, an d the kidney. Edited by Goldfarb S, Ziyadeh F. New York:Churchill Livingstone, 1 991. 18. Edelstein C, Schrier RW: The role of calcium in cell injury. In: Acute Renal Failure: New Concepts and Therapeutic Strategies. Edited by Goligorsky MS, Stein JH. New York:Churchill Livingstone, 1995. 19. Kribben A, Wetzels J, Wiede r E, et al.:Evidence for a role of cytosolic free calcium in hypoxia-induced pro ximal tubule injury. J Clin Invest 1994, 93:1922. 20. Burke T, Arnold P, Gordon J, Schrier RW: Protective effect of intrarenal calcium channel blockers before o r after renal ischemia. J Clin Invest 1984, 74:1830. 21. Kashgarian M: Stress pr oteins induced by injury to epithelial cells. In: Acute Renal Failure: New Conce pts and therapeutic strategies. Edited by Goligorsky MS, Stein JH. New York:Chur chill Livingstone, 1995. 22. J NIH Research 23. Ueda N, Walker P, Shah SV: Oxida nt stress in acute renal failure. In: Acute Renal Failure: New Concepts and Ther apeutic Strategies. Edited by Goligorsky MS, Stein JH. New York:Churchill Living stone, 1995. 24. Kelly KJ, et al.: Antibody to anyi-cellular adhesion molecule-1 protects the kidney against ischemic injury. Proc Natl Acad Sci USA 1994, 91:81 2816. 25. Kroemer G, Petit P, Zamzami N, et al.: The biochemistry of programmed c ell death. FASEB J 1995, 9:12771287.

Pathophysiology of Nephrotoxic Acute Renal Failure Rick G. Schnellmann Katrina J. Kelly H umans are exposed intentionally and unintentionally to a variety of diverse chem icals that harm the kidney. As the list of drugs, natural products, industrial c hemicals and environmental pollutants that cause nephrotoxicity has increased, i t has become clear that chemicals with very diverse chemical structures produce nephrotoxicity. For example, the heavy metal HgCl2, the mycotoxin fumonisin B1, the immunosuppresant cyclosporin A, and the aminoglycoside antibiotics all produ ce acute renal failure but are not structurally related. Thus, it is not surpris ing that the cellular targets within the kidney and the mechanisms of cellular i njury vary with different toxicants. Nevertheless, there are similarities betwee n chemicalinduced acute tubular injury and ischemia/reperfusion injury. The tubu lar cells of the kidney are particularly vulnerable to toxicant-mediated injury due to their disproportionate exposure to circulating chemicals and transport pr ocesses that result in high intracellular concentrations. It is generally though t that the parent chemical or a metabolite initiates toxicity through its covale nt or noncovalent binding to cellular macromolecules or through their ability to produce reactive oxygen species. In either case the activity of the macromolecu le(s) is altered resulting in cell injury. For example, proteins and lipids in t he plasma membrane, nucleus, lysosome, mitochondrion and cytosol are all targets of toxicants. If the toxicant causes oxidative stress both lipid peroxidation a nd protein oxidation have been shown to contribute to cell injury. In many cases mitochondria are a critical target and the lack of adenosine triphosphate (ATP) leads to cell injury due to the dependence of renal function on aerobic metabol ism. The loss of ATP leads CHAPTER 15

15.2 Acute Renal Failure Following exposure to a chemical insult those cells sufficiently injured die by one of two mechanisms, apoptosis or oncosis. Clinically, a vast number of nephro toxicants can produce a variety of clinical syndromes-acute renal failure, chron ic renal failure, nephrotic syndrome, hypertension and renal tubular defects. Th e evolving understanding of the pathophysiology of toxicant-mediated renal injur y has implications for potential therapies and preventive measures. This chapter outlines some of the mechanisms thought to be important in toxicant-mediated re nal cell injury and death that leads to the loss of tubular epithelial cells, tu bular obstruction, backleak of the glomerular filtrate and a decreased glomerular filtration rate. The recovery from the structural and functional damage followin g chemical exposures is dependent on the repair of sublethally-injured and regen eration of noninjured cells. to disruption of cellular ion homeostasis with decreased cellular K+ content, in creased Na+ content and membrane depolarization. Increased cytosolic free Ca2+ c oncentrations can occur in the early or late phase of cell injury and plays a cr itical role leading to cell death. The increase in Ca2+ can activate calcium act ivated neutral proteases (calpains) that appear to contribute to the cell injury that occurs by a variety of toxicants. During the late phase of cell injury, th ere is an increase in Cl- influx, followed by the influx of increasing larger mo lecules that leads to cell lysis. Two additional enzymes appear to play an impor tant role in cell injury, particularly oxidative injury. Phospholipase A2 consis ts of a family of enzymes in which the activity of the cytosolic form increases during oxidative injury and contributes to cell death. Caspases are a family of cysteine proteases that are activated following oxidative injury and contribute to cell death. Clinical Significance of Toxicant-Mediated Acute Renal Failure CLINICAL SIGNIFICANCE OF TOXICANTMEDIATED RENAL FAILURE Nephrotoxins may account for approximately 50% of all cases of acute and chronic renal failure. Nephrotoxic renal injury often occurs in conjunction with ischem ic acute renal failure. Acute renal failure may occur in 2% to 5% of hospitalize d patients and 10% to 15% of patients in intensive care units. The mortality of acute renal failure is approximatley 50% which has not changed significantly in the last 40 years. Radiocontrast media and aminoglycosides are the most common a gents associated with nephrotoxic injury in hospitalized patients. Aminoglycosid e nephrotoxicity occurs in 5% to 15% of patients treated with these drugs. REASONS FOR THE KIDNEY'S SUSCEPTIBILITY TO TOXICANT INJURY Receives 25% of the cardiac output Sensitive to vasoactive compounds Concentrate s toxicants through reabsorptive and secretive processes Many transporters resul t in high intracellular concentrations Large luminal membrane surface area Large biotransformation capacity Baseline medullary hypoxia FIGURE 15-2 Reasons for the kidney's susceptibility to toxicant injury. FIGURE 15-1 Clinical significance of toxicant-mediated renal failure. FIGURE 153 Factors that predispose the kidney to toxicant injury. FACTORS THAT PREDISPOSE THE KIDNEY TO TOXICANT INJURY Preexisting renal dysfunction Dehydration Diabetes mellitus Exposure to multiple nephrotoxins

Pathophysiology of Nephrotoxic Acute Renal Failure 15.3 EXOGENOUS AND ENDOGENOUS CHEMICALS THAT CAUSE ACUTE RENAL FAILURE Antibiotics Aminoglycosides (gentamicin, tobramycin, amikacin, netilmicin) Ampho tericin B Cephalosporins Ciprofloxacin Demeclocycline Penicillins Pentamidine Po lymixins Rifampin Sulfonamides Tetracycline Vancomycin Chemotherapeutic agents A driamycin Cisplatin Methotraxate Mitomycin C Nitrosoureas (eg, streptozotocin, I omustine) Radiocontrast media Ionic (eg, diatrizoate, iothalamate) Nonionic (eg, metrizamide) Immunosuppressive agents Cyclosporin A Tacrolimus (FK 506) Antivir al agents Acyclovir Cidovir Foscarnet Valacyclovir Heavy metals Cadmium Gold Mer cury Lead Arsenic Bismuth Uranium Organic solvents Ethylene glycol Carbon tetrac hloride Unleaded gasoline Vasoactive agents Nonsteroidal anti-inflammatory drugs (NSAIDs) Ibuprofen Naproxen Indomethacin Meclofenemate Aspirin Piroxicam Angiot ensin-converting enzyme inhibitors Captopril Enalopril Lisinopril Angiotensin re ceptor antagonists Losartan Other drugs Acetaminophen Halothane Methoxyflurane C imetidine Hydralazine Lithium Lovastatin Mannitol Penicillamine Procainamide Thi azides Lindane Endogenous compounds Myoglobin Hemoglobin Calcium Uric acid Oxala te Cystine FIGURE 15-4 Exogenous and endogenous chemicals that cause acute renal failure. F IGURE 15-5 Nephrotoxicants may act at different sites in the kidney, resulting i n altered renal function. The sites of injury by selected nephrotoxicants are sh own. Nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting enzym e (ACE) inhibitors, cyclosporin A, and radiographic contrast media cause vasocon striction. Gold, interferon-alpha, and penicillamine can alter glomerular functi on and result in proteinuria and decreased renal function. Many nephrotoxicants damage tubular epithelial cells directly. Aminoglycosides, cephaloridine, cadmiu m chloride, and potassium dichromate affect the S1 and S2 segments of the proxim al tubule, whereas cisplatin, mercuric chloride, and dichlorovinyl-L-cysteine af fect the S3 segment of the proximal tubule. Cephalosporins, cadmium chloride, an d NSAIDs cause interstitial nephritis whereas phenacetin causes renal papillary necrosis. Proximal convoluted tubule (S1/S2 segments) Aminoglycosides Cephaloridine Cadmiu m chloride Potassium dichromate Glomeruli Interferona Gold Penicillamine Proximal straight tubule (S3 segment) Cisp latin Mercuric chloride DichlorovinylLcysteine Renal vessels NSAIDs ACE inhibitors Cyclosporin A Papillae Phenacetin Interstitium Cephalosporins Cadmium NSAIDs

15.4 Acute Renal Failure Renal vasoconstriction Prerenal azotemia Increased tubular pressure Intravascular volume Sympathetic tone E x p o s u r e n e p h r o t o x i t c o a n t Tubular obstruction Intratubular casts "Back-leak" of glomerular filtrate Functional abnormalties GFR Capillary permeab ility Endothelin Nitric oxide Thromboxane Prostaglandins Hypertension Tubular damage Intrarenal factors Persistent medullary hypoxia Physical constric tion of medullary vessels Hemodynamic Glomerular hydrostatic alterations pressur e Intrarenal vasoconstriction Perfusion pressure Efferent tone Afferent tone Glo merular factors Glomerular ultrafiltration Postrenal failure Endothelial injury Renal and systemic vasoconstriction Vascular smooth muscle sensitivity to vasoconstrictors Striped interstitial fibr osis GFR Cyclosporin A Angiotensin II Tubular cell injury Obstruction FIGURE 15-6 Mechanisms that contribute to decreased glomerular filtration rate ( GFR) in acute renal failure. After exposure to a nephrotoxicant, one or more mec hanisms may contribute to a reduction in the GFR. These include renal vasoconstr iction resulting in prerenal azotemia (eg, cyclosporin A) and obstruction due to precipitation of a drug or endogenous substances within the kidney or collectin g ducts (eg, methotrexate). Intrarenal factors include direct tubular obstructio n and dysfunction resulting in tubular backleak and increased tubular pressure. Alterations in the levels of a variety of vasoactive mediators (eg, prostaglandi ns following treatment with nonsteroidal anti-inflammatory drugs) may result in decreased renal perfusion pressure or efferent arteriolar tone and increased aff erent arteriolar tone, resulting in decreased in glomerular hydrostatic pressure . Some nephrotoxicants may decrease glomerular function, leading to proteinuria and decreased renal function. FIGURE 15-7 Renal injury from exposure to cyclosporin A. Cyclosporin A is one ex ample of a toxicant that acts at several sites within the kidney. It can injure both endothelial and tubular cells. Endothelial injury results in increased vasc ular permeability and hypovolemia, which activates the sympathetic nervous syste m. Injury to the endothelium also results in increases in endothelin and thrombo xane A2 and decreases in nitric oxide and vasodilatory prostaglandins. Finally, cyclosporin A may increase the sensitivity of the vasculature to vasoconstrictor s, activate the renin-angiotensin system, and increase angiotensin II levels. Al l of these changes lead to vasoconstriction and hypertension. Vasoconstriction i n the kidney contributes to the decrease in glomerular filtration rate (GFR), an

d the histologic changes in the kidney are the result of local ischemia and hype rtension. Renal Cellular Responses to Toxicant Exposures Nephrotoxic insult to the nephron Uninjured cells Injured cells Cell death Compensatory hypertrophy Cellular adaptation Cellular proliferation Re-epithelialization Cellular repair Cellular adaptation FIGURE 15-8 The nephron's response to a nephrotoxic insult. After a population of cells are exposed to a nephrotoxicant, the cells respond and ultimately the neph ron recovers function or, if cell death and loss is extensive, nephron function ceases. Terminally injured cells undergo cell death through oncosis or apoptosis . Cells injured sublethally undergo repair and adaptation (eg, stress response) in response to the nephrotoxicant. Cells not injured and adjacent to the injured area may undergo dedifferentiation, proliferation, migration or spreading, and differentiation. Cells that were not injured may also undergo compensatory hyper trophy in response to the cell loss and injury. Finally the uninjured cells may also undergo adaptation in response to nephrotoxicant exposure. Differentiation Structural and functional recovery of the nephron

Pathophysiology of Nephrotoxic Acute Renal Failure Loss of polarity, tight junction integrity, cellsubstrate adhesion, simplificatio n of brush border 15.5 Intact tubular epithelium Toxic injury Cell death Necrosis Apoptosis a b Sloughing of viable and nonviable cells with intraluminal cell-cell adhesion Cytoskeleton Extracellular matrix Na+/K+=ATPase b1 Integrin RGD peptide Cast formation and tubuler obstruction FIGURE 15-9 After injury, alterations can occur in the cytoskeleton and in the n ormal distribution of membrane proteins such as Na+, K+ATPase and 1 integrins in sublethally injured renal tubular cells. These changes result in loss of cell p olarity, tight junction integrity, and cell-substrate adhesion. Lethally injured cells undergo oncosis or apoptosis, and both dead and viable cells may be sloughed into the tubular lumen. Adhesion of sloughed cells to other slou ghed cells and to cells remaining adherent to the basement membrane may result i n cast formation, tubular obstruction, and further compromise the glomerular fil tration rate. (Adapted from Fish and Molitoris [1], and Gailit et al. [2]; with permission.) FIGURE 15-10 Potential sites where nephrotoxicants can interfere wi th the structural and functional recovery of nephrons. Sublethally injured cells Migrating spreading cells Cell proliferation Basement membrane Toxicant inhibition of cell repair Toxicant inhibition of cell migration/spreading Toxicant inhibition of cell proliferation

15.6 140 120 Percent of control 100 80 60 40 20 0 0 1 Acute Renal Failure Oncosis Apoptosis Cell number/confluence Mitochondrial function Active Na+ transport + Na -coupled glucose transport GGT activity Blebbing Budding 2 3 4 5 6 Time after exposure, d FIGURE 15-11 Inhibition and repair of renal proximal tubule cellular functions a fter exposure to the model oxidant t-butylhydroperoxide. Approximately 25% cell loss and marked inhibition of mitochondrial function active (Na+) transport and Na+-coupled glucose transport occurred 24 hours after oxidant exposure. The acti vity of the brush border membrane enzyme -glutamyl transferase (GGT) was not aff ected by oxidant exposure. Cell proliferation and migration or spreading was com plete by day 4, whereas active Na+ transport and Na+-coupled glucose transport d id not return to control levels until day 6. These data suggest that selective p hysiologic functions are diminished after oxidant injury and that a hierarchy ex ists in the repair process: migration or spreading followed by cell proliferatio n forms a monolayer and antedates the repair of physiologic functions. (Data fro m Nowak et al. [3].) Necrosis Phagocytosis inflammation Phagocytosis by macrophages or nearby cells FIGURE 15-12 Apoptosis and oncosis are the two generally recognized forms of cel l death. Apoptosis, also known as programmed cell death and cell suicide, is cha racterized morphologically by cell shrinkage, cell budding forming apoptotic bod ies, and phagocytosis by macrophages and nearby cells. In contrast, oncosis, als o known as necrosis, necrotic cell death, and cell murder, is characterized morp hologically by cell and organelle swelling, plasma membrane blebbing, cell lysis , and inflammation. It has been suggested that cell death characterized by cell swelling and lysis not be called necrosis or necrotic cell death because these t erms describe events that occur well after the cell has died and include cell an d tissue breakdown and cell debris. (From Majno and Joris [4]; with permission.) Mechanisms of Toxicant-Mediated Cellular Injury Transport and biotransformation

Toxicants in general Toxicant whose primary mechanism of action is ATP depletion Oncosis Oncosis Cell death Apoptosis Cell death FIGURE 15-13 The general relationship between oncosis and apoptosis after nephro toxicant exposure. For many toxicants, low concentrations cause primarily apopto sis and oncosis occurs principally at higher concentrations. When the primary me chanism of action of the nephrotoxicant is ATP depletion, oncosis may be the pre dominant cause of cell death with limited apoptosis occurring. Apoptosis Toxicant concentration Toxicant concentration

Pathophysiology of Nephrotoxic Acute Renal Failure 15.7 GSH-Hg-GSH GSH-Hg-GSH CYS-Hg-CYS GSH-Hg-GSH GLY-CYS-Hg-CYS-GLY CYS-Hg-CYS Lumen CYS-Hg-CYS Na + g-GT ? Dipeptidase Urine Acivicin Proximal tubular cell R-Hg-R CYS-Hg-CYS GSH-Hg-GSH Na+ a-Ketoglutrte a-Ketoglutrte Dicarboxylate Organi c anion transporter transporter CYS-Hg-CYS Na + Neutral amino acid transporter Blood Na+ Dicarboxylic acids a-Ketoglutrte a-Ketoglutrte R-Hg-R CYS-Hg-CYS GSH-Hg-GSH Organic anions (PAH or probenecid) FIGURE 15-14 The importance of cellular transport in mediating toxicity. Proxima l tubular uptake of inorganic mercury is thought to be the result of the transpo rt of mercuric conjugates (eg, diglutathione mercury conjugate [GSH-Hg-GSH], dic ysteine mercuric conjugate [CYS-Hg-CYS]). At the luminal membrane, GSH-Hg-GSH ap pears to be metabolized by (-glutamyl transferase ((-GT) and a dipeptidase to fo rm CYS-Hg-CYS. The CYS-Hg-CYS may be taken up by an amino acid transporter. At t he basolateral membrane, mercuric conjugates appear to be transported by the org anic anion transporter. (-Ketoglutarate and the dicarboxylate transporter seem t o play important roles in basolateral membrane uptake of mercuric conjugates. Up take of mercuric-protein conjugates by endocytosis may play a minor role in the uptake of inorganic mercury transport. PAHpara-aminohippurate. (Courtesy of Dr. R . K. Zalups.) Toxicant Biotransformation High-affinity binding to macromolecules Reactive intermediate Redox cycling Altered activity of critical macromolecules Covalent binding to macromolecules

Increased reactive oxygen species Damage to critical macromolecules Cell injury Cell repair Oxidative damage to critical macromolecules FIGURE 15-15 Covalent and noncovalent binding versus oxidative stress mechanisms of cell injury. Nephrotoxicants are generally thought to produce cell injury an d death through one of two mechanisms, either alone or in combination. In some c ases the toxicant may have a high affinity for a specific macromolecule or class of macromolecules that results in altered activity (increase or decrease) of th ese molecules, resulting in cell injury. Alternatively, the parent nephrotoxican t may not be toxic until it is biotransformed into a reactive intermediate that binds covalently to macromolecules and in turn alters their activity, resulting in cell injury. Finally, the toxicant may increase reactive oxygen species in th e cells directly, after being biotransformed into a reactive intermediate or thr ough redox cycling. The resulting increase in reactive oxygen species results in oxidative damage and cell injury. Cell death Plasma RSG R + SG 1. R-SG Plasma RSG Glomerular filtration 2. R-SG 3. 4. g-Glu R-Cys Gly R-SG 6. Na+ Plasma R-Cys 7. R-Cys Na+ 5. R-Cys 12. NH3+H3CCOCO2H 10. 11. R-SH 13. Covalent binding Cell injury R-NAC Plasma R-NAC 8. R-NAC Na+ Basolateral membrane 9. Brush border membrane R-NAC FIGURE 15-16 This figure illustrates the renal proximal tubular uptake, biotrans formation, and toxicity of glutathione and cysteine conjugates and mercapturic a cids of haloalkanes and haloalkenes (R). 1) Formation of a glutathione conjugate within the renal cell (R-SG). 2) Secretion of the R-SG into the lumen. 3) Remov al of the -glutamyl residue ( -Glu) by -glutamyl transferase. 4) Removal of the glycinyl residue (Gly) by a dipeptidase. 5) Luminal uptake of the cysteine conju gate (R-Cys). Basolateral membrane uptake of R-SG (6), R-Cys (7), and a mercaptu ric acid (N-acetyl cysteine conjugate; R-NAC)(8). 9) Secretion of R-NAC into the lumen. 10) Acetylation of R-Cys to form R-NAC. 11) Deacetylation of R-NAC to fo rm R-Cys. 12) Biotransformation of the penultimate nephrotoxic species (R-Cys) b y cysteine conjugate -lyase to a reactive intermediate (R-SH), ammonia, and pyru vate. 13) Binding of the reactive thiol to cellular macromolecules (eg, lipids, proteins) and initiation of cell injury. (Adapted from Monks and Lau [5]; with p ermission.)

15.8 Acute Renal Failure FIGURE 15-17 Covalent binding of a nephrotoxicant metabolite in vivo to rat kidn ey tissue, localization of binding to the mitochondria, and identification of th ree proteins that bind to the nephrotoxicant. A, Binding of tetrafluoroethyl-L-c ysteine (TFEC) metabolites in vivo to rat kidney tissue detected immunohistochem ically. Staining was localized to the S3 segments of the proximal tubule, the se gment that undergoes necrosis. B, Immunoreactivity in untreated rat kidneys. C, Isolation and fractionation of renal cortical mitochondria from untreated and TF EC treated rats and immunoblot analysis revealed numerous proteins that bind to the nephrotoxicant (innerinner membrane, matrix-soluble matrix, outer-outer memb rane, inter-intermembrane space). The identity of three of the proteins that bou nd to the nephrotoxicant: P84, mortalin (HSP70-like); P66, HSP 60; and P42, aspa rtate aminotransferase. Mrrelative molecular weight. (From Hayden et al. [6], and Bruschi et al. [7]; with permission.) A Representative starting material B Submitochondrial fractions A. Untreated B. TFEC (30 mg/kg) Mr (kDa) 228 P99 P84 P66 P52 P42 109 70 44 Matrix Matrix Outer Outer Inter Inner C Lipid peroxidation and mitochondrial dysfunction HH HO H Lipid Inner R H 2O Hydrogen abstraction R Lipid radical Diene conjugation H O2 R O O OO H LH R Lipid radical, conjugated diene Oxygen addition R Lipid peroxyl radical FIGURE 15-18 A simplified scheme of lipid peroxidation. The first step, hydrogen abstraction from the lipid by a radical (eg, hydroxyl), results in the formatio n of a lipid radical. Rearrangement of the lipid radical results in conjugated d iene formation. The addition of oxygen results in a lipid peroxyl radical. Addit ional hydrogen abstraction results in the formation of a lipid hydroperoxide. Th e Fenton reaction produces a lipid alkoxyl radical and lipid fragmentation, resu lting in lipid aldehydes and ethane. Alternatively, the lipid peroxyl radical ca

n undergo a series of reactions that result in the formation of malondialdehyde. Hydrogen abstraction L R Lipid hydroperoxide O O Malondialdehyde HOO H Fe(II) Fe(III) O H H H H O H H H H Ethane Fenton reaction HO R Lipid alkoxyl radical Fragmentation R Lipid aldehyde H LH L Inter

Pathophysiology of Nephrotoxic Acute Renal Failure 50 40 LDH release, % 30 20 10 0 0 1 2 3 Time, h 4 5 6 100 80 LDH release, % 60 4 0 20 0 0 1 2 3 Time, h 4 5 15.9 Control TBHP (0.5 mmol) TBHP + DEF (1 mM) TBHP + DPPD (2 M) Control DCVC DCVC + DEF (1 mM) DCVC + DPPD (50M) 6 A B 1.2 1.0 Lipid peroxidation, nmol MDAmg protein1 0.8 0.6 0.4 0.2 0.0 +2 M DPPD Lipid peroxidation, nmol MDAmg protein1 2.0 +1 mM DEF 1.6 1.2 0.8 0.4 0.0 +50 M DPPD C Control TBHP +1 mM DEF D Control DCVC FIGURE 15-19 AD, Similarities and differences between oxidant-induced and halocar bon-cysteine conjugateinduced renal proximal tubular lipid peroxidation and cell death. The model oxidant t-butylhydroperoxide (TBHP) and the halocarbon-cysteine conjugate dichlorovinyl-L-cysteine (DCVC) caused extensive lipid peroxidation a fter 1 hour of exposure and cell death (lactate dehydrogenase (LDH) release) ove r 6-hours' exposure. The iron chelator deferoxamine (DEF) and the antioxidant N,N'-d iphenl-1, 4-phenylenediamine (DPPD) completely blocked both the lipid peroxidation and cell death caused by TBHP. In contrast, while DEF and DPPD comp letely blocked the lipid peroxidation caused by DCVC, cell death was only delaye d. These results suggest that the iron-mediated oxidative stress caused by TBHP is responsible for the observed toxicity, whereas the iron-mediated oxidative st ress caused by DCVC accelerates cell death. One reason that cells die in the abs ence of iron-mediated oxidative stress is that DCVC causes marked mitochondrial dysfunction. (Data from Groves et al. [8], and Schellmann [9].) FIGURE 15-20 Mec hanisms by which nephrotoxicants can alter renal tubular cell energetics. ALTERATION OF RENAL TUBULAR CELL ENERGETICS AFTER EXPOSURE TO TOXICANTS Decreased oxygen delivery secondary to vasoconstriction Inhibition of mitochondr ial respiration Increased tubular cell oxygen consumption

15.10 Acute Renal Failure FIGURE 15-21 Some of the mitochondrial targets of nephrotoxicants: 1) nicotinami de adenine dinucleotide (NADH) dehydrogenase; 2) succinate dehydrogenase; 3) coe nzyme Qcytochrome C reductase; 4) cytochrome C; 5) cytochrome C oxidase; 6) cytoc hrome Aa3; 7) H+-Pi contransporter; 8) F0F1ATPase; 9) adenine triphosphate/dipho sphate (ATP/ADP) translocase; 10) protonophore (uncoupler); 11) substrate transp orters. Substrates Cephaloridine 11 TCA cycle Bromohydroquinone DichlorovinylLcysteine Tet rafluoroethylLcysteine PentachlorobutadienylLcysteine Citrinin Ochratoxin A Hg2+ CN A TP 1 2 3 4 5 6 O2 H 2O Matrix 10 Inner membrane Outer membrane H+ Pi 7 H+ Oligom ycin Pi H+ Ochratoxin A H+ ATP 8 H+ 9 Atractyloside Ochratoxin A ADP PentachlorobutadienylLcysteine H+ Citrinin FCCP Disruption of ion homeostasis Na+ Na+ Na+ ATPase Na+ Na+ H 2O Relative cellular changes ATPase ATP Cl ATP Cl Cl Cl K+ K + A K+ B Antimycin A K+ 100 90 80 70 60 50 40 30 20 10 0 0 Na+ QO2 K+

Membrane potential H 2O ATP 5 Antimycin A 10 15 Time, min 20 25 30 FIGURE 15-22 Early ion movements after mitochondrial dysfunction. A, A control r enal proximal tubular cell. Within minutes of mitochondrial inhibition (eg, by a ntimycin A), ATP levels drop, resulting in inhibition of the Na+, K+-ATPase. B, Consequently, Na+ influx, K+ efflux, membrane depolarization, and a limited degr ee of cell swelling occur. FIGURE 15-23 A graphic of the phenomena diagrammed in Figure 15-22. Na+ Na+ ATPase Na+ ATP Cl K+ ATPase Na+ ATP Cl Cl Cl FIGURE 15-24 The late ion movements after mitochondrial dysfunction that leads t o cell death/lysis. A, Cl- influx occurs as a distinct step subsequent to Na+ in flux and K+ efflux. B, Following Cl- influx, additional Na+ and water influx occ ur resulting in terminal cell swelling. Ultimately cell lysis occurs. K+ A Antimycin A K+ B Antimycin A K+ H 2O

Pathophysiology of Nephrotoxic Acute Renal Failure 15.11 100 90 80 70 60 50 40 30 20 10 0 0 Relative cellular changes Na + FIGURE 15-25 A graph of the phenomena depicted in Figures 15-22 through 1524, il lustrating the complete temporal sequence of events following mitochondrial dysf unction. QO2oxygen consumption. Cl H 2O QO2 K+ Membrane potential Ca++ ATP 5 Antimycin A 10 15 Time, min 20 25 30 Disregulation of regulatory enzymes er Ca2+ BIOCHEMICAL CHARACTERISTICS OF CALPAIN ATP Ca2+ (100 nM) ATP Ca2+ Ca (1 mM) Endopeptidase Heterodimer: 80-kD catalytic subunit, 30-kD regulatory subunit Calpain and -calpain are ubiquitously distribut ed cytosolic isozymes Calpain and -calpain have identical regulatory subunits but distinctive catalytic subunits Calpain requires a higher concentration of Ca2+ f or activation than -calpain Phospholipids reduce the Ca2+ requirement Substrates : cytoskeletal and membrane proteins and enzymes 2+ Mitochondria FIGURE 15-26 A simplified schematic drawing of the regulation of cytosolic free Ca2+. FIGURE 15-27 Biochemical characteristics of calpain. FIGURE 15-28 Calpain transl ocation. Proposed pathways of calpain activation and translocation. Both calpain subunits may undergo calcium (Ca2+)-mediated autolysis within the cytosol and h ydrolyze cytosolic substrates. Calpains may also undergo Ca2+-mediated transloca tion to the membrane, Ca2+-mediated, phospholipid-facilitated autolysis and hydr olyze membrane-associated substrates. The autolyzed calpains may be released fro m the membrane and hydrolyze cytosolic substrates. (From Suzuki and Ohno [10], a nd Suzuki et al. [11]; with permission.)

15.12 35 30 LDH release, % 25 20 15 10 5 0 Acute Renal Failure 40 35 LDH release, % CON TFEC +C12 BHQ +C12 TBHP +C12 30 25 20 15 10 5 0 A B CON TFEC +PD BHQ +PD TBHP +PD FIGURE 15-29 A, B, Dissimilar types of calpain inhibitors block renal proximal t ubular toxicity of many agents. Renal proximal tubular suspensions were pretreat ed with the calpain inhibitor 2 (CI2) or PD150606 (PD). CI2 is an irreversible i nhibitor of calpains that binds to the active site of the enzyme. PD150606 is a reversible inhibitor of calpains that binds to the calcium (Ca2+)-binding domain on the enzyme. The toxicants used were the haloalkane cysteine conjugate tetrafluoroethyl-L-cysteine (TFEC), the alkylating quinone bromohydroquinone (BH Q), and the model oxidant tbutylhydroperoxide (TBHP). The release of lactate deh ydrogenase (LDH) was used as a marker of cell death. CONcontrol. (From Waters et al. [12]; with permission.) FIGURE 15-30 One potential pathway in which calcium (Ca2+) and calpains play a r ole in renal proximal tubule cell death. These events are subsequent to mitochon drial inhibition and ATP depletion. 1) -Calpain releases endoplasmic reticulum ( er) Ca2+ stores. 2) Release of er Ca2+ stores increases cytosolic free Ca2+ conc entrations. 3) The increase in cytosolic free Ca2+ concentration mediates extrac ellular Ca2+ entry. (This may also occur as a direct result of er Ca2+ depletion .) 4) The influx of extracellular Ca2+ further increases cytosolic free Ca2+ con centrations. 5) This initiates the translocation of nonactivated m-calpain to th e plasma membrane (6). 7) At the plasma membrane nonactivated m-calpain is autol yzed and hydrolyzes a membrane-associated substrate. 8) Either directly or indir ectly, hydrolysis of the membrane-associated substrate results in influx of extr acellular chloride ions (Cl-). The influx of extracellular Cl- triggers terminal cell swelling. Steps ad represent an alternate pathway that results in extracell ular Ca2+ entry. (Data from Waters et al. [12,13,14].) FIGURE 15-31 Biochemical characteristics of several identified phospholipase A2s. Ca2+-Independent Cytosolic ~40 kDa None None Membrane unknown None None PROPERTIES OF PHOSPHOLIPASE A2 GROUP Characteristics Localization Molecular mass Arachidonate preference Ca2+ required Ca2+ role Secretory Secreted ~14 kDa mM Catalysis

Cytosolic Cytosolic ~85 kDa (M Memb. Assoc.

Pathophysiology of Nephrotoxic Acute Renal Failure 50 40 AA release, % 30 20 10 0 30 60 Time, min 90 120 LLC-cPLA2 LLC-vector 15.13 80 70 LDH release, % total 60 50 40 30 20 10 0 0.0 0.1 0.2 0.3 [H2O2], mmol 0.4 0.5 LLC-cPLA2 LLC-PK1 LLC-vector A B 80 70 LDH release, % total 60 50 40 30 20 10 0 0.0 0.1 0.2 0.3 [H2O2], mmol 0.4 0.5 LLC-cPLA2 LLC-sPLA2 LLC-vector C FIGURE 15-32 The importance of the cytosolic phospholipase A2 in oxidant injury. A, Time-dependent release of arachidonic acid (AA) from LLC-PK1 cells exposed t o hydrogen peroxide (0.5 mM). B and C, The concentration-dependent effects of hy drogen peroxide on LLC-PK1 cell death (using lactate dehydrogenase [LDH] release as marker) after 3 hours' exposure. Cells were transfected with 1) the cytosolic PLA2 (LLC-cPLA2), 2) the secretory PLA2 (LLC-sPLA2), 3) vector (LLC-vector), or 4) were not transfected (LLC-PK1). Cells transfected with cytosolic PLA2 exhibit ed greater AA release and cell death in response to oxidant exposure than cells transfected with the vector or secretory PLA2 or not transfected. These results suggest that activation of cytosolic PLA2 during oxidant injury contributes to c ell injury and death. (From Sapirstein et al. [15]; with permission.) 200 Residual double-stranded DNA, % Increase in caspase activity, units/mg prote in 50 100 40 Cell death, % Ant imy cin A 150 75 50 25 0 r II rI Con trol bito bito Inhi 30 20 10 0 Ant imy cin A Con trol bito Inhi bito Inhi r II rI 100 50 0 0 30 10 20 Time of antimycin A treatment, min A B Inhi C

FIGURE 15-33 Potential role of caspases in cell death in LLC-PK1 cells exposed t o antimycin A. A, Time-dependent effects of antimycin A treatment on caspase act ivity in LLC-PK1 cells. B, C, The effect of two capase inhibitors on antimycin Ai nduced DNA damage and cell death, respectively. Antimycin A is an inhibitor of m itochondrial electron transport. Inhibitor 1 is IL-1 converting enzyme inhibitor 1 (YVAD-CHO) and inhibitor II is CPP32/apopain inhibitor (DEVD-CHO). These results suggest that caspases are act ivated after mitochondrial inhibition and that caspases may contribute to antimy cin Ainduced DNA damage and cell death. (From Kaushal et al. [16]; with permissio n.)

15.14 Acute Renal Failure References 1. 2. Fish EM, Molitoris BA: Alterations in epithelial polarity and the pathogen esis of disease states. N Engl J Med 1994, 330:1580. Gailit J, Colfesh D, Rabine r I, et al.: Redistribution and dysfunction of integrins in cultured renal epith elial cells exposed to oxidative stress. Am J Physiol 1993, 264:F149. Nowak G, A leo MD, Morgan JA, Schnellmann RG: Recovery of cellular functions following oxid ant injury. Am J Physiol 1998, 274:F509. Majno G, Joris I: Apoptosis, oncosis an d necrosis. Am J Pathol 1995, 146:3. Monks TJ, Lau SS: Renal transport processes and glutathione conjugatemediated nephrotoxicity. Drug Metab Dispos 1987, 15:437 . Hayden PJ, Ichimura T, McCann DJ, et al.: Detection of cysteine conjugate meta bolite adduct formation with specific mitochondrial proteins using antibodies ra ised against halothane metabolite adducts. J Biol Chem 1991, 266:18415. Bruschi SA, West KA, Crabb JW, et al.: Mitochondrial HSP60 (P1 protein) and a HSP70-like protein (mortalin) are major targets for modification during S-(1,1,2,2-tetrafl uoroethyl)-L-cysteineinduced nephrotoxicity. J Biol Chem 1993, 268:23157. Groves CE, Lock EA, Schnellmann RG: Role of lipid peroxidation in renal proximal tubule cell death induced by haloalkene cysteine conjugates. Toxicol Appl Pharmacol 19 91, 107:54. Schnellmann RG: Pathophysiology of nephrotoxic cell injury. In Disea ses of the Kidney. Edited by Schrier RW, Gottschalk CW. Boston:Little Brown; 199 7:1049. 10. Suzuki K, Ohno S: Calcium activated neutral protease: Structure-func tion relationship and functional implications. Cell Structure Function 1990, 15: 1. 11. Suzuki K, Sorimachi H, Yoshizawa T, et al.: Calpain: Novel family members , activation, and physiologic function. Biol Chem HoppeSeyler 1995, 376:523. 12. Waters SL, Sarang SS, Wang KKW, Schnellmann RG: Calpains mediate calcium and ch loride influx during the late phase of cell injury. J Pharmacol Exp Ther 1997, 2 83:1177. 13. Waters SL, Wong JK, Schnellmann RG: Depletion of endoplasmic reticu lum calcium stores protects against hypoxia- and mitochondrial inhibitorinduced c ellular injury and death. Biochem Biophys Res Commun 1997, 240:57. 14. Waters SL , Miller GW, Aleo MD, Schnellmann RG: Neurosteroid inhibition of cell death. Am J Physiol 1997, 273:F869. 15. Sapirstein A, Spech RA, Witzgall R, Bonventre JV: Cytosolic phospholipase A2 (PLA2), but not secretory PLA2, potentiates hydrogen peroxide cytotoxicity in kidney epithelial cells. J Biol Chem 1996, 271:21505. 1 6. Kaushal GP, Ueda N, Shah SV: Role of caspases (ICE/CED3 proteases) in DNA dam age and cell death in response to a mitochondrial inhibitor, antimycin A. Kidney Int 1997, 52:438. 3. 4. 5. 6. 7. 8. 9.

Acute Renal Failure: Cellular Features of Injury and Repair Kevin T. Bush Hiroyuki Sakurai Tatsuo Tsukamoto Sanjay K. Nigam A lthough ischemic acute renal failure (ARF) is likely the result of many differen t factors, much tubule injury can be traced back to a number of specific lesions that occur at the cellular level in ischemic polarized epithelial cells. At the onset of an ischemic insult, rapid and dramatic biochemical changes in the cell ular environment occur, most notably perturbation of the intracellular levels of ATP and free calcium and increases in the levels of free radicals, which lead t o alterations in structural and functional cellular components characteristic of renal epithelial cells [17]. These alterations include a loss of tight junction integrity, disruption of actin-based microfilaments, and loss of the apical baso lateral polarity of epithelial cells. The result is loss of normal renal cell fu nction [712]. After acute renal ischemia, the recovery of renal tubule function i s critically dependent on reestablishment of the permeability barrier, which is crucial to proper functioning of epithelial tissues such as renal tubules. After ischemic injury the formation of a functional permeability barrier, and thus of functional renal tubules, is critically dependent on the establishment of funct ional tight junctions. The tight junction is an apically oriented structure that functions as both the fence that separates apical and basolateral plasma membrane domains and the major paracellular permeability barrier (gate). It is not yet c lear how the kidney restores tight junction structure and function after ischemi c injury. In fact, tight junction assembly under normal physiological conditions remains ill-understood; however, utilization of the CHAPTER 16

16.2 Acute Renal Failure protein, E-cadherin) are membrane proteins. Matrix proteins and their integrin r eceptors may need to be resynthesized, along with growth factors and cytokines, all of which pass through the endoplasmic reticulum (ER). The rate-limiting even ts in the biosynthesis and assembly of these proteins occur in the ER and are ca talyzed by a set of ER-specific molecular chaperones, some of which are homologs of the cytosolic heat-shock proteins [20]. The levels of mRNAs for these protei ns may increase 10-fold or more in the ischemic kidney, to keep up with the cell ular need to synthesize and transport these new membrane proteins, as well as se creted ones. If the ischemic insult is sufficiently severe, cell death and/or de tachment leads to loss of cells from the epithelium lining the kidney tubules. T o recover from such a severe insult, cell regeneration, differentiation, and pos sibly morphogenesis, are necessary. To a limited extent, the recovery of kidney tubule function after such a severe ischemic insult can be viewed as a recapitul ation of various steps in renal development. Cells must proliferate and differen tiate, and, in fact, activation of growth factormediated signaling pathways (some of the same ones involved in kidney development) appears necessary to ameliorat e renal recovery after acute ischemic injury [2130]. calcium switch model with cultured renal epithelial cells has helped to elucidate some of the critical features of tight junction bioassembly. In this model for t ight junction reassembly, signaling events involving G proteins, protein kinase C, and calcium appear necessary for the reestablishment of tight junctions [1319] . Tight junction injury and recovery, like that which occurs after ischemia and reperfusion, has similarly been modeled by subjecting cultured renal epithelial cells to ATP depletion (chemical anoxia) followed by repletion. While there are ma ny similarities to the calcium switch, biochemical studies have recently reveale d major differences, for example, in the way tight junction proteins interact wi th the cytoskeleton [12]. Thus, important insights into the basic and applied bi ology of tight junctions are likely to be forthcoming from further analysis of t he ATP depletion-repletion model. Nevertheless, it is likely that, as in the cal cium switch model, tight junction reassembly is regulated by classical signaling pathways that might potentially be pharmacologically modulated to enhance recov ery after ischemic insults. More prolonged insults can lead to greater, but stil l sublethal, injury. Key cellular proteins begin to break down. Many of these (e g, the tight junction protein, occludin, and the adherens junction The Ischemic Epithelial Cell Functional renal tubules Ischemic insult Injured cells ATP; -[CA2+]i; -Free radicals; Other changes? Uninjured cells FIGURE 16-1 Ischemic acute renal failure (ARF). Flow chart illustrates the cellu lar basis of ischemic ARF. As described above, renal tubule epithelial cells und ergo a variety of biochemical and structural changes in response to ischemic ins ult. If the duration of the insult is sufficiently short, these alterations are readily reversible, but if the insult continues it ultimately leads to cell deta chment and/or cell death. Interestingly, unlike other organs in which ischemic i njury often leads to permanent cell loss, a kidney severely damaged by ischemia can regenerate and replace lost epithelial cells to restore renal tubular functi on virtually completely, although it remains unclear how this happens. Tight junction disruption Apical-basolateral polarity disruption Microfilament disruption Dysfunctional renal tubular epithelial cells Remove insult Cell loss (detachment

or death) Continued insult Cellular repair Cell regenertation, differentiation, and morphogenesis Remove insult

Acute Renal Failure: Cellular Features of Injury and Repair 16.3 Brush border Tight junction Adherens junction Terminal web Actin cortical ring Desmosome Intermediate filaments FIGURE 16-2 Typical renal epithelial cell. Diagram of a typical renal epithelial cell. Sublethal injury to polarized epithelial cells leads to multiple lesions, including loss of the permeability barrier and apical-basolateral polarity [712] . To recover, cells must reestablish intercellular junctions and repolarize to f orm distinct apical and basolateral domains characteristic of functional renal e pithelial cells. These junctions include those necessary for maintaining the per meability barrier (ie, tight junctions), maintaining cell-cell contact (ie, adhe rens junctions and desmosomes), and those involved in cell-cell communication (i e, gap junctions). In addition, the cell must establish and maintain contact wit h the basement membrane through its integrin receptors. Thus, to understand how kidney cells recover from sublethal ischemic injury it is necessary to understan d how renal epithelial cells form these junctions. Furthermore, after lethal inj ury to tubule cells new cells may have to replace those lost during the ischemic insult, and these new cells must differentiate into epithelial cells to restore proper function to the tubules. Gap junction Integrins Na+, K+, ATPase Extracellular matrix Symplekin 7H6 Cingulin p130 ZO1 ZO2 Actin filaments Fodrin Occludin Paracellular space FIGURE 16-3 The tight junction. The tight junction, the most apical component of the junctional complex of epithelial cells, serves two main functions in epithe lial cells: 1) It separates the apical and basolateral plasma membrane domains o f the cells, allowing for vectorial transport of ions and molecules; 2) it provi des the major framework for the paracellular permeability barrier, allowing for generation of chemical and electrical gradients [31]. These functions are critic ally important to the proper functioning of renal tubules. The tight junction is comprised of a number of proteins (cytoplasmic and transmembrane) that interact with a similar group of proteins between adjacent cells to form the permeabilit y barrier [16, 3237]. These proteins include the transmembrane protein occludin [ 35, 38] and the cytosolic proteins zonula occludens 1 (ZO-1), ZO-2 [36], p130, [ 39], cingulin [33, 40], 7H6 antigen [34] and symplekin [41], although other as y et unidentified components likely exist. The tight junction also appears to inte ract with the actin-based cytoskeleton, probably in part through ZO-1fodrin inter actions.

16.4 Acute Renal Failure Reassembly of the Permeability Barrier Reutilization of existing junctional components Synthesis of new junctional comp onents Polarized renal epithelial cells Intact intercellular junctions Nonpolarized renal epithelial cells Compromised intercellular junctions Nonpolarized renal epithelial cells Damaged disassembled intercellular junctions Severe ATP depletion 6+ h Cell death Apoptosis Necrosis Deplete ATP Short-term ATP depletion 01 h Replete ATP Long-term ATP depletion 2.5-4 h Replete ATP FIGURE 16-4 Cell culture models of tight junction disruption and reassembly. The disruption of the permeability barrier, mediated by the tight junction, is a ke y lesion in the pathogenesis of tubular dysfunction after ischemia and reperfusi on. Cell culture models employing ATP depletion and repletion protocols are a co mmonly used approach for understanding the molecular mechanisms underlying tight junction dysfunction in ischemia and how tight junct ion integrity recovers after the insult [6, 12, 42]. After short-term ATP deplet ion (1 hour or less) in Madin-Darby canine kidney cells, although some new synth esis probably occurs, by and large it appears that reassembly of the tight junct ion can proceed with existing (disassembled) components after ATP repletion. Thi s model of short-term ATP depletion-repletion is probably most relevant to trans ient sublethal ischemic injury of renal tubule cells. However, in a model of lon gterm ATP depletion (2.5 to 4 hours), that probably is most relevant to prolonge d ischemic (though still sublethal) insult to the renal tubule, it is likely tha t reestablishment of the permeability barrier (and thus of tubule function) depe nds on the production (message and protein) and bioassembly of new tight junctio n components. Many of these components (membrane proteins) are assembled in the endoplasmic reticulum. occludin ZO-1 fodrin control ATP depletion (1 hr) ATP repletion (3hrs) FIGURE 16-5 Immunofluorescent localization of proteins of the tight junction aft

er ATP depletion and repletion. The cytosolic protein zonula occludens 1 (ZO-1), and the transmembrane protein occludin are integral componen ts of the tight junction that are intimately associated at the apical border of epithelial cells. This is demonstrated here by indirect immunofluorescent locali zation of these two proteins in normal kidney epithelial cells. After 1 hour of ATP depletion this association appears to change, occludin can be found in the c ell interior, whereas ZO-1 remains at the apical border of the plasma membrane. Interestingly, the intracellular distribution of the actin-cytoskeletalassociated protein fodrin also changes after ATP depletion. Fodrin moves from a random, in tracellular distribution and appears to become co-localized with ZO-1 at the api cal border of the plasma membrane. These changes are completely reversible after ATP repletion. These findings suggest that disruption of the permeability barri er could be due, at least in part, to altered association of ZO-1 with occludin. In addition, the apparent co-localization of ZO-1 and fodrin at the level of th e tight junction suggests that ZO-1 is becoming intimately associated with the c ytoskeleton. FIGURE 16-6 ATP depletion causes disruption of tight junctions. Dia gram of the changes induced in tight junction structure by ATP depletion. ATP de pletion causes the cytoplasmic tight junction proteins zonula occludens 1 (ZO-1) and ZO-2 to form large insoluble complexes, probably in association with the cy toskeletal protein fodrin [12], though aggregation may also be significant. Furt hermore, occludin, the transmembrane protein of the tight junction, becomes loca lized to the cell interior, probably in membrane vesicles. These kinds of studie s have begun to provide insight into the biochemical basis of tight junction dis ruption after ATP depletion, although how the tight junction reassembles during recovery of epithelial cells from ischemic injury remains unclear. Occludin ZO1 Occludin Fodrin ZO1 Ischemia ATP depletion Actin filament ZO2 Fodrin ZO2 Actin filament Membrane vesicle?

Acute Renal Failure: Cellular Features of Injury and Repair 16.5 Low calcium (LC) FIGURE 16-7 Madin-Darby canine kidney (MDCK) cell calcium switch. Insight into t he molecular mechanisms involved in the assembly of tight junctions (that may be at least partly applicable to the ischemia-reperfusion setting) has been gained from the MDCK cell calcium switch model [43]. MDCK cells plated on a permeable support form a monolayer with all the characteristics of a tight, polarized tran sporting epithelium. Exposing such cell monolayers to conditions of low extracel lular calcium (less than 5 M) causes the cells to lose cell-cell contact and to r ound up. Upon switching back to normal calcium media (1.8 mM), the cells reestabl ish cell-cell contact, intercellular junctions, and apical-basolateral polarity. These events are accompanied by profound changes in cell shape and reorganizati on of the actin cytoskeleton. (From Denker and Nigam [19]; with permission) Calcium switch (NC) A B C D FIGURE 16-8 Protein kinase C (PKC) is important for tight junction assembly. Imm unofluorescent localization of the tight junction protein zonula occludens 1 (ZO -1) during the Madin-Darby canine kidney (MDCK) cell calcium switch. In low-calc ium media MDCK cells are round and have little cellcell contact. Under these con ditions, ZO-1 is found in the cell interior and has little, if any, membrane sta ining, A. After 2 hours incubation in normal calcium media, MDCK cells undergo s ignificant changes in cell shape and make extensive cell-cell contact along the lateral portions of the plasma membrane. B, Here, ZO-1 has redistributed to area s of cell-cell contact with little apparent intracellular staining. This process is blocked by treatment with either 500 nM calphostin C, C, or 25 M H7, D, inhi bitors of PKC. These results suggest that PKC plays a role in regulating tight j unction assembly. Similar studies have demonstrated roles for a number of other signaling molecules, including calcium and G proteins, in the assembly of tight junctions [12, 13, 1619, 37, 4446]. An analogous set of signaling events is likely responsible for tight junction reassembly after ischemia. (From Stuart and Niga m [16]; with permission.)

16.6 Acute Renal Failure FIGURE 16-9 Signalling molecules that may be involved in tight junction assembly . Model of the potential signaling events involved in tight junction assembly. T ight junction assembly probably depends on a complex interplay of several signal ing molecules, including protein kinase C (PKC), calcium (Ca2+), heterotrimeric G proteins, small guanodine triphosphatases (Rab/Rho), and tyrosine kinases [1316 , 18, 37, 4453]. Although it is not clear how this process is initiated, it depen ds on cell-cell contact and involves wide-scale changes in levels of intracellul ar free calcium. Receptor/CAMcell adhesion molecule; DAGdiacylglycerol; ERendoplasm ic reticulum; G alpha subunit of GTP-binding protein; IP3inositol trisphosphate. ( From Denker and Nigam [19]; with permission.) P-Tyr P-Ser P Ga Tyr-kinases ?TP Rab/Rho PKC Effector DAG 2+ Ca + IP3 ?Receptor/CAM ER The Endoplasmic Reticulum Stress Response in Ischemia mRNA Ribosome Free chaperones reutilization Dissociation of chaperones ATP ADP P rotein folding Peptidyl-prolyl isomerization N-linked glycosylation Disulfide bo nd formation Secretioncompetent protein To Golgi ein ion ot at Pr riz e m go oli Misassembled protein Degradation Misfolded protein Resident ER proteolytic pathway? To proteasome? FIGURE 16-10 Protein processing in the endoplasmic reticulum (ER). To recover fr om serious injury, cells must synthesize and assemble new membrane (tight juncti on proteins) and secreted (growth factors) proteins. The ER is the initial site of synthesis of all membrane and secreted proteins. As a protein is translocated into the lumen of the ER it begins to interact with a group of resident ER prot eins called molecular chaperones [20, 5457]. Molecular chaperones bind transientl y to and interact with these nascent polypeptides as they fold, assemble, and ol igomerize [20, 54, 58]. Upon successful completion of folding or assembly, the m olecular chaperones and the secretioncompetent protein part company via a reacti on that requires ATP hydrolysis, and the chaperones are ready for another round of protein folding [20, 5961]. If a protein is recognized as being misfolded or m isassembled it is retained within the ER via stable association with the molecul ar chaperones and is ultimately targeted for degradation [62]. Interestingly, so me of the more characteristic features of epithelial ischemia include loss of ce llular functions mediated by proteins that are folded and assembled in the ER (i e, cell adhesion molecules, integrins, tight junctional proteins, transporters). This suggests that proper functioning of the proteinfolding machinery of the ER could be critically important to the ability of epithelial cells to withstand a nd recover from ischemic insult. ADPadenosine diphosphate.

Acute Renal Failure: Cellular Features of Injury and Repair 16.7 45' Ischemia GAPDH GAPDH 15' Ischemia BiP BiP grp94 grp94 ERp72 ERp72 1 2 3 1 2 3 A Kidney Cell Line GAPDH A B Thyroid Cell Line 28 S rRNA BiP BiP grp94 grp94 ERp72 ERp72 Hsp70 Hsp70 FIGURE 16-11 Ischemia upregulates endoplasmic reticulum (ER) molecular chaperone s. Molecular chaperones of the ER are believed to function normally to prevent i nappropriate intra- or intermolecular interactions during the folding and assemb ly of proteins [20, 54]. However, ER molecular chaperones are also part of the qu ality control apparatus involved in the recognition, retention, and degradation o f proteins that fail to fold or assemble properly as they transit the ER [20, 54 ]. In fact, the messages encoding the ER molecular chaperones are known to incre ase in response to intraorganelle accumulation of such malfolded proteins [11, 2 0, 54, 55]. Here, Northern blot analysis of total RNA from either whole kidney o r cultured epithelial cells demonstrates that ischemia or ATP depletion induces the mRNAs that encode the ER molecular chaperones, including immunoglobulin bind ing protein (BiP), 94 kDa glucose regulated protein (grp94), and 72 kDa endoplas mic reticulum protein (Erp72) [11]. This suggests not only that ischemia or ATP depletion causes the accumulation of malfolded proteins in the ER but that a maj or effect of ischemia and ATP depletion could be perturbation of the folding envi ronment of the ER and disruption of protein processing. GAPDHglyceraldehyde-3phosp hate dehydrogenase; Hsp7070 kDa heat-shock protein. (From Kuznetsov et al. [11];

with permission.) 1 2 3 4 5 6 1 2 3 4 C D C FIGURE 16-12 ATP depletion perturbs normal endoplasmic reticulum (ER) function. Because ATP and a proper redox environment are necessary for folding and assembl y [20, 54, 63, 64] and ATP depletion alters ATP levels and the redox environment , the secretion of proteins is perturbed under these conditions. Here, Western b lot analysis of the culture media from thyroid epithelial cells subjected to ATP depletion (ie, treatment with antimycin A, an inhibitor of oxidative phosphoryl ation) illustrates this point. A, Treatment with as little as 1 M antimycin A fo r 1 hour completely blocks the secretion of thyroglobulin (Tg) from these cells. (Continued on next page) Antimycin A 10 M 5 1 M 3 5 M 4 MED Tg PBS 2 A 1 B

16.8 Acute Renal Failure FIGURE 16-12 (Continued) BD, Moreover, indirect immunofluorescence with antithyro globulin antibody demonstrates that the nonsecreted protein is trapped almost en tirely in the ER. Together with data from Northern blot analysis, this suggests that perturbation of ER function and disruption of the secretory pathway is like ly to be a key cellular lesion in ischemia [11]. MEDcontrol media; PBSphosphate-bu ffered saline. (From Kuznetsov et al. [11]; with permission.) C Antimycin A MED PBS 1 5 10 D FIGURE 16-13 ATP depletion increases the stability of chaperone-folding polypept ide interactions in the endoplasmic reticulum (ER). Immunoglobulin binding prote in (BiP), and perhaps other ER molecular chaperones, associate with nascent poly peptides as they are folded and assembled in ER [20, 54, 56, 57, 6573]. The disso ciation of these proteins requires hydrolysis of ATP [69]. Thus, when levels of ATP drop, BiP should not dissociate from the secretory proteins and the normally transient interaction should become more stable. Here, the associations of ER m olecular chaperones with a model ER secretory protein is examined by Western blo t analysis of thyroglobulin (Tg) immunoprecipitates from thyroid cells subjected to ATP depletion. After treatment with antimycin A, there is an increase in the amounts of ER molecular chaperones (BiP, grp94 and ERP72) which co-immunoprecip itate with antithyroglobulin antibody [11], suggesting that ATP depletion causes stabilization of the interactions between molecular chaperones and secretory pr oteins folded and assembled in the ER. Moreover, because a number of proteins cr itical to the proper functioning of polarized epithelial cells (ie, occludin, Ecadherin, Na-K-ATPase) are folded and assembled in the ER, this suggests that re covery from ischemic injury is likely to depend, at least in part, on the abilit y of the cell to rescue the protein-folding and assembly apparatus of the ER. Co ntrol media (MED) and phosphate buffered saline (PBS)no ATP depletion; 1, 5, 10 M antimycin AATP-depleting conditions. (From Kuznetsov et al. [11]; with permissio n.) Tg grp94 BiP ERp72 1 2 3 4 5

Acute Renal Failure: Cellular Features of Injury and Repair 16.9 Growth Factors and Morphogenesis Basement membrane degrading proteinases Integrin receptors for interstitial matr ix Proteinases Cell-surface receptors for proteinases (uPA-R, ? for MMPs) Lack o f integrin-mediated basement membrane initiated signaling Cytoskeletal rearrangement Terminal nephron Arcade A B Uninduced mesenchyme Condensing cells S-shaped body C FIGURE 16-14 Kidney morphogenesis. Schematics demonstrate the development of the ureteric bud and metanephric mesenchyme during kidney organogenesis. During emb ryogenesis, mutual inductive events between the metanephric mesenchyme and the u reteric bud give rise to primordial structures that differentiate and fuse to fo rm functional nephrons [74-76]. Although the process has been described morpholo gically, the nature and identity of molecules involved in the signaling and regu lation of these events remain unclear. A, Diagram of branching tubulogenesis of the ureteric bud during kidney organogenesis. The ureteric bud is induced by the metanephric mesenchyme to branch and elongate to form the urinary collecting sy stem [74-76]. B, Model of cellular events involved in ureteric bud branching. To branch and elongate, the ureteric bud must digest its way through its own basem ent membrane, a highly complicated complex of extracellular matrix proteins. It is believed that this is accomplished by cellular projections, invadopodia, which allow for localized sites of proteolytic activity at their tips [77-81]. C, Mese nchymal cell compaction. The metanephric mesenchyme not only induces ureteric bu d branching but is also induced by the ureteric bud to epithelialize and differe ntiate into the proximal through distal tubule [7476]. (From Stuart and Nigam [80 ] and Stuart et al. [81]; with permission.) FIGURE 16-15 Potential of in vitro t ubulogenesis research. Flow chart indicates relevance of in vitro models of kidn ey epithelial cell branching tubulogenesis to basic and applied areas of kidney research. While results from such studies provide critical insight into kidney d evelopment, this model system might also contribute to the elucidation of mechan isms involved in kidney injury and repair for a number of diseases, including tu bular epithelial cell regeneration secondary to acute renal failure. Moreover, t hese models of branching tubulogenesis could lead to therapies that utilize tubu lar engineering as artificial renal replacement therapy [82]. Tubulogenesis in vitro Basic research Applied research Renal development Renal injury and repair Renal cystic diseases Urogenital abnor malities Hypertension Artificial kidneys Renal diseases

16.10 Acute Renal Failure FIGURE 16-16 Cellular response to growth factors. Schematic representation of th e pleiotrophic effects of growth factors, which share several properties and are believed to be important in the development and morphogenesis of organs and tis sues, such as those of the kidney. Among these properties are the ability to reg ulate or activate numerous cellular signaling responses, including proliferation (mitogenesis), motility (motogenesis), and differentiation (morphogenesis). The se characteristics allow growth factors to play critical roles in a number of co mplex biological functions, including embryogenesis, angiogenesis, tissue regene ration, and malignant transformation [83]. Mitogenesis Cell proliferation Motogenesis Cell movement Growth factor Cell organization Morphogenesis Cell survival DD Antiapoptosis Remodeling of cell substratum A B C FIGURE 16-17 Motogenic effect of growth factorshepatocyte growth factor (HGF) ind uces cell scattering. During development or regeneration the recruitment of cells to areas of new growth is vital. Growth factors have the ability to induce cell movement. Here, subconfluent monolayers of either Madin-Darby canine kidney (MDC K) C, D, or murine inner medullary collecting duct (mIMCD) A, B, cells were grow n for 24 hours in the absence, A, C, or presence B, D, of 20 ng/mL HGF. Treatmen t of either D type of cultured renal epithelial cell with HGF induced the dissociation of isla nds of cells into individual cells. This phenomenon is referred to as scattering . HGF was originally identified as scatter factor, based on its ability to induc e the scattering of MDCK cells [83]. Now, it is known that HGF and its receptor, the transmembrane tyrosine kinase c-met, play important roles in development, r egeneration, and carcinogenesis [83]. (From Cantley et al. [84]; with permission .)

Acute Renal Failure: Cellular Features of Injury and Repair 16.11 Growth factors FIGURE 16-18 Three-dimensional extracellular matrix gel tubulogenesis model. Mod el of the three-dimensional gel culture system used to study the branching and tubulogenesis of renal epithelial cells. Analyzing the role of single factors (ie, extracellular matrix, growth factors, cell-signaling proces ses) involved in ureteric bud branching tubulogenesis in the context of the deve loping embryonic kidney is an extremely daunting task, but a number of model sys tems have been devised that allow for such investigation [77, 79, 85]. The simpl est model exploits the ability of isolated kidney epithelial cells suspended in gels composed of extracellular matrix proteins to form branching tubular structu res in response to growth factors. For example, Madin-Darby canine kidney (MDCK) cells suspended in gels of type I collagen undergo branching tubulogenesis remi niscent of ureteric bud branching morphogenesis in vivo [77, 79]. Although the r esults obtained from such studies in vitro might not correlate directly with eve nts in vivo, this simple, straightforward system allows one to easily manipulate individual components (eg, growth factors, extracellular matrix components) inv olved in the generation of branching epithelial tubules and has provided crucial insights into the potential roles that these various factors play in epithelial cell branching morphogenesis [77, 79, 8487]. (mIMCD) or, B, Madin-Darby canine k idney (MDCK) cells suspended in gels of rat-tail collagen (type I). Embryonic ki dneys (EK) induced the formation of branching tubular structures in both mIMCD a nd MDCK cells after 48 hours of incubation at 37oC. EKs produce a number of grow th factors, including hepatocyte growth factor, transforming growth factor-alpha , insulin-like growth factor, and transforming growth factor , which have been sh own to effect tubulogenic activity [8693]. Interestingly, many of these same grow th factors have been shown to be effective in the recovery of renal function aft er acute ischemic insult [2130]. (From Barros et al. [87]; with permission.) A B FIGURE 16-19 An example of the branching tubulogenesis of renal epithelial cells cultured in threedimensional extracellular matrix gels. Microdissected mouse em bryonic kidneys (11.5 to 12.5 days) were cocultured with A, murine inner medulla ry collecting duct Pregnant SV40transgenic mouse Isolate embryos Dissect out embryonic kidney Isolate metanephric mesenchyme Isolate ureteric bud Culture to obtain immortalized cells FIGURE 16-20 Development of cell lines derived from embryonic kidney. Flow chart of the establishment of ureteric bud and metanephric mesenchymal cell lines fro m day 11.5 mouse embryo. Although the results obtained from the analysis of kidn ey epithelial cells Madin-Darby canine kidney (MDCK) or murine inner medullary co llecting duct (mIMCD) seeded in three-dimensional extracellular matrix gels has

been invaluable in furthering our understanding of the mechanisms of epithelial cell branching tubulogenesis, questions can be raised about the applicability to embryonic development of results using cells derived from terminally differenti ated adult kidney epithelial cells [94]. Therefore, kidney epithelial cell lines have been established that appear to be derived from the ureteric bud and metan ephric mesenchyme of the developing embryonic kidney of SV-40 transgenic mice [9 4, 95]. These mice have been used to establish a variety of immortal cell lines.

16.12 Acute Renal Failure A B C vitro model with the greatest relevance to early kidney development [94]. A, UB cells grown for 1 week in the presence of conditioned media collected from cells cultured from the metanephric mesenchyme. Note the formation of multicellular c ords. B, After 2 weeks' growth under the same conditions, UB cells have formed mor e substantial tubules, now with clear lumens. C, Interestingly, after 2 weeks of culture in a three-dimensional gel composed entirely of growth factorreduced Mat rigel, ureteric bud cells have not formed cords or tubules, only multicellular c ysts. Thus, changing the matrix composition can alter the morphology from tubule s to cysts, indicating that this model might also be relevant to renal cystic di sease, much of which is of developmental origin. (From Sakurai et al. [94]; with permission.) FIGURE 16-21 Ureteric bud cells undergo branching tubulogenesis in threedimensio nal extracellular matrix gels. Cell line derived from ureteric bud (UB) and meta nephric mesenchyme from day 11.5 mouse embryonic kidney undergo branching tubulo genesis in three-dimensional extracellular matrix gels. Here, UB cells have been induced to form branching tubular structures in response to conditioned media col lected from the culture of metanephric mesenchymal cells. During normal kidney m orphogenesis, these two embryonic cell types undergo a mutually inductive proces s that ultimately leads to the formation of functional nephrons [7476]. This mode l system illustrates this process, ureteric bud cells being induced by factors s ecreted from metanephric mesenchymal cells. Thus, this system could represent th e simplest in Free HGF and empty c-Met receptor CMet HGF HGF HGF Plasma membrane Gab-1 Gab-1 HGF binding to c-Met receptor CMet HGF HGF Plasma membrane Gab-1 Gab-1 Dimerization of c-Met receptor and activation of Gab 1 HGF CMet HGF HGF Plasma membrane Gab-1 Gab-1 HGF Growth factor binding Transduction of Gab-1 signal leading to branching tubulogenesis Branching morphogenesis Up-regulation of proteases Mitogenic response Motogenic response Alteration of c ytoskeleton Other responses FIGURE 16-22 Signalling pathway of hepatocyte growth factor action. Diagram of t he proposed intracellular signaling pathway involved in hepatocyte growth factor (HGF)mediated tubulogenesis. Although HGF is perhaps the best-characterized of t he growth factors involved in epithelial cell-branching tubulogenesis, very litt le of its mechanism of action is understood. However, recent evidence has shown that the HGF receptor (c-Met) is associated with Gab-1, a docking protein believ ed to be involved in signal transduction [96]. Thus, on binding to c-Met, HGF ac

tivates Gab-1mediated signal transduction, which, by an unknown mechanism, affect s changes in cell shape and cell movement or cell-cellcell-matrix interactions. U ltimately, these alterations lead to epithelial cellbranching tubulogenesis. FIGURE 16-23 Mechanism of growth factor action. Proposed model for the generaliz ed response of epithelial cells to growth factors, which the depends on their en vironment. Epithelial cells constantly monitor their surrounding environment via extracellular receptors (ie, integrin receptors) and respond accordingly to gro wth factor stimulation. If the cells are in the appropriate environment, growth factor binding induces cellular responses necessary for branching tubulogenesis. There are increases in the levels of extracellular proteinases and of structura l and functional changes in the cytoarchitecture that enable the cells to form b ranching tubule structures.

Acute Renal Failure: Cellular Features of Injury and Repair 16.13 GROWTH FACTORS IN DEVELOPMENTAL AND RENAL RECOVERY Growth Factor HGF EGF HB-EGF TGFIGF KGF bFGF GDNF TGFPDGF Expression Following Renal Ischemia Increased [97] Unclear [98,99] Increased [100] Unclear Increased [101] Increased [102] Undetermined Undetermined Increased [98] Increased [98] Effect of Exogenous Administration Enhanced recovery [103] Enhanced recovery [104,105] Undetermined Enhanced recove ry [106] Enhanced recovery [107,108] Undetermined Undetermined Undetermined Unde termined Undetermined Branching/Tubulogenic Activity Facilatory [109,110] Facilatory [111] Facilatory [111] Facilatory [111] Facilato ry [112,113] Undetermined Facilatory [112] Facilatory [114] Inhibitory for branc hing [115] No effect [112] *Increase in endogenous biologically active EGF probably from preformed sources; increase in EGF-receptor mRNA Chemoattractants for macrophages and monocytes (im portant source of growth promoting factors) FIGURE 16-24 Growth factors in development and renal recovery. This table descri bes the roles of different growth factors in renal injury or in branching tubulo genesis. A large variety of growth factors have been tested for their ability ei ther to mediate ureteric branching tubulogenesis or to affect recovery of kidney tubules after ischemic or other in jury. Interestingly, growth factors that facilitate branching tubulogenesis in v itro also enhance the recovery of injured renal tubules. References 1. Zager RA, Gmur DJ, Bredl CR, et al.: Regional responses within the kidney to ischemia: Assessment of adenine nucleotide and catabolite profiles. Biochim Biop hys Acta 1990, 1035:2936. 2. Hays SR: Ischemic acute renal failure. Am J Med Sci 1992, 304:93108. 3. Toback FG: Regeneration after acute tubular necrosis. Kidney Int 1992, 41:226246. 4. Liu S, Humes HD: Cellular and molecular aspects of renal repair in acute renal failure. Curr Opin Nephrol Hypertension 1993, 2:618624. 5. Doctor RB, Bennett V, Mandel LJ: Degradation of spectrin and ankyrin in the isch emic rat kidney. Am J Physiol 1993, 264:C1003C1013. 6. Doctor RB, Bacallao R, Man del LJ: Method for recovering ATP content and mitochondrial function after chemi cal anoxia in renal cell cultures. Am J Physiol 1994, 266:C1803C1811. 7. Edelstei n CL, Ling H, Schrier RW: The nature of renal cell injury. Kidney Int 1997, 51:1 3411351. 8. Fish EM, Molitoris BA: Alterations in epithelial polarity and the pat hogenesis of disease states. N Engl J Med 1994, 330:15801587. 9. Mandel LJ, Bacal lao R, Zampighi G: Uncoupling of the molecular `fence' and paracellular `gate' functions in epithelial tight junctions. Nature 1993, 361:552555. 10. Goligorsky MS, Liebe rthal W, Racusen L, Simon EE: Integrin receptors in renal tubular epithelium: Ne w insights into pathophysiology of acute renal failure. Am J Physiol 1993, 264:F 1F8. 11. Kuznetsov G, Bush KT, Zhang PL, Nigam SK: Perturbations in maturation of secretory proteins and their association with endoplasmic reticulum chaperones in a cell culture model for epithelial ischemia. Proc Natl Acad Sci USA 1996, 93 :85848589. 12. Tsukamoto T, Nigam SK: Tight junction proteins become insoluble, f orm large complexes and associate with fodrin in an ATP depletion model for reve rsible junction disassembly. J Biol Chem 1997, 272:1613316139. 13. Nigam SK, Deni senko N, Rodriguez-Boulan E, Citi S: The role of phosphorylation in development

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Molecular Responses and Growth Factors Steven B. Miller Babu J. Padanilam T he kidney possesses a remarkable capacity for restoring its structure and functi onal ability following an ischemic or toxic insult. It is unique as a solid orga n in its ability to suffer an injury of such magnitude that the organ can fail f or weeks and yet recover full function. Studying the natural regenerative proces s after an acute renal insult has provided new insights into the pathogenesis of acute renal failure (ARF) and possible new therapies. These therapies may limit the extent of injury or even accelerate the regenerative process and improve ou tcomes for patients suffering with ARF. In this chapter we illustrate some of th e molecular responses of the kidney to an acute insult and demonstrate the effec ts of therapy with growth factors in the setting of experimental models of ARF. We conclude by demonstrating strategies that will provide future insights into t he molecular response of the kidney to injury. The regions of the nephron most s usceptible to ischemic injury are the distal segment (S3) of the proximal tubule and the medullary thick ascending limb of the loop of Henle. Following injury, there is loss of the epithelial lining as epithelial cells lose their integrin-m ediated attachment to basement membranes and are sloughed into the lumen. An int ense regenerative process follows. Normally quiescent renal tubule cells increas e their nucleic acid synthesis and undergo mitosis. It is theorized that survivi ng cells situated close to or within the denuded area dedifferentiate and enter mitotic cycles. These cells then redifferentiate until nephron segment integrity is restored. The molecular basis that regulates this process is poorly-understo od. After an injury, there is a spectrum of cell damage that is dependent on the type and severity of the insult. If the intensity of the insult is limited, cel ls become dysfunctional but survive. More severe injury results in detachment of cells from the tubule basement membranes, resulting in necrosis. Still other ce lls have no apparent damage and may proliferate to reepithelialize the damaged n ephron segments. Thus, several CHAPTER 17

17.2 Acute Renal Failure and 3) some damaged cells may actually dienot as a result of the initial insult b ut through a process of programmed cell death known as apoptosis. Figure 17-1 pr ovides a schematic representation of the renal response to an ischemic or toxic injury. different processes are required to achieve structural and functional integrity of the kidney after a toxic or ischemic insult: 1) uninjured cells must prolifer ate and reepithelialize damaged nephron segments; 2) nonlethally damaged cells m ust recover; Subcellular Cytosol Organelles Plasma membrane Noninjured cells Insult ATP -Ca2+ ER blebbing Mitochondrial switching Brush border sloughing Loss of membrane protei n orientation Nonlethally injured cells Cellular 1 Growth factors 1 Nephron/Kidney Cell proliferation 1 Dysfunction morphological changes 2 Reepithelialization of nephron Cell death Cellular recovery 2 Recovery of nephron structure and function FIGURE 17-1 Schematic representation of some of the events pursuant to a renal i nsult and epithelial cell repair. Subcellular; Initial events include a decrease in cellular ATP and an increase in intracellular free calcium. There is blebbin g of the endoplasmic reticulum with mitochondrial swelling and dysfunction. The brush border of the proximal tubules is sloughed into the tubule lumen, and ther e is redistribution of membrane proteins with the loss of cellular polarity. Cel lular; At a cellular level this results in three populations of tubule cells, de pending on the severity of the insult. Some cells are intact and are poised to p articipate in the proliferative process (Pathway 1). Growth factors participate by stimulating cells to undergo mitosis. Nonlethally injured cells have the potenti al to follow one of two pathways. In the appropriate setting, perhaps stimulated by growth factors, these cells may recover with restoration of cellular integri ty and function (Pathway 2); however, if the injury is significant the cell may still die, but through a process of programmed cell death or apoptosis. The thir d population of cells are those with severe injury that undergo necrotic cell de ath. Nephron/Kidney; With the reepithelialization of damaged nephron segments an d cellular recovery of structural and functional integrity, renal function is re stored. (Modified from Toback [1]; with permission.) FIGURE 17-2 Growth regulati on after an acute insult in regenerating renal tubule epithelial cells. Under th e influence of growth-stimulating factors the damaged renal tubule epithelium is capable of regenerating with restoration of tubule integrity and function. The growth factors may be 1) produced by the tubule epithelium itself and act locall y in an autocrine, juxtacrine or paracrine manner; 2) produced by surrounding ce lls to work in a paracrine manner; or 3) presented to the regenerating area via the circulation mediated by an endocrine mechanism. Cells at the edge of an inju

red nephron segment are illustrated on the left. These cells proliferate in resp onse to the growth-stimulating factors. The middle cell is in the process of div iding and the cell on the right is migrating into the area of injury. (Adapted f rom Toback [1]; with permission.) Basement membrane

Molecular Responses and Growth Factors 17.3 Growth Factors in Acute Renal Failure GROWTH FACTORS IN ACUTE RENAL FAILURE FIGURE 17-3 At least three growth factors have now been demonstrated to be usefu l as therapeutic agents in animal models of acute renal failure (ARF). These inc lude epidermal growth factor (EGF), insulin-like growth factor I (IGF-I) and hep atocyte growth factor (HGF). All have efficacy in ischemia models and in a varie ty of toxic models of ARF. In addition, both IGF-I and HGF are beneficial when t herapy is delayed and ARF is established after an ischemic insult. IGF-I has the a dditional advantage in that it also ameliorates the course of renal failure when given prophylactically before an acute ischemic insult. EGF Ischemic and toxic IGF-I Ischemic and toxic Pretreatment and established ARF HGF Ischemic and toxic Established ARF ARFacute renal failure; EGFepidermal growth factor; HGFhepatocyte growth factor; IG F-Iinsulin-like growth factor. Prepro-EGF mRNA DCT PCT CTAL OMCD MTAL FIGURE 17-4 Expression of messenger RNA (mRNA) for preproepidermal growth factor (EGF) in kidney. This schematic depicts the localization of mRNA for prepro-EGF under basal states in kidney. Prepro-EGF mRNA is localized to the medullary thic k ascending limbs (MTAL) and distal convoluted tubules (DCT). Immunohistochemica l studies demonstrate that under basal conditions the peptide is located on the luminal membrane with the active peptide actually residing within the tubule lum en. It is speculated that, during pathologic states, preformed EGF is either tra nsported or routed to the basolateral membrane or can enter the interstitium via backleak. After a toxic or ischemic insult, expression of EGF is rapidly suppre ssed and can remain low for a long time. Likewise, total renal content and renal excretion of EGF decreases. CTALcortical thick ascending limb; IMCDinner medullar y collecting duct; OMCDouter medullary collecting duct; and PCTproximal convoluted tubule. IMCD

17.4 Acute Renal Failure FIGURE 17-5 Production of epidermal growth factor (EGF), insulin-like growth fac tor (IGF-I), and hepatocyte growth factor (HGF) by various tissues. EGF, IGF-I, and HGF have all been demonstrated to improve outcomes in various animal models of acute renal failure (ARF). All three growth-promoting factors are produced in the kidneys and in a variety of other organs. The local production is probably most important for recovery from an acute renal insult. The influence of product ion in other organs in the setting of ARF has yet to be determined. This chapter deals primarily with local production and actions of EGF, IGF-I, and HGF. GROWTH FACTOR PRODUCTION EGF Submandibular salivary glands Kidney Others HGF Liver Spleen Kidney Lung Oth er organs IGF-I Liver Lung Kidney Heart Muscle Other organs EGF-receptor binding DCT PCT CTAL GLOM FIGURE 17-6 Receptor binding for epidermal growth factor (EGF). EGF binding in k idney under basal conditions is extensive. The most significant specific binding occurs in the proximal convoluted (PCT) and proximal straight tubules. There is also significant EGF binding in the glomeruli (GLOM), distal convoluted tubules (DCT), and the entire collecting duct (OMCD, IMCD). After an ischemic renal ins ult, EGF receptor numbers increase. This change in the renal EGF system may be r esponsible for the beneficial effect of exogenously administered EGF is the sett ing of acute renal failure. CTALcortical thick ascending loop. OMCD MTAL IMCD

Molecular Responses and Growth Factors 17.5 EGF P P P P GAP PKC PLCg DAG + IP3 Ca2+ CamK PIP2 Signal transduction RasGDP RasGTP PIP PI3K P I-3,4 P2 SHC Grb2 SOS RAF MAPKK ERK1/ ERK2 Gene transcription Growth differentiation FIGURE 17-7 Epidermal growth factor (EGF)mediated signal transduction pathways. T he EGF receptor triggers the phospholipase C-gamma (PLC-gamma), phosphatidylinos itol-3 kinase (PI3K), and mitogen-activated protein kinase (MAPK) signal transdu ction pathways described in the text that follows. Growth factors exert their do wnstream effects through their plasma membranebound protein tyrosine kinase (PTK) receptors. All known PTK receptors are found to have four major domains: 1) a g lycosylated extracellular ligand-binding domain; 2) a transmembrane domain that anchors the receptor to the plasma membrane; 3) an intracellular tyrosine kinase domain; and 4) regulatory domains for the PTK activity. Upon ligand binding, th e receptors dimerize and autophosphorylate, which leads to a cascade of intracel lular events resulting in cellular proliferation, differentiation, and survival. The tyrosine phosphorylated residues in the cytoplasmic domain of PTK are of ut most importance for its interactions with cytoplasmic proteins involved in EGFmed iated signal transduction pathways. The interactions of cytoplasmic proteins are governed by specific domains termed Src homology type 2 (SH2) and type 3 (SH3) domains. The SH2 domain is a conserved 100amino acid sequence initially character ized in the PTK-Src and binds to tyrosine phosphorylated motifs in proteins; the SH3 domain binds to their targets through proline-rich sequences. SH2 domains h ave been found in a multitude of signal transducers and docking proteins such as growth factor receptorbound protein 2 (Grb2), phophatidylinositol-3 kinase (p85PI3K), phospholipase C-gamma (PLC-gamma), guanosine triphosphatase (GTPase)activa ting protein of ras (ras-GAP), and signal transducer and activator of transcript ion 3 (STAT-3). Upon ligand binding and phosphorylation of PTKs, SH2domain contai ning proteins interact with the receptor kinase domain. PLC-gamma on interaction with the PTK, becomes phosphorylated and catalyzes the turnover of phosphatidyl inositol (PIP2) to two other second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG). DAG activates protein kinase C; IP3 raises the intracellular calcium (Ca2+) leve ls by inducing its release from intracellular stores. Ca2+ is involved in the ac tivation of the calmodulin-dependent CAM-kinase, which is a serine/threonine kin ase. A more important signal transduction pathway activated by PTKs concerns the ras pathway. The ras cycle is connected to activated receptors via the adapter protein Grb2 and the guanosine diphosphateguanosine triphosphate exchange factor Sos (son of sevenless). GDP-ras, upon phosphorylation, is converted to its acti vated form, GTP-ras. The activated ras activates another Ser/Thr kinase called r af-1, which in turn activates another kinase, the mitogen activated protein kina se kinase (MAPKK). MAPKK activates the serine/threonine kinases, and extracellul ar signal-regulated kinases Erk1 and 2. Activation of Erk1/2 leads to translocat ion into the nucleus, where it phosphorylates key transcription factors such as Elk-1, and c-myc. Phosphorylated Elk-1 associates with serum response factor (SR F) and activates transcription of c-fos. The protein products of c-fos and c-jun function cooperatively as components of the mammalian transcription factor AP-1 . AP-1 binds to specific DNA sequences in putative promoter sequences of target genes and regulates gene transcription. Similarly, c-myc forms a heterodimer wit

h another immediate early gene max and regulates transcription. The expression o f c-fos, c-jun, and Egr-1 is found to be upregulated after ischemic renal injury . Immunohistochemical analysis showed the spatial expression of c-fos and Egr-1 to be in thick ascending limbs, where cells are undergoing minimal proliferation as compared with the S3 segments of the proximal tubules. This may suggest that the expression of immediate early genes after ischemic injury is not associated with cell proliferation. Several mechanisms control the specificity of RTK sign aling: 1) the specific ligandreceptor interaction; 2) the repertoire of substrat es and signaling molecules associated with the activated RTK; 3) the existence o f tissue-specific signaling molecules; and 4) the apparent strength and persiste nce of the biochemical signal. Interplay of these factors can determine whether a given ligandreceptor interaction lead to events such as growth, differentiatio n, scatter or survival.

17.6 IGF-1 mRNA Acute Renal Failure DCT DCT IGF-receptor binding PCT PCT CTAL GLOM CTAL GLOM OMCD MTAL OMCD MTAL IMCD IMCD FIGURE 17-8 Expression of mRNA for insulin-like growth factor I (IGF-I). Under b asal conditions, a variety of nephron segments can produce IGF-I. Glomeruli (GLO M), medullary and cortical thick ascending limbs (MTAL/CTAL), and collecting duc ts (OMCD, IMCD) are all reported to produce IGF-I. Within hours of an acute isch emic renal insult, the expression of IGF-I decreases; however, 2 to 3 days after the insult, when there is intense regeneration, there is an increase in the exp ression of IGF-I in the regenerative cells. In addition, extratubule cells, pred ominantly macrophages, express IGF-I in the regenerative period. This suggests t hat IGF-I works by both autocrine and paracrine mechanisms during the regenerati ve process. DCT/PCTdistal/proximal convoluted tubule. FIGURE 17-9 Receptor binding for insulin-like growth factor I (IGF-I). IGF-I bin ding sites are conspicuous throughout the normal kidney. Binding is higher in th e structures of the inner medulla than in the cortex. After an acute ischemic in sult, there is a marked increase in IGF-I binding throughout the kidney. The inc rease appears to be greatest in the regenerative zones, which include structures of the cortex and outer medulla. These findings suggest an important trophic ef fect of IGF-I in the setting of acute renal injury. CTAL/MTALcortical/medullary t hick ascending loop; DCT/PCTdistal/proximal convoluted tubule; GLOMglomerulus; OMC D/IMCDouter/inner medullary collecting duct.

Molecular Responses and Growth Factors 17.7 IGF-I IGF-IR Other substrates SHC Grb2 SOS Crk II IRS-1/IRS-2 C3G SYP P110 p85 PI3-kinase signaling Akt Grb2 SOS nck BAD Cell survival Phosphotyrosine dephosphorylation Growth, differentiation Ras Raf-1 MEKs S6-kinase Gene expression ERKs EGF-R MBP TF FIGURE 17-10 Diagram of intracellular signaling pathways mediated by the insulin -like growth factor I (IGF-IR) receptor. IGF-IR when bound to IGF-I undergoes au tophosphorylation on its tyrosine residues. This enhances its intrinsic tyrosine kinase activity and phosphorylates multiple substrates, including insulin recep tor substrate 1 (IRS-1), IRS-2, and Src homology/collagen (SHC). IRS-1 upon phos phorylation associates with the p85 subunit of the PI3-kinase (PI3K) and phospho rylates PI3-kinase. PI3K upon phosphorylation converts phosphoinositide-3 phosph ate (PI-3P) into PI-3,4-P2, which in turn activates a serine-thronine kinase Akt (protein kinase B). Activated Akt kinase phosphorylates the proapoptotic factor Bad on a serine residue, resulting in its dissociation from B-cell lymphoma-X ( Bcl-XL) . The released Bcl-XL is then capable of suppressing cell death pathways that involve the activity of apoptosis protease activating factor (Apaf-1), cyt ochrome C, and caspases. A number of growth factors, including platelet-derived growth factor (PDGF) and IGF 1 promotes cell survival. Activation of the PI3K ca scade is one of the mechanisms by which growth factors mediate cell survival. Ph osphorylated IRS-1 also associates with growth factor receptor bound protein 2 ( Grb2), which bind son of sevenless (Sos) and activates the ras-raf-mitogen activ ated protein (ras/raf-MAP) kinase cascade. SHC also binds Grb2/Sos and activates the ras/raf-MAP kinase cascade. Other substrates for IGF-I are phosphotyrosine phosphatases and SH2 domain containing tyrosine phosphatase (Syp). Figure 17-7 h as details on the other signaling pathways in this figure. MBPmyelin basic protei n; nckan adaptor protein composed of SH2 and SH3 domains; TFtranscription factor.

17.8 HGF mRNA HGF receptor mRNA Acute Renal Failure FIGURE 17-11 Expression of hepatocyte growth factor (HGF) mRNA and HGF receptor mRNA in kidney. While the liver is the major source of circulating HGF, the kidn ey also produces this growth-promoting peptide. Experiments utilizing in situ hy bridization, immunohistochemistry, and reverse transcriptionpolymerase chain reac tion (RT-PCR) have demonstrated HGF production by interstitial cells but not by any nephron segment. Presumably, these interstitial cells are macrophages and en dothelial cells. Importantly, HGF expression in kidney actually increases within hours of an ischemic or toxic insult. This expression peaks within 6 to 12 hour s and is followed a short time later by an increase in HGF bioactivity. HGF thus seems to act as a renotrophic factor, participating in regeneration via a parac rine mechanism; however, its expression is also rapidly induced in spleen and lu ng in animal models of acute renal injury. Reported levels of circulating HGF in patients with acute renal failure suggest that an endocrine mechanism may also be operational. The receptor for HGF is the c-met proto-oncogene product. Recept or binding has been demonstrated in kidney in a variety of sites, including the proximal convoluted (PCT) and straight tubules, medullary and cortical thick asc ending limbs (MTAL, CTAL), and in the outer and inner medullary collecting ducts (OMCD, IMCD). As with HGF peptide production, expression of c-met mRNA is induc ed by acute renal injury. DCT PCT CTAL OMCD MTAL IMCD

Molecular Responses and Growth Factors Pro-HGF convertase Membrane bound Pro-HGF Mature HGF Matrix soluble pro-HGF uPa HGFR 17.9 Extracellular GTP-gs Raf-1 Urokinase receptor SHC S Y Y P Y Y S BAG-1 Y Y Y Y PIP2 PLC-g Antipoptosis Cytosol DAG mSos1 P Grb2 P IP3 P Gab 1 p85 MAP kinases kinases (MEK S) C-SgC PI3K STAT3 PKC l, b, g activation P MAP kinases (ERK5) TF Growth Focal adhesion SRE TF Scatter Nuclear membrane TF Transcription Gene FIGURE 17-12 Model of hepatocyte growth factor (HGF)/c-met signal transduction. In the extracellular space, single-chain precursors of HGF bound to the proteogl ycans at the cell surface are converted to the active form by urokinase plasmino gen activator (uPA), while the matrix soluble precursor is processed by a serum derived pro-HGF convertase. HGF, upon binding to its receptor c-met, induces its dimerization as well as autophosphorylation of tyrosine residues. The phosphory lated residue binds to various adaptors and signal transducers such as growth fa ctor receptor bound protein-2 (Grb2), p85-PI3 kinase, phospholipase C-gamma (PLC -gamma), signal transducer and activator of transcription-3 (STAT-3) and Src hom ology/collagen (SHC) via Src homology 2 (SH2) domains and triggers various signa l transduction pathways. A common theme among tyrosine kinase receptors is that phosphorylation of different specific tyrosine residues determines which intrace llular transducer will bind the receptor and be activated. In the case of HGF re ceptor, phosphorylation of a single multifunctional site triggers a pleiotropic response involving multiple signal transducers. The synchronous activation of se veral signaling pathways is essential to conferring the distinct invasive growth ability of the HGF receptor. HGF functions as a scattering (dissociation/motili ty) factor for epithelial cells, and this ability seems to be mediated through t he activation of STAT-3. Phosphorylation of adhesion complex regulatory proteins such as ZO-1, betacatenin, and focal adhesion kinase (FAK) may occur via activa tion of c-src. Another Bcl2 interacting protein termed BAG-1 mediates the antiap optotic signal of HGF receptor by a mechanism of receptor association independen t from tyrosine residues.

DETERMINANT MECHANISMS FOR OUTCOMES OF ACUTE RENAL FAILURE Mitogenic Morphogenic Cell migration Hemodynamic Cytoprotective Anabolic Alter leukocyte function Alter inflammatory process Apoptosis Others FIGURE 17-13 Mechanisms by which growth factors may possibly alter outcomes of a cute renal failure (ARF). Epidermal growth factor, insulin-like growth factor, a nd hepatocyte growth factor (HGF) have all been demonstrated to improve outcomes when administered in the setting of experimental ARF. While the results are the same, the respective mechanisms of actions of each of these growth factors are probably quite different. Many investigators have examined individual growth fac tors for a variety of properties that may be beneficial in the setting of ARF. T his table lists several of the properties examined to date. Suffice it to say th at the mechanisms by which the individual growth factors alter the course of exp erimental ARF is still unknown.

17.10 Acute Renal Failure acute renal insult there is an initial decrease in both insulin-like growth fact or (IGF-I) peptide and mRNA, which recovers over several days but only after the regenerative process is under way. The pattern with epidermal growth factor (EG F) is different in that a transient increase in available mature peptide from cl eavage of preformed EGF is followed by a pronounced and prolonged decrease in bo th peptide and message. Both peptide and message for hepatocyte growth factor (H GF) are transiently increased in kidney after a toxic or an ischemic insult. The receptors for all three growth factors are increased after injury, which may be crucial to the response to exogenous administration. The mechanism by which the different growth factors act in the setting of acute renal injury is quite vari able. IGF-I is known to increase renal blood flow and glomerular filtration rate in both normal animals and those with acute renal injury. To the other extreme, EGF is a vasoconstrictor and HGF is vasoneutral. IGF-I has an additional advant age in that it has anabolic properties, and ARF is an extremely catabolic state. Neither EGF nor HGF seems to affect nutritional parameters. Finally, both EGF a nd HGF are potent mitogens for renal proximal tubule cells, the nephron segment is most often damaged by ischemic acute renal injury, whereas IGF-I is only a mo dest mitogen. Likewise, both EGF and HGF appear to be more effective than IGF-I at inhibiting apoptosis in the setting of acute renal injury, but it is not clea r whether this is an advantage or a disadvantage. ACTIONS OF GROWTH FACTORS IN ACUTE RENAL FAILURE Actions Protein mRNA Receptiors Vascular Anabolic Mitogenic Apoptosis IGF-I /- /- - - - - EGF -/ - --FIGURE 17-14 Selected actions of growth factors in the setting of acute renal fa ilure (ARF). After an acute renal injury, a spectrum of molecular responses occu r involving the local expression of growth factors and their receptors. In addit ion, there is considerable variation in the mechanisms by which the growth facto rs are beneficial for ARF. After an Clinical Use of Growth Factors in Acute Renal Failure HGF Serum creatinine, mg/dL - - - --- 4 +Vehicle +IGF-I * * * * 2 * * * 0 0 FIGURE 17-15 Rationale for the use of insulin-like growth factor IGF-I in the se tting of acute renal failure (ARF). Of the growth factors that have been demonst rated to improve outcomes after acute renal injury, the most progress has been m ade with IGF-I. From this table, it is evident that IGF-I has a broad spectrum o f activities, which makes it a logical choice for treatment of ARF. An agent tha

t increased renal plasma flow and glomerular filtration rate and was mitogenic f or proximal tubule cells and anabolic would address several features of ARF. 2 4 Time after ischemia, d 6 FIGURE 17-16 Serial serum creatinine values in rats with ischemic acute renal fa ilure (ARF) treated with insulin-like growth factor (IGF-I) or vehicle. This is the original animal experiment that demonstrated a benefit from IGF-I in the set ting of ARF. In this study, IGF-I was administered beginning 30 minutes after th e ischemic insult (arrow). Data are expressed as mean standard error. Significan t differences between groups are indicated by asterisks. This experiment has bee n reproduced, with variations, by several groups, with similar findings. IGF-I h as now been demonstrated to be beneficial when administered prophylactically bef ore an ischemic injury and when started as late as 24 hours after reperfusion wh en injury is established. It has also been reported to improve outcomes for a va riety of toxic injuries and is beneficial in a model of renal transplantation wi th delayed graft function and in cyclosporine-induced acute renal insufficiency. (From Miller et al. [2]; with permission.)

Molecular Responses and Growth Factors 280 + Vehicle + IGF-I 17.11 * Body weight, g * * 220 * FIGURE 17-17 Body weights of rats with ischemic acute renal failure (ARF) treate d with insulin-like growth factor (IGF-I) or vehicle. Unlike epidermal growth fa ctor or hepatocyte growth factor (HGF), IGF-I is anabolic even in the setting of acute renal injury. These data are from the experiment described in Figure 17-1 6. As the data in this figure demonstrate, ARF is a highly catabolic state: vehi cle-treated animals experience 15% weight reduction. Animals that received IGF-I experienced only a 5% reduction in body weight and were back to baseline by 7 d ays. Data are expressed as mean standard error. Significant differences between groups are indicated by asterisks. (From Miller et al. [2]; with permission.) 160 0 2 4 Time after ischemia, d 6 A FIGURE 17-18 Photomicrograph of kidneys from rats with acute renal failure (ARF) treated with insulin-like growth factor (IGF-I) or vehicle. These photomicrogra phs are of histologic sections stained with hematoxylin and eosin originating fr om kidneys of rats that received vehicle or IGF 1 after ischemic renal injury. K idneys were obtained 7 days after the insult. There is evidence of considerable residual injury in the kidney from the vehicle-treated rat (A): dilation and sim plification of tubules, interstitial calcifiB cations, and papillary proliferations the tubule lumen of proximal tubules. The kidney obtained from the IGF-Itreated rat (B) appears almost normal, showing evid ence of regeneration and restoration of normal renal architecture. In this exper iment the histologic appearance of kidneys from the IGF-Itreated animals was stat istically better than that of the vehicle-treated controls, as determined by a p athologist blinded to therapy. (From Miller et al. [2]; with permission.)

17.12 Acute Renal Failure over- and underexpression of IGF-I, this is the first growth factor that has bee n used in clinical trials for kidney disease. Listed above are a variety of stud ies of the effects of IGF-I in humans. This peptide has now been examined in sev eral published studies of both acute and chronic renal failure. Additional studi es are currently in progress. In the area of acute renal failure there are now t wo reported trials of IGF-I. In the initial study IGF-I or placebo was administe red to patients undergoing surgery involving the suprarenal aorta or the renal a rteries. This group was selected as it best simulated the work that had been rep orted in animal trials of ischemic acute renal injury. Fifty-four patients were randomized in a double-blind, placebo-controlled trial of IGF-I to prevent the a cute decline in renal function frequently associated with this type of surgery. The primary end-point in this study was the incidence of renal dysfunction, defi ned as a reduction of the glomerular filtration rate as compared with a preopera tive baseline, at each of three measurements obtained during the 3 postoperative days. Modern surgical techniques have decreased the incidence of acute renal fa ilure to such a low level, even in this high-risk group, so as to make it imprac tical to perform a single center trial with enough power to obtain differences i n clinically important end-points. Thus, this trial was intended only to offer pr oof of concept that IGF-I is useful for patients with acute renal injuries. RATIONALE FOR INSULIN-LIKE GROWTH FACTOR I (IGF-I) IN ACUTE RENAL FAILURE FIGURE 17-19 Reported therapeutic trials of insulin-like growth factor (IGF-I) i n humans. Based on the compelling animal data and the fact that there are clearl y identified disease states involving both 35 30 25 20 15 10 5 0 *P<0.05 Chi square Renal dysfunction, % Receptors are present on proximal tubules Regulates proximal tubule metabolism a nd transport * Increases renal plasma flow and glomerular filtration rates Mitogenic for proxim al tubule cells Enhanced expression after acute renal injury Anabolic Placebo IG F-I Treatment groups THERAPEUTIC TRIALS OF INSULIN-LIKE GROWTH FACTOR I IN HUMANS FIGURE 17-20 Incidence of postoperative renal dysfunction treated with insulin ( IGF-I) or placebo. IGF-I significantly reduced the incidence of postoperative re nal dysfunction in these high-risk patients. Renal dysfunction occurred in 33% o f those who received placebo but in only 22% of patients treated with IGF-I. The groups were well-matched with respect to age, sex, type of operation, ischemia time, and baseline renal function as defined by serum creatinine or glomerular f iltration rate. The IGF-I was tolerated well: no side effects were attributed to the drug. Secondary end-points such as discharge, serum creatinine, length of h ospitalization, length of stay in the intensive care unit, or duration of intuba tion were not significantly different between the two groups. (Adapted from Fran klin, et al. [3]; with permission.) FIGURE 17-21 Summary of an abstract describing the trial of insulin-like growth

factor (IGF-I) in the treatment of patients with established acute renal failure (ARF). Based on the accumulated animal and human data, a multicenter, double-bl ind, randomized, placebo-controlled trial was performed to examine the effects o f IGF-I in patients with established ARF. Enrolled patients had ARF of a wide va riety of causes, including surgery, trauma, hypertension, sepsis, and nephrotoxi c injury. Approximately 75 patients were enrolled, treatment being initiated wit hin 6 days of the renal insult. Renal function was evaluated by iodothalimate cl earance. Unfortunately, at an interim analysis (the study was originally designe d to enroll 150 patients) there was no difference in renal function or survival between the groups. The investigators recognized several potential problems with the trial, including the severity of many patients' illnesses, the variety of cau ses of the renal injury, and delay in initiating therapy [4].

Molecular Responses and Growth Factors 17.13 Growth hormoneresistant short stature Corticosteroid therapy Postoperative state Laron-type dwarfism Anabolic agent in catabolic states AIDS (Protein wasting mal nutrition) Burns Insulin-dependent and noninsulin-dependent diabetes mellitus Acu te renal failure Chronic renal failure FIGURE 17-22 Advantages of insulin-like growth factor (IGF-I) in the treatment o f acute renal failure. The limited data obtained to date on the use of IGF-I for acute renal failure demonstrate that the peptide is welltolerated and may be us eful in selected patient populations. Additional human trials are ongoing includ ing use in the settings of renal transplantation and chronic renal failure. LACK OF EFFECT OF RECOMBINANT FIGURE 17-23 Limitations in the use of growth factors to treat acute renal failu re (ARF). The disappointing results of several recent clinical trials of ARF the rapy reflect the fact that our understanding of its pathophysiology is still lim ited. Screening compounds using animal models may be irrelevant. Most laboratori es use relatively young animals, even though ARF frequently affects older humans , whose organ regenerative capacity may be limited. In addition, our laboratory models are usually based on a single insult, whereas many of our patients suffer repeated or multiple insults. Until we gain a better understanding of the basic pathogenic mechanisms of ARF, studies in human patients are likely to be frustr ating. Future Directions HUMAN IGF-I IN PATIENTS WITH ARF* Multicenter, doubleblind, randomized, placebo-controlled ARF secondary to surger y, trauma, hypertensive nephropathy, sepsis, or drugs Treated within the first 6 days for 14 days Evaluated renal function and mortality *No difference between the groups were observed in final values or changes in values for glomerular fil tration 1 Hour - - - - 1 Day - 2 Days 5 Days

References Bardella et al. [5] Ouellette et al. [6] Bonventre et al. [7] Witzgall et al. [8 ] Safirstein et al. [9] Goes et al. [10] Singh et al. [11] Soifer et al. [12] F rth and Ratcliffe [13] (Table continued on next page) - - - - FIGURE 17-24 A list of genes whose expression is induced at various time points by ischemic renal injury. The molecular response of the kidney to an ischemic in sult is complex and is the subject of investigations by several laboratories. (C

ontinued on next page) - - - - - - - - (6 h) (6 h) - - - - - - -

17.14 Acute Renal Failure Well-tolerated Safe in short-term studies Experience with diseases of overexpression and undere xpression Did not worsen outcomes IGF-Iinsulin-like growth factor. GROWTH FACTOR LIMITATIONS I N ACUTE RENAL FAILURE Lack of basic knowledge of the pathophysiology of ARF No screening system for co mpounds to treat ARF Animal models may not be relevant Animal studies have not p redicted results in human trials Difficulty of identifying appropriate target po pulations FIGURE 17-24 (Continued) Several genes have already been identified to be induce d or down-regulated after ischemia and reperfusion. This table lists genes whose expression is altered as a result of ischemic injury. It is not clear at present if the varied expression of these genes plays a role in cell injury, survival, or proliferati on.

Molecular Responses and Growth Factors 17.15 ARFacute renal failure. MOLECULAR RESPONSE TO RENAL ISCHEMIC/REPERFUSION INJURY Genes Transcription factors c-jun c-fos Egr-1 Kid 1 Cytokines JE KC IL-2 IL-10 IFNGM-C SF MIP-2 IL-6 IL-11 LIF PTHrP Endothelin 1 Endothelin 3 FIGURE 17-25 Schematic representation of differential display. In a complex orga n like the kidney, ischemic renal injury triggers altered expression of various cell factors and vascular components. Depending on the severity of the insult, e xpression of these genes can vary in individual cells, leading to their death, s urvival, or proliferation. A better understanding of the various factors and the signal transduction pathways transduced by them that contribute to cell death c an lead to development of therapeutic strategies to interfere with the process o f cell death. Similarly, identification of factors that are involved in initiati ng cell migration, dedifferentiation, and proliferation may lead to therapy aime d at accelerating the regeneration program. To identify the various factors invo lved in cell injury and regeneration, powerful methods for identification and cl oning of differentially expressed genes are critical. One such method that has b een used extensively by several laboratories is the differential display polymer ase chain reaction (DD-PCR). In this schematic, mRNA is derived from kidneys of shamoperated (controls) and ischemia-injured rats, some pretreated with insulinlike growth factor (IGF-I). The mRNAs are reverse transcribed using an anchored deoxy thymidine-oligonucleotide (oligo-dT) primer (Example: dT[12]-MX, where M r epresent G, A, or C, and X represents one of the four nucleotides). An anchored primer limits the reverse transcription to a subset of mRNAs. The first strand c DNA is then PCR amplified using an arbitrary 10 nucleotide-oligomer primer and t he anchored primer. The PCR reaction is performed in the presence of radioactive or fluorescence-labeled nucleotides, so that the amplified fragments can be dis played on a sequencing gel. Bands of interest can be excised from the gel and us ed for further characterization. ARFacute renal failure. Sham Sham +IGF-1 ARF ARF + IGF-1 1 2 3 4 FIGURE 17-26 Schematic representation of a differential display gel in which mRN A from kidneys is reverse-transcribed and polymerase chain reaction (PCR) amplif ied (see Figure 17-25). The PCR amplification is conducted in the presence of ra dioactive nucleotides. The cDNA fragments corresponding to the 3' end of the mRNA species are displayed by running them on a sequencing gel, followed by autoradio graphy. The arrows show bands corresponding to mRNA transcripts that are express ed differentially 1) in response to insulin-like growth factor (IGF-I) treatment and induction of ischemic injury; 2) in an IGF-Idependent manner; 3) in response to induction of ischemic injury; and 4) to genes that are down-regulated after induction of ischemic injury. ARFacute renal failure.

17.16 Acute Renal Failure References 1. Toback GF: Regeneration after acute tubular necrosis. Kidney Int 1992, 41:2262 46. 2. Miller SB, Martin DR, Kissane J, Hammerman, MR: Insulin-like growth facto r I accelerates recovery from ischemic acute tubular necrosis in the rat. Proc N atl Acad Sci USA 1992, 89:1187611880. 3. Franklin SC, Moulton M, Sicard GA, et al .: Insulin-like growth factor I preserves renal function postoperatively. Am J P hysiol 1997, 272:F257F259. 4. Kopple JD, Hirschberg R, Guler H-P, et al.: Lack of effect of recombinant human insulin-like growth factor I (IGF-I) in patients wi th acute renal failure (ARF). J Amer Soc Nephro 1996, 7:1375. 5. Bardella L, Com olli R: Differential expression of c-jun, c-fos and hsp 70 mRNAs after folic aci d and ischemia reperfusion injury: effect of antioxidant treatment. Exp Nephrol 1994, 2:158165. 6. Ouellette AJ, et al.: Expression of two immediate early genes, E gr-1 and c-fos, in response to renal ischemia and during compensatory renal hype rtrophy in mice. J Clin Invest 1990, 85:766771. 7. Bonventre JV, et al.: Localiza tion of the protein product of the immediate early growth response gene, Egr-1, in the kidney after ischemia and reperfusion. Cell Regulation 1991, 2:25160. 8. W itzgall R, et al.: Kid-1, a putative renal transcription factor: regulation duri ng ontogeny and in response to ischemia and toxic injury. Mol Cell Biol 1993, 13 :19331942. 9. Safirstein R, et al.: Expression of cytokine-like genes JE and KC i s increased during renal ischemia. Amer J Physiol 1991, 261:F1095F1101. 10. Goes N, et al.: Ischemic acute tubular necrosis induces an extensive local cytokine r esponse. Evidence for induction of interferon-gamma, transforming growth factorbeta 1, granulocyte-macrophage colonystimulating factor, interleukin-2, and inter leukin-10. Transplantation 1995, 59:565572. 11. Singh AK, et al.: Prominent and s ustained upregulation of MIP-2 and gp130 signaling cytokines in murine renal isc hemic-reperfusion injury. J Am Soc Nephrol 1997, 8:595A. 12. Soifer NE, et al.: Expression of parathyroid hormonerelated protein in the rat glomerulus and tubule during recovery from renal ischemia. J Clin Invest 1993, 92:28502857. 13. Firth JD, Ratcliffe PJ: Organ distribution of the three rat endothelin messenger RNAs and the effects of ischemia on renal gene expression. J Clin Invest 1992, 90:102 31031. 14. Witzgall R, et al.: Localization of proliferating cell nuclear antigen , vimentin, c-Fos, and clusterin in the postischemic kidney. Evidence for a hete rogeneous genetic response among nephron segments, and a large pool of mitotical ly active and dedifferentiated cells. J Clin Invest 1994, 93:21752188. 15. Basile DP, Liapis H, Hammerman MR: Expression of bcl-2 and bax in regenerating rat ren al tubules following ischemic injury. Am J Physiol 1997, 272:F640F647. 16. Matejk a GL, Jennische E: IGF-I binding and IGF-1 mRNA expression in the post-ischemic regenerating rat kidney. Kidney Int 1992, 42(5):11131123. 17. Ishibashi K, et al. : Expressions of receptor for hepatocyte growth factor in kidney after unilatera l nephrectomy and renal injury. Biochem Biophys Res Commun 1993, 187:14541459. 18 . Safirstein R, et al.: Changes in gene expression after temporary renal ischemi a. Kidney Int 1990, 37:15151521. 19. Basile DP, et al.: Increased transforming gr owth factor-beta 1 expression in regenerating rat renal tubules following ischem ic injury. Amer J Physiol 1996, 270:F500F509. 20. Padanilam BJ, Hammerman MR: Isc hemia-induced receptor for activated C kinase (RACK1) expression in rat kidneys. Amer J Physiol 1997, 272:F160F166. 21. Pombo CM, et al.: The stress-activated pr otein kinases are major c-Jun amino-terminal kinases activated by ischemia and r eperfusion. J Biol Chem 1994, 269:2654626551. 22. Safirstein R: Gene expression i n nephrotoxic and ischemic acute renal failure [editorial]. J Am Soc Nephrol 199 4, 4:13871395. 23. Safirstein R, Zelent AZ, Price PM: Reduced renal prepro-epider mal growth factor mRNA and decreased EGF excretion in ARF. Kid Int 1989, 36:81081 5. 24. Raju VS, Maines, MD: Renal ischemia/reperfusion up-regulates heme oxygena se-1 (HSP32) expression and increases cGMP in rat heart. J Pharmacol Exp Ther 19 96, 277:18141822. 25. Van Why SK, et al.: Induction and intracellular localizatio n of HSP-72 after renal ischemia. Am J Physiol 1992, 263:F769F775. 26. Padanilam BJ, Martin DR, Hammerman MR: Insulin-like growth factor Ienhanced renal expressio

n of osteopontin after acute ischemic injury in rats. Endocrinology 1996, 137:21 332140. 27. Walker PD: Alterations in renal tubular extracellular matrix componen ts after ischemia-reperfusion injury to the kidney. Lab Invest 1994, 70:339345. 2 8. Van Why SK, et al.: Expression and molecular regulation of Na+-K+ATPase after renal ischemia. Am J Physiol 1994, 267:F75F85. 29. Wang Z, et al.: Ischemic-repe rfusion injury in the kidney: overexpression of colonic H+-K+-ATPase and suppres sion of NHE-3. Kidney Int 1997, 51:11061115. 30. McKanna JA, et al.: Localization of p35 (annexin I, lipocortin I) in normal adult rat kidney and during recovery from ischemia. J Cell Physiol 1992, 153:46776. 31. Nakamura H, et al.: Subcellul ar characteristics of phospholipase A2 activity in the rat kidney. Enhanced cyto solic, mitochondrial, and microsomal phospholipase A2 enzymatic activity after r enal ischemia and reperfusion. J Clin Invest 1991, 87:18101818. 32. Lewington AJP , Padanilam BJ, Hammerman MR: Induction of calcyclin after ischemic injury to ra t kidney. Am J Physiol 1997, 273(42):F380F385.

Nutrition and Metabolism in Acute Renal Failure Wilfred Druml A dequate nutritional support is necessary to maintain protein stores and to corre ct pre-existing or disease-related deficits in lean body mass. The objectives fo r nutritional support for patients with acute renal failure (ARF) are not much d ifferent from those with other catabolic conditions. The principles of nutrition al support for ARF, however, differ from those for patients with chronic renal f ailure (CRF), because diets or infusions that satisfy minimal requirements in CR F are not necessarily sufficient for patients with ARF. In patients with ARF mod ern nutritional therapy must include a tailored regimen designed to provide subs trate requirements with various degrees of stress and hypercatabolism. If nutrit ion is provided to a patient with ARF the composition of the dietary program mus t be specifically designed because there are complex metabolic abnormalities tha t affect not only water, electrolyte, and acid-base-balance but also carbohydrat e, lipid, and protein and amino acid utilization. In patients with ARF the main determinants of nutrient requirements (and outcome) are not renal dysfunction pe r se but the degree of hypercatabolism caused by the disease associated with ARF , the nutritional state, and the type and frequency of dialysis therapy. Pre-exi sting or hospital-acquired malnutrition has been identified as an important cont ributor to the persisting high mortality in critically ill persons. Thus, with m odern nutritional support requirements must be met for all nutrients necessary f or preservation of lean body mass, immunocompetence, and wound healing for a pat ient who has acquired ARFin may instances among other complications. At the same time the specific metabolic alterations and demands in ARF and the impaired excr etory renal function must be respected to limit uremic toxicity. In this chapter the multiple metabolic alterations associated with ARF are reviewed, methods fo r estimating nutrient requirements are discussed and, current concepts for the t ype and composition of nutritional programs are summarized. This information is relevant for designing nutritional support in an individual patient with ARF. CHAPTER 18

18.2 Acute Renal Failure FIGURE 18-1 Nutritional goals in patients with acute renal failure (ARF). The go als of nutritional intervention in ARF differ from those in patients with chroni c renal failure (CRF): One should not provide a minimal intake of nutrients (to minimize uremic toxicity or to retard progression of renal failure, as recommend ed for CRF) but rather an optimal amount of nutrients should be provided for cor rection and prevention of nutrient deficiencies and for stimulation of immunocom petence and wound healing in the mostly hypercatabolic patients with ARF [1]. NUTRITION IN ACUTE RENAL FAILURE Goals Preservation of lean body mass Stimulation of wound healing and reparatory functions Stimulation of immunocompetence Acceleration of renal recovery (?) Bu t not (in contrast to stable CRF) Minimization of uremic toxicity (perform hemod ialysis and CRRT as required) Retardation of progression of renal failure Thus, provision of optimal but not minimal amounts of substrates METABOLIC PERTURBATIONS IN ACUTE RENAL FAILURE Determined by Renal dysfunction (acute uremic state) Underlying illness The acute disease stat e, such as systemic inflammatory response syndrome (SIRS) Associated complicatio ns (such as infections) Plus Specific effects of renal replacement therapy Nonspecific effects of extracorpor eal circulation (bioincompatibility) FIGURE 18-2 Metabolic perturbations in acute renal failure (ARF). In most instan ces ARF is a complication of sepsis, trauma, or multiple organ failure, so it is difficult to ascribe specific metabolic alterations to ARF. Metabolic derangeme nts will be determined by the acute uremic state plus the underlying disease pro cess or by complications such as severe infections and organ dysfunctions and, l ast but not least by the type and frequency of renal replacement therapy [1, 2]. Nevertheless, ARF does not affect only water, electrolyte, and acid base metabo lism: it induces a global change of the metabolic environment with specific alte rations in protein and amino acid, carbohydrate, and lipid metabolism [2]. Metabolic Alterations in Acute Renal Failure Energy metabolism FIGURE 18-3 Energy metabolism in acute renal failure (ARF). In experimental anim als ARF decreases oxygen consumption even when hypothermia and acidosis are corr ected (uremic hypometabolism) [3]. In contrast, in the clinical setting oxygen c onsumption of patients with various form of renal failure is remarkably little c hanged [4]. In subjects with chronic renal failure (CRF), advanced uremia (UA), patients on regular hemodialysis therapy (HD) but also in patients with uncompli cated ARF (ARFNS) resting energy expenditure (REE) was comparable to that seen i n controls (N). However, in patients with ARF and sepsis (ARFS) REE is increased by approximately 20%. Thus, energy expenditure of patients with ARF is more det ermined by the underlying disease than acute uremic state and taken together the se data indicate that when uremia is well-controlled by hemodialysis or hemofilt ration there is little if any change in energy metabolism in ARF. In contrast to many other acute disease processes ARF might rather decrease than increase REE because in multiple organ dysfunction syndrome oxygen consumption was significan tly higher in patients without impairment of renal function than in those with A RF [5]. (From Schneeweiss [4]; with permission.)

Nutrition and Metabolism in Acute Renal Failure 18.3 ESTIMATION OF ENERGY REQUIREMENTS Calculation of resting energy expenditure (REE) (Harris Benedict equation): Male s: 66.47 (13.75 BW) (5 height) (6.76 age) Females: 655.1 (9.56 BW) (1.85 height) (4.67 age) The average REE is approximately 25 kcal/kg BW/day Stress factors to correct calculated energy requirement for hypermetabolism: Postoperative (no co mplications) 1.0 Long bone fracture 1.151.30 Cancer 1.101.30 Peritonitis/sepsis 1. 201.30 Severe infection/polytrauma 1.201.40 Burns ( approxim. REE % burned body su rface area) 1.202.00 Corrected energy requirements (kcal/d) REE stress factor FIGURE 18-4 Estimation of energy requirements. Energy requirements of patients w ith acute renal failure (ARF) have been grossly overestimated in the past and en ergy intakes of more than 50 kcal/kg of body weight (BW) per day (ie, about 100% above resting energy expenditure (REE) haven been advocated [6]. Adverse effect s of overfeeding have been extensively documented during the last decades, and i t should be noted that energy intake must not exceed the actual energy consumpti on. Energy requirements can be calculated with sufficient accuracy by standard f ormulas such as the Harris Benedict equation. Calculated REE should be multiplie d with a stress factor to correct for hypermetabolic disease; however, even in h ypercatabolic conditions such as sepsis or multiple organ dysfunction syndrome, energy requirements rarely exceed 1.3 times calculated REE [1]. Protein metabolism FIGURE 18-5 Protein metabolism in acute renal failure (ARF): activation of prote in catabolism. Protein synthesis and degradation rates in acutely uremic and sha m-operated rats. The hallmark of metabolic alterations in ARF is activation of p rotein catabolism with excessive release of amino acids from skeletal muscle and sustained negative nitrogen balance [7, 8]. Not only is protein breakdown accel erated, but there also is defective muscle utilization of amino acids for protei n synthesis. In muscle, the maximal rate of insulin-stimulated protein synthesis is depressed by ARF and protein degradation is increased, even in the presence of insulin [9]. (From [8]; with permission.)

18.4 Acute Renal Failure FIGURE 18-6 Protein metabolism in acute renal failure (ARF): impairment of cellu lar amino acid transport. A, Amino acid transport into skeletal muscle is impair ed in ARF [10]. Transmembranous uptake of the amino acid analogue methyl-amino-i sobutyrate (MAIB) is reduced in uremic tissue in response to insulin (muscle tis sue from uremic animals, black circles, and from sham-operated animals, open cir cles, respectively). Thus, insulin responsiveness is reduced in ARF tissue, but, as can be seen from the parallel shift of the curves, insulin sensitivity is maintained (see also Fig. 18-14). This abn ormality can be linked both to insulin resistance and to a generalized defect in ion transport in uremia; both the activity and receptor density of the sodium p ump are abnormal in adipose cells and muscle tissue [11]. B, The impairment of r ubidium uptake (Rb) as a measure of Na-K-ATPase activity is tightly correlated t o the reduction in amino acid transport. (From [10,11]; with permission.) FIGURE 18-7 Protein catabolism in acute renal failure (ARF). Amino acids are red istributed from muscle tissue to the liver. Hepatic extraction of amino acids fr om the circulationhepatic gluconeogenesis, A, and ureagenesis, B, from amino acid s all are increased in ARF [12]. The dominant mediator of protein catabolism in ARF is this accelerated hepatic gluconeogenesis, which cannot be suppressed by exogenous substrat e infusions (see Fig. 18-15). In the liver, protein synthesis and secretion of a cute phase proteins are also stimulated. Circleslivers from acutely uremic rats; squareslivers from sham operated rats. (From Frhlich [12]; with permission.).

Nutrition and Metabolism in Acute Renal Failure 18.5 CONTRIBUTING FACTORS TO PROTEIN CATABOLISM IN ACUTE RENAL FAILURE Impairment of metabolic functions by uremia toxins Endocrine factors Insulin res istance Increased secretion of catabolic hormones (catecholamines, glucagon, glu cocorticoids) Hyperparathyroidism Suppression of release or resistance to growth factors Acidosis Systemic inflammatory response syndrome (activation of cytokin e network) Release of proteases Inadequate supply of nutritional substrates Loss of nutritional substrates (renal replacement therapy) FIGURE 18-8 Protein catabolism in acute renal failure (ARF): contributing factor s. The causes of hypercatabolism in ARF are complex and multifold and present a combination of nonspecific mechanisms induced by the acute disease process and u nderlying illness and associated complications, specific effects induced by the acute loss of renal function, and, finally, the type and intensity of renal repl acement therapy. A major stimulus of muscle protein catabolism in ARF is insulin resistance. In m uscle, the maximal rate of insulin-stimulated protein synthesis is depressed by ARF and protein degradation is increased even in the presence of insulin [9]. Ac idosis was identified as an important factor in muscle protein breakdown. Metabo lic acidosis activates the catabolism of protein and oxidation of amino acids in dependently of azotemia, and nitrogen balance can be improved by correcting the metabolic acidosis [13]. These findings were not uniformly confirmed for ARF in animal experiments [14]. Several additional catabolic factors are operative in A RF. The secretion of catabolic hormones (catecholamines, glucagon, glucocorticoi ds), hyperparathyroidism which is also present in ARF (see Fig. 18-22), suppress ion of or decreased sensitivity to growth factors, the release of proteases from activated leukocytesall can stimulate protein breakdown. Moreover, the release o f inflammatory mediators such as tumor necrosis factor and interleukins have bee n shown to mediate hypercatabolism in acute disease [1, 2]. The type and frequen cy of renal replacement therapy can also affect protein balance. Aggravation of protein catabolism, certainly, is mediated in part by the loss of nutritional su bstrates, but some findings suggest that, in addition, both activation of protei n breakdown and inhibition of muscular protein synthesis are induced by hemodial ysis [15]. Last (but not least), of major relevance for the clinical situation i s the fact that inadequate nutrition contributes to the loss of lean body mass i n ARF. In experimental animals, starvation potentiates the catabolic response of ARF [7]. FIGURE 18-9 Amino acid pools and amino acid utilization in acute renal failure ( ARF). As a consequence of these metabolic alterations, imbalances in amino acid pools in plasma and in the intracellular compartment occur in ARF. A typical pla sma amino acid pattern is seen [16]. Plasma concentrations of cysteine (CYS), ta urine (TAU), methionine (MET), and phenylalanine (PHE) are elevated, whereas pla sma levels of valine (VAL) and leucine (LEU) are decreased. Moreover, eliminatio n of amino acids from the intravascular space is altered. As expected from the s timulation of hepatic

extraction of amino acids observed in animal experiments, overall amino acid cle arance and clearance of most glucoplastic amino acids is enhanced. In contrast, clearances of PHE, proline (PRO), and, remarkably, VAL are decreased [16, 17]. A LA alanine; ARGarginine; ASNasparagine; ASPaspartate; CITcitrulline; GLNglutamine; GLU lutamate; GLY glycine; HIShistidine; ORNornithine; PROproline; SER serine; THRthreonin e; TRPtryptophan; TYRtyrosine. (From Druml et al. [16]; with permission.)

18.6 Acute Renal Failure sized or converted by the kidneys and released into the circulation: cysteine, m ethionine (from homocysteine), tyrosine, arginine, and serine [18]. Thus, loss o f renal function can contribute to the altered amino acid pools in ARF and to th e fact that several amino acids, such as arginine or tyrosine, which conventiona lly are termed nonessential, might become conditionally indispensable in ARF (se e Fig. 18-11) [19]. In addition, the kidney is an important organ of protein deg radation. Multiple peptides are filtered and catabolized at the tubular brush bo rder, with the constituent amino acids being reabsorbed and recycled into the me tabolic pool. In renal failure, catabolism of peptides such as peptide hormones is retarded. This is also true for acute uremia: insulin requirements decrease i n diabetic patients who develop of ARF [20]. With the increased use of dipeptide s in artificial nutrition as a source of amino acids (such as tyrosine and gluta mine) which are not soluble or stable in aqueous solutions, this metabolic funct ion of the kidney may also gain importance for utilization of these novel nutrit ional substrates. In the case of glycyl-tyrosine, metabolic clearance progressiv ely decreases with falling creatinine clearance (open circles, 7 healthy subject s and a patient with unilateral nephrectomy*) but extrarenal clearance in the ab sence of renal function (black circles) is sufficient for rapid utilization of t he dipeptide and release of tyrosine [21]. (From Druml et al. [21]; with permiss ion.) patients: histidine, arginine, tyrosine, serine, cysteine [19]. Infusion o f arginine-free amino acid solutions can cause life-threatening complications su ch as hyperammonemia, coma, and acidosis. Healthy subjects readily form tyrosine from phenylalanine in the liver: During infusion of amino acid solutions contai ning phenylalanine, plasma tyrosine concentration rises (circles) [22]. In contr ast, in patients with ARF (triangles) and chronic renal failure (CRF, squares) p henylalanine infusion does not increase plasma tyrosine, indicating inadequate i nterconversion. Recently, it was suggested that glutamine, an amino acid that tr aditionally was designated non-essential exerts important metabolic functions in regulating nitrogen metabolism, supporting immune functions, and preserving the gastrointestinal barrier. Thus, it can become conditionally indispensable in ca tabolic illness [23]. Because free glutamine is not stable in aqueous solutions, dipeptides containing glutamine are used as a glutamine source in parenteral nu trition. The utilization of dipeptides in part depends on intact renal function, and renal failure can impair hydrolysis (see Fig. 18-10) [24]. No systematic st udies have been published on the use of glutamine in patients with ARF, and it m ust be noted that glutamine supplementation increases nitrogen intake considerab ly. FIGURE 18-10 Metabolic functions of the kidney and protein and amino acid metabo lism in acute renal failure (ARF). Protein and amino acid metabolism in ARF are also affected by impairment of the metabolic functions of the kidney itself. Var ious amino acids are syntheFIGURE 18-11 Amino acids in nutrition of acute renal failure (ARF): Conditionall y essential amino acids. Because of the altered metabolic environment of uremic patients certain amino acids designated as nonessential for healthy subjects may become conditionally indispensable to ARF

Nutrition and Metabolism in Acute Renal Failure 18.7 Protein requirements ESTIMATING THE EXTENT OF PROTEIN CATABOLISM Urea nitrogen appearance (UNA) (g/d) Urinary urea nitrogen (UUN) excretion Chang e in urea nitrogen pool (UUN V) (BUN2 BUN1) 0.006 BW (BW2 BW1) BUN2/100 If there are substantial gastrointestinal losses, add urea nitrogen in secretions: volum e of secretions BUN2 Net protein breakdown (g/d) UNA 6.25 Muscle loss (g/d) UNA 6.25 5 V is urine volume; BUN1 and BUN2 are BUN in mg/dL on days 1 and 2 BW1 and BW2 are body weights in kg on days 1 and 2 FIGURE 18-12 Estimation of protein catabolism and nitrogen balance. The extent o f protein catabolism can be assessed by calculating the urea nitrogen appearance rate (UNA), because virtually all nitrogen arising from amino acids liberated d uring protein degradation is converted to urea. Besides urea in urine (UUN), nit rogen losses in other body fluids (eg, gastrointestinal, choledochal) must be ad ded to any change in the urea pool. When the UNA rate is multiplied by 6.25, it can be converted to protein equivalents. With known nitrogen intake from the par enteral or enteral nutrition, nitrogen balance can be estimated from the UNA cal culation. FIGURE 18-13 Amino acid and protein requirements of patients with acute renal fa ilure (ARF). The optimal intake of protein or amino acids is affected more by th e nature of the underlying cause of ARF and the extent of protein catabolism and type and frequency of dialysis than by kidney dysfunction per se. Unfortunately , only a few studies have attempted to define the optimal requirements for prote in or amino acids in ARF: In nonhypercatabolic patients, during the polyuric pha se of ARF protein intake of 0.97 g/kg body weight per day was required to achiev e a positive nitrogen balance [25]. A similar number (1.03g/kg body weight per day) was derived from a study in which, unfortunately, energy in take was not kept constant [6]. In the polyuric recovery phase in patients with sepsis-induced ARF, a nitrogen intake of 15 g/day (averaging an amino acid intak e of 1.3 g/kg body weight per day) as compared to 4.4 g/kg per day (about 0.3 g/ kg amino acids) was superior in ameliorating nitrogen balance [26]. Several rece nt studies have tried to evaluate protein and amino acid requirements of critica lly ill patients with ARF. Kierdorf and associates found that, in these hypercat abolic patients receiving continuous hemofiltration therapy, the provision of am ino acids 1.5 g /kg body weight per day was more effective in reducing nitrogen loss than infusion of 0.7 g ( 3.4 versus 8.1 g nitrogen per day) [27]. An increa se of amino acid intake to 1. 74 g/kg per day did not further ameliorate nitroge n balance. Chima and coworkers measured a mean PCR of 1.7 g kg body weight per d ay in 19 critically ill ARF patients and concluded that protein needs in these p atients range between 1.4 and 1.7 g/kg per day [28]. Similarly, Marcias and cowo rkers have obtained a protein catabolic rate (PCR) of 1.4 g/kg per day and found an inverse relationship between protein and energy provision and PCR and again recommended protein intake of 1.5 to 1.8 g/kg per day [29]. Similar conclusions were drawn by Ikitzler in evaluating ARF patients on intermittent hemodialysis t herapy [30]. (From Kierdorf et al. [27]; with permission.)

18.8 Acute Renal Failure Glucose metabolism FIGURE 18-14 Glucose metabolism in acute renal failure (ARF): Peripheral insulin resistance. ARF is commonly associated with hyperglycemia. The major cause of e levated blood glucose concentrations is insulin resistance [31]. Plasma insulin concentration is elevated. Maximal insulin-stimulated glucose uptake by skeletal muscle is decreased by 50 %, A, and muscular glycogen synthesis is impaired, B. However, insulin concentrations that cause half-maximal stimulation of glucose uptake are normal, pointing to a postreceptor defect rather than impaired insulin sensitivity as the cause of defective glucose metabolism. The factors contributing to insulin resistance are more or less identical to tho se involved in the stimulation of protein breakdown (see Fig. 18-8). Results fro m experimental animals suggest a common defect in protein and glucose metabolism : tyrosine release from muscle (as a measure of protein catabolism) is closely c orrelated with the ratio of lactate release to glucose uptake [9]. (From May et al. [31]; with permission.) FIGURE 18-15 Glucose metabolism in acute renal failu re (ARF): Stimulation of hepatic gluconeogenesis. A second feature of glucose me tabolism (and at the same time the dominating mechanism of accelerated protein b reakdown) in ARF is accelerated hepatic gluconeogenesis, mainly from conversion of amino acids released during protein catabolism. Hepatic extraction of amino a cids, their conversion to glucose, and urea production are all increased in ARF (see Fig. 18-7) [12]. In healthy subjects, but also in patients with chronic ren al failure, hepatic gluconeogenesis from amino acids is readily and completely s uppressed by exogenous glucose infusion. In contrast, in ARF hepatic glucose for mation can only be decreased, but not halted, by substrate supply. As can be see n from this experimental study, even during glucose infusion there is persistent gluconeogenesis from amino acids in acutely uremic dogs () as compared with cont rols dogs (o) whose livers switch from glucose release to glucose uptake [32]. T hese findings have important implications for nutrition support for patients wit h ARF: 1) It is impossible to achieve positive nitrogen balance; 2) Protein cata bolism cannot be suppressed by providing conventional nutritional substrates alo ne. Thus, for future advances alternative means must be found to effectively sup press protein catabolism and preserve lean body mass. (From Cianciaruso et al. [ 32]; with permission.)

Nutrition and Metabolism in Acute Renal Failure 18.9 Lipid metabolism FIGURE 18-16 Lipid metabolism in acute renal failure (ARF). Profound alterations of lipid metabolism occur in patients with ARF. The triglyceride content of pla sma lipoproteins, especially very low-density (VLDL) and low-density ones (LDL) is increased, while total cholesterol and in particular high-density lipoprotein (HDL) cholesterol are decreased [33,34]. The major cause of lipid abnormalities in ARF is impairment of lipolysis. The activities of both lipolytic systems, pe ripheral lipoprotein lipase and hepatic triglyceride lipase are decreased in pat ients with ARF to less than 50% of normal [35]. Maximal postheparin lipolytic ac tivity (PHLA), hepatic triglyceride lipase (HTGL), and peripheral lipoprotein li pase (LPL) in 10 controls (open bars) and eight subjects with ARF (black bars). However, in contrast to this impairment of lipolysis, oxidation of fatty acids i s not affected by ARF. During infusion of labeled long-chain fatty acids, carbon dioxide production from lipid was comparable between healthy subjects and patie nts with ARF [36]. FFAfree fatty acids. (Adapted from Druml et al. [35]; with per mission.) FIGURE 18-17 Impairment of lipolysis and elimination of artificial lip id emulsions in acute renal failure (ARF). Fat particles of artificial fat emuls ions for parenteral nutrition are degraded as endogenous very low-density lipopr otein is. Thus, the nutritional consequence of the impaired lipolysis in ARF is delayed elimination of intravenously infused lipid emulsions [33, 34]. The incre ase in plasma triglycerides during infusion of a lipid emulsion is doubled in pa tients with ARF (N=7) as compared with healthy subjects (N=6). The clearance of fat emulsions is reduced by more than 50% in ARF. The impairment of lipolysis in ARF cannot be bypassed by using medium-chain triglycerides (MCT); the eliminati on of fat emulsions containing long chain triglycerides (LCT) or MCT is equally retarded in ARF [34]. Nevertheless, the oxydation of free fatty acid released fr om triglycerides is not inpaired in patients with ARF [36]. (From Druml et al. [ 34]; with permission.)

18.10 Acute Renal Failure Electrolytes and micronutrients CAUSES OF ELECTROLYTE DERANGEMENTS IN ACUTE RENAL FAILURE Hyperkalemia Decreased renal elimination Increased release during catabolism 2.38 mEq/g nitro gen 0.36 mEq/g glycogen Decreased cellular uptake/ increased release Metabolic a cidosis: 0.6 mmol/L rise/0.1 decrease in pH Hyperphosphatemia Decreased renal elimination Increased release from bone Increased release during catabolism: 2 mmol/g nitrogen Decreased cellular uptake/utilization and/or incr eased release from cells FIGURE 18-18 Electrolytes in acute renal failure (ARF): causes of hyperkalemia a nd hyperphosphatemia. ARF frequently is associated with hyperkalemia and hyperph osphatemia. Causes are not only impaired renal excretion of electrolytes but rel ease during catabolism, altered distribution in intracellular and extracellular spaces, impaired cellular uptake, and acidosis. Thus, the type of underlying dis ease and degree of hypercatabolism also determine the occurrence and severity of electrolyte abnormalities. Either hypophosphatemia or hyperphosphatemia can pre dispose to the development and maintenance of ARF [37]. FIGURE 18-19 Electrolytes in acute renal failure (ARF): hypophosphatemia and hyp okalemia. It must be noted that a considerable number of patients with ARF do no t present with hyperkalemia or hyperphosphatemia, but at least 5% have low serum potassium and more than 12% have decreased plasma phosphate on admission [38]. Nutritional support, especially parenteral nutrition with low electrolyte conten t, can cause hypophosphatemia and hypokalemia in as many as 50% and 19% of patie nts respectively [39,40]. In the case of phosphate, phosphate-free artificial nu trition causes hypophosphatemia within a few days, even if the patient was hyper phosphatemic on admission (black circles) [41]. Supplementation of 5 mmol per da y was effective in maintaining normal plasma phosphate concentrations (open squa res), whereas infusion of more than 10 mmol per day resulted in hyperphosphatemi a, even if the patients had decreased phosphate levels on admission (open circle s). Potassium or phosphate depletion increases the risk of developing ARF and re tards recovery of renal function. With modern nutritional support, hyperkalemia is the leading indication for initiation of extracorporeal therapy in fewer than 5% of patients [38]. (Adapted from Kleinberger et al. [41]; with permission.) FIGURE 18-20 Micronutrients in acute renal failure (ARF): water-soluble vitamins . Balance studies on micronutrients (vitamins, trace elements) are not available for ARF. Because of losses associated with renal replacement therapy, requireme nts for water-soluble vitamins are expected to be increased also in patients wit h ARF. Malnutrition with depletion of vitamin body stores and associated hyperca tabolic underlying disease in ARF can further increase the need for vitamins. De pletion of thiamine (vitamin B1) during continuous hemofiltration and inadequate intake can result in lactic acidosis and heart failure [42]. This figure depict s the evolution of plasma lactate concentration before and after administration of 600 mg thiamine in two patients. Infusion of 600 mg of thiamine reversed the metabolic abnormality within a few hours. An exception to this approach to treat ment is ascorbic acid (vitamin C); as a precursor of oxalic acid the intake shou ld be kept below 200 mg per day because any excessive supply may precipitate sec ondary oxalosis [43]. (From Madl et al. [42]; with permission.)

Nutrition and Metabolism in Acute Renal Failure 18.11 FIGURE 18-21 Micronutrients in acute renal failure (ARF): fat-soluble vitamins ( A, E, K). Despite the fact that fat-soluble vitamins are not lost during hemodia lysis and hemofiltration, plasma concentrations of vitamins A and E are depresse d in patients with ARF and requirements are increased [44]. Plasma concentration s of vitamin K (with broad variations of individual values) are normal in ARF. M ost commercial multivitamin preparations for parenteral infusions contain the re commended daily allowances of vitamins and can safely be used in ARF patients. ( From Druml et al. [44]; with permission.) FIGURE 18-22 Hypocalcemia and the vitamin Dparathyroid hormone (PTH) axis in acut e renal failure (ARF). ARF is also frequently associated with hypocalcemia secon dary to hypoalbuminemia, elevated serum phosphate, plus skeletal resistance to c alcemic effect of PTH and impairment of vitamin-D activation. Plasma concentrati on of PTH is increased. Plasma concentrations of vitamin D metabolites, 25-OH vi tamin D3 and 1,25-(OH)2 vitamin D3, are decreased [44]. In ARF caused by rhabdom yolysis rebound hypercalcemia may develop during the diuretic phase. (Adapted fr om Druml et al. [44]; with permission.) FIGURE 18-23 Micronutrients in acute ren al failure (ARF): antioxidative factors. Micronutrients are part of the organism's defense mechanisms against oxygen free radical induced injury to cellular compo nents. In experimental ARF, antioxidant deficiency of the organism (decreased vi tamin E or selenium status) exacerbates ischemic renal injury, worsens the cours e, and increases mortality, whereas repletion of antioxidant status exerts the o pposite effect [45]. These data argue for a crucial role of reactive oxygen spec ies and peroxidation of lipid membrane components in initiating and mediating is chemia or reperfusion injury. In patients with multiple organ dysfunction syndro me and associated ARF (lightly shaded bars) various factors of the oxygen radica l scavenger system are profoundly depressed as compared with healthy subjects (b lack bars): plasma concentrations of vitamin C, of -carotene, vitamin E, seleniu m, and glutathione all are profoundly depressed, whereas the end-product of lipi d peroxidation, malondialdehyde, is increased (double asterisk, P < 0.01; triple asterisk, P < 0.001). This underlines the importance of supplementation of anti oxidant micronutrients for patients with ARF. (Adapted from Druml et al. [46]; w ith permission.)

18.12 Acute Renal Failure Metabolic Impact of Renal Replacement Therapy METABOLIC EFFECTS OF CONTINUOUS RENAL REPLACEMENT THERAPY Amelioration of uremia intoxication (renal replacement) Plus Heat loss Excessive load of substrates (eg, lactate, glucose) Loss of nutrients (eg, amino acids, v itamins) Elimination of short-chain proteins (hormones, mediators?) Induction or activation of mediator cascades Stimulation of protein catabolism? FIGURE 18-24 Metabolic impact of extracorporeal therapy. The impact of hemodialy sis therapy on metabolism is multifactorial. Amino acid and protein metabolism a re altered not only by substrate losses but also by activation of protein breakd own mediated by release of leukocyte-derived proteases, of inflammatory mediator s (interleukins and tumor necrosis factor) induced by blood-membrane interaction s or endotoxin. Dialysis can also induce inhibition of muscle protein synthesis [15]. In the management of patients with acute renal failure (ARF), continuous r enal replacement therapies (CRRT), such as continuous (arteriovenous) hemofiltration (CHF) and continuous hemodialysis have gained wid e popularity. CRRTs are associated with multiple metabolic effects in addition t o renal replacement [47]. By cooling of the extracorporeal circuit and infusion of cooled substitution fluids, CHF may induce considerable heat loss (350 to 700 k cal per day). On the other hand, hemofiltration fluids contain lactate as anions , oxidation of which in part compensates for the heat loss. This lactate load ca n result in hyperlactemia in the presence of liver dysfunction or increased endo genous lactate formation such as in circulatory shock. Several nutrients with lo w protein binding and small molecular weight (sieving coefficient 0.8 to 1.0), s uch as vitamins or amino acids are eliminated during therapy. Amino acid losses can be estimated from the volume of the filtrate and average plasma concentratio n, and usually this accounts for a loss of approximately 0.2 g/L of filtrate and , depending on the filtered volume, 5 to 10 g of amino acid per day, respectivel y, representing about 10 % of amino acid input, but it can be even higher during continuous hemodiafiltration [48]. With the large molecular size cut-off of mem branes used in hemofiltration, small proteins such as peptide hormones are filte red. In view of their short plasma half-life hormone losses are minimal and prob ably not of pathophysiologic importance. Quantitatively relevant elimination of mediators by CRRT has not yet been proven. On the other hand, prolonged blood-me mbrane interactions can induce consequences of bioincompatibility and activation of various endogenous cascade systems. Nutrition, Renal Function, and Recovery FIGURE 18-25 A, B, Impact of nutritional interventions on renal function and cou rse of acute renal failure (ARF). Starvation accelerates protein breakdown and i mpairs protein synthesis in the kidney, whereas refeeding exerts the opposite ef fects [49]. In experimental animals, provision of amino acids or total parentera l nutrition accelerates tissue repair and recovery of renal function [50]. In pa tients, however, this has been much more difficult to prove, and only one study has reported on a positive effect of TPN on the resolution of ARF [51]. Infusion of amino acids raised renal cortical protein synthesis as evaluated by 14C-leucine incorporation and depressed protein breakdown in rats with mercuric chlorideinduced ARF [49]. On the other hand, in a similar model of ARF, infusions of varying quantities of essential amino acids (EAA) and nonessential amino aci ds (NEAA) did not provide any protection of renal function and in fact increased mortality [52]. However, in balance available evidence suggests that provision of substrates may enhance tissue regeneration and wound healing, and potentially , also renal tubular repair [49]. (From Toback et al. [50]; with permission.)

Nutrition and Metabolism in Acute Renal Failure 18.13 FIGURE 18-26 Impact of nutritional interventions on renal function in acute rena l failure (ARF). Amino acid infused before or during ischemia or nephrotoxicity may enhance tubule damage and accelerate loss of renal function in rat models of ARF. In part, this therapeutic paradox [53] from amino acid alimentation in ARF is related to the increase in metabolic work for transport processes when oxyge n supply is limited, which may aggravate ischemic injury [54]. Similar observati ons have been made with excess glucose infusion during renal ischemia. Amino aci ds may as well exert a protective effect on renal function. Glycine, and to a le sser degree alanine, limit tubular injury in ischemic and nephrotoxic models of ARF [55]. Arginine (possibly by producing nitric oxide) reportedly acts to prese rve renal perfusion and tubular function in both nephrotoxic and ischemic models of ARF, whereas inhibitors of nitric oxide synthase exert an opposite effect [5 6,57]. In myoglobininduced ARF the drop in renal blood flow (black circles, ARF controls) is prevented by L-arginine infusion (black triangles) [57]. (From Waka bayashi et al. [57]; with permission.) FIGURE 18-27 Impact of endocrine-metabolic interventions on renal function and c ourse of acute renal failure (ARF). Various other endocrine-metabolic interventi ons (eg, thyroxine, human growth hormone [HGH], epidermal growth factor, insulin -like growth factor 1 [IGF-1]) have been shown to accelerate regeneration after experimental ARF [51]. In a rat model of postischemic ARF, treatment with IGF-1 starting 5 hours after induction of ARF accelerates recovery from ischemic ARF, A, but also reduces the increase in BUN and improves nitrogen bala nce, B, [58]. (open circles) ARF plus vehicle; (black circles, sham-operated rat s plus vehicle; open squares, ARF plus rhIGF-I; black squares, sham operated rat s plus rhIGFI.) Unfortunately, efficacy of these interventions was not uniformly confirmed in clinical studies [59, 60]. (From Ding et al. [58]; with permission .)

18.14 Acute Renal Failure Decision Making, Patient Classification, and Nutritional Requirements DECISIONS FOR NUTRITION IN PATIENTS WITH ACUTE RENAL FAILURE Decisions dependent on Patients ability to resume oral diet (within 5 days?) Nut ritional status Underlying illness/degree of associated hypercatabolism 1. What patient with acute renal failure needs nutritional support? 2. When should nutri tional support be initiated? 3. At what degree of impairment in renal function s hould the nutritional regimen be adapted for renal failure? 4. In a patient with multiple organ dysfunction, which organ determines the type of nutritional supp ort? 5. Is enteral or parenteral nutrition the most appropriate method for provi ding nutritional support? FIGURE 18-28 Nutrition in patients with acute renal failure (ARF): decision maki ng. Not every patient with ARF requires nutritional support. It is important to identify those who will benefit and to define the optimal time to initiate thera py [1]. The decision to initiate nutritional support is influenced by the patien t's ability to cover nutritional requirements by eating, in addition to the nutrit ional status of the patient as well as the type of underlying illness involved. In any patient with evidence of malnourishment, nut ritional therapy should be instituted regardless of whether the patient will be likely to eat. If a well-nourished patient can resume a normal diet within 5 day s, no specific nutritional support is necessary. The degree of accompanying cata bolism is also a factor. For patients with underlying diseases associated with e xcess protein catabolism, nutritional support should be initiated early. If ther e is evidence of malnourishment or hypercatabolism, nutritional therapy should b e initiated early, even if the patient is likely to eat before 5 days. Modern nu tritional strategies should be aimed at avoiding the development of deficiency s tates and of hospitalacquired malnutrition. During the acute phase of ARF (the fir st 24 hours after trauma or surgery) nutritional support should be withheld beca use nutrients infused during this ebb phase are not utilized, could increase oxyge n requirements, and aggravate tissue injury and renal dysfunction. The nutrition al regimen should be adapted for renal failure when renal function is impaired. The multiple metabolic alterations characteristic of ARF occur when kidney funct ion is below 30% of normal. Thus, when creatinine clearance falls below 50 to 30 mL per minute/1.73 m2 (or serum creatinine rises above 2.5 to 3.0 mg/dL) the nu tritional regimen should be adapted to ARF. With the exception of severe hepatic failure and massively deranged amino acid metabolism (hyperammonemia) or protei n synthesis (depletion of coagulation factors) renal failure is the major determ inant of the nutritional regimen in patients with multiple organ dysfunction. En teral feeding is preferred for all patients, including those with ARF. Neverthel ess, for a large portion of patients, parenteral nutritiontotal or partialwill be necessary to meet nutritional requirements.

Nutrition and Metabolism in Acute Renal Failure 18.15 PATIENT CLASSIFICATION AND SUBSTRATE REQUIREMENTS IN PATIENTS WITH ACUTE RENAL F AILURE Extent of Catabolism Mild Excess urea appearance (above nitrogen intake) Clinical setting (examples) lity Dialysis or hemofiltration frequency Route of nutrient administration y recommendations (kcal/kg BW/d) Energy substrates Glucose (g/kg BW/d) Fat BW/d) Amino acids/protein (g/kg/d) Nutrients used >6 g Drug toxicity 20 % Oral 25 Glucose 3.05.0 0.61.0 EAA ( NEAA) Foods Morta Energ (g/kg Rare

Moderate 612 g Elective surgery infection 60% As needed Enteral or parenteral 2530 Glucose + fat 3.05.0 0.51.0 0.81.2 EAA NEAA Enteral formulas Glucose 50%70% fat emulsions 10 % or 20% Severe >12 g Severe injury or sepsis >80% Frequent Enteral or parenteral 2535 Glucose fa t 3.05.0 (max. 7.0) 0.81.5 1.01.5 EAA NEAA Enteral formulas Glucose 50%70% + fat emu lsions 10% or 20% EAA + specific NEAA solutions (general or nephro) Multivitamin and multitrace elem ent preparations BWbody weight; EAAessential amino acids; NEAAnonessential amino ac ids. FIGURE 18-29 Patient classification: substrate requirements. Ideally, a nutritio nal program should be designed for each individual acute renal failure (ARF) pat ient. In clinical practice, it has proved useful to distinguish three groups of patients based on the extent of protein catabolism associated with the underlyin g disease and resulting levels of dietary requirements. Group I includes patient s without excess catabolism and a UNA of less than 6 g of nitrogen above nitroge n intake per day. ARF is usually caused by nephrotoxins (aminoglycosides, contra st media, mismatched blood transfusion). In most cases, these patients are fed o rally and the prognosis for recovery of renal function and survival is excellent . Group II consists of patients with moderate hypercatabolism and a UNA exceedin g nitrogen intake 6 to 12 g of nitrogen per day. Affected patients frequently su ffer from complicating infections, peritonitis, or moderate injury in associatio n with ARF. Tube feeding or intravenous nutritional support is generally require d, and dialysis or hemofiltration often becomes necessary to limit waste product accumulation. Group III are patients who develop ARF in association with severe trauma, burns, or overwhelming infection. UNA is markedly elevated (more than 1 2 g of nitrogen above nitrogen intake). Treatment strategies are usually complex and include parenteral nutrition, hemodialysis or continuous hemofiltration plu s blood pressure and ventilatory support. To reduce catabolism and avoid protein depletion nutrient requirements are high and dialysis is used to maintain fluid balance and blood urea nitrogen below 100 mg/dL. Mortality in this group of pat ients exceeds 60% to 80%, but it is not the loss of renal function that accounts for the poor prognosis. It is superimposed hypercatabolism and the severity of the underlying illness. (Adapted from Druml [1]; with permission.)

18.16 Acute Renal Failure Enteral Nutrition FIGURE 18-30 Enteral nutrition (tube feeding). The gastrointestinal tract should be used whenever possible because enteral nutrients may help to maintain gastro intestinal function and the mucosal barrier and thus prevent translocation of ba cteria and systemic infection [61]. Even small amounts of enteral diets exert a protective effect on the intestinal mucosa. Recent animal experiments suggest th at enteral feeds may exert additional advantages in acute renal failure (ARF) pa tients [63]: in glycerol-induced ARF in rats enteral feeding improved renal perf usion, A, and preserved renal function, B. For patients with ARF who are unable to eat because of cerebral impairment, anorexia, or nausea, enteral nutrition sh ould be provided through small, soft feeding tubes with the tip positioned in th e stomach or jejunum [61]. Feeding solutions can be administered by pump intermi ttently or continuously. If given continuously, the stomach should be aspirated every 2 to 4 hours until adequate gastric emptying and intestinal peristalsis ar e established. To avoid diarrhea, the amount and concentration of the solution s hould be increased gradually over several days until nutritional requirements ar e met. Undesired, but potentially treatable side effects include nausea, vomitin g, abdominal distension and cramping and diarrhea. (From Roberts et al. [62]; wi th permission.)

Nutrition and Metabolism in Acute Renal Failure 18.17 SPECIFIC ENTERAL FORMULAS FOR NUTRITIONAL SUPPORT OF PATIENTS WITH RENAL FAILURE Travasorb renal* 1050 1400 1.35 7:12:81 389:1 24.0 60 30 3.6 284 100 18.6 30 18 70 363 590 16.1 a b Amin-Aid Volume (mL) Calories (kcal) (cal/mL) Energy distribution Protein:fat:carbohydrat es (%) kcal/g N Proteins (g) EAA (%) NEAA (%) Hydrolysate (%) Full protein (%) N itrogen (g) Carbohydrates (g) Monodisaccharides (%) Oligosaccharides (%) Polysac charides (%) Fat (g) LCT (%) Essential GA (%) MCT (%) Nonprotein (cal/g N) Osmol (mOsm/kg) Sodium (mmol/L) Potassium (mmol/L) Phosphate (mmol) Vitamins Minerals 750 1467 1.96 4:21:75 832:1 14.6 100 1.76 274 100 34.6 Salvipeptide nephro 500 1000 2.00 8:22:70 313:1 20.0 23 20 23 34 3.2 175 3 28 69 24 50 31 50 288 507 7.2 1.5 6.13 a a Survimed renal 1000 1320 1.32 6:10:84 398:1 20.8 Suplena 500 1000 2.00 6:43:51 418:1 15.0 Nepro 500 1000 2.00 14:43:43 179:1 35 100 3.32 276 100 2.4 128 10 100 5.6 108 12 90 47.8 100 0 154 615 34.0 28.5 11.0 a a 88 15.2 52 30 374 600 15.2 8 6.4 a a 502 1095 11 b b 48 100 22 0 393 635 32 27.0 11.0 a a * 3 bags 810 mL 1050 mL component I component II 350 mL = 500 mL 4 bags 800 mL 1 000 mL Liquid formula, cans 8 fl oz ( 237.5 mL), supplemented with carnitine, ta urine with a low-protein (Suplena) or moderate-protein content (Nepro) a 2000 kc al/d meets RDA for most vitamins/trace elements b Must be added EAAessential amin o acids; FAfatty acids; LCTlong-chain triglycerides; MCTmedium-chain triglycerides; Nnitrogen; NEAAnon-essential amino acids. FIGURE 18-31 Enteral feeding formulas. There are standardized tube feeding formu las designed for subjects with normal renal function that can also be given to p atients with acute renal failure (ARF). Unfortunately, the fixed composition of nutrients, including proteins and high content of electrolytes (especially potas sium and phosphate) often limits their use for ARF. Alternatively, enteral feedi ng formulas designed for nutritional therapy of patients with chronic renal fail ure (CRF) can be used. The preparations listed here may have advantages also for patients with ARF. The protein content is lower and is confined to highquality proteins ( in part as oligopeptides and free amino acids), the electrolyte concentrations a

re restricted. Most formulations contain recommended allowances of vitamins and minerals. In part, these enteral formulas are made up of components that increas e the flexibility in nutritional prescription and enable adaptation to individua l needs. The diets can be supplemented with additional electrolytes, protein, an d lipids as required. Recently, ready-touse liquid diets have also become availa ble for renal failure patients.

18.18 Acute Renal Failure Parenteral Nutrition RENAL FAILURE FLUIDALL-IN-ONE SOLUTION Component Glucose 40%70% Fat emulsion 10%20% Amino acids 6.5%10% Water-soluble vitamins Fat-s oluble vitamins* Trace elements* Electrolytes Insulin Quantity 500 mL 500 mL 500 mL Daily Daily Twice weekly As required As required Remarks In the presence of severe insulin resistance switch to D30W Start with 10%, swit ch to 20% if triglycerides are < 350 mg/dL General or special nephro amino acid so lutions, including EAA and NEAA Limit vitamin C intake < 200 mg/d Caveats: toxic effects Caveats: hypophosphatemia or hypokalemia after initiation of TPN Added directly to the solution or given separately * Combination products containing the recommended daily allowances. FIGURE 18-32 Parenteral solutions. Standard solutions are available with amino a cids, glucose, and lipids plus added vitamins, trace elements, and electrolytes contained in a single bag (total admixture solutions, all-in-one solutions). The sta bility of fat emulsions in such mixtures should be tested. If hyperglycemia is p resent, insulin can be added to the solution or administered separately. To ensu re maximal nutrient utilization and avoid metabolic derangements as mineral imba lance, hyperglycemia or blood urea nitrogen rise, the infusion should be started at a slow rate (providing about 50% of requirements) and gradually increased ov er several days. Optimally, the solution should be infused continuously over 24 hours to avoid marked derangements in substrate concentrations in the presence o f impaired utilization for several nutritional substrates in patients with acute renal failure. EAA, NEAAessential and nonessential amino acids; TPNtotal parenter al nutrition.

Nutrition and Metabolism in Acute Renal Failure 18.19 AMINO ACID SOLUTIONS FOR THE TREATMENT OF ACUTE RENAL FAILURE (NEPHRO SOLUTIONS) Aminess (Clintec) 52 5.2 400 416 8.3 5.25 8.25 6.00 8.25 8.25 3.75 1.88 Rose-Requirements Amino acids (g/L) ( g/%) Volume (mL) (mOsm/L) Nitrogen (g/L) Essential amino aci ds (g/L) Isoleucine Leucine Lysine acetate/HCl Methionine Phenylalanine Threonin e Tryptophan Valine Nonessential amino acids (g/L) Alanine Arginine Glycine Hist idine Proline Serine Tyrosine Cysteine * Glycine is a componenet of the dipeptid e. Tyrosine is included as dipeptide (glycyl-L-tyrosine). RenAmin (Clintec) 65 6.5 500 600 10 Aminosyn RF (Abbott) 52 5.2 1000 475 8.3 4.62 7.26 5.35 7.26 7.26 3.30 1.60 5.20 NephrAmine (McGaw) 54 5.4 1000 435 6.5 5.60 8.80 6.40 8.80 8.80 4.00 2.00 6.40 Nephrotect (Fresenius) 100 10 500 908 16.3 5.80 12.80 12.00 2.00 3.50 8.20 3.00 8.70 6.20 8.20 6.30* 9. 80 3.00 7.60 3.00 0.40 1.40 2.20 1.60 2.20 2.20 1.00 0.50 1.60 5.00 6.00 4.50 5.00 4.90 3.80 1.60 8.20 5.60 6.30 3.00 4.20 3.50 3.00 0.40 6.00 4.12 6.00 4.29 2.50 0.20 FIGURE 18-33 Amino acid (AA) solutions for parenteral nutrition in acute renal f ailure (ARF). The most controversial choice regards the type of amino acid solut ion to be used: either essential amino acids (EAAs) exclusively, solutions of EA A plus nonessential amino acids (NEAAs), or specially designed nephro solutions of different proportions of EAA and specific NEAA that might become conditionally e ssential for ARF (see Fig. 18-11). Use of solutions of EAA alone is based on prin ciples established for treating chronic renal failure (CRF) with a low-protein d iet and an EAA supplement. This may be inappropriate as the metabolic adaptation s to low-protein diets in response to CRF may not have occurred in patients with ARF. Plus, there are fundamental differences in the goals of nutritional therap y in the two groups of patients, and consequently, infusion solutions of EAA may be sub-optimal. Thus, a solution should be chosen that includes both essential and nonessential amino acids (EAA, NEAA) in standard proportions or in special proportions designed to counteract the metabolic changes of renal failure (nephro solutions), including the amino acids that might become cond itionally essential in ARF. Because of the relative insolubility of tyrosine in water, dipeptides containing tyrosine (such as glycyl-tyrosine) are contained in modern nephro solutions as the tyrosine source [22, 23]. One should be aware of the fact that the amino acid analogue N-acetyl tyrosine, which previously was u sed frequently as a tyrosine source, cannot be converted into tyrosine in humans

and might even stimulate protein catabolism [21]. Despite considerable investig ation, there is no persuasive evidence that amino acid solutions enriched in bra nched-chain amino acids exert a clinically significant anticatabolic effect. Sys tematic studies using glutamine supplementation for patients with ARF are lackin g (see Fig. 18-11).

18.20 Acute Renal Failure FIGURE 18-34 Energy substrates in total parenteral nutrition (TPN) in acute rena l failure (ARF): glucose and lipids. Because of the well-documented effects of o verfeeding, energy intake of patients with ARF must not exceed their actual ener gy expenditure (ie, in most cases 100% to 130% of resting energy expenditure [RE E]; see Figs. 18-3 and 18-4) [2]. Glucose should be the principal energy substra te because it can be utilized by all organs, even under hypoxic conditions, and has the potential for nitrogen sparing. Since ARF impairs glucose tolerance, ins ulin is frequently necessary to maintain normoglycemia. Any hyperglycemia must b e avoided because of the untoward associated side effectssuch as aggravation of t issue injury, glycation of proteins, activation of protein catabolism, among oth ers [2]. When intake is increased above 5 g/kg of body weight per day infused gl ucose will not be oxidized but will promote lipogenesis with fatty infiltration of the liver and excessive carbon dioxide production and hypercarbia. Often, ene rgy requirements cannot be met by glucose infusion without adding large amounts of insulin, so a portion of the energy should be supplied by lipid emulsions [2] . The most suitable means of providing the energy substrates for parenteral nutr ition for patients with ARF is not glucose or lipids, but glucose and lipids [2] . In experimental uremia in rats, TPN with 30% of nonprotein energy as fat promo ted weight gain and ameliorated the uremic state and survival [63]. (From Wennbe rg et al. [63]; with permission.) FIGURE 18-35 Energy substrates in parenteral n utrition: lipid emulsions. Advantages of intravenous lipids include high specifi c energy content, low osmolality, provision of essential fatty acids and phospho lipids to prevent deficiency syndromes, fewer hepatic side effects (such as stea tosis, hyperbilirubinemia), and reduced carbon dioxide production, especially re levant for patients with respiratory failure. Changes in lipid metabolism associ ated with acute renal failure (ARF) should not prevent the use of lipid emulsion s. Instead, the amount infused should be adjusted to meet the patient's capacity t o utilize lipids. Usually, 1 g/kg of body weight per day of fat will not increas e plasma triglycerides substantially, so about 20% to 25% of energy requirements can be met [1]. Lipids should not be administered to patients with hyperlipidem ia (ie, plasma triglycerides above 350 mg/dL) activated intravascular coagulatio n, acidosis (pH below 7.25), impaired circulation or hypoxemia. Parenteral lipid emulsions usually contain long-chain triglycerides (LCT), most derived from soy bean oil. Recently, fat emulsions containing a mixture of LCT and medium-chain t riglycerides (MCT) have been introduced for intravenous use. Proposed advantages include faster elimination from the plasma owing to higher affinity to the lipo protein lipase enzyme, complete, rapid, and carnitine-independent metabolism, an d a triglyceridelowering effect; however, use of MCT does not promote lipolysis, and elimination of triglycerides of both types of fat emulsions is equally reta rded in ARF [34]. (Adapted from [34]; with permission.)

Nutrition and Metabolism in Acute Renal Failure 18.21 SUGGESTED SCHEDULE FOR MINIMAL MONITORING OF PARENTERAL NUTRITION Metabolic Status Variables Blood glucose Osmolality Electrolytes (Na+, K+, Cl+) Calcium, phosphate, magnesi um Daily BUN increment Urea nitrogen appearance rate Triglycerides Blood gas ana lysis, pH Ammonia Transaminases bilirubin Unstable 16 daily Daily Daily Daily Daily Daily Daily Daily 2 weekly 2 weekly Stable Daily 2 weekly Daily 3 weekly Daily 2 weekly 2 weekly 1 weekly 1 weekly 1 weekly FIGURE 18-36 Complications and monitoring of nutritional support in acute renal failure (ARF). Complications: Technical problems and infectious complications or iginating from the central venous catheter, chemical incompatibilities, and meta bolic complications of parenteral nutrition are similar in ARF patients and in n onuremic subjects. However, tolerance to volume load is limited, electrolyte der angements can develop rapidly, exaggerated protein or amino acid intake stimulat es excessive blood urea nitrogen (BUN) and waste product accumulation and glucos e intolerance, and decreased fat clearance can cause hyperglycemia and hypertrig lyceridemia. Thus, nutritional therapy for ARF patients requires more frequent m onitoring than it does for other patient groups, to avoid metabolic complication s. Monitoring: This table summarizes laboratory tests that monitor parenteral nu trition and avoid metabolic complications. The frequency of testing depends on t he metabolic stability of the patient. In particular, plasma glucose, potassium, and phosphate should be monitored repeatedly after the start of parenteral nutr ition. References 1. Druml W: Nutritional support in acute renal failure. In Nutrition and the Kid ney. Edited by Mitch WE, Klahr S. Philadelphia: LippincottRaven, 1998. 2. Druml W, Mitch WE: Metabolism in acute renal failure. Sem Dial 1996, 9:484490. 3. Om P, Hohenegger M: Energy metabolism in acute uremic rats. Nephron 1980, 25:249253. 4 . Schneeweiss B, Graninger W, Stockenhuber F, et al.: Energy metabolism in acute and chronic renal failure. Am J Clin Nutr 1990, 52:596601. 5. Soop M, Forsberg E , Thrne A, Alvestrand A: Energy expenditure in postoperative multiple organ failu re with acute renal failure. Clin Nephrol 1989, 31:139145. 6. Spreiter SC, Myers BD, Swenson RS: Protein-energy requirements in subjects with acute renal failure receiving intermittent hemodialysis. Am J Clin Nutr 1980, 33:14331437. 7. Mitch WE: Amino acid release from the hindquarter and urea appearance in acute uremia. Am J Physiol 1981, 241:E415E419. 8. Salusky IB, Flgel-Link RM, Jones MR, Kopple J D: Effect of acute uremia on protein degradation and amino acid release in the r at hemicorpus. Kidney Int 1983, 24(Suppl. 16):S41S42. 9. Clark AS, Mitch WE: Musc le protein turnover and glucose uptake in acutely uremic rats. J Clin Invest 198 3, 72:836845. 10. Maroni BJ, Karapanos G, Mitch WE: System A amino acid transport in incubated muscle: Effects of insulin and acute uremia. Am J Physiol 1986, 25 1:F74F80. 11. Druml W, Kelly RA, Mitch WE, May RC: Abnormal cation transport in u remia. J Clin Invest 1988, 81:11971203. 12. Frhlich J, Hoppe-Seyler G, Schollmeyer P, et al.: Possible sites of interaction of acute renal failure with amino acid utilization for gluconeogenesis in isolated perfused rat liver. Eur J Clin Inve st 1977, 7:261268. 13. May RC, Kelly RA, Mitch WE: Mechanisms for defects in musc le protein metabolism in rats with chronic uremia: The influence of metabolic ac idosis. J Clin Invest 1987; 79:10991103. 14. Kuhlmann MK, Shahmir E, Maasarani E, et al.: New experimental model of acute renal failure and sepsis in rats. JPEN 1994, 18:477485. 15. Bergstrm J: Factors causing catabolism in maintenance hemodia

lysis patients. Miner Electrolyte Metab 1992, 18:280283. 16. Druml W, Brger U, Kle inberger G, et al.: Elimination of amino acids in acute renal failure. Nephron 1 986, 42:6267. 17. Druml W, Fischer M, Liebisch B, et al.: Elimination of amino ac ids in renal failure. Am J Clin Nutr 1994, 60:418423. 18. Mitch WE, Chesney RW: A mino acid metabolism by the kidney. Miner Electrolyte Metab 1983, 9:190202. 19. L aidlaw SA, Kopple JD: Newer concepts of indispensable amino acids. Am J Clin Nut r 1987, 46:593605. 20. Naschitz JE, Barak C, Yeshurun D: Reversible diminished in sulin requirement in acute renal failure. Postgrad Med J 1983, 59:269271. 21. Dru ml W, Lochs H, Roth E, et al.: Utilisation of tyrosine dipeptides and acetyl-tyr osine in normal and uremic humans. Am J Physiol 1991, 260:E280E285. 22. Druml W, Roth E, Lenz K, et al.: Phenylalanine and tyrosine metabolism in renal failure. Kidney Int 1989, 36(Suppl 27):S282S286. 23. Frst P. Stehle P: The potential use of dipeptides in clinical nutrition. Nutr Clin Pract 1993, 8:106114. 24. Hbl W, Drum l W, Roth E, Lochs H: Importance of liver and kidney for the utilization of glut amine-containing dipeptides in man. Metabolism 1994, 43:11041107. 25. Hasik J, Hr yniewiecki L, Baczyk K, Grala T: An attempt to evaluate minimum requirements for protein in patients with acute renal failure. Pol Arch Med Wewn 1979, 61:2936. 2 6. Lopez-Martinez J, Caparros T, Perez-Picouto F: Nutrition parenteral en enferm os septicos con fracaso renal agudo en fase poliurica. Rev Clin Esp 1980, 157:17 1178. 27. Kierdorf H: Continuous versus intermittent treatment: Clinical results in acute renal failure. Contrib Nephrol 1991, 93:112.

18.22 Acute Renal Failure 47. Druml W: Impact of continuous renal replacement therapies on metabolism. Int J Artif Organs 1996, 19:118120. 48. Frankenfeld DC, Badellino MM, Reynolds HN, e t al.: Amino acid loss and plasma concentration during continuous hemodiafiltrat ion. JPEN 1993, 17:551561. 49. Toback FG: Regeneration after acute tubular necros is. Kidney Int 1992, 41:226246. 50. Toback FG, Dodd RC, Maier ER, Havener LJ: Ami no acid administration enhances renal protein metabolism after acute tubular nec rosis. Nephron 1983, 33:238243. 51. Abel RM, Beck CH, Abbott WM, et al.: Improved survival from acute renal failure after treatment with intravenuous essential a mino acids and glucose: Results of a prospective double-blind study. N Engl J Me d 1973, 288:695699. 52. Oken DE, Sprinkel M, Kirschbaum BB, Landwehr DM: Amino ac id therapy in the treatment of experimental acute renal failure in the rat. Kidn ey Int 1980, 17:1423. 53. Zager RA, Venkatachalam MA: Potentiation of ischemic re nal injury by amino acid infusion. Kidney Int 1983, 24:620625. 54. Brezis M, Rose n S, Spokes K, et al.: Transport-dependent anoxic cell injury in the isolated pe rfused rat kidney. Am J Pathol 1984, 116:327341. 55. Heyman SN, Rosen S, Silva P, et al.: Protective action of glycine in cisplatin nephrotoxicity. Kidney Int 19 91, 40:273279. 56. Schramm L, Heidbreder E, Lopau K, et al.: Influence of nitric oxide on renal function in toxic renal failure in the rat. Miner Electrolyte Met ab 1996, 22:168177. 57. Wakabayashi Y, Kikawada R: Effect of L-arginine on myoglo bininduced acute renal failure in the rabbit. Am J Physiol 1996, 270:F784F789. 58 . Ding H, Kopple JD, Cohen A, Hirschberg R: Recombinant human insulin-like growt h factor-1 accelerates recovery and reduces catabolism in rats with ischemic acu te renal failure. J Clin Invest 1993, 91:22812287. 59. Franklin SC, Moulton M, Si card GA, et al.: Insulin-like growth factor 1 preserves renal function postopera tively. Am J Physiol 1997, 272:F257F259. 60. Hirschberg R, Kopple JD, Guler HP, P ike M: Recombinant human insulin-like growth factor-1 does not alter the course of acute renal failure in patients. 8th Int. Congress Nutr Metabol Renal Disease , Naples 1996. 61. Druml W, Mitch WE: Enteral nutrition in renal disease. In Ent eral and Tube Feeding. Edited by Rombeau JL, Rolandelli RH. Philadelphia: WB Sau nders, 1997:439461. 62. Roberts PR, Black KW, Zaloga GP: Enteral feeding improves outcome and protects against glycerol-induced acute renal failure in the rat. A m J Respir Crit Care Med 1997, 156:12651269. 63. Wennberg A, Norbeck HE, Sterner G, Lundholm K: Effects of intravenous nutrition on lipoprotein metabolism, body composition, weight gain and uremic state in experimental uremia in rats. J Nutr 1991, 121:14391446. 28. Chima CS, Meyer L, Hummell AC, et al.: Protein catabolic rate in patients wi th acute renal failure on continuous arteriovenous hemofiltration and total pare nteral nutrition. J Am Soc Nephrol 1993, 3:15161521. 29. Macias WL, Alaka KJ, Mur phy MH, et al.: Impact of nutritional regimen on protein catabolism and nitrogen balance in patients with acute renal failure. JPEN 1996, 20:5662. 30. Ikizler TA , Greene JH, Wingard RL, Hakim RM: Nitrogen balance in acute renal failure patie nts. J Am Soc Nephrol 1995, 6:466A. 31. May RC, Clark AS, Goheer MA, Mitch WE: S pecific defects in insulin-mediated muscle metabolism in acute uremia. Kidney In t 1985, 28:490497. 32. Cianciaruso B, Bellizzi V, Napoli R, et al.: Hepatic uptak e and release of glucose, lactate and amino acids in acutely uremic dogs. Metabo lism 1991, 40:261290. 33. Druml W, Laggner A, Widhalm K, et al.: Lipid metabolism in acute renal failure. Kidney Int 1983, 24(Suppl 16):S139S142. 34. Druml W, Fis cher M, Sertl S, et al.: Fat elimination in acute renal failure: Long-chain vers us medium-chain triglycerides. Am J Clin Nutr 1992, 55:468472. 35. Druml W, Zechn er R, Magometschnigg D, et al.: Post-heparin lipolytic activity in acute renal f ailure. Clin Nephrol 1985, 23:289293. 36. Adolph M, Eckart J, Metges C, et al.: O xidative utilization of lipid emulsions in septic patients with and without acut e renal failure. Clin Nutr 1995, 14(Suppl 2):35A. 37. Dobyan DC, Bulger RE, Ekno yan G: The role of phosphate in the potentiation and amelioration of acute renal failure. Miner Electrolyte Metab 1991, 17:112115. 38. Druml W, Lax F, Grimm G, e t al.: Acute renal failure in the elderly 19751990. Clin Nephrol 1994, 41:342349. 3

9. Kurtin P, Kouba J: Profound hypophosphatemia in the course of acute renal fai lure. Am J Kidney Dis 1987, 10:346349. 40. Marik PE, Bedigian MK: Refeeding hypop hosphatemia in critically ill patients in an intensive care unit. Arch Surg 1996 , 131:10431047. 41. Kleinberger G, Gabl F, Gassner A, et al.: Hypophosphatemia du ring parenteral nutrition in patients with renal failure. Wien Klin Wochenschr 1 978, 90:169172. 42. Madl Ch, Kranz A, Liebisch B, et al.: Lactic acidosis in thia mine deficiency. Clin Nutr 1993, 12:108111. 43. Friedman AL, Chesney RW, Gilbert EF, et al.: Secondary oxalosis as a complication of parenteral alimentation in a cute renal failure. Am J Nephrol 1983, 3:248252. 44. Druml W, Schwarzenhofer M, A psner R, Hrl WH: Fat soluble vitamins in acute renal failure. Miner Electrolyte M etab 1998, 24:220226. 45. Zurovsky Y, Gispaan I: Antioxidants attenuate endotoxin -induced acute renal failure in rats. Am J Kidney Dis 1995, 25:5157. 46. Druml W, Bartens C, Stelzer H, et al.: Impact of acute renal failure on antioxidant stat us in multiple organ failure syndrome. JASN 1993, 4:314A.

Supportive Therapies: Intermittent Hemodialysis, Continuous Renal Replacement Th erapies, and Peritoneal Dialysis Ravindra L. Mehta O ver the last decade, significant advances have been made in the availability of different dialysis methods for replacement of renal function. Although the major ity of these have been developed for patients with end-stage renal disease, more and more they are being applied for the treatment of acute renal failure (ARF). The treatment of ARF, with renal replacement therapy (RRT), has the following g oals: 1) to maintain fluid and electrolyte, acid-base, and solute homeostasis; 2 ) to prevent further insults to the kidney; 3) to promote healing and renal reco very; and 4) to permit other support measures such as nutrition to proceed witho ut limitation. Ideally, therapeutic interventions should be designed to achieve these goals, taking into consideration the clinical course. Some of the issues t hat need consideration are the choice of dialysis modality, the indications for and timing of dialysis intervention, and the effect of dialysis on outcomes from ARF. This chapter outlines current concepts in the use of dialysis techniques f or ARF. CHAPTER 19

19.2 Acute Renal Failure Dialysis Methods DIALYSIS MODALITIES FOR ACUTE RENAL FAILURE Intermittent therapies Hemodialysis (HD) Single-pass Sorbent-based Peritoneal (I PD) Hemofiltration (IHF) Ultrafiltration (UF) Continuous therapies Peritoneal (C APD, CCPD) Ultrafiltration (SCUF) Hemofiltration (CAVH, CVVH) Hemodialysis (CAVH D, CVVHD) Hemodiafiltration (CAVHDF, CVVHDF) CVVHDF FIGURE 19-1 Several methods of dialysis are available for renal replacement ther apy. While most of these have been adapted from dialysis procedures developed fo r end-stage renal disease several variations are available specifically for ARF patients [1] . Of the intermittent procedures, intermittent hemodialysis (IHD) i s currently the standard form of therapy worldwide for treatment of ARF in both intensive care unit (ICU) and non-ICU settings. The vast majority of IHD is perf ormed using single-pass systems with moderate blood flow rates (200 to 250 mL/mi n) and countercurrent dialysate flow rates of 500 mL/min. Although this method i s very efficient, it is also associated with hemodynamic instability resulting f rom the large shifts of solutes and fluid over a short time. Sorbent system IHD that regenerates small volumes of dialysate with an in-line Sorbent cartridge ha ve not been very popular; however, they are a useful adjunct if large amounts of water are not available or in disasters [2]. These systems depend on a sorbent cartridge with multiple layers of different chemicals to regenerate the dialysat e. In addition to the advantage of needing a small amount of water (6 L for a ty pical run) that does not need to be pretreated, the unique characteristics of the rege neration process allow greater flexibility in custom tailoring the dialysate. In contrast to IHD, intermittent hemodiafiltration (IHF), which uses convective cl earance for solute removal, has not been used extensively in the United States, mainly because of the high cost of the sterile replacement fluid [3]. Several mo difications have been made in this therapy, including the provision of on-line p reparation of sterile replacement solutions. Proponents of this modality claim a greater degree of hemodynamic stability and improved middle molecule clearance, which may have an impact on outcomes. As a more continuous technique, peritonea l dialysis (PD) is an alternative for some patients. In ARF patients two forms o f PD have been used. Most commonly, dialysate is infused and drained from the pe ritoneal cavity by gravity. More commonly a variation of the procedure for conti nuous ambulatory PD termed continuous equilibrated PD is utilized [4]. Dialysate is instilled and drained manually and continuously every 3 to six hours, and fl uid removal is achieved by varying the concentration of dextrose in the solution s. Alternatively, the process can be automated with a cycling device programmed to deliver a predetermined volume of dialysate and drain the peritoneal cavity a t fixed intervals. The cycler makes the process less labor intensive, but the ut ility of PD in treating ARF in the ICU is limited because of: 1) its impact on r espiratory status owing to interference with diaphragmatic excursion; 2) technic al difficulty of using it in patients with abdominal sepsis or after abdominal s urgery; 3) relative inefficiency in removing waste products in catabolic patients; and 4) a high incidence of associated peritonitis. Several continuous renal rep lacement therapies (CRRT) have evolved that differ only in the access utilized ( arteriovenous [nonpumped: SCUF, CAVH, CAVHD, CAVHDF] versus venovenous [pumped: CVVH, CVVHD, CVVHDF]), and, in the principal method of solute clearance (convect ion alone [UF and H], diffusion alone [hemodialyis (HD)], and combined convectio n and diffusion [hemodiafiltration (HDF)]). CRRT techniques: SCUF A

CRRT techniques: CAVH CVVH VV SCUF A V AV SCUF V V P CAVH R V V P CVVH R V Uf Qb = 50100 mL/min Qf = 26 mL/min UFC Uf Qb = 50200 mL/min Qf = 28 mL/min Uf Qb = 50100 mL/min Qf = 812 mL/min Uf Qb = 50200 mL/min Qf = 1020 mL/min Treatment SCUF Mechanisms of function Pressure profile Membrane Reinfusion Diffusion Convection TMP=30mmHg Treatment CAVHCVVH Mechanisms of function Pressure profile Membrane Reinfusion Diffusion Convection TMP=50mmHg 0 in out Highflux No Low Low 0 in out Highflux Yes Low High

A FIGURE 19-2 Schematics of different CRRT techniques. A, Schematic representati on of SCUF therapy. B, Schematic representation of B continuous arteriovenous or venovenous hemofiltration (CAVH/CVVH) therapy. (Cont inued on next page)

Supportive Therapies: Intermittent Hemodialysis, Continuous Renal Replacement Th erapies, and Peritoneal Dialysis 19.3 CRRT techniques: CAVHD CVVHD A CRRT techniques: CAVHDF CVVHDF A V CAVHD V V Dial. in P CVVHD Dial. in CAVHDF R V V P CVVHDF P V Dial. Out Dial. Out Qb = 50100 mL/min Qf=13 mL/min Qd= 1020 mL/min Qb = 50100 mL/min Qf=15 mL/min Qd=1030 mL/min Dial. Out Dial. In +Uf Qb = 50100 Qd=1020 mL/min Qf = 812 mL/min Dial. Out Dial. In +Uf Qb = 100200 Qd=2040 mL/min Qf = 1020 mL/min Treatment CAVHDCVVHD Mechanisms of function Pressure profile Membrane Reinfusion Diffusion Convection TMP=50mmHg Treatment CAVHDFCVVHDF Mechanisms of function Pressure profile Membrane Reinfusion Diffusion Convection TMP=50mmHg 0 Lowflux No

High Low 0 Highflux Yes High High C FIGURE 19-2 (Continued) C, Schematic representation of continuous arteriovenou s/ venovenous hemodialysis (CAVHD-CVVHD) therapy. D, Schematic representation of continuous arteriovenous/ venovenous hemodiafiltration (CAVHDF/CVVHDF) therapy. Aartery; Vvein; Ufultrafiltrate; Rreplacement fluid; D Pperistaltic pump; Qbblood flow; Qfultrafiltration rate; TMPtransmembrane pressure; indilyzer inlet; out dialyzer outlet; UFCultrafiltration control system; Dial dialys ate; Qddialysate flow rate. (From Bellomo et al. [5]; with permission.) CONTINUOUS RENAL REPLACEMENT THERAPY: COMPARISON OF TECHNIQUES SCUF Access Pump Filtrate (mL/h) Filtrate (L/d) Dialysate flow (L/h) Replacement flui d (L/d) Urea clearance (mL/min) Simplicity* Cost* AV No 100 2.4 0 0 1.7 1 1 CAVH AV No 600 14.4 0 12 10 2 2 CVVH VV Yes 1000 24 0 21.6 16.7 3 4 CAVHD AV No 300 7.2 1.0 4.8 21.7 2 3 CAVHDF AV No 600 14.4 1.0 12 26.7 2 3 CVVHD VV Yes 300 7.2 1.0 4.8 21.7 3 4 CVVHDF VV Yes 800 19.2 1.0 16.8 30 3 4 PD Perit. Cath. No 100 2.4 0.4 0 8.5 2 3 * 1 = most simple and least expensive; 4 = most difficult and expensive cycler can be used to automate exchanges, but they add to the cost and complexit y FIGURE 19-3 In contrast to intermittent techniques, ogy for continuous renal replacement therapy (CRRT) to individual interpretation. Recognizing this lack ational group of experts have proposed standardized until recently, the terminol techniques has been subject of standardization an intern terms for these therapies [5

]. The basic premise in the development of these terms is to link the nomenclatu re to the operational characteristics of the different techniques. In general al l these techniques use highly permeable synthetic membranes and differ in the dr iving force for solute removal. When arteriovenous (AV) circuits are used, the m ean arterial pressure provides the pumping mechanism. Alternatively, external pu mps generally utilize a venovenous (VV) circuit and permit better control of blo od flow rates. The letters AV or VV in the terminology serve to identify the dri ving force in the technique. Solute removal in these techniques is achieved by c onvection, diffusion, or a combination of these two. Convective techniques inclu de ultrafiltration (UF) and hemofiltration (H) and depend on solute removal by s olvent drag [6]. Diffusion-based techniques similar to intermittent hemodialysis (HD) are based o n the principle of a solute gradient between the blood and the dialysate. If bot h diffusion and convection are used in the same technique the process is termed hemodiafiltration (HDF). In this instance, both dialysate and a replacement solu tion are used, and small and middle molecules can both be removed easily. The le tters UF, H, HD, and HDF identify the operational characteristics in the termino logy. Based on these principles, the terminology for these techniques is easier to understand. As shown in Figure 19-1 the letter C in all the terms describes t he continuous nature of the methods, the next two letters [AV or VV] depict the driving force and the remaining letters [UF, H, HD, HDF] represent the operation al characteristics. The only exception to this is the acronym SCUF (slow continu ous ultrafiltration), which remains as a reminder of the initiation of these the rapies as simple techniques harnessing the power of AV circuits. (Modified from Mehta [7]; with permission.)

19.4 Acute Renal Failure Operational Characteristics Anticoagulation Surface Contact activation Initiation FIXa Platelet activation Procoagulant surf ace Propagation Anticoagulation in Dialysis for ARF Dialyzer Membrane Geometry M anufacture Dialysis technique Patient Uremia Drug therapy Dialyzer preparation Anticoagulation Blood flow access Thrombin Fibrin FIGURE 19-4 Pathways of thrombogenesis in extracorporeal circuits. (Modified fro m Lindhout [8]; with permission.) FIGURE 19-5 Factors influencing dialysis-related thrombogenicity. One of the maj or determinants of the efficacy of any dialysis procedure in acute renal failure (ARF) is the ability to maintain a functioning extracorporeal circuit. Anticoag ulation becomes a key component in this regard and requires a balance between an appropriate level of anticoagulation to maintain patency of the circuit and pre vention of complications. Figures 19-4 and 19-5 show the mechanisms of thrombus formation in an extracorporeal circuit and the interaction of various factors in this process. (From Ward [9]; with permission.) FIGURE 19-6 Modalities for anti coagulation for continuous renal replacement therapy. While systemic heparin is the anticoagulant most commonly used for dialysis, other modalities are availabl e. The utilization of these modalities is largely influenced by prevailing local experience. Schematic diagrams for heparin, A, and citrate, B, anticoagulation techniques for continuous renal replacement therapy (CRRT). A schematic of hepar in and regional citrate anticoagulation for CRRT techniques. Regional citrate an ticoagulation minimizes the major complication of bleeding associated with hepar in, but it requires monitoring of ionized calcium. It is now well-recognized tha t the longevity of pumped or nonpumped CRRT circuits is influenced by maintainin g the filtration fraction at less than 20%. Nonpumped circuits (CAVH/HD/HDF) hav e a decrease in efficacy over time related to a decrease in blood flow (BFR), wh ereas in pumped circuits (CVVH/HD/HDF) blood flow is maintained; however, the co nstant pressure across the membrane results in a layer of protein forming over t he membrance reducing its efficacy. This process is termed concentration repolar ization [10]. CAVH/CVVHcontinuous arteriovenous/venovenous hemofiltration. (From Mehta RL, et al. [11]; with permission.) Heparin CRRT Anticoagulant heparin (~400/h) Arterial catheter 3way stop cock (a) Replacement Dialysate solutions 1.5% dianeal (A & B alternating) (1000mL/h) Veno us Filter (b) (d) (c) catheter A Ultrafiltrate (effluent dialysate plus net ultrafiltrate) Citrate CRRT Anticoagulant 4%% trisodium citrate (~170 mL/h) Arterial catheter 3way stop cock

(a) Dialysate Calcium NA 117, K4, Mg 1., 1 mEq/10 mL Cl 122.5 mEq/L; (~40 mL/h) dext rose 0.1%2.5% Replacement zero alkali Central solution zero calcium line 0.9%% sa line (1000 mL/h) Venous Filter (b) (d) (c) catheter B Ultrafiltrate (effluent dialysate plus net ultrafiltrate)

Supportive Therapies: Intermittent Hemodialysis, Continuous Renal Replacement Th erapies, and Peritoneal Dialysis 19.5 Solute Removal Blood Middle molecules Membrane Dialysate Blood Membrane Dialysate Small molecules Diffusion Concentration gradient based transfer. Small molecular weight substanc es (<500 Daltons) are transferred more rapidly. Convection Movement of water across the membrane carries solute across the membr ane. Middle molecules are removed more efficiently. A B Blood Membrane Dialysate FIGURE 19-7 Mechanisms of solute removal in dialysis. The success of any dialysi s procedure depends on an understanding of the operational characteristics that are unique to these techniques and on appropriate use of specific components to deliver the therapy. Solute removal is achieved by diffusion (hemodialysis), A, convection (hemofiltration), B, or a combination of diffusion and convection (he modiafiltration), C. Adsorption Several solutes are removed from circulation by adsorption to the mem brane. This process is influenced by the membrane structure and charge. C

19.6 Acute Renal Failure number of exchanges and the dwell time of each exchange. In continuous arteriove nous and venovenous hemodialysis in most situations ulrafiltration rates of 1 to 3 L/hour are utilized; however recently high-volume hemofiltration with 6 L of ultrafiltrate produced every hour has been utilized to remove middle and largemole cular weight cytokines in sepsis [12]. Fluid balance is achieved by replacing th e ultrafiltrate removed by a replacement solution. The composition of the replac ement fluid can be varied and the solution can be infused before or after the fi lter. Diffusion-based techniques (hemodialysis) are based on the principle of a solute gradient between the blood and the dialysate. In IHD, typically dialysate flow rates far exceed blood flow rates (200 to 400 mL/min, dialysate flow rates 500 to 800 mL/min) and dialysate flow is single pass. However, unlike IHD, the dialysate flow rates are significantly slower than the blood flow rates (typical ly, rates are 100 to 200 mL/min, dialysate flow rates are 1 to 2 L/hr [17 to 34m L/min]), resulting in complete saturation of the dialysate. As a consequence, di alysate flow rates become the limiting factor for solute removal and provide an opportunity for clearance enhancement. Small molecules are preferentially remove d by these methods. If both diffusion and convection are used in the same techni que (hemodiafiltration, HDF) both dialysate and a replacement solution are used and small and middle molecules can both be easily removed. DETERMINANTS OF SOLUTE REMOVAL IN DIALYSIS TECHNIQUES FOR ACUTE RENAL FAILURE IHD Small solutes (MW <300) Diffusion: Qb Membrane width Qd Diffusion Convection: Qf SC Convection Diffusion Adsorption Convection CRRT Diffusion: Qd Convection: Qf Convection: Qf SC Convection Adsorption Convection PD Diffusion: Qd Convection: Qf Convection: Qf SC Convection Middle molecules (MW 5005000) LMW proteins (MW 500050,000) Large proteins (MW >50,000) Convection FIGURE 19-8 Determinants of solute removal in dialysis techniques for acute rena l failure. Solute removal in these techniques is achieved by convection, diffusi on, or a combination of these two. Convective techniques include ultrafiltration (UF) and hemofiltration (H) and they depend on solute removal by solvent drag [ 6]. As solute removal is solely dependent on convective clearance it can be enha nced only by increasing the volume of ultrafiltrate produced. While ultrafiltrat ion requires fluid removal only, to prevent significant volume loss and resultin g hemodynamic compromise, hemofiltration necessitates partial or total replaceme nt of the fluid removed. Larger molecules are removed more efficiently by this p rocess and, thus, middle molecular clearances are superior. In intermittent hemo dialysis (IHD) ultrafiltration is achieved by modifying the transmembrane pressu re and generally does not contribute significantly to solute removal. In periton eal dialysis (PD) the UF depends on the osmotic gradient achieved by the concent ration of dextrose solution (1.55% to 4.25%) utilized the Dialyste flow, L/h 1.5 1 352 Dialysis time 4 h/d 4 h qod

Ultrafiltrate volume, Cycling Manual treatment time, hrs L/d 40 48 20 15 Dialysa te inflow, L/wk 160 96 268 302 140 84 72 FIGURE 19-9 Comparison of weekly urea clearances with different dialysis techniq ues. Although continuous therapies are less efficient than intermittent techniqu es, overall clearances are higher as they are utilized continuously. It is also possible to increase clearances in continuous techniques by adjustment of the ul trafiltration rate and dialysate flow rate. In contrast, as intermittent dialysi s techniques are operational at maximum capability, it is difficult to enhance c learances except by increasing the size of the membrane or the duration of thera py. CAV/CVVHDFcontinuous arteriovenous/venovenous hemodiafiltration; IHDintermitte nt hemodialysis; CAVHcontinuous arteriovenous hemodialysis; PDperitoneal dialysis. CAVHDF/CVVHDF IHD CAVH PD

Supportive Therapies: Intermittent Hemodialysis, Continuous Renal Replacement Th erapies, and Peritoneal Dialysis 19.7 COMPARISON OF DIALYSIS PRESCRIPTION AND DOSE DELIVERED IN CRRT AND IHD Dialysis Prescription IHD Membrane characteristics Anticoagulation Blood flow rate Dialysate flow Duration Clearance Variable permeability Short duration 200 mL/min 500 mL/min 34 hrs High DRUG DOSING IN CRRT* Drug CRRT Amikacin Netilmycin Tobramycin Vancomycin Ceftazidime Cefotaxime Ceftriaxone Cip rofloxacin Imipenem Metronidazole Piperacillin Digoxin Phenobarbital Phenytoin T heophylline Normal Dose (mg/d) 1050 420 350 2000 6000 12,000 4000 400 4000 2100 24,000 0.29 233 524 720 Dose in CRRT (mg) 250 qdbid 100150 qd 100 qd 500 qdbid 1000 bid 2000 bid 2000 qd 200 qd 500 tidqid 500 tidqid 4000 tid 0.10 qd 100 bidqid 250 qdbid 600900 qd High permeability Prolonged <200 mL/min 1734 mL/min Days Low Dialysis Dose Delivered IHD Patient factors Hemodynamic stability Recirculation Infusions Technique factors Blood flow Concentration repolarization Membrane clotting Duration Other factors Nursing errors Interference +++ +++ ++ +++ + + +++ + + CRRT + + + ++ +++ +++ + +++ ++++ * Reflects doses for continuous venovenous hemofiltration with ultrafiltration r ate of 20 to 30 mL/min. FIGURE 19-10 Comparison of dialysis prescription and dose delivered in continuou s renal replacement (CRRT) and intermittent hemodialysis (IHD). The ability of e ach modality to achieve a particular clearance is influenced by the dialysis pre scription and the operational characteristics; however, it must be recognized th at there may be a significant difference between the dialysis dose prescribed an d that delivered. In general, IHD techniques are limited by available time, and in catabolic patients it may not be possible to achieve a desired level of solut e control even by maximizing the operational characteristics. FIGURE 19-11 Drug dosing in continuous renal replacement (CRRT) techniques. Drug removal in CRRT techniques is dependent upon the molecular weight of the drug a nd the degree of protein binding. Drugs with significant protein binding are rem oved minimally. Aditionally, some drugs may be removed by adsorption to the memb rane. Most of the commonly used drugs require adjustments in dose to reflect the continuous removal in CRRT. (Modified from Kroh et al. [13]; with permission.)

19.8 Acute Renal Failure NUTRITIONAL ASSESSMENT AND SUPPORT WITH RENAL REPLACEMENT TECHNIQUES Parameters: Initial Assessment Energy assessment Dialysate dextrose absorption IHD HBE x AF x SF, or indirect calorimetry Negligible CAVH/CVVH Same Not applicable CAVHD/CVVHDF Same 43% uptake 1.5% dextrose dialysate (525 calories/D) 45% uptake 2.5% dextros e dialysate (920 calories/D) Negligible absorption with dextrose free or dialysa te 0.10.15% dextrose Same Nitrogen in: same Nitrogen out: ultrafiltrate/dialysate urea nitrogen losses UUN Insensible losses Ultrafiltrate/dialysate amino acid lo sses (1.52.0 N2/D) Standard TPN/enteral formulations when 0.10.15% dextrose dialys ate used Modified formulations when 1.52.5% dextrose dialysate used TPN: Low-dext rose solutions to prevent carbohydrate overfeeding; amino acid concentration may be increased to meet protein requirements. Enteral: Standard formulas. May requ ire modular protein to meet protein requirements without carbohydrate overfeedin g. Protein assessment Visceral proteins Nitrogen balance: N2 inN2 out Serum prealbumin Nitrogen in: protein in TPN +/enteral solutions/6.25 Nitrogen o ut: urea nitrogen appearance UUN Insensible losses Dialysis amino acid losses (1. 01.5 N2/dialysis therapy) Same Nitrogen in: same Nitrogen out: ultrafiltrate urea nitrogen losses UUN Insen sible losses Ultrafiltrate amino acid losses (1.52.0 N2/D) Standard TPN/enteral f ormulations. No fluid or electrolyte restrictions. Nutrition support prescription: TPN/enteral nutrition Renal formulas with limited fluid, potassium, phosphorus, and magnesium Reassessment of requirements and efficacy of nutrition support Energy assessment Serum prealbumin Nitrogen balance Weekly HBE x AF x SF*, or indirect calorimetry Weekly Weekly Same Same Same Same Same Same * Harris Benedict equation multiplied by acimity and stress factors Collect 24-hour urine for UUN if UOP 400 ml/d FIGURE 19-12 Nutritional assessment and support with renal replacement technique s. A key feature of dialysis support in acute renal failure is to permit an adeq uate amount of nutrition to be delivered to the patient. The modality of dialysi s and operational characteristics affect the nutritional support that can be pro vided. Dextrose absorption occurs form the dialysate in hemodialysis and hemodiafiltration modal ities and can result in hyperglycemia. Intermittent dialysis techniques are limi

ted by time in their ability to allow unlimited nutritional support. (From Monso n and Mehta [14]; with permission.)

Supportive Therapies: Intermittent Hemodialysis, Continuous Renal Replacement Th erapies, and Peritoneal Dialysis 19.9 Fluid Control OPERATING CHARACTERISTICS OF CRRT: FLUID REMOVAL VERSUS FLUID REGULATION Fluid Removal Ultrafiltration rate (UFR) Fluid management Fluid balance Volume removed Applica tion To meet anticipated needs Adjust UFR Zero or negative balance Based on phys ician estimate Easy, similar to intermittent hemodialysis Fluid Regulation Greater than anticipated needs Adjust amount of replacement fluid Positive, nega tive, or zero balance Driven by patient characteristics Requires specific tools and training FIGURE 19-13 Operating characteristics of continuous renal replacement (CRRT): f luid removal versus fluid regulation. Fluid management is an integral component in the management of patients with acute renal failure in the intensive care setting. In the presence of a failing kidney, fluid removal is often a challenge that requires large dos es of diuretics with a variable response. It is often necessary in this setting to institute dialysis for volume control rather than metabolic control. CRRT tec hniques offer a significant advantage over intermittent dialysis for fluid contr ol [14,15]; however, if not carried out appropriately they can result in major c omplications. To utilize these therapies for their maximum potential it is neces sary to recognize the factors that influence fluid balance and have an understan ding of the principles of fluid management with these techniques. In general it is helpful to consider dialysis as a method for fluid removal and fluid regulati on. hours instead of 3 to 4 hours. In Level 2 the ultrafiltrate volume every hou r is deliberately set to be greater than the hourly intake, and net fluid balanc e is achieved by hourly replacement fluid administration. In this method a great er degree of control is possible and fluid balance can be set to achieve any des ired outcome. The success of this method depends on the ability to achieve ultra filtration rates that always exceed the anticipated intake. This allows flexibil ity in manipulation of the fluid balance, so that for any given hour the fluid s tatus could be net negative, positive, or balanced. A key advantage of this tech nique is that the net fluid balance achieved at the end of every hour is truly a reflection of the desired outcome. Level 3 extends the concept of the Level 2 i ntervention to target the desired net balance every hour to achieve a specific h emodynamic parameter (eg, central venous pressure, pulmonary artery wedge pressu re, or mean arterial pressure). Once a desired value for the hemodynamic paramet er is determined, fluid balance can be linked to that value. Each level has adva ntages and disadvantages; in general greater control calls for more effort and c onsequently results in improved outcomes. SCUF ultrafiltration; CAVHD/CVVHDcontinu ous arteriovenous/venovenous hemodialysis; CAVH/CVVHcontinuous arteriovenous/veno venous hemofiltration; CAVHDF/CVVHDFcontinuous arteriovenous/venovenous hemodiafi ltration. APPROACHES FOR FLUID MANAGEMENT IN CRRT Approaches UF volume Replacement Fluid balance UF pump Examples Advantages Simplicity Achie ve fluid balance Regulate volume changes CRRT as support Disadvantages Nursing e ffort Errors in fluid balance Hemodynamic instability Fluid overload Level 1 Limited Minimal 8h Yes SCUF/CAVHD CVVHD +++ + + + + +++ ++ +++

Level 2 Increase intake Adjusted to achieve fluid balance Hourly Yes/No CAVH/CVVH CAVHDF /CVVHDF ++ +++ ++ ++ ++ ++ ++ + Level 3 Increase intake Adjusted to achieve fluid balance Hourly Targeted Yes/No CAVHDF/ CVVHDF CVVH + +++ +++ +++ +++ + + + FIGURE 19-14 Approaches for fluid management in continuous renal replacement the rapy (CRRT). CRRT techniques are uniquely situated in providing fluid regulation , as fluid management can be achieved with three levels of intervention [16]. In Level 1, the ultrafiltrate (UF) volume obtained is limited to match the anticip ated needs for fluid balance. This calls for an estimate of the amount of fluid to be removed over 8 to 24 hours and subsequent calculation of the ultrafiltrati on rate. This strategy is similar to that commonly used for intermittent hemodia lysis and differs only in that the time to remove fluid is 24

19.10 Acute Renal Failure FIGURE 19-15 Composition of dialysate and replacement fluids used for continuous renal replacement therapy (CRRT). One of the key features of any dialysis metho d is the manipulation of metabolic balance. In general, this is achieved by alte ring composition of dialysate or replacement fluid . Most commercially available dialysate and replacement solutions have lactate as the base; however, bicarbon ate-based solutions are being utilized more and more [17,18]. COMPOSITION OF REPLACEMENT FLUID AND DIALYSATE FOR CRRT Replacement Fluid Investigator Na+ ClHCO3K+ Ca2+ Mg2+ Glucose Acetate Golper [19] 147 115 36 0 1.2 0.7 6.7 Kierdorf [20] 140 110 34 0 1.75 0.5 5.6 Lauer [21] 140 2 3.5 1.5 41 Pag anini [22] 140 120 6 2 4 2 10 40 Mehta [11] 140.5 115.5 25 0 4 Mehta [11] 154 15 4 Dialysate Component (mEq/L) Sodium Potassium Chloride Lactate Acetate Calcium Magnesium De xtrose (g/dL) 1.5% Dianeal 132 96 35 3.5 1.5 1.5 Hemosol AG 4D 140 4 119 30 3.5 1.5 0.8 Hemosol LG 4D 140 4 109.5 40 4 1.5 .11 Baxter 140 2 117 30 3.5 1.5 0.1 C itrate 117 4 121 1.5 0.12.5 Replacement 17 mL/min Prefilter Prefilter Prepump Prepump BFR 83 mL/min BFR 117 mL/min Postfilter BFR 100 mL/min Filter Blood pump BFR 100 mL/min Ultrafiltrate FIGURE 19-16 Effect of site of delivery of replacement fluid: pre- versus postfi lter continuous venovenous hemofiltration with ultrafiltration rate of 1 L/hour. Replacement fluids may be administered pre- or postfilter, depending on the cir cuit involved . It is important to recognize that the site of delivery can influ ence the overall efficacy of the procedure. There is a significant effect of flu id delivered prepump or postpump, as the amount of blood delivered to the filter is reduced in prepump dilution. BFRblood flow rate. 50 40 % 30 20 10 0 Prefilter prepump Prefilter postpump Postfilter 22.6 19.5 23.9 47.6 41.6 32.2 26.3 35.7 32.2 FIGURE 19-17 Pre- versus postfilter replacement fluid: effect on filtration frac tion. Prefilter replacement tends to dilute the blood entering the circuit and e nhances filter longevity by reducing the filtration fraction; however, in contin uous venovenous hemofiltration (CVVH) circuits the overall clearance may be redu ced as the amount of solute delivered to the filter is reduced. CVVH 1L/h CVVH 3L/h CVVH 6L/h

Supportive Therapies: Intermittent Hemodialysis, Continuous Renal Replacement Th erapies, and Peritoneal Dialysis 19.11 Applications and Indications for Dialytic Intervention INDICATIONS AND TIMING OF DIALYSIS FOR ACUTE RENAL FAILURE: RENAL REPLACEMENT VE RSUS RENAL SUPPORT Renal Replacement Purpose Timing of intervention Indications for dialysis Dialysis dose Replace re nal function Based on level of biochemical markers Narrow Extrapolated from ESRD Renal Support Support other organs Based on individualized need Broad Targeted for overall sup port FIGURE 19-18 Dialysis intervention in acute renal failure (ARF): renal replaceme nt versus renal support. An important consideration in the management of ARF is defining the goals of therapy. Several issues must be considered, including the timing of the intervention, the amount and frequency of dialysis, and the durati on of therapy. In practice, these issues are based on individual preferences and experience, and no immutable criteria are followed [7,23]. Dialysis interventio n in ARF is usually considered when there is clinical evidence of uremia symptom s or biochemical evidence of solute and fluid imbalance. An important consideration in this regard is to recognize that the patient with ARF is somewhat different than the one with endstage renal disease (ESRD). The rapi d decline of renal function associated with multiorgan failure does not permit m uch of an adaptive response which characterizes the course of the patient with E SRD. As a consequence, the traditional indications for renal replacement may nee d to be redefined. For instance, excessive volume resuscitation, a common strate gy for multiorgan failure, may be an indication for dialysis, even in the absenc e of significant elevations in blood urea nitrogen. In this respect, it may be m ore appropriate to consider dialysis intervention in the intensive care patient as a form of renal support rather than renal replacement. This terminology serve s to distinguish between the strategy for replacing individual organ function an d one to provide support for all organs. FIGURE 19-19 Potential applications for continuous renal replacement therapy (CRRT). CRRT techniques are increasingly b eing utilized as support modalities in the intensive care setting and are partic ularly suited for this function. The freedom to provide continuous fluid managem ent permits the application of unlimited nutrition, adjustments in hemodynamic p arameters, and achievement of steady-state solute control, which is difficult wi th intermittent therapies. It is thus possible to widen the indications for rena l intervention and provide a customized approach for the management of each pati ent. POTENTIAL APPLICATIONS FOR CONTINUOUS RENAL REPLACEMENT THERAPY Renal Replacement Acute renal failure Chronic renal failure Renal Support Fluid management Solute control Acid-base adjustments Nutrition Burn management Extrarenal Applications Cytokine removal ? sepsis Heart failure Cancer chemotherapy Liver support Inheri ted metabolic disorders

19.12 Acute Renal Failure FIGURE 19-20 Advantages ( ) and disadvantages ( ) of dialysis techniques. CRRTcon tinuous renal replacement therapy; IHDintermittent hemodialysis; PDperitoneal dial ysis. RELATIVE ADVANTAGES ( ) AND DISADVANTAGES ( ) OF CRRT, IHD, AND PD Variable Continuous renal replacement Hemodynamic stability Fluid balance achievement Unl imited nutrition Superior metabolic control Continuous removal of toxins Simple to perform Stable intracranial pressure Rapid removal of poisons Limited anticoa gulation Need for intensive care nursing support Need for hemodialysis nursing s upport Patient mobility CRRT IHD PD DETERMINANTS OF THE CHOICE OF TREATMENT MODALITY FOR ACUTE RENAL FAILURE Patient Indication for dialysis Presence of multiorgan failure Access Mobility a nd location of patient Anticipated duration of therapy Dialysis process Componen ts (eg, membrane, anticoagulation) Type (intermittent or continuous) Efficacy fo r solute and fluid balance Complications Outcome Nursing and other support Avail ability of machines Nursing support FIGURE 19-21 Determinants of the choice of treatment modality for acute renal fa ilure. The primary indication for dialysis intervention can be a major determina nt of the therapy chosen because different therapies vary in their efficacy for solute and fluid removal. Each technique has its advantages and limitations, and the choice depends on several factors. Patient selection for each technique ide ally should be based on a careful consideration of multiple factors [1]. The gen eral principle is to provide adequate renal support without adversely affecting the patient. The presence of multiple organ failure may limit the choice of ther apies; for example, patients who have had abdominal surgery may not be suitable for peritoneal dialysis because it increases the risk of wound dehiscence and in fection. Patients who are hemodynamically unstable may not tolerate intermittent hemodialysis (IHD). Additionally, the impact of the chosen therapy on compromis ed organ systems is an important consideration. Rapid removal of solutes and flu id, as in IHD, can result in a disequilibrium syndrome and worsen neurologic sta tus. Peritoneal dialysis may be attractive in acute renal failure that complicat es acute pancreatitis, but it would contribute to additional protein losses in t he hypoalbuminemic patient with liver failure.

Supportive Therapies: Intermittent Hemodialysis, Continuous Renal Replacement Th erapies, and Peritoneal Dialysis 19.13 RECOMMENDATION FOR INITIAL DIALYSIS MODALITY FOR ACUTE RENAL FAILURE (ARF) Indication Uncomplicated ARF Fluid removal Uremia Increased intracranial pressure Shock Nut rition Poisons Electrolyte abnormalities ARF in pregnancy Clinical Condition Antibiotic nephrotoxicity Cardiogenic shock, CP bypass Complicated ARF in ICU Su barachnoid hemorrhage, hepatorenal syndrome Sepsis, ARDS Burns Theophylline, bar biturates Marked hyperkalemia Uremia in 2nd, 3rd trimester Preferred Therapy IHD, PD SCUF, CAVH CVVHDF, CAVHDF, IHD CVVHD, CAVHD CVVH, CVVHDF, CAVHDF CVVHDF, CAVHDF, CVVH Hemoperfusion, IHD, CVVHDF IHD, CVVHDF PD FIGURE 19-22 Recommendation for initial dialysis modality for acute renal failur e (ARF). Patients with multiple organ failure (MOF) and ARF can be treated with various continuous therapies or IHD. Continuous therapies provide better hemodyn amic stability; however, if not monitored carefully they can lead to significant volume depletion. In general, hemodynamically unstable, catabolic, and fluid-ov erloaded patients are best treated with continuous therapies, whereas IHD is bet ter suited for patients who require early mobilization and are more stable. It i s likely that the mix of modalities used will change as evidence linking the cho ice of modality to outcome becomes available. For now, it is probably appropriat e to consider all these techniques as viable options that can be used collective ly. Ideally, each patient should have an individualized approach for management of ARF. Outcomes S Creat, mg/dL BUN, mg/dL 100 80 60 40 0 1 2 3 4 5 Days 6 7 8 9 CRRT IHD 6 5 4 3 2 1 CRRT IHD FIGURE 19-23 Efficacy of continuous renal replacement therapy (CRRT) versus inte rmittent hemodialysis (IHD): effect on blood urea nitrogen, A, and creatinine le vels, B, in acute renal failure. 3 4 5 6 Days 7 8 9 0 1 2 A B Urea, mmol/L 50 40 30 20 0 1 2 3 Days 4 Survivors Non-survivors 5 6

FIGURE 19-24 Blood urea nitrogen (BUN) levels in survivors and non-survivors in acute renal failure treated with continuous renal replacement therapy (CRRT). It is apparent that CRRT techniques offer improved solute control and fluid manage ment with hemodynamic stability, however a relationship to outcome has not been demonstrated. In a recent retrospective analysis van Bommel [24] found no differ ence in BUN levels among survivors and nonsurvivors with ARF While it is clear t hat lower solute concentrations can be achieved with CRRT whether this is an imp ortant criteria impacting on various outcomes from ARF still needs to be determi ned. A recent study form the Cleveland Clinic suggests that the dose of dialysis may be an important determinant of outcome allowing for underlying severity of illness [25]. In this study the authors found that in patients with ARF, 65.4% o f all IHD treatments resulted in lower Kt/V than prescribed. There appeared to b e an influence of dose of dialysis on outcome in patients with intermediate leve ls of severity of illness as judged by the Cleveland Clinic Foundation acuity sc ore for ARF (see Fig. 19-25). Patients receiving a higher Kt/V had a lower morta lity than predicted. These data illustrate the importance of the underlying seve rity of illness, which is likely to be a major determinant of outcome and should be considered in the analysis of any studies.

19.14 1 Survival, % 0.8 0.6 0.4 0.2 0 0 Acute Renal Failure Low Kt/V High Kt/V CCF score BIOCOMPATIBLE MEMBRANES IN INTERMITTENT HEMODIALYSIS (IHD) AND ACUTE RENAL FAILU RE (ARF): EFFECT ON OUTCOMES BCM Group BICM Group 81 35 (43%) 37 (46%) 46 32 (70%) 21 (46%) 22 (48%) 35 14 (40%) 15 (43%) Probability 0.001 0.03 0.03 0.0004 0.003 ns ns 5 10 15 Cleveland clinic ICU ARF score 20 FIGURE 19-25 Effect of dose of dialysis in acute renal failure (ARF) on outcome from ARF. Patients, n All patients recover of renal function Survival Patients nonoliguric before hemodialysis Development of oliguria with dialysis Recovery of renal fun ction Survival Patients oliguric before hemodialysis Recovery of renal function Survival 72 46 (64%) 41 (57%) 39 17 (44%) 31 (79%) 28 (74%) 33 15 (45%) 12 (36%) FIGURE 19-26 Biocompatible membranes in intermittent hemodialysis (IHD) and acut e renal failure (ARF): effect on outcomes. The choice of dialysis membrane and i ts influence on survival from ARF has been of major interest to investigators ov er the last few years. While the evidence tends to support a survival advantage for biocompatible membranes, most of the studies were not well controlled. The m ost recent multicenter study showed an improvement in mortality and recovery of renal function with biocompatible membranes; however, this effect was not signif icant in oliguric patients. Further investigations are required in this area. NSn ot significant. MORTALITY IN ACUTE RENAL FAILURE: COMPARISON OF CRRT VERSUS IHD IHD Investigator Mauritz [32] Alarabi [33] Mehta [34] Kierdorf [20] Bellomo [35] Bellomo [36] Kru czynski [37] Simpson [38] Kierdorf [39] Mehta [40] CRRT No 27 40 18 73 84 76 12 65 48 84 Type of Study Retrospective Retrospective Retrospective Retrospective Retrospective Retrospect ive Retrospective Prospective Prospective Prospective No 31 40 24 73 167 84 23 58 47 82 Mortality, % 90 55 85 93 70 70 82 82 65 41.5 Mortality, % 70 45 72 77 59 45 33 70 60 59.5 Change, %

20 10 13 16 11 25 49 12 4.5 18 P Value ns ns ns < 0.05 ns < 0.01 < 0.01 ns ns ns FIGURE 19-27 Continuous renal replacement therapy (CRRT) versus intermittent hem odialysis (IHD): effect on mortality. Despite significant advances in the manage ment of acute renal failure (ARF) over the last four decades, the perception is that the associated mortality has not changed significantly [26]. Recent publica tions suggest that there may have been some improvement during the last decade [ 27]. Both IHD and peritoneal dialysis (PD) were the major therapies until a deca de ago, and they improved the outcome from the 100% mortality of ARF to its curr ent level. The effect of continuous renal replacement therapy on overall patient outcome is still unclear [28] . The major studies done in this area do not show a survival advantage for CRRT [29,30 ]. Although several investigators have not been able to demonstrate an advantage of these therapies in influencing mortality, we believe this may represent the difficulty in changing a global outcome which is impacted by several other facto rs [31]. It is probably more relevant to focus on other outcomes such as renal f unctional recovery rather than mortality. We believe that continued research is required in this area; however, there appears to be enough evidence to support t he use of CRRT techniques as an alternative that may be preferable to IHD in tre ating ARF in an intensive care setting.

Supportive Therapies: Intermittent Hemodialysis, Continuous Renal Replacement Th erapies, and Peritoneal Dialysis 19.15 Future Directions 1 Blood delivered to lumen of fibers in filter device (only one fiber shown) Fil ter unit Reabsorber unit 6 Transported and synthesized elements added to postfil tered blood, returned to general circulation 4 Postfiltered blood delivered to e xtracapillary space of RAD 2 Filtrate conveyed to tubule lumens 3 Filtrate delivered to interiors of fibers in RAD 7 Concentrated metabolic wastes (urine) voided 5 Renal tubule cells lining fiber s provide transport and metabolic function FIGURE 19-28 Schematic for the bioartificial kidney. As experience with these te chniques grows, innovations in technology will likely keep pace. Over the last 3 years, most of the major manufacturers of dialysis equipment have developed new pumps dedicated for continuous renal replacement therapy (CRRT). Membrane techn ology is also evolving, and antithrombogenic membranes are on the horizon [41]. Finally the application of these therapies is likely to expand to other arenas, including the treatment of sepsis, congestive heart failure [42], and multiorgan failure [43]. An exciting area of innovative research is the development of a b ioartificial tubule utilizing porcine tubular epithelial cells grown in a hollow fiber to add tubular function to the filtrative function provided by dialysis [ 44]. These devices are likely to be utilized in combination with CRRT to truly p rovide complete RRT in the near future. (From Humes HD [44]; with permission.) References 1. Mehta RL: Therapeutic alternatives to renal replacement therapy for criticall y ill patients in acute renal failure. Semin Nephro 1994, 14:6482. Shapiro WB: Th e current status of Sorbent hemodialysis. Semin Dial 1990, 3:4045. Botella J, Ghe zzi P, Sanz-Moreno C, et al.: Multicentric study on paired filtration dialysis a s a short, highly efficient dialysis technique. Nephrol Dial Transplant 1991, 6: 715721. Steiner RW: Continuous equilibration peritoneal dialysis in acute renal f ailure. Perit Dial Intensive 1989, 9:57. Bellomo R, Ronco C, Mehta RL: Nomenclatu re for continuous renal replacement therapies. Am J Kidney Dis 1996, 28(5)S3:27. Henderson LW: Hemofiltration: From the origin to the new wave. Am J Kidney Dis 1 996, 28(5)S3:100104. Mehta RL: Renal replacement therapy for acute renal failure: Matching the method to the patient. Semin Dial 1993, 6:253259. Lindhout T: Bioco mpatability of extracorporeal blood treatment. Selection of hemostatic parameter s. Nephrol Dial Transplant 1994, 9(Suppl. 2):8389. Ward RA: Effects of hemodialys is on corpulation and platelets: Are we measureing membrane biocompatability? Ne phrol Dial Transplant 1995, 10(Suppl. 10):1217. 10. Ronco C, Brendolan A, Crepald i C, et al.: Importance of hollow fiber geometry in CAVH. Contrib Nephrol 1991, 15:175178. 11. Mehta RL, McDonald BR, Aguilar MM, Ward DM: Regional citrate antic oagulation for continuous arteriovenous hemodialysis in critically ill patients. Kidney Int 1990, 38:976981. 12. Grootendorst AF, Bouman C, Hoeben K, et al.: The role of continuous renal replacement therapy in sepsis multiorgan failure. Am J Kidney Dis 1996, 28(5) S3:S50S57. 13. Kroh UF, Holl TJ, Steinhausser W: Manageme nt of drug dosing in continuous renal replacement therapy. Semin Dial 1996, 9:16 1165. 14. Monson P, Mehta RL: Nutritional considerations in continuous renal repl acement therapies. Semin Dial 1996, 9:152160. 15. Golper TA: Indications, technic al considerations, and strategies for renal replacement therapy in the intensive care unit. J Intensiv Care Med 1992, 7:310317. 16. Mehta RL: Fluid management in continuous renal replacement therapy. Semin Dial 1996, 9:140144. 17. Palevsky PM : Continuous renal replacement therapy component selection: replacement fluid an

d dialysate. Semin Dial 1996, 9:107111. 18. Thomas AN, Guy JM, Kishen R, et al.: Comparison of lactate and bicarbonate buffered haemofiltration fluids: Use in cr itically ill patients. Nephrol Dial Transplant 1997, 12(6):12121217. 2. 3. 4. 5. 6. 7. 8. 9.

19.16 Acute Renal Failure 33. Alarabi AA, Danielson BG, Wikstrom B, Wahlberg J: Outcome of continuous arte riovenous hemofiltration (CAVH) in one centre. Ups J Med Sci 1989, 94:299303. 34. McDonald BR, Mehta RL: Decreased mortality in patients with acute renal failure undergoing continuous arteriovenous hemodialysis. Contrib Nephrol 1991, 93:5156. 35. Bellomo R, Mansfield D, Rumble S, et al.: Acute renal failure in critical i llness. Conventional dialysis versus acute continuous hemodiafiltration. Am Soc Artif Intern Organs J 1992, 38:654657. 36. Bellomo R, Boyce N: Continuous venoven ous hemodiafiltration compared with conventional dialysis in critically ill pati ents with acute renal failure. Am Soc Artif Intern Organs J 1993, 39:794797. 37. Kruczynski K, Irvine-Bird K, Toffelmire EB, Morton AR: A comparison of continuou s arteriovenous hemofiltration and intermittent hemodialysis in acute renal fail ure patients in the intensive care unit. Am Soc Artif Intern Organs J 1993, 39:7 78781. 38. Simpson K, Allison MEM: Dialysis and acute renal failure: can mortalit y be improved? Nephrol Dial Transplant 1993, 8:946. 39. Kierdorf H: Einfuss der kontinuierlichen Hamofiltration auf Proteinkatabolismus, Mediatorsubstanzen und Prognose des akuten Nierenversagens [Habilitation-Thesis], Medical Faculty Techn ical University of Aachen, 1994. 40. Mehta RL, McDonald B, Pahl M, et al.: Conti nuous vs. intermittent dialysis for acute renal failure (ARF) in the ICU: Result s from a randomized multicenter trial. Abstract A1044. JASN 1996, 7(9):1456. 41. Yang VC, Fu Y, Kim JS: A potential thrombogenic hemodialysis membranes with imp aired blood compatibility. ASAIO Trans 1991, 37:M229M232. 42. Canaud B, Leray-Mor agues H, Garred LJ, et al.: Slow isolated ultrafiltration for the treatment of c ongestive heart failure. Am J Kidney Dis 1996, 28(5)S3:6773. 43. Druml W: Prophyl actic use of continuous renal replacement therapies in patients with normal rena l function. Am J Kidney Dis 1996, 28(5)S3:114120. 44. Humes HD, Mackay SM, Funke AJ, Buffington DA: The bioartificial renal tuble assist device to enhance CRRT i n acute renal failure. Am J Kidney Dis 1997, 30(Suppl. 4):S28S30. 19. Golper TA: Continuous arteriovenous hemofiltration in acute renal failure. A m J Kidney Dis 1985, 6:373386. 20. Kierdorf H: Continuous versus intermittent tre atment: clinical results in acute renal failure. Contrib Nephrol 1991, 93:112. 21 . Lauer 22. Paganini EP: Slow continuous hemofiltration and slow continuous ultr afiltration. Trans Am Soc Artif Intern Organs 1988, 34:6366. 23. Schrier RW, Abra ham HJ: Strategies in management of acute renal failure in the intensive therapy unit. In Current Concepts in Critical Care: Acute Renal Failure in the Intensiv e Therapy Unit. Edited by Bihari D, Neild G. Berlin:Springer-Verlag, 1990:193214. 24. Van Bommel EFH, Bouvy ND, So KL, et al.: High risk surgical acute renal fai lure treated by continuous arterio venous hemodiafiltration: Metabolic control a nd outcomes in sixty patients. Nephron 1995, 70:185196. 25. Paganini EP, Tapolyai M, Goormastic M, et al.: Establishing a dialysis therapy/patient outcome link i n intensive care unit acute dialysis for patients with acute renal failure. Am J Kidney Dis 1996, 28(5)S3:8190. 26. Wilkins RG, Faragher EB: Acute renal failure in an intensive care unit: Incidence, prediction and outcome. Anesthesiology 198 3, 38:638. 27. Firth JD: Renal replacement therapy on the intensive care unit. Q J Med 1993, 86:7577. 28. Bosworth C, Paganini EP, Cosentino F, et al.: Long term experience with continuous renal replacement therapy in intensive care unit acu te renal failure. Contrib Nephrol 1991, 93:1316. 29. Kierdorf H: Continuous versu s intermittent treatment: Clinical results in acute renal failure. Contrib Nephr ol 1991, 93:112. 30. Jakob SM, Frey FJ, Uhlinger DE: Does continuous renal replac ement therapy favorably influence the outcome of patients? Nephrol Dial Transpla nt 1996, 11:12501235. 31. Mehta RL: Acute renal failure in the intensive care uni t: Which outcomes should we measure? Am J Kidney Dis 1996, 28(5)S3:7479. 32. Maur itz W, Sporn P, Schindler I, et al.: Acute renal failure in abdominal infection: comparison of hemodialysis and continuous arteriovenous hemofiltration. Anasth Intensivther Notfallmed 1986, 21:212217.

Normal Vascular and Glomerular Anatomy Arthur H. Cohen Richard J. Glassock T he topic of normal vascular and glomerular anatomy is introduced here to serve a s a reference point for later illustrations of disease-specific alterations in m orphology. CHAPTER 1

1.2 Glomerulonephritis and Vasculitis FIGURE 1-1 A, The major renal circulation. The renal artery divides into the int erlobar arteries (usually 4 or 5 divisions) that then branch into arcuate arteri es encompassing the corticomedullary junction of each renal pyramid. The interlo bular arteries (multiple) originate from the arcuate arteries. B, The renal micr ocirculation. The afferent arterioles branch from the interlobular arteries and form the glomerular capillaries (hemi-arterioles). Efferent arterioles then refo rm and collect to form the post-glomerular circulation (peritubular capillaries, venules and renal veins [not shown]). The efferent arterioles at the corticomed ullary junction dip deep into the medulla to form the vasa recta, which embrace the collecting tubules and form hairpin loops. (Courtesy of Arthur Cohen, MD.) Interlobar artery Arcuate artery Pyramid Interlobular artery Renal artery Pelvis Ureter A Afferent arteriole Interlobular artery Glomerulus Arcuate artery Efferent arteriole Collecting tubule Interlobar artery B

Normal Vascular and Glomerular Anatomy 1.3 aa ILA FIGURE 1-2 (see Color Plate) Microscopic view of the normal vascular and glomeru lar anatomy. The largest intrarenal arteries (interlobar) enter the kidneys betw een adjacent lobes and extend toward the cortex on the side of a pyramid. These arteries branch dichotomously at the corticomedullary junction, forming arcuate arteries that course between the cortex and medulla. The arcuate arteries branch into a series of interlobular arteries that course at roughly right angles thro ugh the cortex toward the capsule. Blood reaches glomeruli through afferent arte rioles, most of which are branches of interlobular arteries, although some arise from arcuate arteries. ILAinterlobular artery; aaafferent arteriole. FIGURE 1-3 Microscopic view of the juxtaglomerular apparatus. The juxtaglomerula r apparatus (arrow) located immediately adjacent to the glomerular hilus, is a c omplex structure with vascular and tubular components. The vascular component in cludes the afferent and efferent arterioles, and the region between them is know n as the lacis. The tubular component consists of the macula densa (arrowhead). The juxtaglomerular apparatus is an integral component of the renin-angiotensin system. FIGURE 1-4 Electron micrograph of the arterioles. Modified smooth muscle cells o f the arterioles of the juxtaglomerular apparatus produce and secrete renin. Ren in is packaged in characteristic amorphous mature granules (arrow) derived from smaller rhomboid-shaped immature protogranules (arrowhead).

1.4 Glomerulonephritis and Vasculitis FP A FIGURE 1-5 (see Color Plate) Microscopic view of the glomeruli. Glomeruli are sp herical bags of capillaries emanating from afferent arterioles and confined within the urinary space, which is continuous with the proximal tubule. The capillarie s are partially attached to the mesangium, a continuation of the arteriolar wall consisting of B mesangial cells (A, arrow) and the matrix (B, arrow). The free wall of glomerula r capillaries, across which filtration takes place, consists of a basement membr ane (arrowheads) covered by visceral epithelial cells with individual foot proce sses (FP) and lined by endothelial cells. FIGURE 1-6 Schematic illustration of a glomerulus and adjacent hilar structure. Note the relationship of mesangial cel ls to the juxtaglomerular apparatus and distal tubule (macula densa). Redmesangia l cells; bluemesangial matrix; blackbasement membrane; greenvisceral and parietal e pithelial cells; yellowendothelial cells. (From Churg and coworkers [1]; with per mission.) FIGURE 1-7 Electron photomicrograph illustrating a portion of the ultrastructure of the glomerular capillary wall. The normal width of the lamina rara externa ( LRE) plus the lamina densa (LD) plus the lamina rara interna (LRI) equals about 250 to 300 nm. The spaces between the foot processes (FP), having diameters of 2 0 to 60 nm, are called filtration slit pores. It is believed they are the path b y which filtered fluid reaches the urinary space (U). The endothelial cells on t he luminal aspect of the basement membrane (BM) are fenestrated, having diameter s from 70 to 100 nm (see Fig. 1-9). The BM (LRE plus LD plus LRI) is composed of Type IV collagen and negativity charged proteoglycans (heparan sulfate). Llumen. (From Churg and coworkers [1]; with permission.)

Normal Vascular and Glomerular Anatomy 1.5 FIGURE 1-8 Scanning electron microscopy of the glomerulus. The surface anatomy o f the interdigitating foot processes of normal visceral epithelial cells (podocy tes) is demonstrated. These cells and their processes cover the capillary, and u ltrafiltration occurs between the fine branches of the cells. (From Churg and co workers [1]; with permission.) FIGURE 1-9 Scanning electron microscopy of the glomerulus. The surface anatomy o f endothelial cells of a normal glomerulus is demonstrated. Note the fenestrated appearance. (From Churg and coworkers [1]; with permission.) Reference 1. Churg J, Bernstein J, Glassock RJ: Renal Disease. Classification and Atlas of Glomerular Diseases, edn 2. New York: Igaku-Shoin; 1995.

The Primary Glomerulopathies Arthur H. Cohen Richard J. Glassock T he primary glomerulopathies are those disorders that affect glomerular structure , function, or both in the absence of a multisystem disorder. The clinical manif estations are predominately the consequence of the glomerular lesion (such as pr oteinuria, hematuria, and reduced glomerular filtration rate). The combination o f clinical manifestations leads to a variety of clinical syndromes. These syndro mes include acute glomerulomphritis; rapidly progressive glomerulonephritis; chr onic renal failure; the nephrotic syndrome or asymptomatic hematuria, proteinuria, or both. CHAPTER 2

2.2 Glomerulonephritis and Vasculitis FIGURE 2-1 Each of these syndromes arises as a consequence of disturbances of gl omerular structure and function. Acute glomerulonephritis consists of the abrupt onset of hematuria, proteinuria, edema, and hypertension. Rapidly progressive g lomerulonephritis is characterized by features of nephritis and progressive rena l insufficiency. Chronic glomerulonephritis features proteinuria and hematuria w ith indolent progressive renal failure. Nephrotic syndrome consists of massive p roteinuria (>3.5 g/d in adults), hypoalbuminemia with edema, lipiduria, and hype rlipidemia. Asymptomatic hematuria, proteinuria, or both is not associated initial ly with renal failure or edema. Each of these syndromes may be complicated by hy pertension. FIGURE 2-2 Age-associated prevalence of various glomerular lesions i n nephrotic syndrome. This schematic illustrates the age-associated prevalence o f various diseases and glomerular lesions among children and adults undergoing r enal biopsy for evaluation of nephrotic syndrome (Guy's Hospital and the Internati onal Study of Kidney Disease in Children) [1]. Both the systemic and primary cau ses of nephrotic syndrome are included. (Diabetes mellitus with nephropathy is u nderrepresented because renal biopsy is seldom needed for diagnosis.) The bar on the left summarizes the prevalence of various lesions in children aged 0 to 16 years; the bar on the right summarizes the prevalence of various lesions in adul ts aged 16 to 80 years. Note the high prevalence of minimal change disease in ch ildren and the increasing prevalence of membranous glomerulonephritis in the age group of 16 to 60 years. FSGSfocal segmental glomeruosclerosis; MCGNmesangiocapil lary glomerulonephritis. (From Cameron [1]; with permission.) CLINICAL SYNDROMES OF GLOMERULAR DISEASE Acute glomerulonephritis Rapidly progressive glomerulonephritis Chronic glomerul onephritis Nephrotic syndrome Asymptomatic hematuria, proteinuria, or both % 5 4 2 5 1 7 % 100 90 80 70 60 50 Lupus % Others Amyloid Diabetes Other proliferative MCGN 10.8 5.9 1.6 16.0 25.8 9.8 76 Membranous 40 30 FSGS 19.7 11.8 20 10 0 All children 5 10 15 20 30 40 50 Age at onset of NS 60 70 80 All adults Minimal changes 22 PRIMARY GLOMERULAR LESIONS Minimal change disease Focal segmental glomerulosclerosis with hyalinosis Membra nous glomerulonephritis Membranoproliferative glomerulonephritis Mesangial proli ferative glomerulonephritis Crescentic glomerulonephritis Immunoglobulin A nephr

opathy Fibrillary and immunotactoid glomerulonephritis Collagenofibrotic glomeru lopathy Lipoprotein glomerulopathy FIGURE 2-3 The primary glomerular lesions.

The Primary Glomerulopathies 2.3 Minimal Change Disease A FIGURE 2-4 Light and electron microscopy in minimal change disease (lipoid nephr osis). A, This glomerulopathy, one of many associated with nephrotic syndrome, h as a normal appearance on light microscopy. No evidence of antibody (immune) dep osits is seen on immunofluorescence. B, Effacement (loss) of foot processes of v isceral epithelial cells is observed on electron microscopy. This last feature i s the major morphologic lesion indicative of massive proteinuria. B Minimal change disease is considered to be the result of glomerular capillary wa ll damage by lymphokines produced by abnormal T cells. This glomerulopathy is th e most common cause of nephrotic syndrome in children (>70%) and also accounts f or approximately 20% of adult patients with nephrotic syndrome. This glomerulopa thy typically is a corticosteroid-responsive lesion, and usually has a benign ou tcome with respect to renal failure. 100 Complete remission, cumulative % 100 Cumulative percentage sustained remission 80 12 weeks 8 weeks 80 60 60 40 ISKDC children Prednisone + Cyclophosphamide (11) Prednisone (75) Cyclophosphami de (25) 20 0 0 2 4 8 40 20 16 Weeks from starting treatment 28 0 200 Days 400 600 FIGURE 2-5 Therapeutic response in minimal change disease. This graph illustrate s the cumulative complete response rate (absence of abnormal proteinuria) in pat ients of varying ages in relation to type and duration of therapy [1]. Note that most children with minimal change disease respond to treatment within 8 weeks. Adults require prolonged therapy to reach equivalent response rates. Number of p atients are indicated in parentheses. (From Cameron [2]; with permission.) FIGURE 2-6 Cyclophosphamide in minimal change disease. One of several controlled trials of cyclophosphamide therapy in pediatric patients that pursued a relapsi ng steroid-dependent course is illustrated. Note the relative freedom from relap se when children were given a 12-week course of oral cyclophosphamide. An 8-week course of chlorambucil (0.150.2 mg/kg/d) may be equally effective. (From Arbeits gemeinschaft fr pediatrische nephrologie [3]; with permission.)

2.4 100 Glomerulonephritis and Vasculitis FIGURE 2-7 Cyclosporine in minimal change disease. One of several controlled tri als of cyclosporine therapy in this disease is illustrated. Note the relapses th at occur after discontinuing cyclosporine therapy (arrow). Cyclophosphamide was given for 2 months, and cyclosporine for 9 months. Probabilityactuarial probabili ty of remaining relapse-free. (From Ponticelli and coworkers [4]; with permissio n.) Cyclosporine Cyclophosphamide 80 Overall probability 60 40 20 0 0 90 180 270 360 450 Time, d 36 28 540 630 720 Number of patients Cyclosporine 36 Cyclophosphamide 30 36 29 31 26 Focal Segmental Glomerulosclerosis A FIGURE 2-8 Light and immunofluorescent microscopy in focal segmental glomerulosc lerosis (FSGS). Patients with FSGS exhibit massive proteinuria (usually nonselec tive), hypertension, hematuria, and renal functional impairment. Patients with n ephrotic syndrome often are not responsive to corticosteroid therapy. Progressio n to chronic renal failure occurs over many years, although in some patients ren al failure may occur in only a few years. A, This glomerulopathy is defined prim arily by its appearance on light microscopy. Only a portion of the glomerular po pulation, initially B in the deep cortex, is affected. The abnormal glomeruli exhibit segmental oblite ration of capillaries by increased extracellular matrixbasement membrane material , collapsed capillary walls, or large insudative lesions. These lesions are call ed hyalinosis (arrow) and are composed of immunoglobulin M and complement C3 (B, IgM immunofluorescence). The other glomeruli usually are enlarged but may be of normal size. In some patients, mesangial hypercellularity may be a feature. Foc al tubular atrophy with interstitial fibrosis invariably is present.

The Primary Glomerulopathies 2.5 FIGURE 2-9 Electron microscopy of focal segmental glomerulosclerosis. The electr on microscopic findings in the involved glomeruli mirror the light microscopic f eatures, with capillary obliteration by dense hyaline deposits (arrow) and lipids. The other glomeruli exhibit primarily foot process effacement, occasionally in a patchy distribution. CLASSIFICATION OF FOCAL SEGMENTAL GLOMERULOSCLEROSIS WITH HYALINOSIS Primary (Idiopathic) Classic Tip lesion Collapsing CLASSIFICATION OF MEMBRANOUS GLOMERULONEPHRITIS Primary (Idiopathic) Secondary Neoplasia (carcinoma, lymphoma) Autoimmune disease (systemic lupus erythematosus thyroiditis) Infectious diseases (hepatitis B, hepatitis C, schistosomiasis) Dr ugs (gold, mercury, nonsteroidal anti-inflammatory drugs, probenecid, captopril) Other causes (kidney transplantation, sickle cell disease, sarcoidosis) Secondary Human immunodeficiency virusassociated Heroin abuse Vesicoureteric reflux nephrop athy Oligonephronia (congenital absence or hypoplasia of one kidney) Obesity Ana lgesic nephropathy Hypertensive nephrosclerosis Sickle cell disease Transplantat ion rejection (chronic) Vasculitis (scarring) Immunoglobulin A nephropathy (scar ring) FIGURE 2-11 Most adult patients (75%) have primary or idiopathic disease. Most c hildren have some underlying disease, especially viral infection. It is not unco mmon for adults over the age of 60 years to have an underlying carcinoma (especi ally lung, colon, stomach, or breast). FIGURE 2-10 Note that a variety of disease processes can lead to the lesion of f ocal segmental glomerulosclerosis. Some of these are the result of infections, w hereas others are due to loss of nephron population. Focal sclerosis may also co mplicate other primary glomerular diseases (eg, Immunoglobulin A nephropathy).

2.6 Glomerulonephritis and Vasculitis A FIGURE 2-12 Histologic variations of focal segmental glomerulosclerosis (FSGS). Two important variants of FSGS exist. In contrast to the histologic appearance o f the involved glomeruli, with the sclerotic segment in any location in the glom erulus, the glomerular tip lesion (A) is characterized by segmental sclerosis at an early stage of evolution, at the tubular pole (tip) of all affected glomerul i (arrow). Capillaries contain monocytes with abundant cytoplasmic lipids (foam cells), and the overlying visceral epithelial cells are enlarged and adherent to cells of the most proximal portion of the proximal B tubule. Some investigators have described a more favorable response to steroids and a more benign clinical course. The other variant, known as collapsing glomer ulopathy, most likely represents a virulent form of FSGS. In this form of FSGS, most visceral epithelial cells are enlarged and coarsely vacuolated and most cap illary walls are wrinkled or collapsed (B). These features indicate a severe les ion, with a corresponding rapidly progressing clinical course of the disease. In tegral and concomitant acute abnormalities of tubular epithelia and interstitial edema occur. 100 80 Survival, % <15 y (138) 1559 y (68) <15 y (62) >60 y (20) 40 20 0 0 Minimal change disease FSGS >15 y (60) Survival, % 60 5 10 15 Years from onset 20 100 90 80 70 60 50 40 30 20 10 0 0 5 Without nephrotic syndrome With nephrotic syndrome FIGURE 2-13 Evolution of focal segmental glomerulosclerosis (FSGS). This graph c ompares the renal functional survival rate of patients with FSGS to that seen in patients with minimal change disease (in adults and children). Note the poor pr ognosis, with about a 50% rate of renal survival at 10 years. (From Cameron [2]; with permission.) 10 15 Years from onset 20 FIGURE 2-14 The outcome of focal segmental glomerulosclerosis according to the d egree of proteinuria at presentation is shown. Note the favorable prognosis in t he absence of nephrotic syndrome. Spontaneous or therapeutically induced remissi

ons have a similar beneficial effect on long-term outcome. (From Ponticelli, et al. [5]; with permission.)

The Primary Glomerulopathies 2.7 Membranous Glomerulonephritis A B C D antigen(s) of the immune complexes are unknown. In the remainder, membranous glo merulonephritis is associated with welldefined diseases that often have an immun ologic basis (eg, systemic lupus erythematosus and hepatitis B or C virus infect ion); some solid malignancies (especially carcinomas); or drug therapy, such as gold, penicillamine, captopril, and some nonsteroidal anti-inflammatory reagents . Treatment is controversial. The changes by light and electron microscopy mirro r one another quite well and represent morphologic progression that is likely de pendent on duration of the disease. A, At all stages immunofluorescence disclose s the presence of uniform granular capillary wall deposits of immunoglobulin G a nd complement C3. B, In the early stage the deposits are small and without other capillary wall changes; hence, on light microscopy, glomeruli often are normal in appearance. C, On electron microscopy, small electron-dense deposits (arrows) are observed in the subepithelial aspects of capillary walls. D, In the interme diate stage the deposits are partially encircled by basement membrane material. E, When viewed with periodic acid-methenamine stained sections, this abnormality appears as spikes of basement membrane perpendicular to the basement membrane, with adjacent nonstaining deposits. Similar features are evident on electron mic roscopy, with dense deposits and intervening basement membrane (D). Late in the disease the deposits are completely surrounded by basement membranes and are und ergoing resorption. E FIGURE 2-15 (see Color Plate) Light, immunofluorescent, and electron microscopy in membranous glomerulonephritis. Membranous glomerulonephritis is an immune com plexmediated glomerulonephritis, with the immune deposits localized to subepithel ial aspects of almost all glomerular capillary walls. Membranous glomerulonephri tis is the most common cause of nephrotic syndrome in adults in developed countr ies. In most instances (75%), the disease is idiopathic and the

2.8 Glomerulonephritis and Vasculitis FIGURE 2-16 Evolution of deposits in membranous glomerulonephritis. This schemat ic illustrates the sequence of immune deposits in red; basement membrane (BM) al terations in blue; and visceral epithelial cell changes in yellow. Small subepit helial deposits in membranous glomerulonephritis (predominately immunoglobulin G ) initially form (A) then coalesce. BM expansion results first in spikes (B) and later in domes (C) that are associated with foot process effacement, as shown i n gray. In later stages the deposits begin to resorb (dotted and crosshatched ar eas) and are accompanied by thickening of the capillary wall (D). (From Churg, e t al. [6]; with permission.) A B C D 100 80 60 % 40 20 0 0 5 10 Years of known disease 15 Proteinuria Remission Dead/ESRD Nephrotic syndrome FIGURE 2-17 Natural history of membranous glomerulonephritis. This schematic ill ustrates the clinical evolution of idiopathic membranous glomerulonephritis over time. Almost half of all patients undergo spontaneous or therapy-related remiss ions of proteinuria. Another group of patients (2540%), however, eventually devel op chronic renal failure, usually in association with persistent proteinuria in the nephrotic range. (From Cameron [2]; with permission.)

The Primary Glomerulopathies 2.9 Membranoproliferative Glomerulonephritis A B at all common. The first, known as membranoproliferative (mesangiocapillary) glo merulonephritis type I, is a primary glomerulopathy most common in children and adolescents. The same pattern of injury may be observed during the course of man y diseases with chronic antigenemic states; these include systemic lupus erythem atosus and hepatitis C virus and other infections. In membranoproliferative glom erulonephritis type I, the glomeruli are enlarged and have increased mesangial c ellularity and variably increased matrix, resulting in lobular architecture. The capillary walls often are thickened with double contours, an abnormality result ing from peripheral migration and interposition of mesangium (A). Immunofluoresc ence discloses granular to confluent granular deposits of C3 (B), immunoglobulin G, and immunoglobulin M in the peripheral capillary walls and mesangial regions . The characteristic finding on electron microscopy is in the capillary walls. C , Between the basement membrane and endothelial cells are, in order inwardly: (1 ) epithelial cell, (2) basement membrane, (3) electron-dense deposits, (4) mesan gial cell cytoplasm, (5) mesangial matrix, and (6) endothelial cell. Electronden se deposits also are in the central mesangial regions. Subepithelial deposits ma y be present, albeit typically in small numbers. The electron-dense deposits may contain an organized (fibrillar) substructure, especially in association with h epatitis C virus infection and cryoglobulemia. 1 2 3 4 5 6 C FIGURE 2-18 (see Color Plate) Light, immunofluorescence, and electron microscopy in membranoproliferative glomerulonephritis type I. In these types of immune co mplexmediated glomerulonephritis, patients often exhibit nephrotic syndrome accom panied by hematuria and depressed levels of serum complement C3. The morphology is varied, with at least three pathologic subtypes, only two of which are

2.10 Glomerulonephritis and Vasculitis A A B known as dense deposit disease, the glomeruli may be lobular or may manifest onl y mild widening of mesangium. A, The capillary walls are thickened, and the base ment membranes are stained intensely positive periodic acidSchiff reaction, with a refractile appearance. B, On immunofluorescence, complement C3 is seen in all glomerular capillary basement membranes in a coarse linear pattern. With the use of thin sections, it can be appreciated that the linear deposits actually consi st of two thin parallel lines. Round granular deposits are in the mesangium. Coa rse linear deposits also are in Bowman's capsule and the tubular basement membrane s. C, Ultrastructurally, the glomerular capillary basement membranes are thicken ed and darkly stained; there may be segmental or extensive involvement of the ba sement membrane. Similar findings are seen in Bowman's capsule and tubular basemen t membranes; however, in the latter, the dense staining is usually on the inters titial aspect of that structure. Patients with dense deposit disease frequently show isolated C3 depression and may have concomitant lipodystrophy. These patien ts also have autoantibodies to the C3 convertase enzyme C3Nef. C FIGURE 2-19 (see Color Plate) Light, immunofluorescence, and electron microscopy in membranoproliferative glomerulonephritis type II. In this disease, also

The Primary Glomerulopathies 2.11 SERUM COMPLEMENT CONCENTRATIONS IN GLOMERULAR LESIONS Serum Concentration Lesion Minimal change disease Focal sclerosis Membranous glomerulonephritis (idiopathic ) Immunoglobulin A nephropathy Membranoproliferative glomerulonephritis: Type I Type II Acute poststreptococcal glomerulonephritis Lupus nephritis: (World Healt h Organization Class IV) (World Health Organization Class V) Cryoglobulinemia (h epatitis C) Amyloid Vasculitis C'H50serum hemolytic complement activity. C3 Normal Normal Normal Normal Moderate decrease Severe decrease Moderate decrease Moderate to severe decrease Normal or mild decrease Normal or mild decrease Norm al Normal or increased C4 Normal Normal Normal Normal Mild decrease Normal Normal Moderate to severe decre ase Normal or mild decrease Severe decrease Normal Normal or increased C'H50 Norma Normal Normal Normal Mild decrease Mild decrease Mild decrease Mild decre ase Normal or mild decrease Moderate decrease Normal Normal Other C3 nephritic factor+ Antistreptolysin 0 titer increased antidouble-stranded DNA a ntibody+ antidouble-stranded DNA antibody+ Cryoglobulins; hepatitis C ab Antineut rophil cytoplasmic antibody+ FIGURE 2-20 The serum complement component concentration (C3 and C4) and serum h emolytic complement activity (C'H50) in various primary and secondary glomerular lesions are depicted. Note the limited number of disord ers associated with a low C3 or C4 level. FIGURE 2-21 Note that although there i s the wide variety of underlying causes for the lesion of membranoproliferative glomerulonephritis hepatitis C, with or without cryoglobulinemia, accounts for m ost cases. CLASSIFICATION OF MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS TYPE I Primary (Idiopathic) Secondary Hepatitis C (with or without cryoglobulinemia) Hepatitis B Systemic lupus erythe matosus Light or heavy chain nephropathy Sickle cell disease Sjgren's syndrome Sarc oidosis Shunt nephritis Antitrypsin deficiency Quartan malaria Chronic thromboti c microangiopathy Buckley's syndrome

2.12 Glomerulonephritis and Vasculitis Mesangial Proliferative Glomerulonephritis A B mesangial regions. Little if any increased cellularity is seen, despite the pres ence of deposits. In this latter instance, the term mesangial injury glomerulone phritis is more properly applied. The disorders are defined on the basis of the immunofluorescence findings, rather than on the presence or absence of mesangial hypercellularity. There are numerous disorders with this appearance; some have specific immunopathologic or clinical features (such as immunoglobulin A nephrop athy, Henoch-Schonlein purpura, and systemic lupus erythematosus). Patients with primary mesangial proliferative glomerulonephritis typically exhibit the disord er in one of four ways: asymptomatic proteinuria, massive proteinuria often in t he nephrotic range, microscopic hematuria, or proteinuria with hematuria. A, On light microscopy, widening of the mesangial regions is observed, often with diff use increase in mesangial cellularity commonly of a mild degree. No other altera tions are present. B, Depending on the specific entity or lesion, the immunofluo rescence is of granular mesangial deposits. In the most common of these disorder s, immunoglobulin M is the dominant or sole deposit. Other disorders are charact erized primarily or exclusively by complement C3, immunoglobulin G, or C1q depos its. C, On electron microscopy the major finding is of small electron-dense depo sits in the mesangial regions (arrow). Foot process effacement is variable, depe nding on the clinical syndrome (eg, whether massive proteinuria is present). C FIGURE 2-22 (see Color Plate) Light, immunofluorescence, and electron microscopy in mesangial proliferative glomerulonephritis. This heterogeneous group of diso rders is characterized by increased mesangial cellularity in most of the glomeru li associated with granular immune deposits in the

The Primary Glomerulopathies 2.13 Crescentic Glomerulonephritis A B C FIGURE 2-23 (see Color Plate) Crescentic glomerulonephritis. A crescent is the a ccumulation of cells and extracellular material in the urinary space of a glomer ulus. The cells are parietal and visceral epithelia as well as monocytes and oth er blood cells. The extracellular material is fibrin, collagen, and basement mem brane material. In the early stages of the disease, the crescents consist of cel ls and fibrin. In the later stages the crescents undergo organization, with disa ppearance of fibrin and replacement by collagen. Crescents represent morphologic consequences of severe capillary wall damage. A, In most instances, small or la rge areas of destruction of capillary walls (cells and basement membranes) are o bserved (arrow), thereby allowing fibrin, other high molecular weight substances , and blood cells to pass readily from capillary lumina into the urinary space. B, Immunofluorescence frequently discloses fibrin in the urinary space. C, The p roliferating cells in Bowman's space ultimately give rise to the typical crescent shape. Whereas crescents may complicate many forms of glomerulonephritis, they a re most commonly associated with either antiglomerular basement membrane (AGBM) antibodies or antineuD trophil cytoplasmic antibodies (ANCAs). The clinical manifestations are typicall y of rapidly progressive glomerulonephritis with moderate proteinuria, hematuria , oliguria, and uremia. The immunomorphologic features depend on the basic disea se process. On light microscopy in both AGBM antibodyinduced disease and ANCAassoc iated crescentic glomerulonephritis, the glomeruli without crescents often have a normal appearance. It is the remaining glomeruli that are involved with cresce nts. D, Anti-GBM disease is characterized by linear deposits of immunoglobulin G and often complement C3 in all capillary basement membranes, and in approximate ly two thirds of affected patients in tubular basement membranes. The ANCA-assoc iated lesion typically has little or no immune deposits on immunofluorescence; h ence the term pauciimmune crescentic glomerulonephritis is used. By electron mic roscopy, as on light microscopy, defects in capillary wall continuity are easily identified. Both AGBM- and ANCA-associated crescentic glomerulonephritis can be complicated by pulmonary hemorrhage (see Fig. 2-25).

2.14 Glomerulonephritis and Vasculitis CLASSIFICATION OF CRESCENTIC GLOMERULONEPHRITIS Type I II III IV Serologic Pattern Anti-GBM+ ANCAAnti-GBM- ANCAAnti-GBM- ANCA+ Anti-GBM+ANCA+ Primary Anti-GBM antibodymediated crescentic glomerular nephritis Idiopathic crescentic g lomerular nephritis (with or without immune complex deposits) Pauci-immune cresc entic glomerular nephritis (microscopic polyangiitis) Anti-GBM antibodymediated c rescentic glomerular nephritis with ANCA Secondary Goodpasture's disease Systemic lupus erythematosus, immunoglobulin A, MPGN cryoimm unoglobulin (with immune complex deposits Drug-induced crescentic glomerulonephr itis Goodpasture's syndrome with ANCA ANCAantineutrophil cytoplasmic antibody; anti-GBMglomerular basement membrane anti body; MPGN membranoproliferative glomerulonephritis. FIGURE 2-24 Note that the serologic findings allow for a differentiation of the various forms of primary and secondary (eg, multisystem disease) forms of cresce ntic glomerulonephritis. FIGURE 2-25 Chest radiograph of alveolar hemorrhage. Th is patient has antiglomerular basement membranemediated glomerulonephritis compli cated by pulmonary hemorrhage (Goodpasture's disease). Note the butterfly appearan ce of the alveolar infiltrates characteristic of intrapulmonary (alveolar) hemor rhage. Such lesions can also occur in patients with antineutrophil cytoplasmic a utoantibodyassociated vasculitis and glomerulonephritis, lupus nephritis (SLE), c ryoglobulinemia, and rarely in Henoch-Schonlein purpura (HSP).

The Primary Glomerulopathies 2.15 - Serum creatinine Proteinuria "Nephritic" sediment Renal ultrasonography Small kidneys Normal or enlarged kidneys; no obstruction Serology* Obstruction FIGURE 2-26 Evaluation of rapidly progressive glomerulonephritis. This algorithm schematically illustrates a diagnostic approach to the various causes of rapidl y progressive glomerulonephritis (Figure 2-24), Serologic studies, especially me asurement of circulating antiglomerular basement membrane antibodies, antineutro phil cytoplasmic antibodies, antinuclear antibodies, and serum complement compon ent concentrations, are used for diagnosis. Serologic patterns (A through D)perm it categorization of probable disease entities. (D) + + Pattern type (A) aGBMA* + ANCA (B) (C) + Goodpasture's disease Type II IC-mediated Type I primary CrGN CGN SLE, HSP, and MPGN CryoIg, type V primary CrGN (idiopathic) Microscopic Combined polyangiitis; type III form; type IV primary crescentic pri mary CrGN CrGN; Wegener's GN; drug-induced CrGN *Antiglomerular basement membrane autoantibody by radioimmunoassay or enzyme-lin ked immunosorbent assay Antineutrophil cytoplasmic autoantibody by indirect immun ofluorescence, confirmed by antigen-specific assay (anti-MPO, anti-PR3, or both) . C-ANCA P-ANCA FIGURE 2-27 (see Color Plate) Antineutrophil cytoplasmic autoantibodies (ANCA). Frequently, ANCA are found in crescentic glomerulonephritis, particularly type I II (Figure 2-24). Two varieties are seen (on alcohol-fixed slides). A, C-ANCA ar e due to antibodies reacting with cytoplasmic granule antigens (mainly proteinas e-3). B, P-ANCA are due to antibodies reacting with other antigens (mainly myelo peroxidase). A B

2.16 Glomerulonephritis and Vasculitis Immunoglobulin A Nephropathy A B C FIGURE 2-28 (see Color Plate) Light, immunofluorescence, and electron microscopy in immunoglobulin A (IgA) nephropathy. IgA nephropathy is a chronic glomerular disease in which IgA is the dominant or sole component of deposits that localize in the mesangial regions of all glomeruli. In severe or acute cases, these depo sits also are observed in the capillary walls. This disorder may have a variety of clinical presentations. Typically, the presenting features are recurrent macr oscopic hematuria, often coincident with or immediately after an upper respirato ry infection, along with persistent microscopic hematuria and low-grade proteinu ria between episodes of gross hematuria. Approximately 20% to 25% of patients de velop end-stage renal disease over the 20 years after onset. A, On light microsc opy, widening and often an increase in cellularity in the mesangial regions are observed, a process that affects the lobules of some glomeruli to a greater degr ee than others. This feature gives rise D to the term focal proliferative glomerulonephritis. In advanced cases, segmental sclerosis often is present and associated with massive proteinuria. During acut e episodes, crescents may be present. B, Large round paramesangial fuchsinophili c deposits often are identified with Masson's trichrome or other similar stains (a rrows). C, Immunofluorescence defines the disease; granular mesangial deposits o f IgA are seen with associated complement C3, and IgG or IgM, or both. IgG and I gM often are seen in lesser degrees of intensity than is IgA. D, On electron mic roscopy the abnormalities typically are those of large rounded electron-dense de posits (arrows) in paramesangial zones of most if not all lobules. Capillary wal l deposits (subepithelial, subendothelial, or both) may be present, especially i n association with acute episodes. In addition, capillary basement membranes may show segmental thinning and rarefaction.

The Primary Glomerulopathies 2.17 FIGURE 2-29 Natural history of immunoglobulin A (IgA) nephropathy. The evolution of IgA nephropathy over time with respect to the occurrence of end-stage renal failure (ESRF) is illustrated. The percentage of renal survival (freedom from ES RF) is plotted versus the time in years from the apparent onset of the disease. Note that on average about 1.5% of patients enter ESRF each year over the first 20 years of this nephropathy. Factors indicating an unfavorable outcome include elevated serum creatinine, tubulointerstitial lesions or glomerulosclerosis, and moderate proteinuria (>1.0 g/d). (Modified from Cameron [2].) Fibrillary and Immunotactoid Glomerulonephritis A B entity in which abnormal extracellular fibrils, typically ranging from 10- to 20 -nm thick, permeate the glomerular mesangial matrix and capillary basement membr anes. The fibrils are defined only on electron microscopy and have an appearance , at first glance, similar to amyloid. Congo red stain, however, is negative. Pa tients with fibrillary glomerulonephritis usually exhibit proteinuria often in t he nephrotic range, with variable hematuria, hypertension, and renal insufficien cy. A, On light microscopy the glomeruli display widened mesangial regions, with variable increase in cellularity and thickened capillary walls and often with i rregularly thickened basement membranes, double contours, or both. B, On immunof luorescence, there is coarse linear or confluent granular staining of capillary walls for immunoglobulin G and complement C3 and similar staining in the mesangi al regions. Occasionally, monoclonal immunoglobulin G deposits are identified; i n most instances, however, both light chains are equally represented. The nature of the deposits is unknown. C, On electron microscopy the fibrils are roughly 2 0-nm thick, of indefinite length, and haphazardly arranged. The fibrils permeate the mesangial matrix and basement membranes (arrow). The fibrils have been infr equently described in organs other than the kidneys. C FIGURE 2-30 (see Color Plate) Light, immunofluorescent, and electron microscopy in nonamyloid fibrillary glomerulonephritis. Fibrillary glomerulonephritis is an

2.18 Glomerulonephritis and Vasculitis A B FIGURE 2-31 (see Color Plate) Light, immunofluorescent, and electron microscopy in immunotactoid glomerulopathy. Immunotactoid glomerulopathy appears to be an i mmune-mediated glomerulonephritis. On electron microscopy the deposits are compo sed of multiple microtubular structures in subepithelial or subendothelial locat ions, or both, with lesser involvement of the mesangium. Patients with this diso rder typically exhibit massive proteinuria or nephrotic syndrome. This glomerulo pathy frequently is associated with lymphoplasmacytic disorders. A, On light mic roscopy the glomerular capillary walls often are thickened and the mesangial reg ions widened, with increased cellularity. B, On immunofluorescence, granular cap illary wall and mesangial immunoglobulin G and complement C3 deposits are presen t. The ultrastructural findings are of aggregates of microtubular structures in capillary wall locations corresponding to granular deposits by immunofluorescenc e. C, The microtubular structures are large, ranging from 30- to 50-nm thick, or more (arrows). C

The Primary Glomerulopathies 2.19 Collagenofibrotic Glomerulopathy A FIGURE 2-32 (see Color Plate) Collagenofibrotic glomerulopathy (collagen III glo merulopathy). The collagens normally found in glomerular basement membranes and the mesangial matrix are of types IV (which is dominant) and V. In collagenofibr otic glomerulopathy, accumulation of type III collagen occurs largely in capilla ry walls in a subendothelial location. It is likely that this disease is heredit ary; however, because it is very rare, precise information regarding transmissio n is not known. Collagenofibrotic glomerulopathy originally was thought to be a variant of nail-patella syndrome. Current evidence suggests little relationship exists between the two disorders. Patients with collagen III glomerulopathy ofte n B exhibit proteinuria and mild progressive renal insufficiency. For reasons that a re not clear, hemolytic-uremic syndrome has evolved in a small number of pediatr ic patients. A, On light microscopy the capillary walls are thickened and mesang ial regions widened by pale staining material. These features are in sharp contr ast to the normal staining of the capillary basement membranes, as evidenced by the positive period acidSchiff reaction. With this stain, collagen type III is no t stained and therefore is much paler. Amyloid stains (Congo red) are negative. B, On electron microscopy, banded collagen fibrils are evident in the subendothe lial aspect of the capillary wall. References 1. Cameron JS, Glassock RJ: The natural history and outcome of the nephrotic syn drome. In The Nephrotic Syndrome. Edited by Cameron JS and Glassock RJ. New York : Marcel Dekker, 1987. Cameron JS: The long-term outcome of glomerular diseases. In Diseases of the Kidney Vol II, edn 6. Edited by Schrier RW, Gottschalk CW. B oston: Little Brown; 1996. Arbeitsgemeinschaft fr pediatrische nephrologie. Cyclo phosphamide treatment of steroid-dependent nephrotic syndrome: comparison of an eight-week with a 12-week course. Arch Dis Child 1987, 62:11021106. 4. Ponticelli C: Cyclosporine versus cyclophosphamide for patients with steroid-dependent and frequently relapsing idiopathic nephrotic syndrome. A multi-center randomized t rial. Nephrol Dial Transplant 1993, 8:13261332. Ponticelli C, Glassock RJ: Treatm ent of Segmental Glomerulonephritis. Oxford: Oxford Medical Publishers, 1996:110 . Churg J, Bernstein J, Glassock RJ: Renal Disease. Classification and Atlas of Glomerular Disease, edn 2. New York: Igaku-Shoin; 1995. 2. 5. 6. 3.

Heredofamilial and Congenital Glomerular Disorders Arthur H. Cohen Richard J. Glassock T he principal characteristics of some of the more common heredofamilial and conge nital glomerular disorders are described and illustrated. Diabetes mellitus, the most common heredofamilial glomerular disease, is illustrated in Volume IV, Cha pter 1. These disorders are inherited in a variety of patterns (X-linked, autoso mal dominant, or autosomal recessive). Many of these disorders appear to be caus ed by defective synthesis or assembly of critical glycoprotein (collagen) compon ents of the glomerular basement membrane. CHAPTER 3

3.2 Glomerulonephritis and Vasculitis the eyes. The disease is inherited as an X-linked trait; in some families, howev er, autosomal recessive and perhaps autosomal dominant forms exist. Clinically, the disease is more severe in males than in females. End-stage renal disease dev elops in persons 20 to 40 years of age. In some families, ocular manifestations, thrombocytopenia with giant platelets, esophageal leiomyomata, or all of these also occur. In the X-linked form of Alport's syndrome, mutations occur in genes en coding the -5 chain of type IV collagen (COL4A5). In the autosomal recessive for m of this syndrome, mutations of either -3 or -4 chain genes have been described . On light microscopy, in the early stages of the disease the glomeruli appear n ormal. With progression of the disease, however, an increase in the mesangial ma trix and segmental sclerosis develop. Interstitial foam cells are common but are not used to make a diagnosis. Results of immunofluorescence typically are negat ive, except in glomeruli with segmental sclerosis in which segmental immunoglobu lin M and complement (C3) are in the sclerotic lesions. Ultrastructural findings are diagnostic and consist of profound abnormalities of glomerular basement mem branes. These abnormalities range from extremely thin and attenuated to consider ably thickened membranes. The thickened glomerular basement membranes have multi ple layers of alternating medium and pale staining strata of basement membrane m aterial, often with incorporated dense granules. The subepithelial contour of th e basement membrane typically is scalloped. FIGURE 3-2 Schematic of basement mem brane collagen type IV. The postulated arrangement of type IV collagen chains in a normal glomerular basement membrane is illustrated. The joining of noncollage n (NC-1) and 75 domains creates a lattice (chicken wire) arrangement (A). In the glomerular basement membrane, 1 and 2 chains predominate in the triple helix (B ), but 3, 4, 5, and 6 chains are also found (not shown). Disruption of synthesis of any of these chains may lead to anatomic and pathologic alternations, such a s those seen in Alport's syndrome. Arrows indicate fibrils. (From Abrahamson and c oworkers [1]; with permission.) FIGURE 3-1 Alport's syndrome. Alport's syndrome (hereditary nephritis) is a heredita ry disorder in which glomerular and other basement membrane collagen is abnormal . This disorder is characterized clinically by hematuria with progressive renal insufficiency and proteinuria. Many patients have neurosensory hearing loss and abnormalities of NC1 7S 100nm A -S--Sa1 -S--S- a1 a2 -S--S- a2 -S--Sa1 -S--S- a1 -S--SB Hearing loss, dB 20 40 60 80 100 500 2K 4K 8K 10K 12K 14K 16K 18K Frequency FIGURE 3-3 Neurosensory hearing defect in Alport's syndrome. In patients with adul t onset Alport's syndrome, classic X-linked sensorineural hearing defects occur. T hese defects often begin with an auditory loss of high-frequency tone, as shown in this audiogram. The shaded area represents normal ranges. (Modified from Greg ory and Atkin [2]; with permission.)

Heredofamilial and Congenital Glomerular Disorders 3.3 FIGURE 3-4 Thin basement membrane nephropathy. Glomeruli with abnormally thin ba sement membranes may be a manifestation of benign familial hematuria. Glomeruli with thin basement membranes many also occur in persons who do not have a family history of renal disease but who have hematuria, low-grade proteinuria, or both . Although the ultrastructural abnormalities have some similarities in common wi th the capillary basement membranes of Alport's syndrome, these two glomerulopathi es are not directly related. Clinically, persistent microscopic hematuria or occ asional episodic gross hematuria are important features. Nonrenal abnormalities are absent. On light microscopy, the glomeruli are normal; no deposits are seen on immunofluorescence. Here, the electron microscopic abnormalities are diagnost ic; all or virtually all glomerular basement membranes are markedly thin (<200 n m in adults) without other features such as splitting, layering, or abnormal sub epithelial contours. A B of the enzyme -galactosidase with accumulation of sphingolipids in many cells. I n the kidney, accumulation of sphingolipids especially affects glomerular viscer al epithelial cells. Deposition of sphingolipids in the vascular tree may lead t o premature coronary artery occlusion (angina or myocardial infarction) or cereb rovascular insufficiency (stroke). Involvement of nerves leads to painful acropa resthesias and decreased perspiration (anhidrosis). The most common renal manife station is that of proteinuria with progressive renal insufficiency. On light mi croscopy, the morphologic abnormalities of the glomeruli primarily consist of en largement of visceral epithelial cells and accumulation of multiple uniform smal l vacuoles in the cytoplasm (arrow in Panel A). Ultrastructurally, the inclusion s are those of whorled concentric layers appearing as zebra bodies or myeloid bodi es representing sphingolipids (B). These structures also may be observed in mesa ngial and endothelial cells and in arterial and arteriolar smooth muscle cells a nd tubular epithelia. At considerably higher magnification, the inclusions are o bserved to consist of multiple concentric alternating clear and dark layers, wit h a periodicity ranging from 3.9 to 9.8 nm. This fine structural appearance (bes t appreciated at the arrow) is characteristic of stored glycolipids (C). C FIGURE 3-5 (see Color Plate) Fabry's disease. Fabry's disease, also known as angioke ratoma corporis diffusum or Anderson-Fabry's disease, is the result of deficiency

3.4 Glomerulonephritis and Vasculitis FIGURE 3-6 Electron microscopy of nail-patella syndrome. This disorder having sk eletal and renal manifestations affects the glomeruli, with accumulation of band ed collagen fibrils within the substance of the capillary basement membrane. Thi s accumulation appears as empty lacunae when the usual stains with electron micr oscopy (lead citrate and uranyl acetate) are used. However, as here, the fibrils easily can be identified with the use of phosphotungstic acid stain in conjunct ion with or instead of typical stains. Note that this disorder differs structura lly from collagen type III glomerulopathy in which the collagen fibrils are sube ndothelial and not intramembranous in location. Patients with nail-patella syndr ome may develop proteinuria, sometimes in the nephrotic range, with variable pro gression to end-stage renal failure. No distinguishing abnormalities are seen on light microscopy. FIGURE 3-7 Radiography of nail-patella syndrome. The skeletal manifestations of nail-patella syndrome are characteristic and consist of absent patella and absen t and dystrophic nails. These photographs illustrate absent patella (A) and the characteristic nail changes (B) that occur in patients with the disorder. (From Gregory and Atkin [2]; with permission.) B A

Heredofamilial and Congenital Glomerular Disorders 3.5 A FIGURE 3-8 (see Color Plate) Lecithin-cholesterol acyl transferase deficiency. L ipid accumulation occurs in this hereditary metabolic disorder, especially in ex tracellular sites throughout glomerular basement membranes and the mesangial mat rix. A, On electron microscopy the lipid appears as multiple small lacunae, ofte n with small round dense granular or membranous structures (arrows). Lipid-conta ining monocytes may be in the capillary lumina. B, The mesangial regions are wid ened on light microscopy, usually with expansion of the matrix that stains less intensely than normal. Basement B membranes are irregularly thickened. Some capillary lumina may contain foam cell s. Although quite rare, this autosomal recessive disease has been described in m ost parts of the world; however, it occurs most commonly in Norway. Patients exh ibit proteinuria, often with microscopic hematuria usually noted in childhood. R enal insufficiency may develop in the fourth or fifth decade of life and may pro gress rapidly. Nonrenal manifestations include corneal opacification, hemolytic anemia, early atherosclerosis, and sea-blue histocytes in the bone marrow and sp leen. A FIGURE 3-9 (see Color Plate) Lipoprotein glomerulopathy. Patients with this rare disease, which often is sporadic (although some cases occur in the same family) , exhibit massive proteinuria. Lipid profiles are characterized by increased pla sma levels of cholesterol, triglycerides, and very low density lipoproteins. Mos t patients have heterozygosity for apolipoprotein E2/3 or E2/4. A, The glomeruli are the sites of massive intracapillary accumulation of lipoproteins, which app ear as slightly tan masses (thrombi) dilating capillaries (arrows). Segmental B mesangial hypercellularity or mesangiolysis may be present. With immunostaining for -lipoprotein, apolipoproteins E and B are identified in the luminal masses. B, Electron microscopic findings indicate the thrombi consist of finely granular material with numerous vacuoles (lipoprotein). Lipoprotein glomerulopathy may p rogress to renal insufficiency over a long period of time. Recurrence of the les ions in a transplanted organ has been reported infrequently. Lipid-lowering agen ts are mostly ineffective.

3.6 Glomerulonephritis and Vasculitis A FIGURE 3-10 (see Color Plate) Nephropathic cystinosis. In older children and you ng adults, compared with young children, patients with cystinosis commonly exhib it glomerular involvement rather than tubulointerstitial disease. Proteinuria an d renal insufficiency are the typical initial manifestations. A, As the most con stant abnormality on light microscopy, glomeruli B have occasionally enlarged and multinucleated visceral epithelial cells (arrow). As the disease progresses, segmental sclerosis becomes evident as in the photom icrograph. B, Crystalline inclusions are identified on electron microscopy. The crystals of cysteine are usually dissolved in processing, leaving an empty space as shown here by the arrows. A FIGURE 3-11 (see Color Plate) Finnish type of congenital nephrotic syndrome. Sev eral disorders are responsible for nephrotic syndrome within the first few month s to first year of life. The most common and important of these is known as cong enital nephrotic syndrome of Finnish type because the initial descriptions empha sized the more common occurrence in Finnish families. This nephrotic syndrome is an inherited disorder in which infants exhibit massive proteinuria shortly afte r birth; typically, the placenta is enlarged. This disorder can be diagnosed in utero; increased -fetoprotein levels in amniotic fluid is a common feature. A, T he microscopic appearance of B the kidneys is varied. Some glomeruli are small and infantile without other alte rations, whereas others are enlarged, more mature, and have diffuse mesangial hy percellularity. Because of the massive proteinuria, some tubules are microcystic ally dilated, a finding responsible for the older term for this disorder, microc ystic disease. Because this syndrome is primarily a glomerulopathy, the tubular abnormalities are a secondary process and should not be used to designate the na me of the disease. B, On electron microscopy, complete effacement of the foot pr ocesses of visceral epithelial cells is observed.

Heredofamilial and Congenital Glomerular Disorders 3.7 FIGURE 3-12 Diffuse mesangial sclerosis. This disorder is exhibited within the f irst few months of life with massive proteinuria, often with hematuria and progressive renal insufficiency. Currently, no evidence exists tha t this disorder is an inherited process with genetic linkage. The glomeruli char acteristically are small compact masses of extracellular matrix with numerous or all capillary lumina being obliterated. As here, the visceral epithelial cells typically are arranged as a corona or crown overlying the contracted capillary t ufts. Earlier stages of glomerular involvement are characterized by variable inc rease in mesangial cellularity. Immunofluorescence is typically negative for imm unoglobulin deposits because this disorder is not immune mediated. In some patie nts, diffuse mesangial sclerosis may be part of the triad of the Drash syndrome characterized by ambiguous genitalia, Wilms' tumor, and diffuse mesangial sclerosi s. In some patients, only two of the three components may be present; however, s ome investigators consider all patients with diffuse mesangial sclerosis to be a t risk for the development of Wilms' tumor even in the absence of genital abnormal ities. Thus, close observation or bilateral nephrectomy as prophylaxis against t he development of Wilms' tumor is employed occasionally. References 1. Abrahamson D, Van der Heurel GB, Clapp WL, et al.: Nephritogenic antigens in the glomerular basement membrane. In Immunologic Renal Diseases. Edited by Niels on EG, Couser, WG. Philadelphia: Lippincott-Raven, 1997. 2. Gregory M, Atkin C: Alport's syndrome, Fabry disease and nail-patella syndrome. In Diseases of the Kid ney, Vol. I. edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little Brown, 1 995.

Infection-Associated Glomerulopathies Arthur H. Cohen Richard J. Glassock M any glomerular diseases may be associated with acute and chronic infectious dise ases of bacterial, viral, fungal, or parasitic origin. In many instances, the gl omerular activators are transient and of little clinical consequence. In other i nstances, distinct clinical syndromes such as acute nephritis or nephrotic syndr ome may be provoked. Some of the more important infection-related glomerular dis eases are illustrated here. Others diseases, including human immunodeficiency vi rus and hepatitis, are also discussed in Volume IV. CHAPTER 4

4.2 Glomerulonephritis and Vasculitis A B streptococcus. Typically, patients with glomerulonephritis exhibit hematuria, ed ema, proteinuria, and hypertension. Renal function frequently is depressed, some times severely. Most patients recover spontaneously, and a few go on to rapidly progressive or chronic indolent disease. A, On light microscopy the glomeruli ar e enlarged and hypercellular, with numerous leukocytes in the capillary lumina a nd a variable increase in mesangial cellularity. The leukocytes are neutrophils and monocytes. The capillary walls are single-contoured, and crescents may be pr esent. B, On immunofluorescence, granular capillary wall and mesangial deposits of immunoglobulin G and complement C3 are observed (starry-sky pattern). Three p redominant patterns occur depending on the location of the deposits; these inclu de garlandlike, mesangial, and starry-sky patterns. C, The ultrastructural findi ngs are those of electron-dense deposits, characteristically but not solely in t he subepithelial aspects of the capillary walls, in the form of large gumdrop or hump-shaped deposits (arrow). However, electron-dense deposits also are found i n the mesangial regions and occasionally subendothelial locations. Endothelial c ells often are swollen, and leukocytes are not only found in the capillary lumin a but occasionally in direct contact with basement membranes in capillary walls with deposits. Similar findings may be observed in glomerulonephritis after infe ctious diseases other than certain strains of Streptococci. C FIGURE 4-1 (see Color Plate) Light, immunofluorescent, and electron microscopy o f poststreptococcal (postinfectious) glomerulonephritis. Glomerulonephritis may follow in the wake of cutaneous or pharyngeal infection with a limited number of nephritogenic serotypes of group A -hemolytic

Infection-Associated Glomerulopathies 4.3 FIGURE 4-2 Infective endocarditis and shunt nephritis. The glomerulonephritis ac companying infective endocarditis or infected ventriculoatrial shunts or other i ndwelling devices is that of a postinfectious glomerulonephritis or membranoprol iferative glomerulonephritis type I pattern, or both (see Fig. 2-18). In reality , the changes often are a combination of both. As shown here, this glomerulopath y is characterized by increased mesangial cellularity, with slight lobular archi tecture; occasionally thickened capillary walls, with double contours (arrow); a nd leukocytes in some capillary lumina. This glomerulus also has a small crescen t. A B (focal segmental) glomerulosclerosis with significant tubular and interstitial a bnormalities. A, In HIVAN, many visceral epithelial cells are enlarged, coarsely vacuolated, contain protein reabsorption droplets, and overlay capillaries with varying degrees of wrinkling and collapse of the walls (arrows). B, In HIVAN, t he tubules are dilated and filled with a precipitate of plasma protein, and the tubular epithelial cells display various degenerative features (arrow). Ultrastr uctural findings are a combination of those expected for the glomerulopathy as w ell as those common to HIV infection. Thus, the foot processes of visceral epith elial cells are effaced and often detached from the capillary basement membranes . C, Common in HIV infection are tubuloreticular structures, modifications of th e cytoplasm of endothelial cells in which clusters of microtubular arrays are in many cells (arrow). Some evidence suggests that HIV or viral proteins localize in renal epithelial cells and perhaps are directly or indirectly responsible for the cellular and functional damage. HIVAN often has a rapidly progressive downh ill course, culminating in end-stage renal disease in as few as 4 months. HIVAN has a striking racial predilection; over 90% of patients are black. The other gl omerulopathy that may be an integral feature of HIV infection is immunoglobulin A nephropathy. In this setting, HIV antigen may be part of the glomerular immune complexes and circulating immune complexes. The morphology and clinical course generally are the same as in immunoglobulin A nephropathy occurring in the non-H IV setting. C FIGURE 4-3 (see Color Plate) Human immunodeficiency virus (HIV) infection. Many forms of renal disease have been described in patients infected with HIV. Variou s immune complexmediated glomerulonephritides associated with complicating infect ions are known; however, several disorders appear to be directly or indirectly r elated to HIV itself. Perhaps the more common of these is known as HIV-associate d nephropathy (HIVAN). This disease is a form of the collapsing

4.4 Glomerulonephritis and Vasculitis A B HT C FIGURE 4-4 (see Color Plate) Hepatitis C virus infection. The most common glomer ulonephritis in patients infected with the hepatitis C virus is membranoprolifer ative glomerulonephritis with, in some instances, cryoglobulinemia and cryoglobu lin precipitates in glomerular capillaries. Thus, the morphology is basically th e same as in membranoproliferative glomerulonephritis type I (Fig. 2-18AC). A, Wi th cryoglobulins, precipitates of protein representing cryoglobulin in the capil lary lumina and appearing as hyaline thrombi (HT)are observed (arrows), often wi th numerous monocytes in most capillaries. B, Immunofluorescence microscopy disc loses D peripheral granular to confluent granular capillary wall deposits of immunoglobu lin M (IgM) and complement C3; the same immune proteins are in the luminal masse s corresponding to hyaline thrombi (arrow). C, Electron microscopy indicates the luminal masses (HT). D, On electron microscopy the deposits also appear to be c omposed of curvilinear or annular structures (arrows). Hepatitis C viral antigen has been documented in the circulating cryoglobulins. Membranous glomerulonephr itis with a mesangial component also has been infrequently described in patients infected with the hepatitis C virus.

Infection-Associated Glomerulopathies 4.5 A B the isolation of the hepatitis C virus and its separation from the hepatitis B v irus, membranoproliferative glomerulonephritis was considered a common immune co mplexmediated manifestation of hepatitis B virus infection. However, more recent data indicate that this form of glomerulonephritis is a feature of hepatitis C v irus infection rather than hepatitis B virus infection. In contrast, membranous glomerulonephritis, often with mesangial deposits and variable mesangial hyperce llularity, is the glomerulopathy that is a common accompaniment of hepatitis B v irus infection. Hepatitis B virus surface, core, or e antigens have been identif ied in the glomerular deposits. The morphology of the glomerular capillary walls is similar to the idiopathic form of membranous glomerulonephritis. A, Some deg ree of mesangial widening with increased cellularity occurs in most affected pat ients. B, Similarly, on immunofluorescence, uniform granular capillary wall depo sits of immunoglobulin G (IgG), complement C3, and both light chains are disclos ed (IgG). It sometimes is very difficult to identify mesangial deposits in this setting. C, In addition to the expected capillary wall changes, electron microsc opy discloses deposits in mesangial regions of many lobules (the arrow indicates mesangial deposits; the arrowheads indicate subepithelial deposits). C FIGURE 4-5 (see Color Plate) Hepatitis B virus infection. Several glomerulopathi es have been described in association with hepatitis B viral infection. Until

Vascular Disorders Arthur H. Cohen Richard J. Glassock V ascular disorders of the kidney comprise a very heterogeneous array of lesions a nd abnormalities, depending on the site of the lesion and underlying pathogenesi s. Here, three common disorders are the focus: thrombotic microangiopathies, ben ign and malignant nephrosclerosis, and vascular occlusive disease (atheroembolis m). Vasculitis and renovascular hypertension are discussed in other chapters. CHAPTER 5

5.2 Glomerulonephritis and Vasculitis A B E C D thrombocytopenic purpura, malignant hypertension, and renal disease in progressi ve systemic sclerosis (scleroderma renal crises). A, These lesions are character ized primarily by fibrin deposition in the walls of the glomeruli (fibrin). B, T his fibrin deposition is associated with endothelial cell swelling (arrow) and t hickened capillary walls, sometimes with a double contour. Variable capillary wa ll wrinkling and luminal narrowing occur. Mesangiolysis (dissolution of the mesa ngial matrix and cells) is not uncommon and may be associated with microaneurysm formation. With further endothelial cell damage, capillary thrombi ensue. C, Ar teriolar thrombi also may be present. In arterioles, fibrin deposits in the wall s and lumina are known as thrombonecrotic lesions, with extension of this proces s into the glomeruli on occasion (arrow). The arterial walls are thickened, with loose concentric intimal proliferation. D, On electron microscopy, the subendot helial zones of the glomerular capillary wall are widened (arrows). Flocculent m aterial accumulates, corresponding to mural fibrin, with associated endothelial cell swelling. E, With widespread arterial thrombosis, cortical necrosis is a co mmon complicating feature. The necrotic cortex consists of pale confluent multif ocal zones throughout the cortex. E FIGURE 5-1 Light microscopy of thrombotic microangiopathies. This group of disor ders includes hemolytic-uremic syndrome and thrombotic

Vascular Disorders 5.3 FIGURE 5-2 (see Color Plate) Microangiopathic hemolytic anemia. Bizarrely shaped and fragmented erythrocytes are commonly seen in Wright's stained peripheral bloo d smears from patients with active lesions of thrombotic microangiopathy. These abnormally shaped erythrocytes presumably arise when the fibrin strands within s mall blood vessels shear the cell membrane, with imperfect resolution of the bic oncave disk shape. The resultant intravascular hemolysis causes anemia, reticulo cytosis, and reduced plasma haptoglobin level. FIGURE 5-3 (see Color Plate) Disseminated intravascular coagulation. In dissemin ated intravascular coagulation, fibrin thrombi are typically found in many glome rular capillary lumina. In contrast to the thrombotic microangiopathies, in diss eminated intravascular coagulation, fibrin is not primarily in vessel walls but in the lumina. Consequently, the capillary wall thickening, endothelial cell swe lling, and fibrin accumulation in subendothelial locations are not features of t his lesion. In the glomerulus illustrated, the fibrin is in many capillary lumin a and appears as bright fuchsin positive (red) masses. A FIGURE 5-4 Benign and malignant nephrosclerosis. In benign nephrosclerosis the a rtery walls are thickened with intimal fibrosis and luminal narrowing. Arteriola r walls are thickened with insudative lesions, a process affecting afferent arte rioles almost exclusively. Both of these processes, which can be quite patchy, r esult in chronic ischemia. A, In glomeruli, chronic ischemia is manifested by gr adual capillary wall wrinkling, luminal narrowing, and shrinkage and solidificat ion of the tufts. B, As these processes progress, collagen forms internal to Bow man's capsule, beginning at the vascuB lar pole and growing as a collar around the wrinkled ischemic tufts. This collag en formation ultimately is associated with tubular atrophy and interstitial fibr osis. In malignant nephrosclerosis the changes are virtually identical to those of thrombotic microangiopathies (Fig. 5-1 C). Malignant nephrosclerosis may be s een in essential hypertension, scleroderma, unilateral renovascular hypertension (with a contralateral or unprotected kidney), and as a complicating event in many chronic renal parenchymal diseases.

5.4 Glomerulonephritis and Vasculitis A B instrumentation of patients with severe arteriosclerosis. Most commonly, aortic plaques are complicated with ulceration and often adherent fibrin, A. Portions o f plaques are dislodged and travel distally in the aorta. Because the kidneys re ceive a disproportionately large share of the cardiac output, they are a favored site of emboli. Typically, the emboli are in small arteries and arterioles, alt hough glomerular involvement with a few cholesterol crystals in capillaries is n ot uncommon. Because of the size of the crystals, it is sometimes difficult if n ot impossible to identify them in glomerular capillaries in paraffin-embedded se ctions. In plastic-embedded sections prepared for electron microscopy, however, the crystals are quite easy to detect. On light microscopy, cholesterol is repre sented by empty crystalline spaces. In the early stages of the disease the cryst als lie free in the vascular lumina. In time, the crystals are engulfed by multi nucleated foreign body giant cells. B, In this light microscopic photograph, a f ew crystals are evident in the glomerular capillary lumina and in an arteriole ( arrows). C, In the electron micrograph the elongated empty space represents diss olved cholesterol. Note that no cellular reaction is evident. C FIGURE 5-5 Vascular occlusive disease and thrombosis. Atheroemboli (cholesterol emboli) are most commonly associated with intravascular

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis Garabed Eknoyan Luan D. Truong A s a rule, diseases of the kidney primarily affect the glomeruli, vasculature, or remainder of the renal parenchyma that consists of the tubules and interstitium . Although the interstitium and the tubules represent separate functional and st ructural compartments, they are intimately related. Injury initially involving e ither one of them inevitably results in damage to the other. Hence the term tubu lointerstitial diseases is used. Because inflammatory cellular infiltrates of va riable severity are a constant feature of this entity, the terms tubulointerstit ial diseases and tubulointerstitial nephritis have come to be used interchangeab ly. The clinicopathologic syndrome that results from these lesions, commonly ter med tubulointerstitial nephropathy, may pursue an acute or chronic course. The c hronic course is discussed here. The abbreviation TIN is used to refer synonymou sly to chronic tubulointerstitial nephritis and tubulointerstitial nephropathy. TIN may be classified as primary or secondary in origin. Primary TIN is defined as primary tubulointerstitial injury without significant involvement of the glom eruli or vasculature, at least in the early stages of the disease. Secondary TIN is defined as secondary tubulointerstitial injury, which is consequent to lesio ns initially involving either the glomeruli or renal vasculature. The presence o f secondary TIN is especially important because the magnitude of impairment in r enal function and the rate of its progression to renal failure correlate better with the extent of TIN than with that of glomerular or vascular damage. Renal in sufficiency is a common feature of chronic TIN, and its diagnosis must be consid ered in any patient who exhibits renal insufficiency. In most cases, however, ch ronic TIN is insidious in onset, renal insufficiency is slow to develop, and ear liest manifestations of the disease are those of tubular dysfunction. As such, i t is important to maintain a high CHAPTER 6

6.2 Tubulointerstitial Disease the two principal hallmarks of glomerular and vascular diseases of the kidney: s alt retention, manifested by edema and hypertension; and proteinuria, which usua lly is modest and less than 1 to 2 g/d in TIN. These clinical considerations not withstanding, a definite diagnosis of TIN can be established only by morphologic examination of kidney tissue. index of suspicion of this entity whenever any evidence of tubular dysfunction i s detected clinically. At this early stage, removal of a toxic cause of injury o r correction of the underlying systemic or renal disease can result in preservat ion of residual renal function. Of special relevance in patients who exhibit ren al insufficiency caused by primary TIN is the absence or modest degree of Structure of the Interstitium CCortex ISInner stripe of outer medulla OSOuter stripe of outer medulla IZInner zone of medulla C OS IS IZ FIGURE 6-1 Diagram of the approximate relative volume composition of tissue comp artments at different segments of the kidney in rats. The interstitium of the ki dney consists of peritubular and periarterial spaces. The relative contribution of each of these two spaces to interstitial volume varies, reflecting in part th e arbitrary boundaries used in assessing them, but increases in size from the co rtex to the papilla. In the cortex there is little interstitium because the peri tubular capillaries occupy most of the space between the tubules. The cortical i nterstitial cells are scattered and relatively inconspicuous. In fact, a loss of the normally very close approximation of the cortical tubules is the first evid ence of TIN. In the medulla there is a noticeable increase in interstitial space . The interstitial cells, which are in greater evidence, have characteristic str uctural features and an organized arrangement. The ground substance of the renal interstitium contains different types of fibrils and basementlike material embe dded in a glycosaminoglycan-rich substance. (From Bohman [1]; with permission.) 100% 10 Extracellular space Vessels 50 Interstitial cells Tubules Cortex FIGURE 6-2 A, Electron micrograph of a rat kidney cortex, where C is the cortex. B, Schematic rendering, where the narrow interstitium is shown in black and the wide interstitium is shown by dots. The relative volume of the interstitium of the cortex is approximately 7%, consisting of about 3% interstitial cells and 4% extracellular space. The vasculature occupies another 6%; the remainder (ie, so me 85% or more) is occupied by the tubules. The cortical interstitial space is u nevenly distributed and has been divided into narrow and wide structural compone nts. The tubules and peritubular capillaries either are closely apposed at sever al points, sometimes to the point of sharing a common basement membrane, or are separated by a very narrow space. This space, the so-called narrow interstitium, has been estimated to occupy 0.6% of cortical volume in rats. The narrow inters titium occupies about one-half to two-thirds of the cortical peritubular capilla ry surface area. The remainder of the cortical interstitium consists of irregula rly shaped clearly discernible larger areas, the so-called wide interstitium. Th e wide interstitium has been estimated to occupy 3.4% of cortical volume in rats . The capillary wall facing the narrow interstitium is significantly more fenest rated than is that facing the wide interstitium. Functional heterogeneity of the se interstitial spaces has been proposed but remains to be clearly defined. (Fro

m Bohman [1]; with permission.) A B

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.3 Medulla FIGURE 6-3 Scanning electron micrograph of the inner medulla, showing a prominen t collecting duct, thin wall vessels, and abundant interstitium. A gradual incre ase in interstitial volume from the outer medullary stripe to the tip of the pap illa occurs. In the outer stripe of the outer medulla, the relative volume of th e interstitium is slightly less than is that of the cortex. This volume has been estimated to be approximately 5% in rats. It is in the inner stripe of the oute r medulla that the interstitium begins to increase significantly in volume, in i ncrements that gradually become larger toward the papillary tip. The inner strip e of the outer medulla consists of the vascular bundles and the interbundle regi ons, which are occupied principally by tubules. Within the vascular bundles the interstitial spaces are meager, whereas in the interbundle region the interstiti al spaces occupy some 10% to 20% of the volume. In the inner medulla the differe ntiation into vascular bundles and interbundle regions becomes gradually less ob vious until the two regions merge. A gradual increase in the relative volume of the interstitial space from the base of the inner medulla to the tip of the papi lla also occurs. In rats, the increment in interstitial space is from 10% to 15% at the base to about 30% at the tip. In rabbits, the increment is from 20% to 2 5% at the base to more than 40% at the tip. Cell types B. RENAL INTERSTITIAL CELLS Cortex Fibroblastic cells Mononuclear cells Outer medulla Fibroblastic cells Mononuclear cells Inner medulla Pericytes Lipid-laden cells Mononuclear cells A FIGURE 6-4 A, High-power view of the medulla showing the wide interstitium and i nterstitial cells, which are abundant, varied in shape, and arranged as are the rungs of a ladder. B, Renal interstitial cells. The interstitium contains two ma in cell types, whose numbers increase from the cortex to the papilla. Type I int erstitial cells are fibroblastic cells that are active in the deposition and deg radation of the interstitial matrix. Type I cells contribute to fibrosis in resp onse to chronic irritation. Type II cells are macrophage-derived mononuclear cel ls with phagocytic and immunologic properties. Type II cells are important in antigen presentation. Their cytokines contribute to recru itment of infiltrating cells, progression of injury, and sustenance of fibrogene sis. In the cortex and outer zone of the outer medulla, type I cells are more co mmon than are type II cells. In the inner zone of the medulla, some type I cells form pericytes whereas others evolve into specialized lipid-laden interstitial cells. These specialized cells increase in number toward the papillary tip and a re a possible source of medullary prostaglandins and of production of matriceal glycosaminoglycans. A characteristic feature of these medullary cells is their c onnection to each other in a characteristic arrangement, similar to the rungs of a ladder. These cells have a distinct close and regular transverse apposition t o their surrounding structures, specifically the limbs of the loop of Henle and capillaries, but not to the collecting duct cells.

6.4 Tubulointerstitial Disease Matrix FIGURE 6-5 Peritubular interstitium in the cortex at the interface of a tubule ( T) on the left and a capillary (C) on the right. The inset shows the same space in cross section, including the basement membrane (BM) of the two compartments. The extracellular loose matrix is a hydrated gelatinous substance consisting of glycoproteins and glycosaminoglycans (hyaluronic acid, heparan sulfate, dermatan sulfate, and chondroitin sulfate) that are embedded within a fibrillar reticulu m. This reticulum consists of collagen fibers (types I, III, and VI) and unbande d microfilaments. Collagen types IV and V are the principal components of the ba sement membrane lining the tubules. Glycoprotein components (fibronectin and lam inin) of the basement membrane connect it to the interstitial cell membranes and to the fibrillar structures of the interstitial matrix. The relative increase i n the interstitial matrix of the medulla may be important for providing support to the delicate tubular and vascular structures in this region. (From Lemley and Kriz [2]; with permission.) Pathologic Features of Chronic TIN FIGURE 6-6 Primary chronic TIN. The arrow indicates a normal glomerulus. Apart f rom providing structural support, the interstitium serves as a conduit for solut e transport and is the site of production of several cytokines and hormones (ery thropoietin and prostaglandins). For the exchange processes to occur between the tubules and vascular compartment, the absorbed or secreted substances must trav erse the interstitial space. The structure, composition, and permeability charac teristics of the interstitial space must, of necessity, exert an effect on any s uch exchange. Although the normal structural and functional correlates of the in terstitial space are poorly defined, changes in its composition and structure in chronic TIN are closely linked to changes in tubular function. In addition, rep lacement of the normal delicate interstitial structures by fibrosclerotic change s of chronic TIN would affect the vascular perfusion of the adjacent tubule, the reby contributing to tubular dysfunction and progressive ischemic injury.

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.5 FIGURE 6-7 Secondary chronic TIN. The arrow indicates a glomerulus with a cellul ar crescent. The diagnosis of TIN can be established only by morphologic examina tion of kidney tissue. The extent of the lesions of TIN, whether focal or diffus e, correlates with the degree of impairment in renal function. Tubular atrophy and dilation comprise a principal feature of TIN. The changes ar e patchy in distribution, with areas of atrophic chronically damaged tubules adj acent to dilated tubules displaying compensatory hypertrophy. In atrophic tubule s the epithelial cells show simplification, decreased cell height, loss of brush border, and varying degrees of thickened basement membrane. In dilated tubules the epithelial cells are hypertrophic and the lumen may contain hyalinized casts , giving them the appearance of thyroid follicles. Hence the term thyroidization is used. The interstitium is expanded by fibrous tissue, in which are intersper sed proliferating fibroblasts and inflammatory cells comprised mostly of activat ed T lymphocytes and macrophages. Rarely, B lymphocytes, plasma cells, neutrophi ls, and even eosinophils may be present. The glomeruli, which may appear crowded in some areas owing to tubulointerstitial loss, usually are normal in the early stages of the disease. Ultimately, the glomeruli become sclerosed and develop p eriglomerular fibrosis. The large blood vessels are unremarkable in the early ph ases of the disease. Ultimately, these vessels develop intimal fibrosis, medial hypertrophy, and arteriolosclerosis. These vascular changes, which also are asso ciated with hypertension, can be present even in the absence of elevated blood p ressure in cases of chronic TIN. CONDITIONS ASSOCIATED WITH PRIMARY CHRONIC TIN Urinary tract obstructions Vesicoureteral reflux Mechanical Immunologic diseases Systemic lupus erythematosus Sjgren syndrome Transplanted kidney Cryoglobulinemia Goodpasture's syndrome Immunoglobulin A nephropathy Amyloidosis Pyelonephritis Hematologic diseases Sickle hemoglobinopathies Multiple myeloma Lymphoproliferative disorders Aplasti c anemia Miscellaneous Vascular diseases Nephrosclerosis Atheroembolic disease Radiation nephritis Diab etes mellitus Sickle hemoglobinopathies Vasculitis Hereditary diseases Medullary cystic disease Hereditary nephritis Medullary sponge kidney Polycystic kidney disease Endemic diseases Balkan nephropathy Nephropathia epidemica Infections Systemic Renal Bacterial Viral Fungal Mycobacterial Drugs Analgesics Cyclosporine Nitrosourea Cisplatin Lithium Miscellaneous Heavy metals Lead Cadmium

Metabolic disorders Hyperuricemiahyperuricosuria Hypercalcemiahypercalciuria Hyperoxaluria Potassium depletion Cystinosis Granulomatous disease Sarcoidosis Tuberculosis Wegener's granulomatosis Idiopathic TIN FIGURE 6-8 Tubulointerstitial nephropathy occurs in a motley group of diseases o f varied and diverse causes. These diseases are arbitrarily grouped together because of the unifying structural changes associated with TIN noted on morphologic examination of the kidneys.

6.6 Tubulointerstitial Disease Pathogenesis of Chronic TIN Glomerular disease Vascular damage Altered filtration Tubular ischemia Reabsorption of noxious macromolecules Chronic tubular cell injury -NH3-C3b-C5 Release of cytokines, proteinases adhesion molecules, growth factors Cell balance Fibroblast proliferation -Matrix deposition - Recruitment of antigenically activated cells Tubular atrophy Interstitial fibrosis Interstitial infiltrates Tubular dysfunction Capillary perfusion FIGURE 6-9 Schematic presentation of the potential pathways incriminated in the pathogenesis of chronic TIN caused by primary tubular injury (dark boxes) or sec ondary to glomerular disease (light boxes). The mechanism by which TIN is mediat ed remains to be elucidated. Chronic tubular epithelial cell injury appears to b e pivotal in the process. The injury may be direct through cytotoxicity or indir ect by the induction of an inflammatory or immunologic reaction. Studies in expe rimental models and humans provide compelling evidence for a role of immune mech anisms. The infiltrating lymphocytes have been shown to be activated immunologic ally. It is the inappropriate release of cytokines by the infiltrating cells and loss of regulatory balance of normal cellular regeneration that results in incr eased fibrous tissue deposition and tubular atrophy. Another potential mechanism of injury is that of increased tubular ammoniagenesis by the residual functioni ng but hypertrophic tubules. Increased tubular ammoniagenesis contributes to the immunologic injury by activating the alternate complement pathway. Altered glom erular permeability with consequent proteinuria appears to be important in the d evelopment of TIN in primary glomerular diseases. By the same token, the protein uria that develops late in the course of primary TIN may contribute to the tubul ar cell injury and aggravate the course of the disease. In primary vascular dise ases TIN has been attributed to ischemic injury. In fact, hypertension is probab ly the most common cause of TIN. The vascular lesions that develop late in the c ourse of primary TIN, in turn, can contribute to the progression of TIN. (From E knoyan [3]; with permission.) b-9 Progressive loss of renal function

ROLE OF TUBULAR EPITHELIAL CELLS Chemoattractant cytokines Monocyte chemoattractant peptide-1 Osteopontin Chemoattractant lipids Endothelin -1 RANTES Pro-inflammatory cytokines Interleukin-6 (IL-6), IL-8 Platelet-derived growth factorGranulocyte -macrophage colony-stimulating factor Transforming growth factor- 1 Tumor necrosis factorCell surface markers Human leukocyte antigen class II Intercellular adhesion molecule-1 Vascular cell adhesion molecule-1 Matrix proteins Collagen I, III, IV Laminin, fibronectin From Palmer [4]; with permission. FIGURE 6-10 The infiltrating interstitial cells contribute to the course TIN. Ho wever, increasing evidence exists for a primary role of the tubular epithelial c ells in the recruitment of interstitial infiltrating cells and in perpetuation o f the process. Injured epithelial cells secrete a variety of cytokines that have both chemoattractant and pro-inflammatory properties. These cells express a num ber of cell surface markers that enable them to interact with infiltrating cells . Injured epithelial cells also participate in the deposition of increased inter stitial matrix and fibrous tissue. Listed are cytokines, cell surface markers, a nd matrix components secreted by the renal tubular cell that may play a role in the development of tubulointerstitial disease.

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.7 Role of Infiltrating Cells FIGURE 6-11 TIN showing early phase with focal (A) and more severe and diffuse ( B) interstitial inflammatory cell infiltrates. Late phase showing thickened tubu lar basement membrane, distorted tubular shape, and cellular infiltration of the tubules, called tubulitis (C). The extent and severity of interstitial cellular infiltrates show a direct correlation with the severity of tubular atrophy and interstitial fibrosis. Experimental studies show the sequential accumulation of T cells and monocytes after the initial insult. Accumulation of these cells impl icates their important role both in the early inflammatory stage of the disease and in the progression of subsequent injury. Immunohistologic examination utiliz ing monoclonal antibodies, coupled with conventional and electron microscopy, in dicates that most of the mononuclear inflammatory cells comprising renal interst itial infiltrates are T cells. These T cells are immunologically activated in th e absence of any evidence of tubulointerstitial immune deposits, even in classic examples of immune complexmediated diseases such as systemic lupus erythematosus . The profile of immunocompetent cells suggests a major role for cell-mediated i mmunity in the tubulointerstitial lesions. The infiltrating cells may be of the helper-inducer subset or the cyotoxic-suppressor subset, although generally ther e seems to be a selective prevalence for the former variety. Lymphocytes that ar e peritubular and are seen invading the tubular epithelial cells, so-called tubu litis, are generally of the cytotoxic (CD8+) variety. The interstitial accumulat ion of monocytes and macrophages involves osteopontin (uropontin). Osteopontin i s a secreted cell attachment glycoprotein whose messenger RNA expression becomes upregulated, and its levels are increased at the sites of tubular injury in pro portion to the severity of tubular damage. The expression of other cell adhesion molecules (intercellular adhesion molecule-1, vascular cellular adhesion molecu le-1, and E-selectin) also is increased at the sites of tubular injury. This inc reased expression may contribute to the recruitment of mononuclear cells and inc rease the susceptibility of renal cells to cell-mediated injury. Fibroblastic (t ype I) interstitial cells, which normally produce and maintain the extracellular matrix, begin to proliferate in response to injury. They increase their well-de veloped rough endoplasmic reticulum and acquire smooth muscle phenotype (myofibr oblast). Growth kinetic studies of these cells reveal a significant increase in their proliferating capacity and generation time, indicating hyperproliferative growth. A B C

6.8 Tubulointerstitial Disease Mechanisms Involved in Renal Interstitial Fibrosis Macrophage Virus Protein Sig na l Lymphocyte DO HLA DR DP IL 2 IL 4 IFN TNF4 IL 1 TGF3 PDGF GMCSF l na Sig Proliferating TH-Cell Proliferating B-cell Epithelial cell IL 1 PDGF IL1 IL6 IL7 IL8 IIFNb GM-CSF G-CSF M-CSF Factor x P (30/7.3) ICAM1

Proliferation -- Differentiation MF I MF III PMF IV PMF VI Synthesis -- and Secretion collagen Fibrosin P 53/6.1 Interstitial fibrosis Proximal tubulus Fibroblast FIGURE 6-12 Expression of human leukocyte antigen class II and adhesion molecule s released by injured tubular epithelial cells, as well as by infiltrating cells , modulate and magnify the process to repair the injury (Figure 6-10). When the process becomes unresponsive to controlling feedback mechanisms, fibroblasts pro liferate and increase fibrotic matrix deposition. The precise mechanism of TIN r emains to be identified. A number of pathogenetic pathways have been proposed to operate at different stages of the disease proces s. Each of these individual pathways usually is part of a recuperative process t hat works in concert in response to injury. However, it is the loss of their con trolling feedback in chronic TIN that seems to account for the altered balance a nd results in persistent cellular infiltrates, progressive fibrosis, and tubular degeneration.

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.9 Patterns of Tubular Dysfunction PATTERNS OF TUBULAR DYSFUNCTION IN CHRONIC TIN Site of injury Cortex Proximal tubule Heavy metals Multiple myeloma Immunologic diseases Cystin osis Immunologic diseases Granulomatous diseases Hereditary diseases Hypercalcem ia Urinary tract obstruction Sickle hemoglobinopathy Amyloidosis Analgesic nephr opathy Sickle hemoglobinopathy Uric acid disorders Hypercalcemia Infection Hered itary disorders Granulomatous diseases Analgesic nephropathy Diabetes mellitus I nfection Urinary tract obstruction Sickle hemoglobinopathy Transplanted kidney D ecreased reabsorption of sodium, bicarbonate, glucose, uric acid, phosphate, ami no acids Cause Tubular dysfunction Distal tubule Decreased secretion of hydrogen, potassium Decreased reabsorption of sodium Medulla Decreased ability to concentrate urine Decreased reabsorption of sodium Papilla Decreased ability to concentrate urine Decreased reabsorption of sodium FIGURE 6-13 The principal manifestations of TIN are those of tubular dysfunction . Because of the focal nature of the lesions that occur and the segmental nature of normal tubular function, the pattern of tubular dysfunction that results var ies, depending on the major site of injury. The extent of damage determines the severity of tubular dysfunction. The hallmarks of glomerular disease (such as sa lt retention, edema, hypertension, proteinuria, and hematuria) are characteristi cally absent in the early phases of chronic TIN. The type of insult determines t he segmental location of injury. For example, agents secreted by the organic pat hway in the pars recta (heavy metals) or reabsorbed in the proximal tubule (ligh t chain proteins) cause predominantly proximal tubular lesions. Depositional dis orders (amyloidosis and hyperglobulinemic states) cause predominantly distal tub ular lesions. Insulting agents that are affected by the urine concentrating mech anism (analgesics and uric acid) or medullary tonicity (sickle hemoglobinopathy) cause medullary injury. The tubulointerstitial lesions are localized either to the cortex or medulla. Co rtical lesions mainly affect either the proximal or distal tubule. Medullary les ions affect the loop of Henle and the collecting duct. The change in the normal function of each of these affected segments then determines the manifestations o f tubular dysfunction. Essentially, the proximal nephron segment reabsorbs the b ulk of bicarbonate, glucose, amino acids, phosphate, and uric acid. Changes in p roximal tubular function, therefore, result in bicarbonaturia (proximal renal ac idosis), 2-microglobinuria, glucosuria (renal glucosuria), aminoaciduria, phosph aturia, and uricosuria. The distal nephron segment secretes hydrogen and potassi um and regulates the final amount of sodium chloride excreted. Lesions primarily affecting this segment, therefore, result in the distal form of renal tubular a cidosis, hyperkalemia, and salt wasting. Lesions that primarily involve the medu lla and papilla disproportionately affect the loops of Henle, collecting ducts,

and the other medullary structures essential to attaining and maintaining medull ary hypertonicity. Disruption of these structures, therefore, results in differe nt degrees of nephrogenic diabetes insipidus and clinically manifests as polyuri a and nocturia. Although this general framework is useful in localizing the site of injury, considerable overlap may be encountered clinically, with different d egrees of proximal, distal, and medullary dysfunction present in the same indivi dual. Additionally, the ultimate development of renal failure complicates the is sue further because of the added effect of urea-induced osmotic diuresis on tubu lar function in the remaining nephrons. In this later stage of TIN, the absence of glomerular proteinuria and the more common occurrence of hypertension in glom erular diseases can be helpful in the differential diagnosis.

6.10 Tubulointerstitial Disease Correlates of Tubular Dysfunction with Severity of Chronic TIN 160 Chronic GN Acute GN PTIN Nephrosclerosis 1200 1100 1000 900 Maximal osmolality, mOs/kg 800 700 600 500 400 300 200 Chronic GN Acute GN PTIN Nephrosclerosis 140 120 Inulin clearance, mL/min 100 80 60 40 20 100 0 0 1 2 3 4 5 6 7 8 9 Interstitial disease (total score) 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12 0 A B Interstitial disease (total score) 1200 110 100 90 Ammonium excretion, Eq/min 80 70 60 50 40 30 20 10 0 0 1 2 3 Chronic GN Acute GN PTIN Nephrosclerosis FIGURE 6-14 Relationship of inulin clearance (A), maximum urine concentration (B ), and ammonium excretion in response to an acute acid load (C) to the severity of tubulointerstitial nephritis. A close correlation exists between the severity of chronic TIN and impaired renal tubular and glomerular function. Repeated eva luations of kidney biopsy for the extent of tubulointerstitial lesions have show n a close correlation with renal function test results in tests performed before biopsy. These tests include those for inulin clearance, maximal ability to conc entrate the urine, and ability to acidify the urine. This correlation has been v alidated in a variety of renal diseases, including primary and secondary forms o f chronic TIN. (From Shainuck and coworkers [5]; with permission.) C 4 5 6 7 8 9 Interstitial disease (total score) 10 11

12

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.11 Correlates of Chronic TIN with Progressive Renal Failure Probability of maintaining renal function, % 100 80 60 40 20 0 0 2 4 6 8 Followup, y 10 12 14 16 Interstitial fibrosis Normal interstitium FIGURE 6-15 Effect on long-term prognosis of the presence of cortical chronic tu bulointerstitial nephritis in patients with mesangioproliferative glomerulonephr itis (n = 455), membranous nephropathy (n = 334), and membranoproliferative glom erulonephritis (n = 220). The extent of tubulointerstitial nephritis correlates not only with altered glomerular and tubular dysfunction at the time of kidney b iopsy but also provides a prognostic index of the progression rate to endstage r enal disease. As shown, the presence of interstitial fibrosis on the initial bio psy exerts a significant detrimental effect on the progression rate of renal fai lure in a variety of glomerular diseases. (From Eknoyan [3]; with permission.) Drugs Analgesic Nephropathy Acetaminophen Metabolism nOHpacetophenetidine pphenetidine Methhemoglobin Sulfhemoglobin Phenactin pacetophenetidine Glucoronide sulfate Paracetamol nacetylpaminophenol Cytochrome P450 Reactive toxic metabolites Glutathione Covalent binding to cellular sulfhydryl Glutathione conjugate Cell death Mercapturic acid FIGURE 6-16 Metabolism of acetaminophen and its excretion by the kidney. Prolong ed exposure to drugs can cause chronic TIN. Although a number of drugs (eg, lith ium, cyclosporine, cisplatin, and nitrosoureas) have been implicated, the more c ommonly responsible agents are analgesics. As a rule, the lesions of analgesic n ephropathy develop in persons who abuse analgesic combinations (phenacetin, or i ts main metabolite acetaminophen, plus aspirin, with or without caffeine). Exper imental evidence indicates that phenacetin, or acetaminophen, plus aspirin taken alone are only moderately nephrotoxic and only at massive doses, but that the l esions can be more readily induced when these drugs are taken together. In all e xperimental studies the extent of renal injury has been dose-dependent and, when examined, water diuresis has provided protection from analgesic-induced renal injury. Relative t o plasma levels, both acetaminophen (paracetamol) and its excretory conjugate at tain significant (fourfold to fivefold) concentrations in the medulla and papill a, depending on the state of hydration of the animal studied. The toxic effect o f these drugs apparently is related to their intrarenal oxidation to reactive in termediates that, in the absence of reducing substances such as glutathione, bec

ome cytotoxic by virtue of their capacity to induce oxidative injury. Salicylate s also are significantly (sixfold to thirteenfold above plasma levels) concentra ted in the medulla and papilla, where they attain a level sufficient to uncouple oxidative phosphorylation and compromise the ability of cells to generate reduc ing substances. Thus, both agents attain sufficient renal medullary concentratio n to individually exert a detrimental and injurious effect on cell function, whi ch is magnified when they are present together. By reducing the medullary tonici ty, and therefore the medullary concentration of drug attained, water diuresis p rotects from analgesic-induced cell injury. A direct role of analgesic-induced i njury can be adduced from the improvement of renal function that can occur after cessation of analgesic abuse.

6.12 Tubulointerstitial Disease FIGURE 6-17 Course of the renal lesions in analgesic nephropathy. The intrarenal distribution of analgesics provides an explanation for the medullary location o f the pathologic lesions of analgesic nephropathy. The initial lesions are patch y and consist of necrosis of the interstitial cells, thin limbs of the loops of Henle, and vasa recta of the papilla. The collecting ducts are spared. The quant ities of tubular and vascular basement membrane and ground substance are increas ed. At this stage the kidneys are normal in size and no abnormalities have occur red in the renal cortex. With persistent drug exposure the changes extend to the outer medulla. Again, the lesions are initially patchy, involving the interstit ial cells, loops of Henle, and vascular bundles. With continued analgesic abuse, the severity of the inner medullary lesions increases with sclerosis and oblite ration of the capillaries, atrophy and degeneration of the loops of Henle and co llecting ducts, and the beginning of calcification of the necrotic foci. Ultimat ely, the papillae become entirely necrotic, with sequestration and demarcation o f the necrotic tissue. The necrotic papillae may then slough and are excreted in to the urine or remain in situ, where they atrophy further and become calcified. Cortical scarring, characterized by interstitial fibrosis, tubular atrophy, and periglomerular fibrosis, develops over the necrotic medullary segments. The med ullary rays traversing the cortex are usually spared and become hypertrophic, th ereby imparting a characteristic cortical nodularity to the now shrunken kidneys . Visual observation of these configurational changes by computed tomography sca n can be extremely useful in the diagnosis of analgesic nephropathy. in men and 96 mm in women. Bumpy contours are considered to be present if at least three in dentations are evident (panels B and C). The scan can reveal papillary calcifica tions (panels B and D). Visual observation of the configurational changes illust rated in Figure 6-18 can be extremely useful in diagnosing the scarred kidney in analgesic nephropathy. A series of careful studies using CT scans without contr ast material have provided imaging criteria for the diagnosis of analgesic nephr opathy. Validation of these criteria currently is underway by a study at the Nat ional Institutes of Health. From studies comparing analgesic abusers to persons in control groups, it has been shown that a decrease in kidney size and bumpy co ntours of both kidneys provide a diagnostic sensitivity of 90% and a specificity of 95%. The additional finding of evidence of renal papillary necrosis provides a diagnostic sensitivity of 72% and specificity of 97%, giving a positive predi ctive value of 92%. RA renal artery; RV renal vein. (From DeBroe and Elseviers [6] ; with permission.) Pathogenesis of renal lesion associated with analgesic abuse Cortex normal Outer medula patchy tubular damage a. tubular dilatation b. increase d interstitial tissue c. casts: pigment Stage I Papilla possible microscopic chan ges Cortex normal Outer medula increase in changes Papilla necrosis and atrophy attache d or separated Cortex a. atrophy area overlying necrotic papilla b. hypertrophy P apilla atrophic, necrotic Stage III Stage II Size Right kidney RA Spine a RV RA Left kidney a A b

b C Appearance Bumpy contours Papillary calcifications 0 B 12 35 >5 D Number of indentations FIGURE 6-18 Computed tomography (CT) imaging criteria for diagnosing analgesic n ephropathy. Renal size (A) is considered decreased if the sum of a and b (panels A and B) is less than 103 mm

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 1 a b c Female predominance, 6085% Age, >30 y Personality disorders: introvert, d ependent, anxiety, neurosis, family instability Addictive habits: smoking, alcoh ol, laxatives, psychotropics, sedatives Causes of analgesic dependency: headache , 4060%; mood, 630%; musculoskeletal pain, 2030% acortical nephron bjuxta medullary nephron 6.13 3 a CLINICAL FEATURES 2 a b c b c cmidcortical nephron FIGURE 6-19 Certain personality features and clinical findings characterize pati ents prone to analgesic abuse. These patients tend to deny analgesic use on dire ct questioning; however, their history can be revealing. In all cases, a relatio nship exists between renal function and the duration, intensity, and quantity of analgesic consumed. The magnitude of injury is related to the quantity of analg esic ingested chronically over years. In persons with significant renal impairme nt, the average dose ingested has been estimated at about 10 kg over a mean peri od of 13 years. The minimum amount of drug consumption that results in significa nt renal damage is unknown. It has been estimated that a cumulative dose of 3 kg of the index compound, or a daily ingestion of 1 g/d over 3 years or more, is a minimum that can result in detectable renal impairment. FIGURE 6-20 Diagram of cortical and juxtamedullary nephrons in the normal kidney (1). Papillary necrosis (2) and sloughing (3) result in loss of juxtamedullary nephrons. Cortical nephrons are spared, thereby preserving normal renal function in the early stages of the disease. The course of analgesic nephropathy is slow ly progressive, and deterioration of renal function is insidious. One reason for these characteristics of the disease is that lesions beginning in the papillary tip affect only the juxtamedullary nephrons, sparing the cortical nephrons. It is only when the lesions are advanced enough to affect the whole medulla that th e number of nephrons lost is sufficient to result in a reduction in filtration r ate. However, renal injury can be detected by testing for sterile pyuria, reduce d concentrating ability, and a distal acidifying defect. These features may be e vident at levels of mild renal insufficiency and become more pronounced and prev alent as renal function deteriorates. Proximal tubular function is preserved in patients with mild renal insufficiency but can be abnormal in those with more ad vanced renal failure. Cyclosporine A FIGURE 6-21 A, Chronic TIN caused by cyclosporine. The arrow indicates the chara cteristic hyaline-type arteriolopathy of cyclosporine nephrotoxicity. B, Patchy nature of chronic TIN caused by cyclosporine. Note the severe TIN on the right a djacent to an otherwise intact area on the left. Tubulointerstitial nephritis ha s emerged as the most serious side effect of cyclosporine. Cyclosporine-mediated vasoconstriction of the cortical microvasculature has been implicated in the de velopment of an occlusive arteriolopathy and tubular B epithelial cell injury. Whereas these early lesions tend to be reversible with c essation of therapy, an irreversible interstitial fibrosis and mononuclear cellu

lar infiltrates develop with prolonged use of cyclosporine, especially at high d oses. The irreversible nature of TIN associated with the use of cyclosporine and its attendant reduction in renal function have raised concerns regarding the lo ng-term use of this otherwise efficient immunosuppressive agent.

6.14 Tubulointerstitial Disease Heavy Metals Lead Nephropathy exposure to lead are lead-based paints; lead leaked into food during storage or processing, particularly in illegal alcoholic beverages (moonshine); and increas ingly, through environmental exposure (gasoline and industrial fumes). This insi dious accumulation of lead in the body has been implicated in the causation of h yperuricemia, hypertension, and progressive renal failure. Gout occurs in over h alf of cases. Blood levels of lead usually are normal. The diagnosis is establis hed by demonstrating increased levels of urinary lead after infusion of 1 g of t he chelating agent erthylenediamine tetraacetic acid (EDTA). The renal lesions o f lead nephropathy are those of chronic TIN. Cases examined early, before the on set of end-stage renal disease, show primarily focal lesions of TIN with relativ ely little interstitial cellular infiltrates. In more advanced cases the kidneys are fibrotic and shrunken. On microscopy, the kidneys show diffuse lesions of T IN. As expected from the clinical features, hypertensive vascular changes are pr ominent. Other heavy metals associated with TIN are cadmium, silicon, copper, bi smuth, and barium. Sufficient experimental evidence and some weak epidemiologic evidence suggest a possible role of organic solvents in the development of chron ic TIN. FIGURE 6-22 Lead nephropathy. Arrows indicate the characteristic intranuclear in clusions. Exposure to a variety of heavy metals results in development of chroni c TIN. Of these metals, the more common and clinically important implicated agen t is lead. Major sources of Ischemic Vascular Disease Hypertensive Nephrosclerosis FIGURE 6-23 Chronic TIN associated with hypertension. The arrows indicate arteri oles and small arteries with thickened walls. Tubular degeneration, interstitial fibrosis, and mononuclear inflammatory cell infiltration are part of the degene rative process that affects the kidneys in all vascular diseases involving the i ntrarenal vasculature with any degree of severity as to cause ischemic injury. R arely, if the insult is sudden and massive (such as in fulminant vasculitis), th e lesions are those of infarction and acute deterioration of renal function. Mor e commonly, the vascular lesions develop gradually and go undetected until renal insufficiency supervenes. This chronic form of TIN accounts for the tubulointer stitial lesions of arteriolar nephrosclerosis in persons with hypertension. Isch emic vascular changes also contribute to the lesions of TIN in patients with dia betes, sickle cell hemoglobinopathy, cyclosporine nephrotoxicity, and radiation nephritis.

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.15 FIGURE 6-24 Gross appearance of the kidney as a result of arteriolonephroscleros is, showing the granular and scarified cortex. Obstruction FIGURE 6-25 (see Color Plate) Chronic TIN secondary to vesicoureteral reflux (VU R). Clearly demonstrated is an area that is fairly intact (lower left corner) ad jacent to one that shows marked damage. Urinary tract obstruction, whether conge nital or acquired, is a common cause of chronic TIN. Clinically, superimposed in fection plays a secondary, adjunctive, and definitely aggravating role in the pr ogressive changes of TIN. However, the entire process can occur in the absence o f infection. As clearly demonstrated in experimental models of obstruction, mono nuclear inflammatory cell infiltration is one of the earliest responses of the k idney to ureteral obstruction. The infiltrating cells consist of macrophages and suppressor-cytotoxic lymphocytes. The release of various cytokines by the infil trating cells of the hydronephrotic kidney appears to exert a significant modula ting role in the transport processes and hemodynamic changes seen early in the c ourse of obstruction. With persistent obstruction, changes of chronic TIN set in within weeks. Fibrosis gradually becomes prominent. FIGURE 6-26 Gross appearanc e of a hydronephrotic kidney caused by vesicoureteral reflux.

6.16 Tubulointerstitial Disease Obstructive Nephropathy FIGURE 6-27 Glomerular lesion of advanced chronic TIN secondary to vesicouretera l reflux in a patient with massive proteinuria. Note the segmental sclerosis of the glomerulus and the reactive proliferation of the visceral epithelial cells. In persons with obstructive nephropathy, the onset of significant proteinuria (> 2g/d) is an ominous sign of progressive renal failure. As a rule, most of these patients will have coexistent hypertension, and the renal vasculature will show changes of hypertensive arteriolosclerosis. The glomerular changes are ischemic in nature. In those with significant proteinuria, the lesions are those of focal and segmental glomerulosclerosis and hyalinosis. The affected glomeruli commonl y contain immunoglobulin M and C3 complement on immunofluorescent microscopy. Th e role of an immune mechanism remains unclear. Autologous (Tamm-Horsfall protein and brush-border antigen) or bacterial antigen derivatives have been incriminat ed. Adaptive hemodynamic changes (hyperfiltration) in response to a reduction in renal mass, by the glomeruli of remaining intact nephrons of the hydronephrotic kidney, also have been implicated. Hematopoietic Diseases Sickle Hemoglobinopathy that of chronic TIN. By far more prevalent and severe in patients with sickle ce ll disease, variable degrees of TIN also are common in those with the sickle cel l trait, sickle cellhemoglobin C disease, or sickle cellthalassemia disease. The p redisposing factors that lead to a propensity of renal involvement are the physi cochemical properties of hemoglobin S that predispose its polymerization in an e nvironment of low oxygen tension, hypertonicity, and low pH. These conditions ar e characteristic of the renal medulla and therefore are conducive to the intraer ythrocyte polymerization of hemoglobin S. The consequent erythrocyte sickling ac counts for development of the typical vascular occlusive lesions. Although some of these changes occur in the cortex, the lesions begin and are predominantly lo cated in the inner medulla, where they are at the core of the focal scarring and interstitial fibrosis. These lesions account for the common occurrence of papil lary necrosis. Examples of tubular functional abnormalities common and detectabl e early in the course of the disease are the following: impaired concentrating a bility, depressed distal potassium and hydrogen secretion, tubular proteinuria, and decreased proximal reabsorption of phosphate, and increased secretion of uri c acid and creatinine. FIGURE 6-28 The kidney in sickle cell disease. Note the tubular deposition of he mosiderin. The principal renal lesion of hemoglobinopathy S is

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.17 Hematologic Diseases Plasma Cell Dyscrasias FIGURE 6-29 (see Color Plate) A, Myeloma cast nephropathy. The arrow indicates a multinucleated giant cell. B, Light chain deposition disease. Note the changes indicative of chronic TIN and light chain deposition along the tubular basement membrane (dark purple). C, Immunofluorescent stain for light chain deposition al ong the tubular basement membrane. The renal complications of multiple myeloma a re a major risk factor in the morbidity and mortality of this neoplastic disorde r. Whereas the pathogenesis of renal involvement is multifactorial (hypercalcemi a and hyperuricemia), it is the lesions that result from the excessive productio n of light chains that cause chronic TIN. These lesions are initiated by the pre cipitation of the light chain dimers in the distal tubules and result in what ha s been termed myeloma cast nephropathy. The affected tubules are surrounded by m ultinucleated giant cells. Adjoining tubules show varying degrees of atrophy. Th e propensity of light chains to lead to myeloma cast nephropathy appears to be r elated to their concentration in the tubular fluid, the tubular fluid pH, and th eir structural configuration. This propensity accounts for the observation that increasing the flow rate of urine or its alkalinization will prevent or reverse the casts in their early stages of formation. Direct tubular toxicity of light c hains also may contribute to tubular injury. Light chains appear to be more inju rious than are light chains. Binding of human and light chains to human and rat proximal tubule epithelial cell brush-border membrane has been demonstrated. Epi thelial cell injury associated with the absorption of these light chains in the proximal tubules has been implicated in the pathogenesis of cortical TIN. Anothe r mechanism relates to the perivascular deposition of paraproteins, either as am yloid fibrils that are derived from chains or as fragments of light chains that are derived from kappa chains, and produce the so-called light chain deposition disease. Of the various lesions, myeloma cast nephropathy appears to be the most common, being observed at autopsy in one third of cases, followed by amyloid de position, which is present in 10% of cases. Light chain deposition is relatively rare, being present in less than 5% of cases. A B C

6.18 Tubulointerstitial Disease Metabolic Disorders Hyperuricemia A FIGURE 6-30 A, Intratubular deposits of uric acid. B, Gouty tophus in the renal medulla. The kidney is the major organ of urate excretion and a primary target o rgan affected in disorders of its metabolism. Renal lesions result from crystall ization of urate in the urinary outflow tract or the renal parenchyma. Depending on the load of urate, one of three lesions result: acute urate nephropathy, uri c acid nephrothiasis, or chronic urate nephropathy. Whereas any of these lesions produce tubulointerstitial lesions, it is those of chronic urate nephropathy th at account for most cases of chronic TIN. The principal lesion of chronic urate nephropathy is due to deposition of microtophi of amorphous urate crystals in th e interstitium, with a surrounding giant-cell reaction. An earlier change, howev er, probably is due to the precipitation of birefringent uric acid crystals in t he collecting tubules, with consequent tubular obstruction, dilatation, atrophy, and interstitial fibrosis. The renal injury in persons who develop lesions has been attributed to B hyperacidity of their urine caused by an inherent abnormality in the ability to produce ammonia. The acidity of urine is important because uric acid is 17 times less soluble than is urate. Therefore, uric acid facilitates precipitation in t he distal nephron of persons who do not overproduce uric acid but who have a per sistently acidic urine. The previous notion that chronic renal disease was commo n in patients with hyperuricemia is now considered doubtful in light of prolonge d follow-up studies of renal function in persons with hyperuricemia. Renal dysfu nction could be documented only when the serum urate concentration was more than 10 mg/dL in women and more than 13 mg/dL in men for prolonged periods. The dete rioration of renal function in persons with hyperuricemia of a lower magnitude h as been attributed to the higher than expected occurrence of concurrent hyperten sion, diabetes mellitus, abnormal lipid metabolism, and nephrosclerosis.

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.19 Hyperoxaluria A FIGURE 6-31 (see Color Plate) A, Calcium oxalate crystals (arrow) seen on light microscopy. B, Dark field microscopy. When hyperoxaluria is sudden and massive ( such as after ethylene glycol ingestion) acute renal failure develops. Otherwise , in most cases of hyperoxaluria the overload is insidious and B chronic. As a result, interstitial fibrosis, tubular atrophy, and dilation resul t in chronic TIN with progressive renal failure. The propensity for recurrent ca lcium oxalate nephrolithiasis and consequent obstructive uropathy contribute to the tubulointerstitial lesions. Granulomatous Diseases Malacoplakia 3 5 1 2 7 4 6 FIGURE 6-32 Schematic representation of the forms and course of renal involvemen t by malacoplakia: 1, normal kidney; 2, enlarged kidney resulting from interstit ial nephritis without nodularity; 3, unifocal nodular involvement; 4, multifocal nodular involvement; 5, abscess formation with perinephric spread of malacoplak ia; 6, cystic lesions; and 7, atrophic multinodular kidney after treatment. Inte rstitial granulomatous reactions are a rare but characteristic hallmark of certain forms of tubulointerstitial disease. The best-known form is that of sarcoidosis. Interstitial granulomatous reactions also have been noted i n renal tuberculosis, xanthogranulomatous pyelonephritis, renal malacoplakia, We gener's granulomatosis, renal candidiasis, heroin abuse, hyperoxaluria after jejun oileal bypass surgery, and an idiopathic form in association with anterior uveit is. The inflammatory lesions of malacoplakia principally affect the urinary blad der but may involve other organs, most notably the kidneys. The kidney lesions m ay be limited to one focus or may be multifocal. In three fourths of cases the r enal involvement is multifocal, and in one third of cases both kidneys are invol ved. The lesions are nodular, well-demarcated, and variable in size. They may co alesce, developing foci of suppuration that may become cystic or calcified. The lesions usually are located in the cortex but may be medullary and result in pap illary necrosis. (From Dobyan and coworkers [7]; with permission.)

6.20 Tubulointerstitial Disease Endemic Diseases in a geographic area bordering the Danube River as it traverses Romania, Bulgari a, and the former Yugoslavia. The cause of Balkan nephropathy is unknown; howeve r, it has been attributed to genetic factors, heavy metals, trace elements, and infectious agents. The disease evolves in emigrants from endemic regions, sugges ting a role for inheritance or the perpetuation of injury sustained before emigr ation. Initially thought to be restricted to Scandinavian countries, and thus te rmed Scandinavian acute hemorrhagic interstitial nephritis, Nephropathia epidemi ca has been shown to have a more universal occurrence. It therefore has been mor e appropriately renamed hemorrhagic fever with renal syndrome. As a rule the dis ease presents as a reversible acute tubulointerstitial nephritis but can progres s to a chronic form. It is caused by a rodent-transmitted virus of the Hantaviru s genus of the Bunyaviridae family, the so-called Hantaan virus. Humans appear t o be infected by respiratory aerosols contaminated by rodent excreta. Antibodies to the virus are detected in the serum, and viruslike structures have been demo nstrated in the kidneys of persons infected with the virus. Tubulointerstitial n ephropathy caused by viral infection also has been reported in polyomavirus, cyt omegalovirus, herpes simplex virus, human immunodeficiency virus, infectious mon onucleosis, and Epstein-Barr virus. FIGURE 6-33 Hemorrhagic TIN associated with Hantavirus infection. Two endemic di seases in which tubulointerstitial lesions are a predominant component are Balka n nephropathy and nephropathia epidemica. Endemic Balkan nephropathy is a progre ssive chronic tubulointerstitial nephritis whose occurrence is mostly clustered Hereditary Diseases Hereditary Nephritis A FIGURE 6-34 A, Interstitial foam cells in Alport's syndrome. B, Late phase Alport's syndrome showing chronic TIN and glomerular changes in a patient with massive pr oteinuria. Tubulointerstitial lesions are a prominent component of the renal pat hology of a variety of hereditary diseases of the kidney, such as medullary cyst ic disease, familial juvenile nephronophthisis, medullary sponge kidney, and pol ycystic kidney disease. The primary disorder of these conditions is a tubular de fect that results in the cystic dilation of the affected segment in some patient s. Altered tubular basement membrane composition and B associated epithelial cell proliferation account for cyst formation. It is the c ontinuous growth of cysts and their progressive dilation that cause pressure-ind uced ischemic injury, with consequent TIN of the adjacent renal parenchyma. Tubu lointerstitial lesions also are a salient feature of inherited diseases of the g lomerular basement membrane. Notable among them are those of hereditary nephriti s or Alport's syndrome, in which a mutation in the encoding gene localized to the X chromosome results in a defect in the -5 chain of type IV collagen.

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.21 Papillary Necrosis A FIGURE 6-35 A, Renal papillary necrosis. The arrow points to the region of a slo ughed necrotic papilla. B, Whole mount of a necrotic papilla. Arrows delineate f ocal necrosis principally affecting the medullary inner stripe. Renal papillary necrosis (RPN) develops in a variety of diseases that cause chronic tubulointers titial nephropathy in which the lesion is more severe in the inner medulla. The basic lesion affects the vasculature with consequent focal or diffuse ischemic n ecrosis of the distal segments of one or more renal pyramids. In the affected pa pilla, the sharp demarcation of the lesion and coagulative necrosis seen in the early stages of the disease closely resemble those of infarction. The fact that the necrosis is anatomically limited to the papillary tips can be attributed to a variety of features unique to this site, especially those affecting the vascul ature. The renal papilla receives its blood supply from the vasa recta. Measurem ents of medullary blood flow notwithstanding, it should be noted that much of th e blood flow in the vasa recta serves the countercurrent exchange mechanism. Nut rient blood supply is provided by small capillary vessels that originate in each given region. The net effect is that the blood supply to the papillary tip is l ess than that to the rest of the medulla, hence its predisposition to ischemic n ecrosis. The necrotic lesions may be limited to only a few of the papillae or ma y involve several of the papillae in B either one or both kidneys. The lesions are bilateral in most patients. In patie nts with involvement of one kidney at the time of initial presentation, RPN will develop in the other kidney within 4 years, which is not unexpected because of the systemic nature of the diseases associated with RPN. RPN may be unilateral i n patients in whom predisposing factors (such as infection and obstruction) are limited to one kidney. Azotemia may be absent even in bilateral papillary necros is, because it is the total number of papillae involved that ultimately determin es the level of renal insufficiency that develops. Each human kidney has an aver age of eight pyramids, such that even with bilateral RPN affecting one papilla o r two papillae in each kidney, sufficient unaffected renal lobules remain to mai ntain an adequate level of renal function. As a rule, RPN is a disease of an old er age group, the average age of patients being 53 years. Nearly half of cases o ccur in persons over 60 years of age. More than 90% of cases occur in persons ov er 40 years of age, except for those caused by sickle cell hemoglobinopathy. RPN is much less common in children, in whom the chronic conditions associated with papillary necrosis are rare. However, RPN does occur in children in association with hypoxia, dehydration, and septicemia.

6.22 Tubulointerstitial Disease Total Papillary Necrosis Renal Papillary Necrosis Papillary Form Lesion Normal Early necrosis, mucosa normal, papilla swollen. Progressive necros is, swelling, mucosal loss. Sequestrian of necrotic area. Sinus formation begins . Sinus surrounds sequestrum. Sequestrum extruded or resorbed. "Ring Shadow" Pye logram Normal calyx Irregular or fuzzy calyx Sinus or "Arc Shadow" "Clubbing" "Clubbed calyx" "Caliectasis" "Ring Shadow" Obstruction Sequestrum calcifies. Extruded sequestrum FIGURE 6-36 Schematic of the progressive stages of the papillary form of renal p apillary necrosis and their associated radiologic changes seen on intravenous py elography. Papillary necrosis occurs in one of two forms. In the medullary form, also termed partial papillary necrosis, the inner medulla is affected; however, the papillary tip and fornices remain intact. In the papillary form, also terme d total papillary necrosis, the calyceal fornices and entire papillary tip are n ecrotic. In total papillary necrosis shown here, the lesion is characterized fro m the outset by necrosis, demarcation, and sequestration of the papillae, which ultimately slough into the pelvis and may be recovered in the urine. In most of these cases, howev er, the necrotic papillae are not sloughed but are either resorbed or remain in situ, where they becomes calcified or form the nidus of a calculus. In these pat ients, excretory radiologic examination and computed tomography scanning are dia gnostic. Unfortunately, these changes may not be evident until the late stages o f RPN, when the papillae already are shrunken and sequestered. In fact, even whe n the papillae are sloughed out, excretory radiography can be negative. The pass age of sloughed papillae is associated with lumbar pain, which is indistinguisha ble from ureteral colic of any cause and is present in about half of patients. O liguria occurs in less than 10% of patients. A definitive diagnosis of RPN can b e made by finding portions of necrotic papillae in the urine. A deliberate searc h should be made for papillary fragments in urine collected during or after atta cks of colicky pain of all suspected cases, by straining the urine through filte r paper or a piece of gauze. The separation and passage of papillary tissue may be associated with hematuria, which is microscopic in some 40% to 45% of patient s and gross in 20%. The hematuria can be massive, and occasionally, instances of exsanguinating hemorrhage requiring nephrectomy have been reported. (From Eknoy an and coworkers [8]; with permission.) FIGURE 6-37 Schematic of the progressive stages of the medullary form of renal papillary necrosis and their associated r adiologic appearance seen on intravenous pyelography. In partial papillary necro sis the lesion begins as focal necrosis within the substance of the medullary in ner stripe. The lesion progresses by coagulative necrosis to form a sinus to the papillary tip, with subsequent extrusion or resorption of the sequestered necro tic tissue. The medullary form of papillary necrosis is commonly encountered in persons with sickle cell hemoglobinopathy. The incidence of radiographically dem onstrative papillary necrosis is as high as 33% to 65% in such persons. Renal Papillary Necrosis Medullary Form Normal Lesion Early focal, necrosis of medullary inner stripe. Progressive necro sis, coalescence of necrotic areas. Swelling. Mucosa normal. Mucosal break. Sequ estration and sinus formation. Progressive sequestration, extrusion, or resorpti on of necrotic tissue. Healing. Irregular medullary cavity with communicating si nus tract. Pyelogram Normal calyx

Normal calyx Sinus Irregular sinus Irregular medullary cavity

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.23 CONDITIONS ASSOCIATED WITH RENAL PAPILLARY NECROSIS Diabetes mellitus Urinary tract obstruction Pyelonephritis Analgesic nephropathy Sickle hemoglobinopathy Rejection of transplanted kidney Vasculitis Miscellaneo us FIGURE 6-38 Diabetes mellitus is the most common condition associated with papil lary necrosis. The occurrence of capillary necrosis is likely more common than i s generally appreciated, because pyelography (the best diagnostic tool for detec tion of papillary necrosis) is avoided in these patients because of dye-induced nephrotoxicity. When sought, pa pillary necrosis has been reported in as many as 25% of cases. Analgesic nephrop athy accounts for 15% to 25% of papillary necrosis in the United States but acco unts for as much as 70% of cases in countries in which analgesic abuse is common . Papillary necrosis also has been reported in patients receiving nonsteroidal a nti-inflammatory drugs. Sickle hemoglobinopathy is another common cause of papil lary necrosis, which, when sought by intravenous pyelography, is detected in wel l over half of cases. Infection is usually but not invariably a concomitant find ing in most cases of RPN. In fact, with few exceptions, most patients with RPN u ltimately develop a urinary tract infection, which represents a complication of papillary necrosis: that is, the infection develops after the primary underlying disease has initiated local injury to the renal medulla, with foci of impaired blood flow and poor tubular drainage. Infection contributes significantly to the symptomatology of RPN, because fever and chills are the presenting symptoms in two thirds of patients and a positive urine culture is obtained in 70%. However, RPN is not an extension of severe pyelonephritis. In most patients with florid acute pyelonephritis, RPN does not occur. Spectrum of Renal Papillary Necrosis Obstruction Diabetes Infection Sickle Hgb Analgesic abuse FIGURE 6-39 Spectrum and overlap of diseases principally associated with renal p apillary necrosis (RPN). Although each disease can cause RPN, it is their coexis tence (darkly shaded areas) that increases the risk, which is even greater after the onset of infection (lightly shaded areas). In most cases of RPN, more than one of the conditions associated with RPN is present. Thus, in most cases, the l esion seems to be multifactorial in origin. The pathogenesis of the lesion may b e considered the result of an overlapping phenomenon, in which a combination of detrimental factors appear to operate in concert to cause RPN. As such, whereas each of the conditions alone can cause RPN, the coexistence of more than one pre disposing factor in any one person significantly increases the risk for RPN. The contribution of any one of these factors to RPN would be expected to differ amo ng individuals and at various periods during the course of the disease. To the e xtent that the natural course of RPN itself predisposes patients to development of infection of necrotic foci and obstruction by sloughed papillae, it may be di fficult to assign a primary role for any of these processes in an individual pat ient. Furthermore, the occurrence of any of these factors (necrosis, obstruction

, or infection) may itself initiate a vicious cycle that can lead to another of these factors and culminate in RPN. References 1. 2. 3. Bohman S: The ultrastructure of the renal interstitium. Contemp Issues Nephrol 10:134, 1983. Lemley KV, Kriz W: Anatomy of the renal interstitium. Kidne y Int 1991, 39:370381. Eknoyan G: Chronic tubulointerstitial nephropathies. In Di seases of the Kidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little Brown; 1997:19832015. Palmer BF: The renal tubule in the progression of chronic renal failure. J Invest Med 1997, 45:346361. 5. 6. 7. 8. Schainuck LI, Striker GE , Cutler RE, Benditt EP: Structural-functional correlations in renal disease II. The correlations. Hum Pathol 1970, 1:631641. DeBroe ME, Elseviers MM: Analgesic nephropathy. N Engl J Med 1998, 338:446451. Dobyan DC, Truong LD, Eknoyan G: Rena l malacoplakia reappraised. Am J Kidney Dis 1993, 22:243252. Eknoyan G, Qunibi WY , Grissom RT, et al.: Renal papillary necrosis: an update. Medicine 1982, 61:5573 . 4.

6.24 Tubulointerstitial Disease Selected Bibliography Renal Interstitium Neilson EG: Symposium on the cell biology of tubulointerstitium. Kidney Int 1991 , 39:369556. Strutz F, Mueller GA: Symposium on Renal Fibrosis: prevention and pr ogression. Kidney Int 1996, 49(suppl 54):190. Drugs Boton R, Gaviria M, Battle DC: Prevalence, pathogenesis, and treatment of renal dysfunction associated with chronic lithium therapy. Am J Kidney Dis 1990, 10:32 9345. Myer BD, Newton L: Cyclosporine induced chronic nephropathy: an obliterativ e microvascular renal injury. J Am Soc Nephrol 1991, 2(suppl 1):4551. Chronic Tubulointerstitial Nephritis Eknoyan G, McDonald MA, Appel D, Truong LD: Chronic tubulointerstitial nephritis : correlation between structural and functional findings. Kidney Int 1990, 38:73 6743. Jones CL, Eddy AA: Tubulointerstitial nephritis. Ped Nephrol 1992, 6:572586. Nath KA: Tubulointerstitial changes as a major determinant in progression of re nal damage. Am J Kidney Dis 1992, 20:117. Heavy Metals Batuman V: Lead nephropathy, gout, hypertension. Am J Med Sci 1993, 305:241247. B atuman V, Maesaka JK, Haddad B et al.: Role of lead in gouty nephropathy. N Engl J Med 1981, 304:520523. Fowler BA: Mechanisms of kidney cell injury from metals. Environ Health Perspec 1993, 100:5763. Hu H: A 50-year follow-up of childhood pl umbism. Hypertension, renal function and hemoglobin levels among survivors. Am J Dis Child 1991, 145:681687. Staessen JA, Lauwerys RR, Buchet JP et al.: Impairme nt of renal function with increasing lead concentrations in the general populati on. N Engl J Med 1992, 327:151156. Vedeen RP: Environmental renal disease: lead. cadmium, and Balkan endemic nephropathy. Kidney Int 34(suppl):48. Pathogenesis Bohle A, Muller GA, Wehrmann M et al.: Pathogenesis of chronic renal failure in the primary glomerulopathies, renal vasculopathies and chronic interstitial neph ritides. Kidney Int 1996, 49(suppl 54):29. Dodd S: The pathogenesis of tubulointe rstitial disease and mechanisms of fibrosis. Curr Top Pathol 1995, 88:117143. Hag gerty DT, Allen DM: Processing and presentation of self and foreign antigens by the renal proximal tubule. J Immunol 1992, 148:23242331. Nath KA: Reshaping the i nterstitium by platelet-derived growth factor. Implications for progressive rena l disease. Am J Path 1996, 148:10311036. Sedor JR: Cytokines and growth factors i n renal injury. Semin Nephrol 1992, 12:428440. Wilson CB: Nephritogenic tubuloint ers-titial antigens. Kidney Int 1991, 39:501517. Yamato T, Noble NA, Miller DE, B order WA: Sustained expression of TGF-B1 underlies development of progressive ki dney fibrosis. Kidney Int 1994, 45:916927. Ischemic Vascular Disease Freedman BI, Ishander SS, Buckalew VM et al.: Renal biopsy findings in presumed hypertensive nephrosclerosis. Am J Nephrol 1994, 14:9094. Meyrier A, Simon P: Nep hroangiosclerosis and hypertension: things are not as simple as you might think. Nephrol Dial Transplant 1996, 11:21161220. Schlesinger SD, Tankersley MR, Curtis JJ: Clinical documentation of end stage renal disease due to hypertension. Am J Kidney Dis 1994, 23:655660. Correlation with Renal Failure D'Amico G, Ferrario F, Rastaldi MP: Tubulointerstitial damage in glomerular diseas es: its role in the progression of renal damage. Am J Kidney Dis 1995, 26:124132. Eddy AA: Experimental insights into tubulointerstitial disease accompanying pri

mary glomerular lesions. J Am Soc Nephrol 1994, 5:12731287. Magil AB: Tubulointer stitial lesions in human membranous glomerulonephritis: relationship to proteinu ria. Amer J Kidney Dis 1995, 25:375379. Obstructive Nephropathy Arant BS Jr: Vesicoureteric reflux and renal injury. Am J Kidney Dis 1991, 17:49 1511. Diamond JR: Macrophages and progressive renal disease in experimental hydro nephrosis. Am J Kidney Dis 1995, 26:133140. Klahr S: New insight into consequence s and mechanisms of renal impairment in obstructive nephropathy. Am J Kidney Dis 1991, 18:689699. Hematologic Diseases Allon M: Renal abnormalities in sickle cell disease. Arch Intern Med 1990, 150:5 01504. Falk RJ, Scheinmann JI, Phillips G et al.: Prevalence and pathologic featu res of sickle cell nephropathy and response to inhibition of angiotensin convert ing enzyme. N Engl J Med 1992, 326:910915. Ivanyi B: Frequency of light chain dep osition nephropathy relative to renal amyloidosis and Bence Jones cast nephropat hy in a necropsy study of patients with myeloma. Arch Pathol Lab Med 1990, 114:9 86987. Rota S, Mougenot B, Baudouin M: Multiple myeloma and severe renal failure: a clinicopathologic study of outcome and prognosis in 34 patients. Medicine 198 7, 66:126137. Sanders PW, Herrera GA, Kirk KA: Spectrum of glomerular and tubuloi nterstitial renal lesions associated with monotypical immunoglobulin light chain deposition. Lab Invest 1991, 64:527537. Analgesic Nephropathy Henrich WL, Agodoa LE, Barrett B, Bennett WM et al.: Analgesics and the Kidney. Summary and Recommendations to the Scientific Advisory Board of the National Kid ney Foundation. Am J Kidney Dis 1996, 27:162165 Nanra RS: Pattern of renal dysfun ction in analgesic nephropathy. Comparison with glomerulonephritis. Nephrol Dial ysis Transpl 1992, 7:384390. Noels LM, Elseviers NM, DeBroe ME: Impact of legisla tive measures of the sales of analgesics and the subsequent prevalence of analge sic nephropathy: a comparative study in France, Sweden and Belgium. Nephrol Dial Transplant 1995, 10:167174. Perneger TV, Whelton PK, Klag MJ: Risk of kidney fai lure associated with the use of acetaminophen, aspirin, and nonsteroidal anti-in flammatory drugs. N Engl J Med 1994, 331:16751679. Sandler DP, Burr FR, Weinberg CR: Nonsteroidal anti-inflammatory drugs and risk of chronic renal failure. Ann Intern Med 1991, 115:165172. Sandler DP, Smith JC, Weinberg CR et al.: Analgesic use and chronic renal disease. N Engl J Med 1989, 320:12381243.

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis Metabolic Disorders Chaplin AJ: Histopathological occurrence and characterization of calcium oxalate . A review. J Clin Pathol 1977, 30:800811. Foley RJ, Weinman EJ: Urate nephropath y. Am J Med Sci 1984, 288:208211. Hanif M, Mobarak MR, Ronan A: Fatal renal failu re caused by diethylene glycol in paracetamol elixir: the Bangladesh epidemic. B r Med J 1995, 311:8891. Schneider JA, Lovell H, Calhoun F: Update on nephropathic cystinosis. Ped Nephrol 1990, 4:645653. Zawada ET, Johnson VH, Bergstein J: Chro nic interstitial nephritis. Its occurrence with oxalosis and antitubular basemen t membrane antibodies after jejunal bypass. Arch Pathol Ub Med 1981, 105:379383. 6.25 Viral Infections Ito M, Hirabayashi N, Uno Y: Necrotizing tubulointerstitial nephritis associated with adenovirus infection. Human Pathol 1991, 22:12251231. Papadimitriou M.: Han tavirus nephropathy. Kidney Int 1995, 48:887902. Hereditary Diseases Fick GM, Gabow PA: Hereditary and acquired cystic disease of the kidney. Kidney Int 1994, 46:951964. Gabow PA, Johnson AM, Kaehny VM: Factors affecting the progr ession of renal disease in autosomal-dominant polycystic kidney disease. Kidney Int 1992, 41:13111319. Gregory MC, Atkin CL: Alports syndrome, Fabry's disease and nail patella syndrome. In Diseases of the Kidney, edn 6. Edited by Schrier RW, G ottschalk CW. Boston: Little Brown; 1997:561590. Granulomatous Diseases Mignon F, Mery JP, Mougenot B, et al.: Granulomatous interstitial nephritis. Adv Nephrol 1984, 13:219245. Viero RM, Cavallo T: Granulomatous interstitial nephrit is. Hum Pathol 1995, 26:13451353. Papillary Necrosis Griffin MD, Bergstralk EJ, Larson TS: Renal papillary necrosis. A sixteen year c linical experience. J Am Soc Nephrol 1995, 6:248256. Sabatini S, Eknoyan G, edito rs: Renal papillary necrosis. Semin Nephrol 1984, 4:1106.

Urinary Tract Infection Alain Meyrier T he concern of renal specialists for urinary tract infections (UTIs) had declined with the passage of time. This trend is now being reversed, owing to new imagin g techniques and to substantial progress in the understanding of host-parasite r elationships, of mechanisms of bacterial uropathogenicity, and of the inflammato ry reaction that contributes to renal lesions and scarring. UTIs account for mor e than 7 million visits to physicians' offices and well over 1 million hospital ad missions in the United States annually [1]. French epidemiologic studies evaluat ed its annual incidence at 53,000 diagnoses per million persons per year, which represents 1.05% to 2.10% of the activity of general practitioners. In the Unite d States, the annual number of diagnoses of pyelonephritis in females was estima ted to be 250,000 [2]. The incidence of UTI is higher among females, in whom it commonly occurs in an anatomically normal urinary tract. Conversely, in males an d children, UTI generally reveals a urinary tract lesion that must be identified by imaging and must be treated to suppress the cause of infection and prevent r ecurrence. UTI can be restricted to the bladder (essentially in females) with on ly superficial mucosal involvement, or it can involve a solid organ (the kidneys in both genders, the prostate in males). Clinical signs and symptoms, hazards, imaging, and treatment of various types of UTIs differ. In addition, the patient's background helps to further categorize UTIs according to age, type of urinary t ract lesion(s), and occurrence in immunocompromised patients, especially with di abetes or pregnancy. Such various forms of UTI explain the wide spectrum of trea tment modalities, which range from ambulatory, single-dose antibiotic treatment of simple cystitis in young females, to rescue nephrectomy for pyonephrosis in a diabetic with septic shock. This chapter categorizes the various forms of UTI, describes progress in diagnostic imaging and treatment, and discusses recent dat a on bacteriology and immunology. CHAPTER 7

7.2 Tubulointerstitial Disease Diagnosis would be the only way of proving it. Urinary tract infection (UTI) cannot be ide ntified simply by the presence of bacteria in a voided specimen, as micturition flushes saprophytic urethral organisms along with the urine. Thus a certain numb er of colonyforming units of uropathogens are to be expected in the urine sample . Midstream collection is the most common method of urine sampling used in adult s. When urine cannot be studied without delay, it must be stored at 4C until it i s sent to the bacteriology laboratory. The urine test strip is the easiest means of diagnosing UTI qualitatively. This test detects leukocytes and nitrites. Sim ultaneous detection of the two is highly suggestive of UTI. This test is 95% sen sitive and 75% specific, and its negative predictive value is close to 96% [3]. The test does not, however, detect such bacteria as Staphyloccocus saprophyticus , a strain responsible for some 3% to 7% of UTIs. Thus, treating UTI solely on t he basis of test strip risks failure in about 15% of simple community-acquired i nfections and a much larger proportion of UTIs acquired in a hospital. immersed in the urine, shaken, and incubated overnight. The most specific results, howeve r, are provided by laboratory analysis, which allows precise counting of bacteri a and leukocytes. Normal values for a midstream specimen are less than or equal to 105 Escherichia coli organisms and 104 leukocytes per milliliter. These class ical Kass criteria, however, are not always reliable. In some cases of incipient c ystitis the number of E. coli per milliliter can be lower, on the order of 102 t o 104 [4]. When fecal contamination has been ruled out, growth of bacteria that are not normally urethral saprophytes indicates infection. This is the case for Pseudomonas, Klebsiella, Enterobacter, Serratia, and Moraxella, among others, es pecially in a hospital setting or after urologic procedures. A B C FIGURE 7-1 Urine test strips. Normal urine is sterile, but suprapubic aspiration of the bladder, which is by no means a routine procedure, Schematic set up of a dip-slide container Interpretation after 24-hour incubation at 37C Significant Paddle-holding Nonsignificant stopper Agar Moist sponge 103 104 105 106 107 FIGURE 7-2 Culture interpretation. Urinalysis must examine bacterial and leukocy

te counts (per milliliter). An approximate way of estimating bacterial counts in the urine uses a dip-slide method: a plastic paddle covered on both sides with culture medium is

Urinary Tract Infection 7.3 CAUSES OF ASEPTIC LEUKOCYTURIA Self-medication before urine culture Sample contamination by cleansing solution Vaginal discharge Urinary stone Urinary tract tumor Chronic interstitial nephrit is (especially due to analgesics) Fastidious microorganisms requiring special cu lture medium (Ureaplasma urealyticum, Chlamydia, Candida) FIGURE 7-3 Leukocyturia. A significant number of leukocytes (more than 10,000 pe r milliliter) is also required for the diagnosis of urinary tract infection, as it indicates urothelial inflammation. Abundant leukocyturia can originate from t he vagina and thus does not necessarily indicate aseptic urinary leukocyturia [1 ]. Bacterial growth without leukocyturia indicates contamination at sampling. Si gnificant leukocyturia without bacterial growth (aseptic leukocyturia) can devel op from various causes, among which self-medication before urinalysis is the mos t common. Bacteriology A. MAIN MICROBIAL STRAINS RESPONSIBLE FOR URINARY TRACT INFECTION First Episode or Delayed Relapse 71%79% 1.1%9.7% 1.0%9.2% 1.0%3.2% 3%7% 2%6% Microbial Strain Escherichia coli Proteus mirabilis Klebsiella Enterobacter Enterococcus Staphylo coccus saprophyticus Other species Relapse Due to Early Reinfection 60% 15% 20% 5% FIGURE 7-4 Principal pathogens of urinary tract infection (UTI). A and B, Most p athogens responsible for UTI are enterobacteriaceae with a high predominance of Escherichia coli. This is especially true of spontaneous UTI in females (cystiti s and pyelonephritis). Other strains are less common, including Proteus mirabili s and more rarely gram-positive microbes. Among the latter, Staphylococcus sapro phyticus deserves special mention, as this gram-positive pathogen is responsible for 5% to 15% of such primary infections, is not detected by the leukocyte este rase dipstick, and is resistant to antimicrobial agents that are active on gramnegative rods. C, Acute simple pyelonephritis is a common form of upper UTI in f emales and results from the encounter of a parasite and a host. In the absence o f urologic abnormality, this renal infection is mostly due to uropathogenic stra ins of bacteria [5,6], a majority of cases to community-acquired E. coli. The cl inical picture consists of fever, chills, renal pain, and a general discomfort. Tissue invasion is associated with a high erythrocyte sedimentation rate and C-r eactive protein level well above 2 mg/dL. 100 Minimum Maximum Percent Other 5% 50 P. mirabilis 15% Klebsiella 20% 0 E. coli P. mirabilis Klebsiella En terococcus S. saprophyticus Other Enterobacter E. coli 60% B

7.4 Tubulointerstitial Disease Virulence Factors of Uropathogenic Strains Escherichia coli Fimbriae P S Type 1 Flagella Hemolysin Fe3+ + Na+ Na Aerobactin Erythrocyte FIGURE 7-5 Bacterial uropathogenicity plays a major role in host-pathogen intera ctions that lead to urinary tract infection (UTI). For Escherichia coli, these f actors include flagella necessary for motility, aerobactin necessary for iron ac quisition in the iron-poor environment of the urinary tract, a pore-forming hemo lysin, and, above all, presence of adhesins on the bacterial fimbriae, as well a s on the bacterial cell surface. (From Mobley et al. [7]; with permission.) FIGURE 7-6 An electron microscopic view of an Escherichia coli organism showing the fimbriae (or pili) bristling from the bacterial cell. Proteus mirabilis Fimbriae MR/P PMF ATF NAF Flagella Urea Urease Ni 2+ Deaminase [Keto acid]3Fe3+ Amino acid Na+ NH3+CO2 IgA protease Hemolysin Renal epithelial cell FIGURE 7-7 Proteus mirabilis is endowed with other nonfimbrial virulence factors , including the property of secreting urease, which splits urea into NH3 and CO2 . FIGURE 7-8 Staghorn calculi. Ammonium generation alkalinizes the urine, creating conditions favorable for build-up of voluminous struvite stones, which can prog ressively invade the entire pyelocalyceal system, forming staghorn calculi. Thes e stones are an endless source of microbes, and the urinary tract obstruction pe rpetuates infection.

Urinary Tract Infection Fimbrial adhesive structures Type 1 Fimbriae Type P Fimbriae Adhesin PapG PapF F ibrillum PapE FimH FimH, FimG FimF, FimG FimA ~100 FimA Nonfimbrial adhesive str ucture 7.5 PapK Rigid fiber PapA Adhesins PapH Pilin Minor subunits Adhesin FIGURE 7-9 Schematic representation of morphology and composition of type P and type 1 adhesive structures. Bacterial adhesins are paramount in fostering attach ment of the bacteria to the mucous membranes of the perineum and of the urotheli um. There are several molecular forms of adhesins. The most studied is the pap G adhesin, which is located at the tip of the bacterial fimbriae (or pili). This lectin recognizes binding site conformations provided by oligosaccharide sequenc es present on the mucosal surface [8]. FIGURE 7-10 Uropathogenic strains of Escherichia coli readily adhere to epitheli al cells. This figure shows two epithelial cells incubated in urine infected wit h E. colicarrying pap adhesins. Numerous bacteria are scattered on the epithelial cell membranes. About half of all cases of cystitis are due to uropathogenic st rains of E. colicarrying adhesins. Females with primary pyelonephritis and no uro logic abnormality harbor a uropathogenic strain in almost 100% of cases [5]. APPROPRIATE ANTIBIOTICS FOR URINARY TRACT INFECTIONS Antibiotics Aminoglycosides Aminopenicillins Carboxypenicillins Ureidopenicillins Quinolones Fluoroquinolones Cephalosporins First generation Second generation Third genera tion Monobactams Carbapenem Cotrimoxazole Fosfomycin trometamole Nitroturantoin General Indications + + + + + + + + + + + + +** + Pregnancy +* + + + + + + + + Prophylaxis + + + + + FIGURE 7-11 Appropriate antibiotics for urinary tract infections (UTI). An appro priate antibiotic for treating UTI must be bactericidal and conform to the follo wing general specifications: 1) its pharmacology must include, in case of oral a dministration, rapid absorption and attainment of peak serum concentrations; 2) its excretion must be predominantly renal; 3) it must achieve high concentration s in the renal or prostate tissue; 4) it must cover the usual spectrum of entero bacteria with reasonable chance of being effective on an empirical basis. Exclud ing special considerations for childhood and pregnancy, several classes of antib iotics fulfill these specifications and can be used alone or in combination. The choice also depends on market availability, cost, patient tolerance, and potent ial for inducing emergence of resistant strains. * Aminoglycosides should not be prescribed during pregnancy except for very seve re infection and for the shortest possible duration. With the exception of amoxicillin plus clavulanic acid, amino

penicillins should not be prescribed as first-line treatment, owing to the frequ ency of primary resistance to this class of antibiotics. According to antibiotic sensitivity tests. Fluoroquinolones carry a risk of tendon rupture (especially Achilles tendon). Oral administration only. ** Single-dose treatment of cystitis . Simple cystitis; not pyelonephritis or prostatitis.

7.6 Tubulointerstitial Disease Classification of Urinary Tract Infection Upper versus lower urinary tract infection FIGURE 7-12 Cystitis in a female patient. In case of urinary tract infection (UT I), distinguishing between lower and upper tract infection is classical, but the distinction is also beside the point. The real point is to determine whether in fection is confined to the bladder mucosa, which is the case in simple cystitis in females, or whether it involves solid organs (ie, prostatitis or pyelonephrit is). The dots in this figure symbolize the presence of bacteria and leukocytes ( ie, infection) in the relevant organ. Here, infection is confined to the bladder mucosa, which can be severely inflamed and edematous. This could be reflected r adiographically by mucosal wrinkling on the cystogram. In some cases inflammatio n is severe enough to be accompanied by bladder purpura, which induces macroscop ic hematuria but is not a particular grave sign. FIGURE 7-13 Prostatitis. Anatomically, prostatitis involves the lower urinary tr act, but invasion of prostate tissue affords easy passage of pathogens to the pr ostatic venous system and, usually, poor penetration by antibiotics. Presence of bacteria in the bladder is also symbolized in this picture, but owing to free co mmunication between bladder urine and prostate tissue, it can be accepted that p ure cystitis does not exist in males. FIGURE 7-14 Acute prostatitis can be complicated by ascending infection, that is , pyelonephritis. FIGURE 7-15 Pyelonephritis in females. Essentially, this is an ascending infecti on caused by uropathogens. From the perineum the bacteria gain access to the bla dder, ascending to the renal pelvocalyceal system and thence to the renal medull a, from which they spread toward the cortex. It has been shown that pyelitis canno t be considered a pathologic entity, as renal pelvis infection is invariably ass ociated with nearby contamination of the renal medulla.

Urinary Tract Infection 7.7 CRITERIA FOR TISSUE INVASION Clinical Kidney or prostate infection is marked by fever over 38C, chills, and pa in. The patient appears acutely ill. Laboratory Tissue invasion is invariably ac companied by an erythrocyte sedimentation rate over 20 mm/h and serum C-reactive protein levels over 2.0 mg/dL. Blood cultures grow in 30%50% of cases, which in an immunocompetent host indicates simply bacteremia, not septicemia. This reflec ts easy permeability between the urinary and the venous compartments of the kidn ey. Imaging When indicated, ultrasound imaging, tomodensitometry, and scintigrap hy provide objective evidence of pyelonephritis. In case of vesicoureteral reflu x, urinary tract infection necessarily involves the upper urinary tract. FIGURE 7-17 Criteria for tissue invasion. FIGURE 7-16 Renal abscess formation. A s specified elsewhere, renal abscess due to enterobacteriaceae (as opposed to he matogenous renal abscess, often of staphylococcal origin) can be considered a se vere form of pyelonephritis with renal tissue liquefaction, ending in a walled-o ff cavity. Primary versus secondary urinary tract infection FIGURE 7-19 Cystogram of a 65-year-old woman. A voluminous bladder tumor (arrows ) infiltrates the bladder floor and the initial segment of the urethra. FIGURE 7-18 An episode of urinary tract infection (UTI) should prompt considerat ion of whether it involves a normal urinary tract or, alternatively, if it is a complication of an anatomic malformation. This is especially true of relapsing U TI in both genders, and this hypothesis should be systematically raised in males and in children. Recurrent cystitis in females can be explained by hymeneal sca rs that pull open the urethral outlet during intercourse. Although rarely, other malformations that promote recurrent female cystitis are occasionally discovere d, such as urethral diverticula (arrows). Finally, it should be recalled that re current or chronic cystitis in an older woman can also reveal an unsuspected bla dder tumor.

7.8 Tubulointerstitial Disease FIGURE 7-20 Urethrocystogram of a man following acute prostatitis. In males, acu te prostatitis may reveal urethral stenosis. Urethral stenosis is a good explana tion for acute prostatitis. The beaded appearance of the stenosis (arrow) sugges ts an earlier episode of gonorrheal urethritis. I II III IV V FIGURE 7-21 The severity of vesicoureteral reflux (VUR) as graded in 1981 by the International Reflux Study Committee. When children have pyelonephritis, the possibility of VUR should always be considered. Childhood ve sicoureteral reflux is five times more common in girls than in boys. It has a ge netic background: several cases occasionally occur in the same family. Unless de tected and corrected early, especially the most severe forms of this class and w hen urine is infected (one episode of pyelonephritis suffices), childhood VUR is a major cause of cortical scarring, renal atrophy, and in bilateral cases chron ic renal insufficiency. The International Reflux Study classifies reflux grades as follows: I) ureter only; II) ureter, pelvis, and calyces, no dilation, and no rmal calyceal fornices; III) mild or moderate dilation or tortuosity of ureter a nd mild or moderate dilation of renal pelvis but no or slight blunting of fornic es; IV) moderate dilation or tortuosity of ureter and moderate dilation of renal pelvis and calyces, complete obliteration of sharp angle of fornices but mainte nance of papillary impressions in majority of calyces; V) gross dilation and tor tuosity of ureter, gross dilation of renal pelvis and calyces. Papillary impress ions are no longer visible in the majority of calyces. (From International Reflu x Study Committee [9]; with permission.) A FIGURE 7-22 Cystogram demonstrating left ureteral reflux (A). The consequences o n the left kidney (B) consist of calyceal distension and a clubbed appearance du e to the destruction of the papillae and of B the adjacent renal tissue. The calyceal cavities are very close to the renal cap sule, indicating complete cortical atrophy. This picture is typical of chronic p yelonephritis secondary to vesicoureteral reflux.

Urinary Tract Infection 7.9 FIGURE 7-23 In case of bilateral, neglected vesicoureteral reflux, chronic pyelo nephritis is bilateral and asymmetric. Here, the right kidney is globally atroph ic. A typical cortical scar is seen on the outer aspect of the left kidney. The lower pole, however, is fairly well-preserved with nearly normal parenchymal thi ckness. FIGURE 7-24 When intravenous pyelography discloses two ureters, the one draining the lower pyelocalyceal system crosses the upper ureter and opens into the blad der less obliquely than normally, allowing reflux of urine and explaining repeat ed attacks of pyelonephritis followed by atrophy of the lower pole of the kidney . Retrograde cystography is indicated for repeated episodes of pyelonephritis an d when intravenous pyelography or computed tomography renal examination discover s cortical scars. In adults, retrograde cystography is obtained by direct cathet erization of the bladder. FIGURE 7-26 In the paraplegic, and more generally in p atients with spinal disease, neurogenic bladder is responsible for stasis, bladd er distension, and diverticula. These functional and anatomic factors explain th e frequency of chronic urinary tract infection complicated with bladder and uppe r urinary tract infectious stones. FIGURE 7-25 (see Color Plate) In children, isotopic cystography allows a diagnos is of vesicoureteral reflux with much less radiation than if cystography were ca rried out with iodinated contrast medium.

7.10 Tubulointerstitial Disease Imaging FIGURE 7-27 When acute pyelonephritis occurs in a sound, immunocompetent female with no history of urologic disease, imaging can be limited to a plain abdominal film (to rule out renal and ureteral stones) and renal ultrasonography. Ultraso nography typically discloses a swollen kidney with loss of corticomedullary diff erentiation, denoting renal inflammatory edema. Images corresponding to the infe cted zones are more dense than normal renal tissue (arrows). FIGURE 7-28 The ultrasound procedure occasionally discloses the cavity of a smal l renal abscess, a common complication of acute pyelonephritis, even in simple f orms. A FIGURE 7-29 Computed tomodensitometry. Simple pyelonephritis does not require mu ch imaging; however, it should be remembered that there is no correlation betwee n the severity of the clinical picture and the renal lesions. Therefore, a diagn osis of simple pyelonephritis at first contact can be questioned when response to treatment is not clear after 3 or 4 days. This is an indication for uroradiologi c imaging, such as renal tomodensitometry followed by radiography of the urinary tract while it is still opacified by the contrast medium. The typical picture o f acute pyelonephritis observed after contrast medium injection [10] consists of hypodensities of the infected B areas in an edematous, swollen kidney. The pathophysiology of hypodense images h as been elucidated by animal experiments in the primates [11] which have shown t hat renal infection with uropathogenic Escherichia coli induces intense vasocons triction. Computed tomodensitometric images of acute pyelonephritis can take var ious appearances. The most common findings consist of one or several wedge-shape d or streaky zones of low attenuation extending from papilla to cortex, A. Hypod ense images can be round, B. On this figure, the infected zone reaches the renal cortex and is accompanied with adjacent perirenal edema. Several such (Continue d on next page)

Urinary Tract Infection 7.11 C D FIGURE 7-29 (Continued) images can coexist in the same kidney, C. Marked juxtaco rtical, circumscribed hypodense zones, bulging under the renal capsule, D, usual ly correspond to lesions close to liquefaction and should be closely followed, a s they can lead to abscess formation and opening into the perinephric space, E a nd F. (E and F from Talner et al. [10]; with permission.) E F FIGURE 7-30 Comparative sensitivity of four diagnostic imaging techniques for ac ute pyelonephritis. Renal cortical scintigraphy using 99mTc-dimethyl succinic ac id (DMSA) or 99mTc-gluconoheptonate (GH) is very sensitive for diagnosing acute pyelonephritis. It entails very little irradiation as compared with conventional radiography using contrast medium. Some nephrologists consider 99mTc-DMSA corti cal scintigraphy as the first-line diagnostic imaging method for renal infection in children. It is interesting to compare its sensitivity with that of more con ventional imaging methods. (From Meyrier and Guibert [5]; with permission.) 24 100 86 75 Percent 50 42 0 Renal scintigraphy CT scan Ultrasonography IVP (intravenous pyelography)

7.12 Tubulointerstitial Disease FIGURE 7-31 (see Color Plate) cortical imaging of simple pyelonephritis in a fem ale. The clinical signs implicated the right kidney. (Contrary to conventional r adiology, the right kidney appears on the right of the image.) The false colors indicate cortical renal blood supply from red (normal) to blue (ischemia). The r ight kidney is obviously involved with pyelonephritis, especially its poles. How ever, contrary to the results of computed tomography, which indicated right-side d pyelonephritis only, a focus of infection also occupies the lower pole of the right kidney. This picture illustrates the greater sensitivity of renal scintigr aphy for diagnosing renal infection. It also indicates that clinically unilatera l acute pyelonephritis can, in fact, be bilateral. 99mTc-DMSA A FIGURE 7-32 Renal pathology in acute pyelonephritis. Renal pathology of human ac ute pyelonephritis is quite comparable to what is observed in experimental pyelo nephritis in primates [11]. However, our knowledge of renal pathology in this co ndition in humans is based mainly on the most catastrophic cases, which required nephrectomy, like B the diabetes patient whose kidney is shown here. A, The surgically removed kidne y is swollen, and its surface shows whitish zones. B, A section of the same orga n shows white suppurative areas (scattered with small abscesses) extending eccen trically from the medulla to the cortex. There also were sloughed papillae (see Fig. 7-37). A FIGURE 7-33 Histologic appearance of pyelonephritic kidney. A, The renal tissue is severely edematous and interspersed with inflammatory cells and hemorrhagic s treaks. B, On another section, severe inflammation, B comprising a majority of polymorphonuclear leukocytes, induces tubular destructi on and is accompanied by a typical infectious cast in a tubular lumen (arrow).

Urinary Tract Infection 7.13 Clinical picture compatible with acute pyelonephritis (APN) Urine culture and cy tology ESR CRP Renal scintigraphy and/or CT scan No renal lesion. Seek other inf ection Negative. Reconsider diagnosis of APN Renal lesions. Maintain diagnosis o f APN Previous history of upper UTI Positive Initial work-up No previous history of upper UTI Abnormal. Call urologist Secondary APN Treat Treat cause infection IVP Yes Possible urinary tract obstruction or stone? No Plain abdominal radiograph Ultrasonography Primary APN Drug therapy only Normal FIGURE 7-34 A general algorithm for the investigation and treatment of acute pye lonephritis. Treatment of acute pyelonephritis is based on antibiotics selected from the list in Figure 7-11. Preferably, initial treatment is based on parenter al administration. It is debatable whether common forms of simple pyelonephritis initially require both an aminoglycoside and another antibiotic. Initial parent eral treatment for an average of 4 days should be followed by about 10 days of o ral therapy based on bacterial sensitivity tests. It is strongly recommended tha t urine culture be carried out some 30 to 45 days after the end of treatment, to verify that bacteriuria has not recurred. APNacute pyelonephritis; ESRerythrocyte sedimentation rate; CRPC-reactive protein; UTIurinary tract infection; IVPintraven ous pyelography. (From Meyrier and Guibert [5]; with permission.) Start treatment with first-line antibiotics Good clinical response and lab. Conf irmation of appropriate initial antibiotic choice Continue same treatment Day 1 Further imaging (IVP, CT) Atypical clinical response or Wrong initial antibiotic choice Adapt antibiotic t reatment Days 2 to 4 or 5 Normal. Consider drug intolerance Abnormal. Call urologist Days 5 to 15 End treatment Recurrence of bacteriuria Radiourological work-up. New treatment V erify urine sterility Day 15 Between days 30 and 45 Sterile No further investigations or treatment

7.14 Tubulointerstitial Disease FIGURE 7-35 (see Color Plate) Renal abscess. Like acute pyelonephritis, one thir d of cases of renal abscess occur in a normal urinary tract; in the others it is a complication of a urologic abnormality. The clinical picture is that of sever e pyelonephritis. In fact, it can be conceptualized as an unfavorably developing form of acute pyelonephritis that progresses from presuppurative to suppurative renal lesions, leading to liquefaction and formation of a walled-off cavity. Th e diagnosis of renal abscess is suspected when, despite adequate treatment of py elonephritis (described in Fig. 7-34), the patient remains febrile after day 4. Here, necrotic renal tissue is visible close to the abscess wall. The tubules ar e destroyed, and the rest of the preparation shows innumerable polymorphonuclear leukocytes within purulent material. A FIGURE 7-36 Renal computed tomography (CT). In addition to ultrasound examinatio n, CT is the best way of detecting and localizing a renal abscess. The abscess c avity can be contained entirely within B the renal parenchyma, A, or bulge outward under the renal capsule, risking ruptu re into Gerota's space, B.

Urinary Tract Infection 7.15 A B FIGURE 7-37 Urinary tract infection (UTI) in the immunocompromised host. UTI res ults from the encounter of a pathogen and a host. Natural defenses against UTI r est on both cellular and humoral defense mechanisms. These defense mechanisms ar e compromised by diabetes, pregnancy, and advanced age. Diabetic patients often harbor asymptomatic bacteriuria and are prone to severe forms of pyelonephritis requiring immediate hospitalization and aggressive treatment in an intensive car e unit. A particular complication of upper renal infection in diabetes is papill ary necrosis (see Fig. 7-32). The pathologic appearance of a sloughing renal pap illa, A. The sloughed papilla is eliminated and can be recovered by sieving the urine, B. In other cases, the necrotic papilla obstructs the ureter, causing ret ention of infected urine and severely aggravating the pyelonephritis. C, It can lead to pyonephrosis (ie, complete destruction of the kidney), as shown on CT. C Nonpregnant Pregnant IgG 500 0 1000 FIGURE 7-38 Urinary tract infection (UTI) in an immunocompromised host. Pregnanc y is associated with suppression of the host's immune response, in the form of red uced cytotoxic T-cell activity and reduced circulating immunoglobulin G (IgG) le vels. Asymptomatic bacteriuria is common during pregnancy and represents a major risk of ascending infection complicated by acute pyelonephritis. (Continued on next page) IgA Antibody activity, % of control 500 0 1000 IgM 500 0 A 0 0 2 Time of sampling, wks 2

7.16 Tubulointerstitial Disease Nonpregnant Pregnant >250 1000 IgG 250 200 500 Antibody activity, Abs 405 nm Levels of IL-6, units/mL 150 0 1000 100 IgA 50 500 20 20 0 0 0 0 2 0 Time of sampling, wks 2 Nonpregnant Pregnant Nonpregnan t Pregnant Serum Urine B C FIGURE 7-38 (Continued) Petersson and coworkers [12] recently demonstrated that the susceptibility of the pregnant woman to acute UTI is accompanied by reduced serum antibody activity (IgG, IgA, IgM), reduced urine antibody activity (IgG, I gA), and low interleukin 6 (IL-6) response, AC, respectively. The last may indicate that pregnant women have a generally reduced level of muco sal inflammation. These factors may be crucial for explaining the frequency and the severity of acute pyelonephritis during pregnancy. (From Petersson et al. [1 2]; with permission.) FIGURE 7-39 Acute prostatitis as visualized sonographicall y. Acute prostatitis is common after urethral or bladder infection (usually by E scherichia coli or Proteus organisms). Another cause is prostate hematogenous co ntamination, especially by Staphylococcus. Signs and symptoms of acute prostatit is, in addition to fever, chills, and more generally the signs and symptoms of t issue invasion by infection described above, are accompanied by dysuria, pelvic pain, and septic urine. Acute prostatitis is an indication for direct ultrasound (US) examination of the prostate by endorectal probe. In this case of acute pro statitis in a young male, US examination disclosed a prostatic abscess (1) compl icating acute prostatitis in the right lobe (2). Acute prostatitis is an indicat ion for thorough radiologic imaging of the whole urinary tract, giving special a ttention to the urethra. Urethral stricture may favor prostate infection (see Fi g. 7-20).

Urinary Tract Infection 7.17 Special Forms of Renal Infection A FIGURE 7-40 (see Color Plate) Xanthogranulomatous pyelonephritis (XPN). XPN is a special form of chronic renal inflammation caused by an abnormal immune respons e to infected obstruction [13]. This case in a middle-aged woman with a long his tory of renal stones is typical. For several months she complained of flank pain , fever, fatigue, anorexia and weight loss. Laboratory workup found inflammatory anemia and increased erythrocyte sedimentation rate and C-reactive protein leve ls. Urinalysis showed pyuria and culture grew Escherichia coli. CT scan of the r ight kidney showed replacement of the renal tissue by several rounded, low-densi ty areas and detected an B obstructive renal stone. Nephrectomy was performed. A, The obstructive renal sto ne is shown by an arrowhead. The renal cavities are dilated. The xanthogranuloma tous tissue (arrows) consists of several round, pseudotumoral masses with a typi cal yellowish color due to presence of lipids. In some instances such xanthogran ulomatous tissue extends across the capsule into the perirenal fat and fistulize s into nearby viscera such as the colon or duodenum. B, Microscopic view of the xanthogranulomatous tissue. This part of the lesion is made of lipid structures composed of innumerable clear droplets. Spectrum of renal malakoplakia Inflammation Mononuclear cells (nonspecific) von Hansemann cells (prediagnostic) Ca2+ Defective cell function Michaelis-Gutmann ( MG) bodies (diagnostic) Malakoplakia Interstitial nephritis Persistent inflammation Megalocytic interstitial nephritis B Destuctive granulomas xanthogranulomatous pyelonephritis Fibrosis "pseudosarcoma " A FIGURE 7-41 Malakoplakia. Malakoplakia (or malacoplakia), like xanthogranulomato us pyelonephritis, is also a consequence of abnormal macrophage response to gram -negative bacteria, A. Malakoplakia occurs in association with chronic UTI [14]. In more than 20% of cases, affected persons have some evidence of immunosuppres sion, especially corticosteroid therapy for autoimmune disease. In 13% of the published cases, malakoplak ia involved a transplanted kidney. The female-male ratio is 3:1. Lesions can inv olve the kidney, the bladder, or the ureter and form pseudotumors. B, Histologic ally, malakoplakia is distinguished by large, pale, periodic acidSchiffpositive ma crophages (von Hansemann cells) containing calcific inclusions (Michaelis-Gutman n bodies). The larger ones are often free in the interstitium. Malakoplakia, an unusual form of chronic tubulointerstitial nephritis, must be recognized by earl y renal biopsy and can resolve, provided treatment consisting of antibiotics wit h intracellular penetration is applied for several weeks. (B, Courtesy of Gary S . Hill, MD.)

7.18 Tubulointerstitial Disease References 1. Stamm WE, Hooton TM: Management of urinary tract infections in adults. N Engl J Med 1993, 329:13281334. 2. Pinson AG, Philbrick JT, Lindbeck GH, Schorling JB: ED management of acute pyelonephritis in women: A cohort study. Am J Emerg Med 1994, 12:271278. 3. Pappas PG: Laboratory in the diagnosis and management of urin ary tract infections. Med Clin North Am 1991, 75:313325. 4. Kunin CM, VanArsdale White L, Tong HH: A reassessment of the importance of low-count bacteriuria in you ng women with acute urinary symptoms. Ann Intern Med 1993, 119:454460. 5. Meyrier A, Guibert J: Diagnosis and drug treatment of acute pyelonephritis. Drugs 1992, 44:356367. 6. Meyrier A: Diagnosis and management of renal infections. Curr Opin Nephrol Hypertens 1996, 5:151157. 7. Mobley HLT, Island MD, Massad G: Virulence determinants of uropathogenic Escherichia coli and Proteus mirabilis. Kidney Int 1994, 46(Suppl. 47):S129S136. 8. Roberts JA, Marklund BI, Ilver D, et al.: The G al( 1-4)Gal specific tip adhesin of Escherichia coli P-fimbriae is needed for pye lonephritis to occur in the normal urinary tract. Proc Natl Acad Sci USA 1994, 9 1:1188911893. 9. International Reflux Study Committee: Medical versus surgical tr eatment of primary vesicoureteral reflux. J Urol 1981, 125:277. 10. Talner LB, D avidson AJ, Lebowitz RL, et al.: Acute pyelonephritis: Can we agree on terminolo gy? Radiology 1994, 192:297306. 11. Roberts JA: Etiology and pathophysiology of p yelonephritis. Am J Kidney Dis 1991, 17:19. 12. Petersson C, Hedges S, Stenqvist K, et al.: Suppressed antibody and interleukin-6 responses to acute pyelonephrit is in pregnancy. Kidney Int 1994, 45:571577. 13. Case records of the Massachusett s General Hospital. N Engl J Med 1995, 332:174179. 14. Dobyan DC, Truong LD, Ekno yan G: Renal malacoplakia reappraised. Am J Kidney Dis 1993, 22:243252.

Reflux and Obstructive Nephropathy James M. Gloor Vicente E. Torres R eflux nephropathy, or renal parenchymal scarring associated with vesicoureteral reflux (VUR), is an important cause of renal failure. Some studies have shown th at in up to 10% of adults and 30% of children requiring renal replacement therap y for end-stage renal disease, reflux nephropathy is the cause of the renal fail ure. Reflux nephropathy is thought to result from the combination of VUR of infe cted urine into the kidney by way of an incompetent ureterovesical junction valv e mechanism and intrarenal reflux. Acute inflammatory responses to the infection result in renal parenchymal damage and subsequent renal scarring. Loss of funct ioning renal mass prompt compensatory changes in renal hemodynamics that, over t ime, are maladaptive and result in glomerular injury and sclerosis. Clinically, reflux nephropathy may cause hypertension, proteinuria, and decreased renal func tion when the scarring is extensive. The identification of VUR raises the theore tic possibility of preventing reflux nephropathy. The inheritance pattern of VUR clearly is suggestive of a strong genetic influence. Familial studies of VUR ar e consistent with autosomal dominant transmission, and linkage to the major hist ocompatibility genes has been reported. Identification of infants with reflux de tected on the basis of abnormalities seen on prenatal ultrasound examinations be fore urinary tract infection occurs may provide an opportunity for prevention of reflux nephropathy. In persons with VUR detected at the time of diagnosis of a urinary tract infection, avoidance of further infections may prevent renal injur y. Nevertheless, the situation is far from clear. Most children with reflux neph ropathy already have renal scars demonstrable at the time of the urinary tract i nfection that prompts the diagnosis of VUR. Most children found to have VUR do n ot develop further renal scarring after diagnosis, even after subsequent urinary tract infections. Other children may develop renal scars in the absence of furt her urinary tract infections. The best treatment of CHAPTER 8

8.2 Tubulointerstitial Disease usually is accompanied by hydronephrosis, an abnormal dilation of the renal pelv is, and calices. However, because hydronephrosis can occur without functional ob struction, the terms obstructive nephropathy and hydronephrosis are not synonymo us. Hydronephrosis is found at autopsy in 2% to 4% of cases. Obstructive nephrop athy is responsible for approximately 4% of end-stage renal failure. Obstruction to the flow of urine can occur anywhere in the urinary tract and has many diffe rent causes. FIGURE 8-1 Obstructive nephropathy is responsible for end-stage renal failure in approximately 4% of persons. Obstruction to the flow of urine can occur anywher e in the urinary tract. Obstruction can be caused by luminal bodies; mural defec ts; extrinsic compression by vascular, neoplastic, inflammatory, or other proces ses; or dysfunction of the autonomic nervous system or smooth muscle of the urin ary tract. The functional and clinical consequences of urinary tract obstruction depend on the developmental stage of the kidney at the time the obstruction occ urs, severity of the obstruction, and whether the obstruction affects one or bot h kidneys. VUR has not yet been firmly established. No clear advantage has been demonstrate d for surgical correction of VUR versus medical therapy with prophylactic antibi otics after 5 years of follow-up examinations. New surgical techniques such as t he submucosal injection of bioinert substances may have a role in select cases. The term obstructive nephropathy is used to describe the functional and patholog ic changes in the kidney that result from obstruction to the flow of urine. Obst ruction to the flow of urine CAUSES OF OBSTRUCTIVE NEPHROPATHY Intraluminal Calculus, clot, renal papilla, fungus ball Intrinsic Congenital: Ca lyceal infundibular obstruction Ureteropelvic junction obstruction Ureteral stri cture or valves Posterior urethral valves Anterior urethral valves Urethral stri cture Meatal stenosis Prune-belly syndrome Neoplastic: Carcinoma of the renal pe lvis, ureter, or bladder Polyps Extrinsic Congenital (aberrant vessels): Congeni tal hydrocalycosis Ureteropelvic junction obstruction Retrocaval ureter Neoplast ic tumors: Benign tumors: Benign prostatic hypertrophy Pelvic lipomatosis Cysts Primary retroperitoneal tumors: Mesodermal origin (eg, sarcoma) neurogenic origi n (eg, neurofibroma) Embryonic remnant (eg, teratoma) Retroperitoneal extension of pelvic or abdominal tumors: Uterus, cervix Bladder, prostate Rectum, sigmoid colon Metastatic tumor: Lymphoma Inflammatory: Retroperitoneal fibrosis Inflamma tory bowel disease Diverticulitis Infection or abscess Gynecologic: Pregnancy Ut erine prolapse Surgical disruption or ligation Functional Neurogenic bladder Dru gs(anticholinergics, antidepressants, calcium channel blockers)

Reflux and Obstructive Nephropathy 8.3 Anatomy of Vesicoureteric Reflux FIGURE 8-2 Anatomy of the ureterovesical junction. The ureterovesical junction p ermits free antegrade urine flow from the upper urinary tract into the bladder a nd prevents retrograde urinary reflux from the bladder into the ureter and kidne y. Passive compression of the distal submucosal portion of the ureter against th e detrusor muscle as a result of bladder filling impedes vesicoureteral reflux ( VUR). An active mechanism preventing reflux also has been proposed in which cont raction of longitudinally arranged distal ureteral muscle fibers occludes the ur eteral lumen, impeding retrograde urine flow [13]. (From Politano [4]; with permi ssion.) Intramural ureter Submucosal ureter Bladder wall Ureter A 12 mm B 8 mm C 5 mm D 2 mm E 0 mm FIGURE 8-3 Tissue sagittal sections (upper panels) and cystoscopic appearances ( lower panels) of the ureterovesical junction illustrating varying submucosal tun nel lengths. The length of the submucosal segment of the distal ureter is an imp ortant factor in determining the effectiveness of the ureteral valvular mechanis m in preventing vesicoureteral reflux (VUR). In children without VUR, the ratio of tunnel length to ureteral diameter is significantly greater than in children with VUR [5,6]. (From Kramer [7]; with permission.) A' B' C' Cytoscopic view D' E' FIGURE 8-4 Simple and compound papillae are illustrated [8,9]. Two types of rena l papillae have been identified. Simple papillae are the most common type. They have slitlike papillary duct openings on their convex surface. These papillae ar e compressed by increases in pelvic pressure, preventing urine from entering the papillary ducts (intrarenal reflux). Compound papillae are formed by the fusion

of two or more simple papillae. In compound papillae, some ducts open onto a fl at or concave surface at less oblique angles. Increased intrapelvic pressure may permit intrarenal reflux. Compound papillae usually are found in the renal pole s.

8.4 Tubulointerstitial Disease Pathogenesis of Vesicoureteric Reflux and Reflux Nephropathy FIGURE 8-5 Experimental vesicoureteric reflux in pigs. This pathology specimen d emonstrates surgically induced vesicoureteric reflux in a 2-weekold male piglet. Note that the submucosal canal of one of the ureters has been unroofed. FIGURE 8-6 Experimental vesicoureteric reflux in pigs: cystourethrogram showing intrarenal reflux. Reflux of radiocontrast medium into the renal parenchyma is s een. The pressure required to produce intrarenal reflux is lower in young childr en than it is in older children or adults, which is consistent with the observat ion that reflux scars occur more commonly in younger children [10]. A B C scars. In urinary tract infections, reflux of urine from the renal pelvis into t he papillary ducts of compound papillae predominantly (Continued on next page) FIGURE 8-7 Experimental vesicoureteric reflux in pigs. The polar location of acu te suppurative pyelonephritis and evolution of parenchymal

Reflux and Obstructive Nephropathy 8.5 D E F reflux nephropathy: Hemorrhagic with polymorphonuclear cell infiltrate (A, B); w hite, not retracted, with prominent mononuclear cell infiltrate (C, D), and retr acted scan with prominent fibrosis (E, F). FIGURE 8-8 (see Color Plate) Experime ntal vesicoureteric reflux (VUR) in pigs: mesangiopathic lesions. Reflux of infe cted urine can result in glomerular lesions characterized by activation of mesan gial cells, mesangial expansion, mesangial hypercellularity, and the presence of large granules. The granules test positive on periodic acidSchiff reaction and a re located inside cells with the appearance of macrophages. These glomerulopathi c lesions occur by a process that does not require contiguity with the infected interstitium nor intrarenal reflux. These lesions are not related to reduction o f renal mass. Similar glomerular lesions have been identified in piglets after i ntravenous administration of endotoxin. Whether similar glomerular lesions occur in infants or young children with VUR and reflux nephropathy is not known [13]. FIGURE 8-7 (Continued) located in the poles (intrarenal reflux) provides bacteri a access to the renal parenchyma, resulting in suppurative pyelonephritis and su bsequent polar scarring [11,12]. Intact (A, C, E) and coronally sectioned (B, D, F) kidneys illustrating the three stages of FIGURE 8-9 (see Color Plate) Experimental vesicoureteric reflux (VUR) in pigs: 9 9mTechnetium-dimercaptosuccinic acid (DMSA) scan demonstrating reflux nephropath y. Radionuclide imaging using DMSA has been found to be safe and effective in in vestigating reflux nephropathy [14]. DMSA is localized to the proximal renal tub ules of the renal cortex. Parenchymal scars appear as a defect in the kidney out line, with reduced uptake of DMSA or by contraction of the whole kidney. Current ly, DMSA radionuclide renal scanning is the most sensitive modality used to dete ct renal scars relating to reflux. New areas of renal scarring can be seen earli er with DMSA than with intravenous pyelography [15].

8.6 Tubulointerstitial Disease FIGURE 8-10 Integrative view of pathogenetic mechanisms in reflux nephropathy. A bnormalities of ureteral embryogenesis may result in a defective antireflux mech anism, permitting vesicoureteral reflux (VUR), incomplete bladder emptying, urin ary stasis, and infection. Bacterial virulence factors modify the pathogenicity of different bacterial strains. Bacterial surface appendages such as fimbriae ma y interact with epithelial cell receptors of the urinary tract, enhancing bacter ial adhesion to urothelium. Endotoxin is capable of inhibiting ureteral peristal sis, contributing to the extension of the infection into the upper urinary tract even in the absence of VUR. Inoculation of the renal parenchyma with bacteria p roduces an acute inflammatory response, resulting in the release of inflammatory mediators into the surrounding tissue. The acute inflammatory response elicited by the presence of infecting bacteria is responsible for the subsequent renal p arenchymal injury. In addition, it is possible that immune complexes, bacterial fragments, and endotoxin resulting from infection may produce a glomerulopathy. Even in the absence of urinary tract infection, VUR associated with elevated int ravesical pressure is capable of producing renal parenchymal scars. The developi ng kidney appears to be particularly susceptible. Renal tubular distention resul ting from high intrapelvic pressure may exert an injurious effect on renal tubul ar epithelium. Compression of the surrounding peritubular capillary network by d istended renal tubules may produce ischemia. During micturition, elevated intrav esical pressure is transmitted to the renal pelvis and renal tubule. This transi ent pressure elevation may produce tubular disruption. Extravasation of urine in to the surrounding parenchyma results in an immune-mediated interstitial nephrit is and further renal injury. The reduction in functional renal mass produced by the interaction of the pathogenetic factors listed here induces compensatory hem odynamic changes in renal blood flow and the glomerular filtration rate. Over ti me, these compensatory changes may be maladaptive, may produce hyperfiltration a nd glomerulosclerosis, and may eventuate in renal insufficiency. (From Kramer [1 6]; with permission.) Integrative View of Pathogenetic Mechanisms in Reflux Nephropathy Defective meso nephric mesoderm (ureteral bud) Abnormal induction of metanephric mesoderm VUR ( In utero) + IRR + Virulent bacterial strain + Immune complexes Bacterial fragmen ts Endotoxin Susceptible host Inhibition of ureteral peristalsis Toxic urine com ponent Delayed hypersensitivity High-voiding pressures Focal exudative reaction Glomerulopathy Pyelonephritic scar Sterile scar Back-pressure atrophy Diffuse interstitial fibr osis High-protein diet Hypertension Pregnancy Dysplasia Reduced nephron population Hyperfiltration Glomerulosclerosis Progressive renal insufficiency FIGURE 8-11 Vesicoureteral reflux and renal dysplasia. An abnormal ureteral bud resulting from defective ureteral embryogenesis may penetrate the metanephric bl astema at a site other than that required for optimum renal development, potenti ally resulting in renal dysplasia or hypoplasia [17].

Reflux and Obstructive Nephropathy 8.7 Diagnosis of Vesicoureteric Reflux and Reflux Nephropathy FIGURE 8-12 International system of radiographic grading of vesicoureteral reflu x (VUR). The severity of VUR is most frequently classified according to the Inte rnational Grading System of Vesicoureteral Reflux, using a standardized techniqu e for performance of voiding cystourethrography. The definitions of this system are illustrated in Figure 8-4 and are as follows. In grade I, reflux only into t he ureter occurs. In grade II, reflux into the ureter, pelvis, and calyces occur s. No dilation occurs, and the calyceal fornices are normal. In grade III, mild or moderate dilation, tortuosity, or both of the ureter are observed, with mild or moderate dilation of the renal pelvis. No or only slight blunting of the forn ices is seen. In grade IV, moderate dilation, tortuosity, or both of the ureter occur, with moderate dilation of the renal pelvis and calyces. Complete oblitera tion of the sharp angle of the fornices is observed; however, the papillary impr essions are maintained in most calyces. In grade V, gross dilation and tortuosit y of the ureter occur; gross dilation of the renal pelvis and calyces is seen. T he papillary impressions are no longer visible in most calyces [18]. Internation al Reflux Study Committee consisting of four grades of severity. In grade 1, mil d scarring in no more than two locations is seen. More severe and generalized sc arring is seen in grade 2 but with normal areas of renal parenchyma between scar s. In grade 3, or so-called backpressure type, contraction of the whole kidney o ccurs and irregular thinning of the renal cortex is superimposed on widespread d istortion of the calyceal anatomy, similar to changes seen in obstructive uropat hy. Grade 4 is characterized by end-stage renal disease and a shrunken kidney ha ving very little renal function [19]. Parenchymal scarring detected by radionucl ide renal scintigraphy is classified similarly. A, In grade 1, no more than two scarred areas are detected. B, In grade 2, more than two affected areas are seen , with some areas of normal parenchyma between them. C, Grade 3 renal scarring i s characterized by general damage to the entire kidney, similar to obstructive n ephropathy. D, In grade 4, a contracted kidney in end-stage renal failure is see n, with less than 10% of total overall function [14]. I II III IV V Types of renal scarring A Mild B Severe C "Back-pressure" D End-stage FIGURE 8-13 Grading of renal scarring associated with vesicoureteral reflux. Ref

lux renal parenchymal scarring detected on intravenous pyelography can be classi fied according to the system adopted by the FIGURE 8-14 Voiding cystourethrogram demonstrating bilateral grade 5 vesicourete ral reflux. Voiding cystourethrography is performed by filling the bladder with radiocontrast material and observing for reflux under fluoroscopy, either during the phase of bladder filling or during micturition. Contrast material is infuse d through a small urethral catheter under gravity flow.

8.8 Tubulointerstitial Disease FIGURE 8-15 Radionuclide cystogram demonstrating bilateral vesicoureteral reflux (VUR). This method using 99mtechnetium pertechnetate is useful in detecting VUR . Advantages of radionuclide cystography include lower radiation exposure, less interference with overlying bowel contents and bones, and higher sensitivity in detection of VUR. Radionuclide cystography is useful in follow-up examinations o f patients known to have VUR, as a screening test in asymptomatic siblings of ch ildren with reflux and girls with urinary tract infections, and in serial examin ations of children with neuropathic bladders at risk for developing VUR. Disadva ntages of this method include less anatomic detail and inadequacy in evaluating the male urethra, making it unsuitable for screening boys for urinary tract infe ctions [7]. A FIGURE 8-16 A, Intravenous pyelogram and, B, nephrotomogram demonstrating grade 2 reflux nephropathy. Historically, this testing modality has been the one most commonly used to evaluate reflux nephropathy [7]. Irregular renal contour, paren chymal thinning, small renal size, and calyceal blunting all are radiographic si gns of reflux nephropathy on intravenous pyelography [17]. Radiographic changes may B not be visible immediately after renal infection, because scars may not be fully developed for several years [20]. The advantages of intravenous pyelography in evaluating reflux nephropathy include precision in delineating renal anatomic de tail and providing baseline measurements for future follow-up evaluations, renal growth, and scar formation. FIGURE 8-17 A, Posterior and, B, anterior views of 99mtechnetium-dimercaptosuccinic acid (DMSA) renal scan showing bilateral grade 2 reflux nephropathy. This nephropathy is characterized by focal areas of decrea sed radionuclide uptake predominantly affecting the lower renal poles. A B

Reflux and Obstructive Nephropathy 13 12 11 10 Renal length, cm 9 8 7 6 5 4 3 2 0 2 4 6 8 10 12 5 10 Years 15 8.9 Predicted mean 95% predicted limits A C Months FIGURE 8-18 Prenatal detection of vesicoureteral reflux (VUR). A, Ultrasonograph y showing mild fetal hydronephrosis. B, Postnatal voiding cystourethrogram (VCUG ) showing grade 4 VUR. C, Graph showing small renal size in the same infant. Ves icoureteral reflux has been identified in neonates in whom prenatal ultrasonogra phy examination reveals hydronephrosis [2128]. Normal infants do not have VUR, ev en when born prematurely [29,30]. The severity of reflux often is not predictabl e on the basis of appearance on ultrasonography [22,31]. Hydronephrosis greater than 4 mm and less than 10 mm in the anteroposterior dimension on ultrasound exa mination after 20 weeks' gestational age has been termed mild fetal hydronephrosis . Mild fetal hydronephrosis is associated with VUR in a significant percentage o f infants [26,31]. Despite the absence of a previous urinary tract infection, ma ny kidneys affected prenatally exhibit decreased function [22,24,32,33]. Unlike the focal parenchymal scars seen in infectionassociated reflux nephropathy, the parenchymal abnormalities seen in prenatal VUR are most commonly manifested by a generalized decrease in renal size (reflux nephropathy grade 3 or 4) [34,35]. B

8.10 90 80 70 60 50 40 30 20 10 0 Tubulointerstitial Disease FIGURE 8-19 Prenatal detection of vesicoureteral reflux (VUR): gender distributi on versus VUR detected after urinary tract infection (UTI). VUR detected as part of the evaluation of prenatal hydronephrosis is most commonly identified in boy s. In an analysis of six published studies of VUR diagnosed in a total of 124 in fants with antenatally detected hydronephrosis, 83% of those affected were boys [33]. Conversely, VUR detected after a UTI most commonly affects girls. In the I nternational Reflux Study in Children (IRSC) and Southwest Pediatric Nephrology Study Group (SWPNSG) investigations of VUR detected in a total of 380 children a fter UTI, 77% of those affected were girls [20,36]. 83 Male Female 77 % 17 23 Prenatally detected Detected after UTI Clinical Course of Vesicoureteric Reflux 50 40 % 30 20 10 0 1 2 3 4 5 Vesicoureteral reflux grade 30 20 21 50 50 90 80 70 60 50 40 30 20 10 0 0 Resolved VUR, % Grade 1 Grade 2 Grade 3 1 2 3 Years follow-up 4 5 FIGURE 8-20 Resolution of vesicoureteral reflux (VUR) detected prenatally at fol low-up examinations over 2 years. Spontaneous resolution of VUR can occur in inf ants with reflux detected during the postnatal evaluation of prenatal urinary tr act abnormalities. In an analysis of six investigations of VUR detected neonatal ly with a follow-up period of 2 years, resolution was seen in 50% of infants wit h grades I and II. High-grade reflux (grades IV to V) resolved in only 20% [33]. FIGURE 8-21 Resolution of vesicoureteral reflux (VUR) detected postnatally after urinary tract infection: mild to moderate VUR. The Southwest Pediatric Nephrolo gy Study Group (SWPNSG) prospectively observed 113 patients aged 4 months to 5 y

ears with grades I to III VUR detected after urinary tract infection. The SWPNSG reported on 59 children followed up with serial excretory urograms and voiding cystourethrography for 5 years. Mild (grade I and II) VUR resolved after 5 years in the ureters of 80% of these children, and in most cases within 2 to 3 years. Grade III VUR resolved in only 46% of ureters in children with VUR [20]. FIGURE 8-22 Resolution of vesicoureteral reflux (VUR) detected postnatally after urina ry tract infection at follow-up examinations over 5 years. Mild to moderate VUR spontaneously resolves in a significant percentage of children, whereas high-gra de reflux resolves only rarely. The Southwest Pediatric Nephrology Study Group ( SWPNSG) found that grades I and II VUR resolved in 80% of children with refluxin g ureters at follow-up examinations over 5 years. In the Birmingham Reflux Study Group (BRSG), International Reflux Study in Children (IRSC), and SWPNSG investi gations of high-grade VUR (grades III to V) in children, improvement in reflux s everity was seen in 30% to 40% of affected ureters. Spontaneous resolution was r are and occurred in only 16% to 17% of children with refluxing ureters at follow -up examinations over 5 years [20,37,38]. 90 80 70 60 50 40 30 20 10 0 82 80 Patients studied, % Grade 1 Grade 2 Grade 3 Grade 45 40 31 17 16 18 20 43 53 Resolution Improvement Unchanged

Reflux and Obstructive Nephropathy 40 35 Resolved VUR, % 30 25 20 15 10 5 0 0 3 9 21 33 Months follow-up 45 57 Unilateral Bilateral 8.11 FIGURE 8-23 Resolution of grades III to V vesicoureteral reflux (VUR) detected p ostnatally after urinary tract infection: bilateral versus unilateral VUR. Spont aneous resolution of high-grade VUR is much more likely to occur in unilateral r eflux. The International Reflux Study in Children (IRSC) showed that grades III to V VUR resolved in children in whom both kidneys were affected nearly five tim es as often (39%) as in those in whom VUR was bilateral (8%). In bilateral VUR, spontaneous resolution did not occur after 2 years of observation [38]. 60 Scarred or thinned, % 50 40 30 20 10 0 New scar formation, % IRSC BRSG 18 16 14 12 10 8 6 4 2 0 0 IRSC SWPNSG 0 III III IV Dilated 1 2 Vesicoureteral reflux grade 3 Years follow-up 4 5 FIGURE 8-24 Frequency of parenchymal scarring at the time of diagnosis of vesico ureteral reflux (VUR). Many children in whom VUR is detected after a urinary tra ct infection already have evidence of renal parenchymal scarring. In two large p rospective studies the frequency of scars seen in persons with VUR increased wit h VUR severity. The International Reflux Study in Children (IRSC) studied 306 ch ildren under 11 years of age with grades III to V VUR [36]. The frequency of par enchymal scarring or thinning increased from 10% in children with nonrefluxing r enal units (in children with contralateral VUR) to 60% in those with severely re fluxing grade V kidneys. In another large prospective study, the Birmingham Refl ux Study Group (BRSG) reported renal scarring in 54% of 161 children under 14 ye ars of age with severe VUR resulting in ureteral dilation (greater than grade 3 using the classification system adopted by the International Reflux Study in Chi ldren group) at the time reflux was detected [39]. Participants in these studies were children previously diagnosed as having had urinary tract infection.

FIGURE 8-25 Development of parenchymal scarring after diagnosis of vesicouretera l reflux (VUR). Parenchymal scarring occurs after diagnosis and initiation of th erapy as well. The Southwest Pediatric Nephrology Study Group (SWPNSG) followed up 59 children with mild to moderate VUR (grades I to III) diagnosed after urina ry tract infection [20]. None of the children studied had parenchymal scarring o n intravenous pyelography at the time of diagnosis. Parenchymal scars were seen to develop in 10% of children over the course of 5 years of follow-up examinatio ns, including some children without documented urinary tract infections during t he period of observation. In this group, renal scarring occurred nearly three ti mes more commonly in grade 3 VUR than it did in grades 1 and 2 VUR. In the Inter national Reflux Study in Children (IRSC) (European group), a prospective study o f high-grade VUR (grades III and IV), new scars developed in 16% of 236 children after 5 years' observation [40]. FIGURE 8-26 Development of new renal scars versus age at diagnosis of vesicouret eral reflux (VUR). The frequency of new scar formation appears to be inversely r elated to age. The International Reflux Study in Children (IRSC) examined childr en with high-grade VUR and found that new scars developed in 24% under 2 years o f age, 10% from 2 to 4 years of age, and 5% over 4 years of age [40].

8.12 Tubulointerstitial Disease Treatment of Vesicoureteric Reflux 18 16 14 12 10 8 6 4 2 0 0 5 Surgical Medical 10 15 20 25 30 35 40 Months follow-up 45 50 55 60 FIGURE 8-27 Effectiveness of medical versus surgical treatment: new scar formati on at follow-up examinations over 5 years in children with highgrade vesicourete ral reflux (VUR). The International Reflux Study in Children (IRSC) (European gr oup) was designed to compare the effectiveness of medical versus surgical therap y of VUR in children diagnosed after urinary tract infection. Surgery was succes sful in correcting VUR in 97.5% of 231 reimplanted ureters in 151 children randomized to surgical therapy. Medical therapy consisted of long-term antibiotic uroprophyla xis using nitrofurantoin, trimethoprim, or trimethoprim-sulfa. No statistically significant advantage was demonstrable for either treatment modality with respec t to new scar formation after 5 years of observation in either study. New scars were identified in 20 of the 116 children treated surgically (17%) and 19 of the 155 children treated medically (16%) at follow-up examinations over 5 years. Th ose children treated surgically who developed parenchymal scars generally did so within the first 2 years after ureteral repeat implantation, whereas scarring o ccurred throughout the observation period in the group that did not have surgery . VUR persisted in 80% of children randomized to medical treatment after followup examinations over 5 years. The results of the IRSC paralleled the findings of the Birmingham Reflux Study Group (BRSG) investigation of medical versus surgic al therapy for VUR in 161 children. After 2 years of observation, progressive or new scar formation was seen in 16% of children with refluxing ureters in the gr oup treated surgically and 19% in the group treated medically. In contrast to th e IRSC, however, new scar formation was rare after 2 years of observation in bot h groups [37,40]. FIGURE 8-28 Effectiveness of medical versus surgical treatment : incidence of urinary tract infections. Vesicoureteral reflux (VUR) predisposes affected persons to urinary tract infection owing to incomplete bladder emptyin g and urinary stasis. Medical therapy with uroprophylactic antibiotics and surgi cal correction of VUR have as a goal the prevention of urinary tract infection. In three prospective studies of 400 children with VUR (Southwest Pediatric Nephr ology Study Group [SWPNSG], International Reflux Study in Children [IRSC], Birmi ngham Reflux Study Group [BRSG]) treated either medically or surgically and who were observed over 5 years the rate of infection was similar, ranging from 21% t o 39%. The rate of infection was no different between the group treated medicall y and that treated surgically [20,37,39].

Renal scarring, % Urinary tract infections, % 40 35 30 25 20 15 10 5 0 38 28 21 39 34 BRSG-Surgical BRSG- Medical IRSC-Medical IRSC-Surgical SWPNSG 40 35 30 25 20 15 10 5 0 UTI versus pyelonephritis, % Nonpyelonephritic UTI Pyelonephritis 17 29 21 10 FIGURE 8-29 Effectiveness of medical versus surgical treatment: incidence of uri nary tract infection versus pyelonephritis in severe vesicoureteral reflux (VUR) . Although the incidence of urinary tract infections (UTIs) is the same in surgi cally and medically treated children with VUR, the severity of infection is grea ter in those treated medically. The International Reflux Study in Children (IRSC ) (European group) studied 306 children with VUR and observed them over 5 years; 155 were randomized to medical therapy, and 151 had surgical correction of thei r reflux. Although the incidence of UTI statistically was no different between t he groups (38% in the medical group, 39% in the surgical group), children treate d medically had an incidence of pyelonephritis twice as high (21%) as those trea ted surgically (10%) [41]. Medical Surgical therapy therapy

Reflux and Obstructive Nephropathy 8.13 VUR detected Associated GU anomalies expected to affect VUR? Yes Treat appropriately No Severity of VUR Mild (I-III) Uroprophylaxis Hygiene education Surveillance urine cultures Annual VCUG Urinary tract infections? Severe (IV-V) Functional study (Radionuclide or ExU) Nonfunctioning kidney Consider nephrectomy Functioning kidney Yes Consider surgery No Resolution of VUR after 2 years Uroprophylaxis Annual VCUG Surgical correction Yes Long term followup to detect UTI No Resolution of VUR after 2 years Female Male Yes No Consider surgery Consider surgery Consider observation off antibiotics Long term followup Surgery FIGURE 8-30 Proposed treatment of vesicoureteral reflux (VUR) in children. This algorithm provides an approach to evaluate and treat VUR in children. In VUR ass ociated with other genitourinary anomalies, therapy for reflux should be part of a comprehensive treatment plan directed toward correcting the underlying urolog ic malformation. Children with mild VUR should be treated with prophylactic anti biotics, attention to perineal hygiene and regular bowel habits, surveillance ur ine cultures, and annual voiding cystourethrogram (VCUG). Children with recurren t urinary tract infection on this regimen should be considered for

surgical correction. In children in whom VUR resolves spontaneously, a high inde x of suspicion for urinary tract infection should be maintained, and urine cultu res should be obtained at times of febrile illness without ready clinical explan ation. In persons in whom mild VUR fails to resolve after 2 to 3 years of observ ation, consideration should be given to voiding pattern. A careful voiding histo ry and an evaluation of urinary flow rate may reveal abnormalities in bladder fu nction that impede resolution of reflux. Correction of dysfunctional voiding pat terns may result in resolution of VUR. In the absence of dysfunctional voiding, it is controversial whether older women with persistent VUR are best served by s urgical correction or close observation with uroprophylactic antibiotic therapy and surveillance urine cultures, especially during pregnancy. Males with persist ent low-grade VUR may be candidates for close observation with surveillance urin e cultures while not receiving antibiotic therapy, especially if they are over 4 years of age and circumcised. Circumcision lowers the incidence of urinary trac t infection. In severe VUR the function of the affected kidney should be evaluat ed with a functional study (radionuclide renal scan). High-grade VUR in nonfunct ioning kidneys is unlikely to resolve spontaneously, and nephrectomy may be indi cated to decrease the risk of urinary tract infection and avoid the need for uro prophylactic antibiotic therapy. In patients with functioning kidneys who have h igh-grade VUR, the likelihood for resolution should be considered. Severe VUR, e specially if bilateral, is unlikely to resolve spontaneously. Proceeding directl y to repeat implantation may be indicated in some cases. Medical therapy with ur oprophylactic antibiotics and serial VCUG may also be used, reserving surgical t herapy for those in whom resolution fails to occur. Complications of Reflux Nephropathy 25 Hypertensive, % 20 15 10 5 0 0 5 Years 10 15 FIGURE 8-31 Development of hypertension in 55 normotensive subjects with reflux nephropathy at follow-up examinations over 15 years. The incidence of hypertensi on in persons with reflux nephropathy increases with age and appears to develop most commonly in young adults within 10 to 15 years of diagnosis. In a cohort of 55 normotensive persons with reflux nephropathy observed for 15 years, 5% becam e hypertensive after 5 years. This percentage increased to 16% at 10 years, and 21% at 15 years. The grading system for severity of scarring was different from the system adopted by the International Reflux Study Committee. Nevertheless, us ing this system, 78% of persons in the group could be classified as having reflu x nephropathy severity scores between 1 and 4 [42].

8.14 100 Hypertensive, % 80 60 40 20 0 Tubulointerstitial Disease FIGURE 8-32 Frequency of hypertension versus severity of parenchymal scarring. T he frequency of hypertension in persons with vesicoureteral refluxrelated renal s cars is higher than in the normal population. In adults with reflux nephropathy the incidence of hypertension can be correlated with the severity of renal scarr ing. Adding the individual grade of reflux (04) for the two kidneys results in a scale ranging from 0 (no scars) to 8 (severe bilateral scarring). Persons with c umulative scores of parenchymal scarring from 1 to 4 have a 30% incidence of hyp ertension, whereas 60% of those with scarring scores ranging from 5 to 8 have hy pertension [42,43]. 14 58 Cumulative reflux scarring severity score A B C D FIGURE 8-33 Glomerular hypertrophy and focal segmental glomerulosclerosis (FSGS) in severe reflux nephropathy. Reflux nephropathy resulting in reduced renal fun ctional mass induces compensatory changes in glomerular and vascular hemodynamics. These chan ges initially maintain the glomerular filtration rate but are maladaptive over t ime. AD, Compensatory hyperfiltration results in renal injury manifested histolog ically by glomerular hypertrophy and FSGS and clinically as persistent proteinur ia [44]. In reflux nephropathy, proteinuria is a poor prognostic sign, indicatin g that renal injury has occurred. The severity of proteinuria is inversely propo rtional to functioning renal mass and the glomerular filtration rate and directl y proportional to the degree of global glomerulosclerosis. Surgical correction o f vesicoureteral reflux has not been found to prevent further deterioration of r enal function after proteinuria has developed. Hyperfiltration resulting from de creased renal mass continues and produces progressive glomerulosclerosis and los s of renal function. Evidence exists that inhibition of the renin-angiotensin sy stem through the use of angiotensin-converting enzyme inhibitors decreases the c ompensatory hemodynamic changes that produce hyperfiltration injury. Thus, these inhibitors may be effective in slowing the progress of renal failure in reflux nephropathy.

Reflux and Obstructive Nephropathy 8.15 Pathogenesis of Obstructive Nephropathy Birth Fetus Neonate Adult Dysplasia Number of nephrons Renal growth Compensatory hypertrophy* Recovery of function after relief of obstruction *When unilateral FIGURE 8-34 Consequences of urinary tract obstruction for the developing kidney in animals. The effects of urinary tract obstruction on the developing kidney de pend on the time of onset, location, and degree of obstruction. Ureteral obstruc tion during early pregnancy results in disorganization of the renal parenchyma ( dysplasia) and a reduction in the number of nephrons. Partial or complete ureter al obstruction in neonates causes vasoconstriction, glomerular hypoperfusion, im paired ipsilateral renal growth, and interstitial fibrosis. The degree of impair ment of the ipsilateral kidney, in the case of partial unilateral ureteral obstr uction, and of compensatory hypertrophy of the contralateral kidney, in the case of partial or complete unilateral ureteral obstruction, is inversely related to the age of the animal at the time of obstruction. The older the animal, the les s the impairment of the ipsilateral kidney and the less the compensatory growth of the contralateral kidney. In addition, the recovery of renal function after r elief of urinary tract obstruction also decreases with the age of the animal [45 ]. PGE2, PGI2 Angiotensin II RA PGC Kf RE FIGURE 8-35 Renal hemodynamic response to mild partial ureteral obstruction. Ren al blood flow and the glomerular filtration rate may not change in mild partial ureteral obstruction, despite a significant reduction in glomerular capillary ul trafiltration coefficient (Kf). This is due to the increase in glomerular capill ary hydraulic pressure (PGC) caused by a prostaglandin E2induced reduction of aff erent arteriolar resistance (RA) and an angiotensin IIinduced elevation of effere nt arteriolar resistance (RE). It is likely that other vasoactive factors, such as thromboxane A2, also play a role, particularly in more severe ureteral obstru ction accompanied by reductions in renal blood flow and glomerular filtration ra te [46]. PGE2prostaglandin E2; PGI2prostaglandin I2; Pttubule hydrostatic pressure. Pt 2 h post-obstruction PGE2, PGI2 N0 RA PGC RE RBF (120%) GFR (80%) Pt RA PGC RE + ANP RBF (120%) GFR (80%) Pt Bilateral (Macrophage infiltration) (Activation of renin-angiotensin) Unilateral 24 h post-obstruction Endothelin TBX A 2 RA PGC Angiotensin II RE RBF (50%) GFR (20%) Pt RA PGC RE RBF (50%) GFR (20%) Pt FIGURE 8-36 Acute renal hemodynamic response to unilateral or bilateral complete ureteral obstruction. In the first 2 hours after unilateral complete ureteral o bstruction, there is a reduction in preglomerular vascular resistance and an increase in renal blood flow mediated by increased pr oduction of prostaglandin E2 (PGE2), prostacyclin, and nitric oxide (NO). The in crease in renal blood flow (RBF) and glomerular capillary pressure maintain the glomerular filtration rate (GFR) at approximately 80% of normal, despite an incr ease in intratubular pressure. As the ureteral obstruction persists, activation of the renin-angiotensin system and increased production of thromboxane A2 (TBXA 2) and endothelin result in progressive vasoconstriction, with reductions in ren

al blood flow and glomerular capillary pressure. The glomerular filtration rate decreases to approximately 20% of baseline, despite normalization of the intratu bular pressures. The hemodynamic changes in the early phase (02 h) of bilateral u reteral obstruction are similar to those observed after unilateral obstruction. As bilateral obstruction persists, however, there is an accumulation of atrial n atriuretic peptide (ANP) that does not occur after unilateral obstruction. The i ncreased ANP levels attenuate the afferent and enhance the efferent vasoconstric tions, with maintenance of normal glomerular capillary and elevated tubular pres sures. Despite these differences in hemodynamic changes between unilateral and b ilateral ureteral obstruction, the reductions in renal blood flow and glomerular filtration rate 24 hours after obstruction are similar [4749]. PGCglomerular capi llary hydraulic pressure; PGI2prostaglandin I2; Pttubule hydrostatic pressure; RAaf ferent arteriolar resistance; REefferent arteriolar resistance.

8.16 300 Change from baseline, % 200 100 Baseline 50 0 Tubulointerstitial Disease FIGURE 8-37 Chronic renal hemodynamic response to complete unilateral ureteral o bstruction. During complete ureteral obstruction, renal blood flow progressively decreases. Renal blood flow is 40% to 50% of normal after 24 hours, 30% at 6 da ys, 20% at 2 weeks, and 12% at 8 weeks [48]. Intrapelvic pressure Renal blood flow Glomerular filtration rate 1 2 3 4 5 6 7 8 Weeks after obstruction Cortex 40 Leukocytes, 105/g 30 20 10 Medulla 40 Leukocytes, 105/g 30 20 10 0 Cortex Release of obstruction Medulla Release of obstruction 0 0 Control 4 h 12 h 24 h Control 4 h 12 h 24 h 1 2 A C 3 4 Days 5 6 7 0

1 2 3 4 Days 5 6 7 Cortex FIGURE 8-38 Development of interstitial cellular infiltrates in the renal cortex and medulla after ureteral obstruction. After ureteral obstruction there is a r apid influx of macrophages and suppressor T lymphocytes in the cortex and medull a (A) that is accompanied by an increase in urinary thromboxane B2 and a decreas e in the glomerular filtration rate. The production of thromboxane A2 by the inf iltrating macrophages (B) contributes to the renal vasoconstriction of chronic u rinary tract obstruction. After release of the obstruction the cellular infiltra tion is slowly reversible, requiring several days to revert to near normal level s (C) [50,51]. Medulla B

Reflux and Obstructive Nephropathy 8.17 Tubular obstruction Pt PDGF Osteopontin MCP Renin, angiotensinogen, ACE, AT1 receptor Bradykinin EGF bcl2 Macrophages O 2 H 2O 2 Fibroblasts, myofibroblasts TGF- Nitric oxide CuZnSOD Catalase TIMP Collagen Apoptosis, tubular drop-out Tubulointerstitial fibrosis FIGURE 8-39 Pathogenesis of tubulointerstitial fibrosis in obstructive nephropat hy. This pathogenesis has been extensively studied. Increased expression of reni n, angiotensinogen, angiotensinconverting enzyme (ACE), and the angiotensin II t ype 1 (AT1) receptor occurs in the obstructed kidney. Angiotensin II can induce the synthesis of transforming growt h factor (TGF- ), a cytokine that stimulates extracellular matrix synthesis and inhibits its degradation. Obstructive nephropathy is accompanied by downregulati on of the kallikrein-kinin system and nitric oxide production that can be revers ed by administration of a converting enzyme inhibitor or of L-arginine. The rapi d upregulation of chemotactic factors such as monocyte chemoattractant peptide 1 (MCP-1) and osteopontin in the tubular epithelial cells, in response to increas ed intratubular pressure, contributes to the recruitment of macrophages. Macroph ages produce fibroblast growth factor and induce fibroblast proliferation and my ofibroblast transformation. The downregulation of epidermal growth factor (EGF), Bcl 2, and antioxidant enzymes and the increased production of superoxide and h ydrogen peroxide (H2O2) contribute to an increased rate of apoptosis and tubular dropout [51 57]. PDGFplatelet-derived growth factor; SODsuperoxide dismutase; TIMPt issue inhibitor of metalloproteinases. Obstruction 100 80 60 40 20 0 0 2 4 6 8 12 14 16 18 20 22 24 Weeks after obstruction FIGURE 8-40 Recovery of renal function after relief of complete unilateral urete ral obstruction of variable duration. The recovery of the ipsilateral glomerular filtration rate after relief of a unilateral complete ureteral obstruction has been best studied in dogs and depends on the duration of the obstruction. Comple te recovery occurs after 1 week of obstruction. The degree of recovery after 2 a nd 4 weeks of obstruction is only of 58% and 36%, respectively. No recovery occu

rs after 6 weeks of obstruction [58]. Rare reports of recovery of renal function in patients with longer periods of unilateral ureteral obstruction may represen t high-grade partial obstruction rather than complete obstruction or may reflect differences in lymphatic drainage and renal anatomy between the human and canin e kidneys [59].

8.18 Tubulointerstitial Disease Clinical Manifestations of Obstructive Nephropathy Functional abnormalities in obstructed kidneys (unilteral or bilateral) Damage t o inner medulla Medullary blood flow Corticomedullary concentration gradient Res istance to ADH Consequences of bilateral obstruction Na+ wasting Na+reabsorption Loop of Henle ( Na+/K+ ATPase) Collecting duct Intraluminal negative potential H+ secretion K+ secretion H+-ATPase Na+/K+ ATPase Concentration defect ECFV excess ANP Osmotic load (urea) Clinical correlates Excessive replacement Hypernatremia when free water intake is inadequate Postobs tructive diuresis after relief of bilateral obstruction (volume contraction, hyp omagnesemia, other electrolyte abnormalities) Hyperkalemic metabolic acidosis in partial bilateral ureteral obstruction FIGURE 8-41 Clinical correlates of abnormalities of tubular function in obstruct ive nephropathy. Acute ureteral obstruction stimulates tubular reabsorption, res ulting in increased urine osmolality and reduced urine sodium concentration [60] . In contrast, obstructive nephropathy is characterized by a reduced ability to concentrate the urine, reabsorb sodium, and secrete hydrogen ions (H+) and potas sium. In unilateral obstructive nephropathy, these functional abnormalities do n ot have a clinical correlate because of the reduced glomerular filtration rate a nd immaterial contribution of the obstructed kidney to total renal function. Hyp erkalemic metabolic acidosis and, when the intake of free water is not adequate, hypernatremia can occur in patients with partial bilateral ureteral obstruction or partial ureteral obstruction in a solitary kidney. Similarly, postobstructiv e diuresis can occur only after relief of bilateral ureteral obstruction or uret eral obstruction in a solitary kidney but not after relief of unilateral obstruc tion [6167]. ADH>\#209>antidiuretic hormone; ANPatrial natriuretic peptide; ECFV ex tracellular fluid volume; Na-K ATPase sodium-potassium adenosine triphosphatase. Urinary tract obstruction FIGURE 8-42 Clinical manifestations of obstructive nephropathy. These manifestat ions depend on the cause of the obstruction, its anatomic location, its severity , and its rate of development [61,68,69]. Unilateral Bilateral or solitary kidney Partial or complete Pain (dull aching Renin-dependent renal colic) hypertension Susceptibility to Erythrocytosis urinary tract (rare) infection and nephrolithia sis Partial Complete

Polyuria, polydipsia Anuria Bladder Uremia symptoms Hypernatremia Fluctuating V lume contraction urine Hyperkalemic output metabolic acidosis Uremia Volume-depe ndent hypertension

Reflux and Obstructive Nephropathy 8.19 Diagnosis of Obstructive Nephropathy 1.0 Furosemide Obstruction 0.8 0.6 RI Tracer activity Baseline Saline Saline + furosemide Hydronephrosis without obstruction 0.4 0.2 Normal 0.0 Time A B Partial obstruction Contralateral kidney C D FIGURE 8-43 Diagnosis of obstructive nephropathy. A, Diuresis renography. B, Dop pler ultrasonography. C, D, Magnetic resonance urogram utilizing a single shot f ast spin echo technique with anterior-posterior projection (C) and left posterio r oblique projection (D). Images demonstrate a widely patent right ureteropelvic junction in a patient with abdominal pain and suspected ureteropelvic junction obstruction. Administration of gadolinium is not required for this technique. No te also the urine in the bladder, cerebrospinal fluid in the spinal canal, and f luid in the small bowel. Ultrasonography is the procedure of choice to determine the presence or absence of a dilated renal pelvis or calices and to assess the degree of associated parenchymal atrophy. Nevertheless, obstruction rarely can occur without hydronephrosis, when the uret er and renal pelvis are encased in a fibrotic process and unable to expand. In c ontrast, mild dilation of the collecting system of no functional significance is not unusual. Even obvious hydronephrosis in some cases may not be associated wi th functional obstruction [70]. Diuresis renography is helpful when the function al significance of the dilation of the collecting system is in question [71,72]. Renal Doppler ultrasonography before and after administration of normal saline and furosemide also has been used to differentiate obstructive from nonobstructi ve pyelocaliectasis [73]. Other techniques such as excretory urography, computed tomography, and retrograde or antegrade ureteropyelography are helpful to deter mine the cause of the urinary tract obstruction. The utility of excretory urogra phy is limited in patients with advanced renal insufficiency. In these cases mag netic resonance urography can provide coronal imaging of the renal collecting sy stems and ureters similar to that of conventional urography without the use of i odinated contrast. RI resistive index. (C, D, Courtesy of B. F. King, MD.)

FIGURE 8-44 Diagnosis of obstructive nephropathy by postnatal renal ultrasonogra phy, showing hydronephrosis in ureteropelvic junction obstruction. Renal ultraso nography is a sensitive test to detect hydronephrosis. The absence of ureteral d ilation is consistent with obstruction at the level of the ureteropelvic junctio n.

8.20 Tubulointerstitial Disease FIGURE 8-45 Mercaptoacetyltriglycine-3 renal scan with furosemide in a newborn w ith left ureteropelvic junction obstruction. A diuretic renal scan using 99mtech netium-mercaptoacetyltriglycine (99mTc-MAG-3) showing differential renal functio n (47% right kidney; 53% left kidney) at 1 to 2 minutes after radionuclide admin istration is seen. A significant amount of radionuclide remains in each kidney 1 5 minutes after administration. After administration of furosemide, however, the isotope is seen to disappear rapidly from the right kidney (t1/2 of radioisotop e washout in 4.9 minutes) but persists in the hydronephrotic left kidney (t1/2 i n 50.1 minutes). A t1/2 of the radioisotope in less than 10 minutes is thought t o reflect a lack of significant obstruction. A t1/2 of over 20 minutes is sugges tive of obstruction. Intermediate values of washout are indeterminate. The most appropriate therapy for infants with delayed renal pelvic radioisotope washout a nd diagnosis of ureteropelvic junction obstruction is controversial. Some author s advocate pyeloplasty to alleviate the obstruction based on renal scan results, whereas others advocate withholding surgery unless renal function deteriorates or hydronephrosis progresses. Before Furosemide After Furosemide 1 min. 5 min. 10 min. 15 min. Lt Rt Lt Rt

Reflux and Obstructive Nephropathy 8.21 Posterior Urethral Valves FIGURE 8-46 Posterior urethral valves. A, Illustrative diagram. B, Pathology spe cimen. Valvular obstruction at the posterior urethra is the most common cause of lower urinary tract obstruction in boys. Anatomically, the lesion most commonly is comprised of an oblique diaphragm with a slitlike perforation arising from t he posterior urethra distal to the verumontanum and inserting at the midline ant erior urethra. (From Kaplan and Scherz [74]; with permission.) Type I A FIGURE 8-47 Excretory urogram of a patient with posterior urethral valves. Bladd er outlet obstruction results in bladder wall thickening, trabeculation, and for mation of diverticula. Increased intravesical pressure may result in vesicourete ral reflux, as is seen on the left. Obstruction resulting in increased intrarena l pressure may result in rupture at the level of a renal fornix, producing a uri noma, or perirenal collection of urine, as seen on the right. B FIGURE 8-48 Voiding cystourethrogram (VCUG) demonstrating posterior urethral val ves and dilation of the posterior urethra. Urethral valves are best detected by VCUG. The obstructing valves are seen as oblique or perpendicular folds with pro ximal urethral dilation and elongation. Distal to the valves the urinary stream is diminished. Alleviating the bladder outlet obstruction is indicated, either b y lysis of the valves themselves or by way of vesicostomy, in small infants unti l sufficient growth occurs to make valve resection technically feasible.

8.22 Tubulointerstitial Disease Ureterovesical Junction Obstruction FIGURE 8-49 Excretory urogram showing ureterovesical junction obstruction in a 2 -year-old girl. Retroperitoneal Fibrosis A FIGURE 8-50 AH, Idiopathic retroperitoneal fibrosis: computed tomography scans of the abdomen before (left panels, note right ureteral stent and mild left ureter opyelocaliectasis) and 7 years after ureterolysis (right panels, note omental in terposition). Retroperitoneal fibrosis is characterized by the accumulation of i nflammatory and fibrotic tissue around the aorta, between the renal hila and the pelvic brim. Most cases are idiopathic; the remainder are associated with immun e-mediated connective tissue diseases, ingestion of drugs such as methysergide, abdominal aortic aneurysms, or malignancy. Idiopathic retroperitoneal fibrosis c an be associated with mediastiB nal fibrosis, sclerosing cholangitis, Riedel's thyroiditis, and fibrous pseudotumo r of the orbit. In the clinical setting, patients with idiopathic retroperitonea l fibrosis exhibit systemic symptoms such as malaise, anorexia and weight loss, and abdominal or flank pain. Renal insufficiency is often seen and is caused by bilateral ureteral obstruction. Laboratory test results usually demonstrate anem ia and an elevated sedimentation rate. The treatment is directed to the release of the ureteral obstruction, which initially can be achieved by placement of ure teral stents. Administration of corticosteroids is helpful to control the system ic manifestations of the disease and (Continued on next page)

Reflux and Obstructive Nephropathy 8.23 C D E F G FIGURE 8-50 (Continued) often to reduce the bulk of the tumor and relieve the ur eteral obstruction. Administration of corticosteroids, however, should be consid ered only when malignancy and retroperitoneal infection can be ruled out. As in other chronic renal diseases, administration of corticosteroids should be kept a t the minimal level capable of controlling symptoms. Surgical ureterolysis, whic h consists of freeing H the ureters from the fibrotic mass, lateralizing them, and wrapping them in omen tum to prevent repeat obstruction, is often necessary. Other immunosuppressive a gents have been used rarely when the systemic manifestations of the disease cann ot be controlled with safe doses of corticosteroids. In most cases the long-term outcome of idiopathic retroperitoneal fibrosis is satisfactory [7577].

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neal fibrosis: a true connective tissue disease. Rheum Dis North Am 1996, 22:2338 . 76. Kottra JJ, Dunnick NR: Retroperitoneal fibrosis. Radiol Clin North Am 1996 , 34:12591275. 77. Massachusetts General Hospital: Case recordscase 271996: N Engl J Med 1996, 335:650655.

Cystic Diseases of the Kidney Yves Pirson Dominique Chauveau A kidney cyst is a fluid-filled sac arising from a dilatation in any part of the n ephron or collecting duct. A sizable fraction of all kidney diseasesperhaps 10% t o 15%are characterized by cysts that are detectable by various imaging techniques . In some, cysts are the prominent abnormality; thus, the descriptor cystic (or polycystic). In others, kidney cysts are an accessory finding, or are only somet imes present, so that some question whether they are properly classified as cyst ic diseases of the kidney. In fact, the commonly accepted complement of cystic k idney diseases encompasses a large variety of disorders of different types, pres entations, and courses. Dividing cystic disorders into genetic and nongenetic cond itions makes sense, not only conceptually but clinically: in the former cystic i nvolvement of the kidney often leads to renal failure and is most often associat ed with extrarenal manifestations of the inherited defect, whereas in the latter cysts rarely jeopardize renal function and generally are not part of a systemic disease. In the first section of this chapter we deal with nongenetic (ie, acqu ired and developmental) cystic disorders, emphasizing the imaging characteristic s that enable correct identification of each entity. Some common pitfalls are de scribed. A large part of the section on genetic disorders is devoted to the most common ones (eg, autosomal-dominant polycystic kidney disease), focusing on gen etics, clinical manifestations, and diagnostic tools. Even in the era of molecul ar genetics, the diagnosis of the less common inherited cystic nephropathies rel ies on proper recognition of their specific renal and extrarenal manifestations. Most of these features are illustrated in this chapter. CHAPTER 9

9.2 Tubulointerstitial Disease General Features PRINCIPAL CYSTIC DISEASES OF THE KIDNEY Nongenetic Acquired disorders Simple renal cysts (solitary or multiple) Cysts of the renal sinus (or peripelvic lymphangiectasis) Acquired cystic kidney disease (in patien ts with chronic renal impairment) Multilocular cyst (or multilocular cystic neph roma) Hypokalemia-related cysts Developmental disorders Medullary sponge kidney Multicystic dysplastic kidney Pyelocalyceal cysts Genetic Autosomal-dominant Autosomal-dominant polycystic kidney disease Tuberous scleros is complex von Hippel-Lindau disease Medullary cystic disease Glomerulocystic ki dney disease Autosomal-recessive Autosomal-recessive polycystic kidney disease N ephronophthisis X-linked Orofaciodigital syndrome, type I FIGURE 9-1 Principal cystic diseases of the kidney. Classification of the renal cystic disorders, with the most common ones printed in bold type. (Adapted from Fick and Gabow [1]; Welling and Grantham [2]; Pirson, et al. [3].) IMAGING CHARACTERISTICS OF THE MOST COMMON RENAL CYSTIC DISEASES Disease Simple renal cysts Acquired renal cystic disease Medullary sponge kidney ADPKD A RPKD NPH Kidney Size Normal Most often small, sometimes large Normal or slightly enlarged Enlarged En larged Small Cyst Size Variable (mm10 cm) 0.52 cm mm Variable (mm10 cm) mm increase with age mm2 cm (when p resent) Cyst Location All All Precalyceal All All Medullary Liver Normal Normal Normal (most often) Cysts (most often) CHF Normal FIGURE 9-2 Characteristics of the most common renal cystic diseases detectable b y imaging techniques (ultrasonography, computed tomography, magnetic resonance). In the context of family history and clinical findings, these allow the clinici an to establish a definitive diagnosis in the vast majority of patients. ADPKDautosomal-dominant polycystic kidney disea se; ARPKDautosomal-recessive polycystic kidney disease; CHFcongenital hepatic fibr osis; NPH nephronophthisis.

Cystic Diseases of the Kidney 9.3 Nongenetic Disorders FIGURE 9-3 Solitary simple cyst. Large solitary cyst found incidentally at ultra sonography (longitudinal scan) in the lower pole of the right kidney. Criteria f or the diagnosis of simple cyst include absence of internal echoes, rounded outl ine, sharply demarcated, smooth walls, bright posterior wall echo (arrows). The latter occur because less sound is absorbed during passage through cyst than thr ough the adjacent parenchyma. If these criteria are not satisfied, computed tomo graphy can rule out complications and other diagnoses. PREVALENCE OF SIMPLE RENAL CYSTS DETECTED BY ULTRASONOGRAPHY Prevalence, % 1 Cyst 2 Cysts* 3 Cysts* 1 Cyst in Each Kidney Age group, y 1529 3049 5069 70 M 0 2 15 32 F 0 1 7 15 M 0 0 2 17 F 0 1 1 8 M 0 0 1 6 F 0 1 1 3 M 0 0 2 9 F 0 1 1 3 *Unilateral or bilateral. Mmale; FFemale. FIGURE 9-4 Prevalence of simple renal cysts detected by ultrasonography accordin g to age in an Australian population of 729 persons prospectively screened by ul trasonography. The prevalence increases with age and is higher in males. Cyst size also increases with age. Mo st simple cysts are located in the cortex. (From Ravine et al. [4]; with permiss ion.)

9.4 Tubulointerstitial Disease A FIGURE 9-5 A and B, Multiple simple cysts (one 7 cm in diameter in the lower pol e of the left kidney and three 4 to 5 cm in diameter in the right kidney) detect ed by contrast-enhanced computed tomography (CT). Additional millimetric cysts m ight be suspected in both kidneys. B Each cyst exhibits the typical features of an uncomplicated simple cyst on CT: 1 ) homogeneous low density, unchanged by contrast medium; 2) rounded outline; 3) very thin (most often indetectable) wall; 4) distinct delineation from adjacent parenchyma. A FIGURE 9-6 A, Contrast-enhanced computed tomography (CT) shows a simple, 3-cm wi de cyst of the renal sinus (arrows) found during investigation of renal calculi. Note subcapsular hematoma (arrowheads) detected after lithotripsy. B, Contrastenhanced CT shows bilateral multiple cysts of the renal sinus, leading to chroni c compression of the pelvis and subsequent renal atrophy. B Ultrasonographic appearance mimicked hydronephrosis. Also known as hilar lymphan giectasis or peripelvic (or parapelvic) cysts, this acquired disorder consists o f dilated hilar lymph channels. Its frequency is about 1% in autopsy series. Alt hough usually asymptomatic, cysts of the renal sinus can cause severe urinary ob struction, B.

Cystic Diseases of the Kidney 9.5 A FIGURE 9-7 A, Acquired cystic kidney disease (ACKD) detected by contrastenhanced computed tomography (CT) in a 71-year-old man on hemodialysis for 4 years. A, N ote the several intrarenal calcifications, which are not unusual in dialysis pat ients. ACKD is characterized by the development of many cysts in the setting of chronic uremia. It can occur at any age, including childhood, whatever the origi nal nephropathy. The diagnosis is based on detection of at least three to five c ysts in each kidney in a patient who has chronic renal failure but not hereditar y cystic disease. The prevalence of ACKD averages 10% at onset of dialysis treat ment and subsequently increases, to reach 60% and 90% at 5 and 10 years into B hemodialysis and peritoneal dialysis, respectively [5]. In the early stage, kidn eys are small or even shrunken and cysts are usually smaller than 0.5 cm. Cyst n umbers and kidney volume increase with time, as seen on this patient's scan (B) re peated 8 years into dialysis. Advanced ACKD can mimic autosomal-dominant polycys tic disease. ACKD sometimes regresses after successful transplantation; it can i nvolve chronically rejected kidney grafts. Although ACKD is usually asymptomatic it may be complicated by bleedingconfined to the cysts or extending to either th e collecting system (causing hematuria) or the perinephric spacesand associated w ith renal cell carcinoma. (Courtesy of M. Jadoul.) Age <55 and > 3 years No on RRT and good clinical condition? Yes Echography: ACK D? Yes Suspicion of renal neoplasm? Yes No Enhanced CT: confirmed neoplasm? Yes Nephrectomy and annual follow-up of contralateral kidney No No No screening Biennial echo FIGURE 9-8 Screening for acquired cystic kidney disease (ACKD) and renal neoplas ms in patients receiving renal replacement therapy (RRT). The major clinical con cern with ACKD is the risk of renal cell carcinoma, often the tubulopapillary ty pe, associated with this disorder: the incidence is 50-times greater than in the general population. Moreover, ACKD-associated renal carcinoma is more often bil ateral and multicentric; however, only a minority of them evolve into invasive c arcinomas or cause metastases [5]. There is no doubt that imaging should be perf ormed when a dialysis patient has symptoms such as flank pain and hematuria, the question of periodic screening for ACKD and neoplasms in asymptomatic dialysis patients is still being debated. Using decision analysis incorporating morbidity and mortality associated with nephrectomy in dialysis patients, Sarasin and cow orkers [6] showed that only the youngest patients at risk for ACKD benefit from periodic screening. On the basis of this analysis, it has been proposed that scr eening be restricted to patients younger than 55 years, who have been on dialysi s at least 3 years and are in good general condition. Recognized risk factors fo r renal cell carcinoma in ACKD are male gender, uremia of long standing, large k idneys, and analgesic nephropathy.

9.6 Tubulointerstitial Disease FIGURE 9-9 Multilocular cyst (or multilocular cystic nephroma) of the right kidn ey, detected by ultrasonography (A) and contrast-enhanced CT-scan (B). Both tech niques show the characteristic septa (arrow) dividing the mass into multiple son olucent locules. This rare disorder is usually a benign tumor, though some lesio ns have been found to contain foci of nephroblastoma or renal clear cell carcino ma. The imaging appearance is actually indistinguishable from those of the cysti c forms of Wilms' tumor and renal clear cell carcinoma. (Courtesy of A. Dardenne.) A B A B FIGURE 9-10 A, contrast-enhanced computed tomography (CT) for evaluation of a le ft renal stone in a 67-year-old man. A cystic mass was found at the lower pole o f the right kidney. Only careful examination revealed that the walls of the mass (arrows) were too thick for a simple cyst (see Fig. 9-5 for comparison). B, The echo pattern of the mass was very heterogeneous (arrows), clearly different fro m the echo-free appearance of a simple cyst (see Fig. 9-3 for comparison). C, Ma gnetic resonance imaging showed thick, irregular walls and a hyperintense centra l area (arrows). At surgery, the mass proved to be a largely necrotic renal cell carcinoma. Thus, although renal carcinoma is not a true cystic disease, it occa sionally has a cystic appearance on CT and can mimic a simple cyst. (Courtesy of A. Dardenne.) C

Cystic Diseases of the Kidney 9.7 FIGURE 9-11 Medullary sponge kidney (MSK) diagnosed by intravenous urography in 53-year-old woman with a history of recurrent kidney stones. Pseudocystic collec tions of contrast medium in the papillary areas (arrows) are the typical feature of MSK. They result from congenital dilatation of collecting ducts (involving p art or all of one or both kidneys), ranging from mild ectasia (appearing on urog raphy as linear striations in the papillae, or papillary blush) to frank cystic po ols, as in this case (giving a spongelike appearance on section of the kidney). MSK has an estimated prevalence of 1 in 5000 [2]. It predisposes to stone format ion in the dilated ducts: on plain films, clustering of calcifications in the pa pillary areas is very suggestive of the condition. MSK may be associated with a variety of other congenital and inherited disorders, including corporeal hemihyp ertrophy, Beckwith-Wiedemann syndrome (macroglossia, omphalocele, visceromegaly, microcephaly, and mental retardation), polycystic kidney disease (about 3% of p atients with autosomal-dominant polycystic kidney disease have evidence of MSK), congenital hepatic fibrosis, and Caroli's disease [7]. FIGURE 9-12 Multicystic dysplastic kidney (MCDK) found incidentally by enhanced CT in a 34-year-old patient. The dysplastic kidney is composed of cysts with mur al calcifications (arrows). Note the compensatory hypertrophy of the right kidne y and the incidental simple cysts in it. MCDK consists of a collection of cysts frequently described as resembling a bunch of grapes and an atretic ureter. No f unction can be demonstrated. Only unilateral involvement is compatible with life . Usually, the contralateral kidney is normal and exhibits compensatory hypertro phy. In some 30% of cases, however, it is also affected by some congenital abnor malities such as dysplasia or pelviureterical junction obstruction. In fact, amo ng the many forms of renal dysplasia, MCDK is thought to represent a cystic vari ety. FIGURE 9-13 Intravenous urography demonstrates multiple calyceal diverticula (ar rows) in a 38-year-old woman who complained of intermittent flank pain. Previous ly, the ultrasonographic appearance had suggested the existence of polycystic ki dney disease. Although usually smaller than 1 cm in diameter, pyelocalyceal dive rticula occasionally are much larger, as in this case. They predispose to stone formation. Since ultrasonography is the preferred screening tool for cystic rena l diseases, clinicians must be aware of both its pitfalls (exemplified in this c ase and in the case of parapelvic cysts; see Fig. 9-6) and its limited power to detect very small cysts.

9.8 Tubulointerstitial Disease Genetic disorders GENETICS OF ADPKD Gene PKD1 PKD2 PKD3 Chromosome 16 4 ? Product Polycystin 1 Polycystin 2 ? Patients with ADPKD, % 8090 1020 Very few FIGURE 9-14 Genetics of autosomal-dominant polycystic kidney disease (ADPKD). AD PKD is by far the most frequent inherited kidney disease. In white populations, its prevalence ranges from 1 in 400 to 1 in 1000. ADPKD is characterized by the development of multiple renal cysts that are variably associated with extrarenal (mainly hepatic and cardiovascular) abnormalities [1,2,3]. It is caused by muta tions in at least three different genes. PKD1, the gene responsible in approxima tely 85% of the patients, located on chromosome 16, was cloned in 1994 [8]. It e ncodes a predicted protein of 460 kD, called polycystin 1. The vast majority of the remaining cases are accounted for by a mutation in PKD2, located on chromoso me 4 and cloned in 1996 [9]. The PKD2 gene encodes a predicted protein of 110 kD called polycystin 2. Phenotypic differences between the two main genetic forms are detailed in Figure 9-19. The existence of (at least) a third gene is suggest ed by recent reports. FIGURE 9-15 Autosomal-dominant polycystic kidney disease: predicted structure of polycystin 1 and polycystin 2 and their interaction. Poly cystin 1 is a 4302-amino acid protein, which anchors itself to cell membranes by seven transmembrane domains [10]. The large extracellular portion includes two leucine-rich repeats usually involved in protein-protein interactions and a C-ty pe lectin domain capable of binding carbohydrates. A part of the intracellular t ail has the capacity to form a coiled-coil motif, enabling either self-assemblin g or interaction with other proteins. Polycystin 2 is a 968-amino acid protein w ith six transmembrane domains, resembling a subunit of voltage-activated calcium channel. Like polycystin 1, the C-terminal end of polycystin 2 comprises a coil ed-coil domain and is able to interact in vitro with PKD2 [11]. This C-terminal part of polycystin 2 also includes a calcium-binding domain. On these grounds, i t has been hypothesized that polycystin 1 acts like a receptor and signal transd ucer, communicating information from outside to inside the cell through its inte raction with polycystin 2. This coordinated function could be crucial during lat e renal embryogenesis. It is currently speculated that both polycystins play a r ole in the maturation of tubule epithelial cells. Mutation of polycystins could thus impair the maturation process, maintaining some tubular cells in a state of underdevelopment. This could result in both sustained cell proliferation and pr edominance of fluid secretion over absorption, leading to cyst formation (see Fi g. 9-16 and references 12 and 13 for review). (From Hughes et al. [10] and Germi no [12].) NH2 Cysteine-rich domain Leucine-rich domain PKD1 domain C L B C L B C-type lectin domain Lipoprotein A domain R E J

REJ domain Transmembrane segment Alpha helix coiled-coil R E J Out Membrane In NH2 HOOC Polycystin 1 COOH Polycystin 2

Cystic Diseases of the Kidney 9.9 Thickened tubular basement membrane Fluid Accumulation Normal tubule with germinal PKD1 mutation in each cell Occurrence of somatic mutation of the normal PKD1 allele in one tubular cell (th e "second hit") Monoclonal proliferation leading to cyst formation Isolated cyst disconnected from its tubule of origin FIGURE 9-16 Hypothetical model for cyst formation in autosomal-dominant polycyst ic kidney disease (ADPKD), relying on the two-hit mechanism as the primary event. The observation that only a minority of nephrons develop cysts, despite the fact that every tubular cell harbors germinal PKD1 mutation, is best accounted for b y the two-hit model. This model implies that, in addition to the germinal mutati on, a somatic (acquired) mutation involving the normal PKD1 allele is required to trigger cyst formation (ie, a mechanism similar to that de monstrated for tumor suppressor genes in tuberous sclerosis complex and von Hipp el-Lindau disease). The hypothesis is supported by both the clonality of most cy sts and the finding of loss of heterozygosity in some of them [12]. Cell immatur ity resulting from mutated polycystin would lead to uncontrolled growth, elabora tion of abnormal extracellular matrix, and accumulation of fluid. Aberrant cell proliferation is demonstrated by the existence of micropolyps, identification of mitotic phases, and abnormal expression of proto-oncogenes. Abnormality of extr acellular matrix is evidenced by thickening and lamination of the tubular baseme nt membrane; involvement of extracellular matrix would explain the association o f cerebral artery aneurysms with ADPKD. As most cysts are disconnected from thei r tubule of origin, they can expand only through net transepithelial fluid secre tion, just the reverse of the physiologic tubular cell function [13]. Figure 9-1 7 summarizes our current knowledge of the mechanisms that may be involved in int racystic fluid accumulation. Basolateral Aden Na+ cAMP K+ 2Cl PKA ylate cycla Apical se ATP (CFTR) Cl DPC Lumen H 2O QP) (A

Bumetanide + + (Na -K -ATPase) 3Na+ 2K ATP ADP + Pi + Ouabain H 2O Na+ ( AQP) FIGURE 9-17 Autosomal-dominant polycystic kidney disease (ADPKD): mechanisms of intracystic fluid accumulation [13,14]. The primary mechanism of intracystic flu id accumulation seems to be a net transfer of chloride into the lumen. This secr etion is mediated by a bumetanide-sensitive Na+-K+-2Cl- cotransporter on the bas olateral side and cystic fibrosis transmembrane regulator (CFTR) chloride channe l on the apical side. The activity of the two transporters is regulated by prote in kinase A (PKA) under the control of cyclic adenosine monophosphate (AMP). The chloride secretion drives movement of sodium and water into the cyst lumen thro ugh electrical and osmotic coupling, respectively. The pathway for transepitheli al Na+ movement has been debated. In some experimental conditions, part of the N a+ could be secreted into the lumen via a mispolarized apical Na+-K+-ATPase (sodi um pump); however, it is currently admitted that most of the Na+ movement is para cellular and that the Na+-K+-ATPase is located at the basolateral side. The move ment of water is probably transcellular in the cells that express aquaporins on both sides and paracellular in others [13, 14]. AQPaquaporine; DPCdiphenylamine ca rboxylic acid.

9.10 Tubulointerstitial Disease Odds ratio (95% Cl) PKD2 vs. PKD1 ADPKD: CLINICAL MANIFESTATIONS Manifestation Renal Hypertension Pain (acute and chronic) Gross hematuria Urinary tract infect ion Calculi Renal failure Hepatobiliary (see Fig. 923) Cardiovascular Cardiac val vular abnormality Intracranial arteries Aneurysm Dolichoectasia ? Ascending aort a dissection ? Coronary arteries aneurysm Other Pancreatic cysts Arachnoid cysts Hernia Inguinal Umbilical Spinal Meningeal Diverticula 1.0 0.8 0.6 0.4 0.2 0.0 0.28 (0.16-0.48) 0.47 (0.28-0.81) 0.46 (0.22-0.98) Prevalence, % Increased with age (80 at ESRD) 60 50 Men 20; women 60 20 50 at 60 y Reference [15] [3,16] [3,16] [3] [17] [18] 0.18 (0.07-0.47) 20 8 2 Rare Rare 9 8 13 7 0.2 [16] [3] [19] 80 70 60 50 Age, y 40 30 20 Hypertension Renal infection Subarachnoid history hemorrhage PKD2 PKD1 61 74 75 Abdominal hernia 70 60 [20] [21] [22] [22] [23] 35 FIGURE 9-18 Main clinical manifestations of autosomal-dominant polycystic kidney disease (ADPKD). Renal involvement may be totally asymptomatic at early stages. Arterial hypertension is the presenting clinical finding in about 20% of patien ts. Its frequency increases with age. Flank or abdominal pain is the presenting symptom in another 20%. The differential diagnosis of acute abdominal is detaile d in Figure 9-22. Gross hematuria is most often due to bleeding into a cyst, and more rarely to stone. Renal infection, a frequent reason for hospital admission , can involve the upper collecting system, renal parenchyma or renal cyst. Diagn ostic data are obtained by ultrasonography, excretory urography and CT: use of C T in cyst infection is described in Figure 9-21. Frequently, stones are radioluc ent or faintly opaque, because of their uric acid content. The main determinants of progression of renal failure are the genetic form of the disease (see Fig. 9 -19) and gender (more rapid progression in males). Hepatobiliary and intracrania l manifestations are detailed in Figures 9-23 to 9-26. Pancreatic and arachnoid cysts are most usually asymptomatic. Spinal meningeal diverticula can cause post ural headache. ESRDend-stage renal disease. 10 0 Clinical presentation End-stage renal failure Median age Death

FIGURE 9-19 Autosomal-dominant polycystic kidney disease (ADPKD): phenotype PKD2 versus PKD1. Families with a PKD2 mutation have a milder phenotype than those w ith a PKD1 mutation. In this study comparing 306 PKD2 patients (from 32 families ) with 288 PKD1 patients (17 families), PKD2 patients were, for example, less li kely to be hypertensive, to have a history of renal infection, to suffer a subar achnoid hemorrhage, and to develop an abdominal hernia. As a consequence of the slower development of clinical manifestations, PKD2 patients were, on average, 2 6 years older at clinical presentation, 14 years older when they started dialysi s, and 5 years older when they died. Early-onset ADPKD leading to renal failure in childhood has been reported only in the PKD1 variety. (Data from Hateboer [24 ].)

Cystic Diseases of the Kidney 9.11 A B C FIGURE 9-20 Autosomal-dominant polycystic kidney disease (ADPKD): kidney involve ment. Examples of various cystic involvements of kidneys in ADPKD. Degree of inv olvement depends on age at presentation and disease severity. A, With advanced d isease as in this 54-year-old woman, renal parenchyma is almost completely repla ced by innumerable cysts. Note also the cystic involvement of the liver. B, Mark ed asymmetry in the number and size of cysts between the two D kidneys may be observed, as in this 36-year-old woman. In the early stage of the disease, making the diagnosis may be more difficult (see Fig. 9-28 for the mini mal sonographic criteria to make a diagnosis of ADPKD in PKD1 families). C, D, C ontrast-enhanced CT is more sensitive than ultrasonography in the detection of s mall cysts. The presence of liver cysts helps to establish the diagnosis, as in this 38year-old man with PKD2 disease and mild kidney involvement.

9.12 Tubulointerstitial Disease A FIGURE 9-21 Autosomal-dominant polycystic kidney disease (ADPKD): kidney cyst in fection. Course of severe cyst infection in the right kidney of a patient with A DPKD who was admitted for fever and acute right flank pain. Blood culture was po sitive for Escherichia coli. A, CT performed on admission showed several heterog eneous cysts in the right kidney (arrows). Infection did not respond to appropri ate B antibiotherapy (fluoroquinolone). B, CT repeated 17 days later showed considerab le enlargement of the infected cysts (arrows). Percutaneous drainage failed to c ontrol infection, and nephrectomy was necessary. This case illustrates the poten tial severity of cyst infection and the contribution of sequential CT in the dia gnosis and management of complicated cysts. FIGURE 9-22 Autosomal-dominant polyc ystic kidney disease (ADPKD): specific causes of acute abdominal pain. The most frequent cause of acute abdominal pain related to ADPKD is intracyst bleeding. D epending on the amount of bleeding, it may cause mild, transient fever. It may o r may not cause gross hematuria. Cyst hemorrhage is responsible for most high-de nsity cysts and cyst calcifications demonstrated by CT. Spontaneous resolution i s the rule. Excretory urography or enhanced CT is needed mostly to locate obstru ctive, faintly opaque stones. Stones may be treated by percutaneous or extracorp oral lithotripsy. Renal infection may involve the upper collecting system, renal parenchyma, or cyst. Parenchymal infection is evidenced by positive urine cultu re and prompt response to antibiotherapy; cyst infection by the development of a new area of renal tenderness, quite often a negative urine culture (but a posit ive blood culture), and a slower response to antibiotherapy. CT demonstrates the heterogeneous contents and irregularly thickened walls of infected cysts. Cyst infection warrants prolonged anti-biotherapy [3]. An example of severe, intracta ble cyst infection is shown in Figure 9-21. ADPKD: SPECIFIC CAUSES OF ACUTE ABDOMINAL PAIN Cause Renal Cyst Bleeding Stone Infection Liver Cyst Infection Bleeding Frequency ++++ ++ + Rare Very Rare Fever Mild (<38C, maximum 2 days) or none With pyonephrosis High; prolonged with cyst i nvolved High, prolonged Mild (<38C, maximum 2 days) or none

Cystic Diseases of the Kidney 9.13 ADPKD: HEPATOBILIARY MANIFESTATIONS Finding Asymptomatic liver cysts Symptomatic polycystic liver disease Complicated cysts (hemorrhage, infection) Massive hepatomegaly Chronic pain/discomfort Early satie ty Supine dyspnea Abdominal hernia Obstructive jaundice Hepatic venous outflow o bstruction Congenital hepatic fibrosis Idiopathic dilatation of intrahepatic or extrahepatic biliary tract Cholangiocarcinoma Frequency Very common; increased prevalence with age (up to 80% at age 60) Uncommon (male/ female ratio: 1/10) Rare (not dominantly transmitted) Very rare Very rare FIGURE 9-23 Autosomal-dominant polycystic kidney disease (ADPKD): hepatobiliary manifestations. Liver cysts are the most frequent extrarenal manifestation of AD PKD. Their prevalence increases dramatically from the third to the sixth decade of life, reaching a plateau of 80% thereafter [25, 26]. They are observed earlie r and are more numerous and extensive in women than in men. Though usually mild and asymptomatic, cystic liver involvement occasionally is massive and symptomat ic (see Figure 9-24). Rare cases have been reported of congenital hepatic fibros is or idiopathic dilatation of the intrahepatic or extrahepatic tract associated with ADPKD [25, 26]. FIGURE 9-24 Autosomal-dominant polycystic kidney disease (ADPKD): polycystic liv er disease. Contrast-enhanced CT in a 32-year-old woman with ADPKD, showing mass ive polycystic liver disease contrasting with mild kidney involvement. Massive p olycystic liver disease can cause chronic pain, early satiety, supine dyspnea, a bdominal hernia, and, rarely, obstructive jaundice, or hepatic venous outflow ob struction. Therapeutic options include cyst sclerosis and fenestration, hepatic resection, and, ultimately, liver transplantation [25, 26]. A FIGURE 9-25 Autosomal-dominant polycystic kidney disease (ADPKD): intracranial a neurysm detection. Magnetic resonance angiography (MRA), A, and spiral computed tomography (CT) angiography, B, in two different patients, both with ADPKD, show an asymptomatic intracranial aneurysm (ICA) on the posterior communicating arte ry (arrow), A, and the anterior communicating artery (arrow), B, respectively. T he prevalence of asymptomatic ICA in ADPKD is 8%, as compared with 1.2% in the g eneral population. It reaches 16% in ADPKD patients with a family history of ICA [27]. The risk of B ICA rupture in ADPKD is ill-defined. ICA rupture entails 30% to 50% mortality. I t is generally manifested by subarachnoid hemorrhage, which usually presents as an excruciating headache. In this setting, the first-line diagnostic procedure i s CT. Management should proceed under neurosurgical guidance [27]. Given the sev ere prognosis of ICA rupture and the possibility of prophylactic treatment, scre ening ADPKD patients for ICA has been considered. Screening can be achieved by e ither MRA or spiral CT angiography. Current indications for screening are presen ted in Figure 9-26. (Courtesy of T. Duprez and F. Hammer.)

9.14 Age 1840 years and family history of ICA? Yes Tubulointerstitial Disease FIGURE 9-26 Autosomal-dominant polycystic kidney disease (ADPKD): intracranial a neurysm (ICA) screening. On the basis of decision analyses (taking into account ICA prevalence, annual risk of rupture, life expectancy, and risk of prophylacti c treatment), it is currently proposed to screen for ICA 18 to 40-year-old ADPKD patients with a family history of ICA [25, 27]. Screening could also be offered to patients in high-risk occupations and those who want reassurance. Guidelines for prophylactic treatment are the same ones used in the general population: th e neurosurgeon and the interventional radiologist opt for either surgical clippi ng or endovascular occlusion, depending on the site and size of ICA. No No screening Brain MR angiography No or spiral CT scan: ICA? Yes Conventional angiography Dis cuss management with neurosurgeon Repeat every 5 years ADPKD: PRESYMPTOMATIC DIAGNOSIS Presymptomatic diagnosis Is advisable in families when early management of affec ted patients would be altered (eg, because of history of intracranial aneurysm) Should be made available to persons at risk who are 18 years or older who reques t the test Should be preceded by information about the possibility of inconclusi ve results and the consequences of the diagnosis: If negative, reassurance If po sitive, regular medical follow-up, possible psychological burden, risk of disqua lification from employment and insurances ADPKD: ULTRASONOGRAPHIC DIAGNOSTIC CRITERIA Age 1529 3059 60 Cysts 2, uni- or bilateral 2 in each kidney 4 in each kidney Minimal number of cysts to establish a diagnosis of ADPKD in PKD1 families at ri sk. FIGURE 9-27 Autosomal-dominant polycystic kidney disease (ADPKD): presymptomatic diagnosis. Presymptomatic diagnosis is aimed at both detecting affected persons (to provide follow-up and genetic counseling) and reassuring unaffected ones. U ntil a specific treatment for ADPKD is available, presymptomatic diagnosis in ch ildren is not advised except in rare families where early-onset disease is typic al. Presymptomatic diagnosis is recommended when a family is planned and when ea rly management of affected patients would be altered. The mainstay of screening is ultrasonography; diagnostic echographic criteria according to age in PKD1 fam ilies are depicted in Figure 9-28, and diagnosis by gene linkage in Figure 9-29. FIGURE 9-28 Autosomal-dominant polycystic kidney disease (ADPKD): ultrasonograph ic diagnostic criteria. Ultrasound diagnostic criteria for the PKD1 form of ADPK D, as established by Ravine's group on the basis of both a sensitivity and specifi city study [4, 28]. Note that the absence of cyst before age 30 years does not r ule out the diagnosis, the false-negative rate being inversely related to age. W hen ultrasound diagnosis remains equivocal, the next step should be either contr ast-enhanced CT (more sensitive than ultrasonography in the detection of small c ysts) or gene linkage (see Figure 9-29). A similar assessment is not yet availab

le for the PKD2 form. (From Ravine et al. [28]; with permission.)

Cystic Diseases of the Kidney 9.15 I ? 1 ? 2 Deceased Unaffected Affected ? Unknown status II 1 2 3 4 1 b 1 2 a 3 b 2 b 2 5 a 4 a 3 2 a 5 1 b III FIGURE 9-29 Example of the use of gene linkage to identify ADPKD gene carriers a mong generation IV of a PKD1 family. Two markers flanking the PKD1 gene were use d. The first one (3' HVR) has six possible alleles (1 through 6) and the other (p 26.6) is biallelic (a, b). In this family, the haplotype 2a is transmitted with the disease (see affected persons II5, III1, and III3). Thus, IV4 has a 99% chan ce of being a carrier of the mutated PKD1 gene, whereas her sisters (IV1, IV2, I V3) have a 99% chance of being disease free. Until direct gene testing for PKD1 and PKD2 is readily available, genetic diagnosis will rest on gene linkage. Such analysis requires that other affected and unaffected family members (preferably from two generations) be available for study. Use of markers on both sides of t he tested gene is required to limit potential errors due to recombination events . Linkage to PKD1 is to be tested first, as it accounts for about 85% of cases. IV 2 b ? 1 3 b 3 b ? 2 2 b 3 b ? 3 5 a 2 a ? 4 5 a Life expectancy <5 yrs or contraindication to surgery or to immunosuppressants? No Pretransplant workup: Eligibility for transplantation? No No Very large kidne ys or abdominal hernia? No Remove kidney(s)? or Yes Yes History of cyst infection? Yes Yes FIGURE 9-30 Autosomal-dominant polycystic kidney disease (ADPKD): renal replacem

ent therapy. Transplantation nowadays is considered in any ADPKD patient with a life expectancy of more than 5 years and with no contraindications to surgery or immunosuppression. Pretransplant workup should include abdominal CT, echocardio graphy, myocardial stress scintigraphy, and, if needed (see Figure 9-26), screen ing for intracranial aneurysm. Pretransplant nephrectomy is advised for patients with a history of renal cyst infection, particularly if the infections were rec ent, recurrent, or severe. Patients not eligible for transplantation may opt for hemodialysis or peritoneal dialysis. Although kidney size is rarely an impedime nt to peritoneal dialysis, this option is less desirable for patients with very large kidneys, because their volume may reduce the exchangeable surface area and the tolerance for abdominal distension. Outcome for ADPKD patients following re nal replacement therapy is similar to that of matched patients with another prim ary renal disease [29, 30]. Transplantation Peritoneal dialysis Hemodialysis

9.16 Tubulointerstitial Disease FIGURE 9-31 Tuberous sclerosis complex (TSC): clinical features. TSC is an autos omal-dominant multisystem disorder with a minimal prevalence of 1 in 10,000 [30, 31]. It is characterized by the development of multiple hamartomas (benign tumo rs composed of abnormally arranged and differentiated tissues) in various organs . The most common manifestations are dermatologic (see Fig. 9-32) and neurologic (see Fig. 9-33). Renal involvement occurs in 60% of cases and includes cysts (s ee Fig. 9-34). Retinal involvement, occurring in 50% of cases, is almost always asymptomatic. Liver involvement, occurring in 40% of cases, includes angiomyolip omas and cysts. Involvement of other organs is much rarer [31, 32]. CLINICAL FEATURES Finding Skin Hypomelanotic macules Facial angiofibromas Forehead fibrous plaques Shagreen patches (lower back) Periungual fibromas Central nervous system Cortical tubers Subependymal tumors (may be calcified) focal or generalized seizures Mental reta rdation/ behavioral disorder Kidney Angiomyolipomas Cysts Renal cell carcinoma E ye Retinal hamartoma Retinal pigmentary abnormality Liver (angiomyolipomas, cyst s) Heart (rhabdomyoma) Lung (lymphangiomyomatosis; affects females) Frequency, % 90 80 30 30 30 90 90 80 50 Age at onset, y Childhood 515 5 10 15 Birth Birth 01 05 60 30 2 50 10 40 2 1 Childhood Childhood Adulthood Childhood Childhood Childhood Childhood 20 B FIGURE 9-32 (see Color Plate) Tuberous sclerosis complex (TSC): skin involvement . Facial angiofibromas, forehead plaque, A, and ungual fibroma, B, characteristi c of TSC. Previously (and inappropriately) called adenoma sebaceum, facial angio fibromas are pink to red papules or nodules, often concentrated in the nasolabia l folds. Forehead fibrous plaques appear as raised, soft patches of red or yello w skin. Ungual fibromas appear as peri- or subungual pink tumors; they are found more often on the toes than on the fingers and are more common in females. Othe r skin lesions include hypomelanotic macules and shagreen patches (slightly elevat ed patches of brown or pink skin). (Courtesy of A. Bourloud and C. van Ypersele. ) A

Cystic Diseases of the Kidney 9.17 FIGURE 9-33 Tuberous sclerosis complex (TSC): central nervous system involvement . Brain CT shows several subependymal, periventricular, calcified nodules charac teristic of TSC. Subependymal tumors and cortical tubers are the two characteris tic neurologic features of TSC. Calcified nodules are best seen on CT, whereas n oncalcified tumors are best detected by magnetic resonance imaging. Clinical man ifestations are seizures (including infantile spasms) occurring in 80% of infant s, and varying degrees of intellectual disability or behavioral disorder, report ed in 50% of children [32]. A FIGURE 9-34 Tuberous sclerosis complex (TSC): kidney involvement. Contrastenhanc ed CT, A, and gadolinium-enhanced T1 weighted magnetic resonance images, B, of a 15-year-old woman with TSC, show both a large, hypodense, heterogeneous tumor i n the right kidney (arrows) characteristic of angiomyolipoma (AML) and multiple bilateral kidney cysts. Kidney cysts had been detected at birth. AML is a benign tumor composed of atypical blood vessels, smooth muscle cells, and fat tissue. While single AML is the most frequent kidney tumor in the general population, mu ltiple and bilateral AMLs are characteristic of TSC. In TSC, AMLs develop at a y ounger age in females; frequency and size of the tumors increase with age. Diagn osis of AML by imaging techniques (ultrasonography [US], CT, magnetic resonance imagine [MRI]) relies on identification B of fat into the tumor, but it is not always possible to distinguish between AML and renal cell carcinoma. The main complication of AML is bleeding with subseque nt gross hematuria or potentially lifethreatening retroperitoneal hemorrhage. Cy sts seem to be restricted to the TSC2 variety (see Fig. 9-35) [33]. Their extent varies widely from case to case. Occasionally, polycystic kidneys are the prese nting manifestation of TSC2 in early childhood: in the absence of renal AML, the imaging appearance is indistinguishable from ADPKD. Polycystic kidney involveme nt leads to hypertension and renal failure that reaches end stage before age 20 years. Though the frequency of renal cell carcinoma in TSC is small, the inciden ce is increased as compared with that of the general population. (Courtesy of J. F. De Plaen and B. Van Beers.)

9.18 Tubulointerstitial Disease VHL: ORGAN INVOLVEMENT Mean age (range) at diagnosis, y 30 (971) 60 20 Rare 60 40 30 15 HG loci PKD1 TSC2 Death 16 pter Findings Central nervous system Hemangioblastoma Cerebellar Spinal cord Endolymphatic sac tumor Eye/Retinal hemangioblastoma Kidney Clear cell carcinoma Cysts Adrenal gl ands/ Pheochromocytoma Pancreas Cysts Microcystic adenoma Islet cell tumor Carci noma Liver (cysts) Frequency, % Chromosome 16 FIGURE 9-35 Tuberous sclerosis complex (TSC): genetics. Representative examples of various contiguous deletions of the PKD1 and TSC2 genes in five patients with TSC and prominent renal cystic involvement (the size of the deletion in each pa tient is indicated). TSC is genetically heterogeneous. Two genes have been ident ified. The TSC1 gene is on chromosome 9, and TSC2 lies on chromosome 16 immediat ely adjacent and distal to the PKD1 gene. Half of affected families show linkage to TSC1 and half to TSC2. Nonetheless, 60% of TSC cases are apparently sporadic , likely representing new mutations (most are found in the TSC2 gene) [34]. The proteins encoded by the TSC1 and TSC2 genes are called hamartin and tuberin, res pectively. They likely act as tumor suppressors; their precise cellular role rem ains largely unknown. The diseases caused by type 1 and type 2 TSC are indisting uishable except for renal cysts, which, so far, have been observed only in TSC2 patients [33], and for intellectual disability, which is more common in TSC2 pat ients [34]. (Adapted from Sampson, et al. [33].) 25 (870) 40 (1870) 35 (1560) 20 (560) 30 (1370) 40 4 2 1 Rare ? FIGURE 9-36 Von Hippel-Lindau disease (VHL): organ involvement. VHL is an autoso mal-dominant multisystem disorder with a prevalence rate of roughly 1 in 40,000 [32, 35]. It is characterized by the development of tumors, benign and malignant , in various organs. VHL-associated tumors tend to arise at an earlier age and m ore often are multicentric than the sporadic varieties. Morbidity and mortality are mostly related to central nervous system hemangioblastoma and renal cell car cinoma. Involvement of cerebellum, retinas, kidneys, adrenal glands, and pancrea s is illustrated (see Figures 9-37 to 9-41). The VHL gene is located on the shor t arm of chromosome 3 and exhibits characteristics of a tumor suppressor gene. M utations are now identified in 70% of VHL families [36]. FIGURE 9-37 Von HippelLindau disease (VHL): central nervous system involvement. Gadolinium-enhanced br

ain magnetic resonance image of a patient with VHL, shows a typical cerebellar h emangioblastoma, appearing as a highly vascular nodule (arrow) in the wall of a cyst (arrowheads) located in the posterior fossa. Hemangioblastomas are benign t umors whose morbidity is due to mass effect. Cerebellar hemangioblastomas may pr esent with symptoms of increased intracranial pressure. Spinal cord involvement may be manifested as syringomyelia. (Courtesy of S. Richard.)

Cystic Diseases of the Kidney 9.19 FIGURE 9-38 (see Color Plate) Von Hippel-Lindau disease (VHL): retinal involveme nt. Ocular fundus, A, and corresponding fluorescein angiography, B, in a patient with VHL, shows two typical retinal hemangioblastomas. The smaller tumor (arrow ) appears at the fundus as an intense red spot, whereas the larger (arrow heads) appears as a pink-orange lake with dilated, tortuous afferent and efferent vess els. Small peripheral lesions are usually asymptomatic, whereas large central tu mors can impair vision. (Courtesy of B. Snyers.) B A FIGURE 9-39 Von Hippel-Lindau disease (VHL): kidney involvement. Contrastenhance d CT of a patient with VHL, showing the polycystic aspect of the kidneys. Renal involvement of VHL includes cysts (simple, atypical, and cystic carcinoma) and r enal cell carcinoma [36, 37]. The latter is the leading cause of death from VHL. Occasionally, polycystic kidney involvement may mimic autosomal-dominant polycy stic kidney disease. Both cystic involvement and sequelae of surgery can lead to renal failure. Nephron-sparing surgery is recommended [37]. FIGURE 9-40 Von Hippel-Lindau disease (VHL): adrenal gland involvement. Gadolini um-enhanced abdominal magnetic resonance image of a patient with VHL shows bilat eral pheochromocytoma (arrows). Renal lesions include cysts and solid carcinomas (arrow heads). Pheochromocytoma may be the first manifestation of VHL. It tends to cluster within certain VHL families [36]. (Courtesy of H. Neumann.)

9.20 Tubulointerstitial Disease FIGURE 9-41 Von Hippel-Lindau disease (VHL): pancreas involvement. Contrastenhan ced abdominal CT in a patient with VHL shows multiple cysts in both pancreas (es pecially the tail, arrows) and kidneys. The majority of pancreatic cysts are asy mptomatic. When they are numerous and large, they can induce diabetes mellitus o r steatorrhea. Other, rare pancreatic lesions include microcystic adenoma, islet cell tumor, and carcinoma. VHL: SCREENING PROTOCOL Study Physical examination 24-h Urine collection for metadrenaline and normetadrenalin e Funduscopy Gadolinium MRI brain scan Abdomen Affected persons Annual Annual Relatives at risk Annual Annual FIGURE 9-42 Von Hippel-Lindau disease. As most manifestations of VHL are potenti ally treatable, periodic examination of affected patients is strongly recommende d. Though genetic testing is now very useful for presymptomatic identification o f affected persons, it must be remembered that a mutation in the VHL gene curren tly is detected in only 70% of families. For persons at risk in the remaining fa milies, a screening program is also proposed. Annual Every 3 y (from age 10) Annual gadolinium MRI Annual (age 5 to 60) Every 3 y (age 15 to 60) Annual echography or gadolinium MR I (age 15 to 60) FIGURE 9-43 Medullary cystic disease (MCD). Contrast-enhanced CT in a 35year-old man with MCD. Multiple cysts are seen in the medullary area. Two daughters were also found to be affected. MCD is a very rare autosomal-dominant disorder chara cterized by medullary cysts detectable by certain imaging techniques (preferably computed tomography) and progressive renal impairment leading to endstage disea se between 20 and 40 years of age. Dominant inheritance and early detection of k idney cysts distinguish MCD from autosomal-recessive nephronophthisis (see Fig. 9-48), even though the two may be indistinguishable on histologic examination.

Cystic Diseases of the Kidney 9.21 THERE IS A WHITE BOX PLACED OVER HANDWRITTEN TYPE. A B multiple cysts, typically small cortical ones. This cystic pattern was verified in the nephrectomy specimen, B, obtained 8 months later at the time of kidney tr ansplantation, and GCKD was confirmed by histopathologic examination with Masson's trichrome stain. C, Cysts consisted of a dilatation of Bowman's space surrounding a primitive-looking glomerulus. GCKD may be sporadic or genetically dominant. A mong the familial cases, some patients are infants who have early-onset autosoma l-dominant polycystic disease. In others (children or adults) the disease is unr elated to PKD1 and PKD2 and may or not progress to end-stage renal failure [38]. (Courtesy of D. Droz.) FIGURE 9-45 Autosomal-recessive polycystic kidney diseas e (ARPKD): clinical manifestations. ARPKD is characterized by the development of cysts originating from collecting tubules and ducts, invariably associated with congenital hepatic fibrosis. Its prevalence is about 1 in 40,000 [39]. In the m ost severe cases, with marked oligohydramnios and an empty bladder, the diagnosi s may be suspected as early as the 12th week of gestation. Some neonates die fro m either respiratory distress or renal failure. In most survivors, the disease i s recognized during the first year of life. The ultrasonographic (US) kidney app earance is depicted in Figure 9-46. Excretory urography shows medullary striatio ns owing to tubular ectasia. Kidney enlargement may regress with time. End-stage renal failure develops before age 25 in 70% of patients. Liver involvement cons ists of portal fibrosis (see Fig. 9-47) and intrahepatic bilary ectasia, frequen tly resulting in portal hypertension (leading to hypersplenism and esophageal va rices) and less often in cholangitis, respectively. US may show dilatation of th e biliary ducts, and even cysts. The respective severity of kidney and liver inv olvement vary widely between families and even in a single kindred. A comparison of the diagnostic features of autosomal-dominant polycystic kidney disease (ADP KD) and ARPKD is summarized in Figure 9-2. Renal US of the parents of a child wi th ARPKD is, of course, normal. It should be noted that congenital hepatic fibro sis is found in rare cases of ADPKD with early-onset renal disease. The gene res ponsible for ARPKD has been mapped to chromosome 6. There is no evidence of gene tic heterogeneity [40]. C FIGURE 9-44 Glomerulocystic kidney disease (GCKD). Contrast-enhanced CT, A, in a 23-year-old woman with the sporadic form of GCKD shows ARPKD: CLINICAL MANIFESTATIONS Renal Antenatal (ultrasonographic changes) Oligohydramnios with empty bladder In creased renal volume and echogenicity Neonatal period Dystocia and oligohydramni os Enlarged kidneys Renal failure Respiratory distress with pulmonary hypoplasia (possibly fatal) Infancy of childhood Nephromegaly (may regress with time) Hype rtension (often severe in the first year of life) Chronic renal failure (slowly progressive, with a 60% probability of renal survival at 15 years of age and 30% at 25 years of age) Hepatic Portal fibrosis Intrahepatic biliary tract ectasia

9.22 Tubulointerstitial Disease FIGURE 9-46 A and B, Autosomal-recessive polycystic kidney disease (ARPKD): rena l imaging. On ultrasonography of a child with ARPKD the kidneys appear typically enlarged and uniformly hyperechogenic (owing to the presence of multiple small cysts), and demarcations of cortex, medulla, and sinus are lost. The ultrasonogr aphic appearance is different in older children, because cysts can grow and beco me round; then they resemble the appearance of ADPKD. Figure 9-2 describes how t o differentiate the two conditions. (Courtesy of P. Niaudet.) A B FIGURE 9-47 Autosomal-recessive polycystic kidney disease (ARPKD): liver histolo gy. Liver biopsy specimen from a child with ARPKD shows typical congenital hepat ic fibrosis (hematoxylin eosin safran [HES] stain). This portal space is enlarge d by fibrosis, and the number of biliary channels is increased, many of them bei ng enlarged and all being irregular in outline. (Courtesy of S. Gosseye.) FIGURE 9-48 Nephronophthisis (NPH): renal involvement. Kidney biopsy specimen vi sualized by light microscopy with periodic acidSchiff stain, in a patient with ju venile NPH of an early stage. Note the typical thickening and disruption of the tubular basement membrane (appearing in red); the histiolymphocytic infiltration present at this stage is progressively replaced by interstitial fibrosis. NPH i s an autosomal recessive disorder, accounting for 10% to 15% of all children adm itted for end-stage renal failure. Although classified as a renal cystic disorde r, NPH is characterized by chronic diffuse tubulointerstitial nephritis; the pre sence of cysts at the corticomedullary boundary (thus, the alternative term medul lary cystic disease, now preferably reserved for the autosomal-dominant form; see Fig. 9-43) is a late manifestation of the disease. Clinical features include ea rly polyuria-polydypsia, unremarkable urinalysis, frequent absence of hypertensi on, and eventually, end-stage renal failure at a median age of 13 (range 3 to 23 ) years. Ultrasonographic features are summarized in Figure 9-2; medullary cysts are sometimes detected. Associated disorders are detailed in Figure 9-49. A gen e called NPH1 that has been identified on chromosome 2 accounts for about 80% of cases [41, 42]. In two thirds of them, a large homozygous deletion is detected in this gene [43]. (Courtesy of P. Niaudet.)

Cystic Diseases of the Kidney 9.23 NPH: EXTRARENAL INVOLVEMENT Retinitis pigmentosa (Senior-Loken syndrome) Multiple organ involvement, includi ng Liver fibrosis Other rare features Skeletal changes (cone-shaped epiphyses) C erebellar ataxia Mental retardation FIGURE 9-49 Nephronophthisis (NPH): extrarenal involvement. Extrarenal involveme nt occurs in 20% of NPH cases. The most frequent finding is tapetoretinal degene ration (known as Senior-Loken syndrome), which often results in early blindness or progressive visual impairment. Other rare manifestations include liver (hepat omegaly, hepatic fibrosis), bone (cone-shaped epiphysis), and central nervous sy stem (mental retardation, cerebellar ataxia) abnormalities, quite often in assoc iation. A FIGURE 9-50 Orofaciodigital syndrome (OFD). Contrast-enhanced CT, A, and the han ds, B, of a 26-year-old woman with OFD type 1 (OFD1) [43]. Multiple cysts involv e both kidneys. Note that they are smaller and more uniform than in ADPKD and th at renal contours are preserved. Some cysts were also detected in liver and panc reas (arrow). Syndactyly was surgically corrected, and the digits of the hands a re shortened (brachydactyly). OFD1 is a rare X-linked, dominant disorder, diagno sed almost exclusively in females, as affected males die in utero. B Characteristic dysmorphic features include oral (hyperplastic frenulum, cleft to ngue, cleft palate or lip, malposed teeth), facial (asymmetry, broad nasal root) , and digit (syn-brachy-polydactyly) abnormalities. Mental retardation is presen t in about half the cases. Kidneys may be involved by multiple (usually small) c ysts, mostly of glomerular origin; renal failure occurs between the second and t he seventh decade of life. Recognition of the dysmorphic features is the key to the diagnosis [44, 45]. (Courtesy of F. Scolari.) References 1. 2. Fick GM, Gabow PA: Hereditary and acquired cystic disease of the kidney. K idney Int 1994, 46:951964. Welling LW, Grantham JJ: Cystic and developmental dise ases of the kidney. In The Kidney. Edited by Brenner M. Philadelphia:WB Saunders Company; 1996:18281863. Pirson Y, Chauveau D, Grnfeld JP: Autosomal dominant poly cystic kidney disease. In Oxford Textbook of Clinical Nephrology. Edited by Davi son AM, Cameron JS, Grnfeld JP, et al. Oxford:Oxford University Press; 1998:239324 15. Ravine D, Gibson RN, Donlan J, Sheffield LJ: An ultrasound renal cyst preval ence survey: Specificity data for inherited renal cystic diseases. Am J Kidney D is 1993, 22:803807. Levine E: Acquired cystic kidney disease. Radiol Clin North A m 1996, 34:947964. 6. Sarasin FP, Wong JB, Levey AS, Meyer KB: Screening for acqu ired cystic kidney disease: A decision analytic perspective. Kidney Int 1995, 48 :207219. 7. Hildebrandt F, Jungers P, Grnfeld JP: Medullary cystic and medullary s ponge renal disorders. In Diseases of the Kidney. Edited by Schrier RW, Gottscha lk CW. Boston: Little Brown; 1997:499520. 8. The European Polycystic Kidney Disea se Consortium: The polycystic kidney disease 1 gene encodes a 14 kb transcript a nd lies within a duplicated region on chromosome 16. Cell 1994, 77:881894. 9. Moc hizuki T, Wu G, Hayashi T, et al.: PKD2, a gene for polycystic kidney disease th at encodes an integral membrane protein. Science 1996, 272:13391342. 10. Hughes J , Ward CJ, Peral B, et al.: The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. Nature Genet 1995, 10:15 1160. 3.

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9.24 Tubulointerstitial Disease 30. Culleton B, Parfrey PS: Management of end-stage renal failure and problems o f transplantation in autosomal dominant polycystic kidney disease. In Polycystic Kidney Disease. Edited by Watson ML, Torres VE. Oxford:Oxford University Press; 1996:450461. 31. Torres VE: Tuberous sclerosis complex. In Polycystic Kidney Dis ease. Edited by Watson ML, Torres VE. Oxford:Oxford University Press; 1996:283308 . 32. Huson SM, Rosser EM: The Phakomatoses. In Principles and Practice of Medic al Genetics. Edited by Rimoin DL, Connor JM, Pyeritz RE. New York:Churchill Livi ngstone; 1997: 22692302. 33. Sampson JR, Maheshwar MM, Aspinwall R, et al.: Renal cystic disease in tuberous sclerosis: Role of the polycystic kidney disease 1 g ene. Am J Human Genet 1997, 61:843851. 34. Jones AC, Daniells CE, Snell RG, et al .: Molecular genetic and phenotypic analysis reveals differences between TSC1 an d TSC2 associated familial and sporadic tuberous sclerosis. Hum Molec Genet 1997 , 6:21552161. 35. Michels V: Von Hippel-Lindau disease. In Polycystic Kidney Dise ase. Edited by Watson ML, Torres VE. Oxford:Oxford University Press; 1996:309330. 36. Neumann HPH, Zbar B: Renal cysts, renal cancer and von HippelLindau disease . Kidney Int 1997, 51:1626. 37. Chauveau D, Duvic C, Chretien Y, et al.: Renal in volvement in von Hippel-Lindau disease. Kidney Int 1996, 50:944951. 38. Sharp CK, Bergman SM, Stockwin JM, et al.: Dominantly transmitted glomerulocystic kidney disease: A distinct genetic entity. J Am Soc Nephrol 1997, 8:7784. 39. Gagnadoux MF, Broyer M: Polycystic kidney disease in children. In Oxford Textbook of Clini cal Nephrology. Edited by Davison AM, Cameron JS, Grnfeld JP, et al. Oxford:Oxfor d University Press; 1998:23852393. 40. Zerres K, Mcher G, Bachner L, et al.: Mappi ng of the gene for autosomal recessive polycystic kidney disease (ARPKD) to chro mosome 6p21-cen. Nature Genet 1994, 7:429432. 41. Antignac C, Arduy CH, Beckmann JS, et al.: A gene for familial juvenile nephronophthisis (recessive medullary c ystic kidney disease) maps to chromosome 2p. Nature Genet 1993, 3:342345. 42. Hil debrandt F, Otto E, Rensing C, et al.: A novel gene encoding an SH3 domain prote in is mutated in nephronophthisis type 1. Nature Genet 1997, 17:149153. 43. Konra d M, Saunier S, Heidet L, et al.: Large homozygous deletions of the 2q13 region are a major cause of juvenile nephronophthisis. Hum Molec Genet 1996, 5: 367371. 44. Scolari F, Valzorio B, Carli O, et al.: Oral-facial-digital syndrome type I: An unusual cause of hereditary cystic kidney disease. Nephrol Dial Transplant 1 997, 12:12471250. 45. Feather SA, Winyard PJD, Dodd S, Woolf AS: Oral-facial-digi tal syndrome type 1 is another dominant polycystic kidney disease: Clinical, rad iological and histopathological features of a new kindred. Nephrol Dial Transpla nt 1997, 12:13541361. 11. Qian F, Germino FJ, Cai Y, et al.: PKD1 interacts with PKD2 through a probab le coiled-coil domain. Nature Genet 1997, 16:179183. 12. Germino GG: Autosomal do minant polycystic kidney disease: a twohit model. Hospital Pract 1997, 81102. 13. Grantham JJ: The etiology, pathogenesis, and treatment of autosomal dominant po lycystic kidney disease: Recent advances. Am J Kidney Dis 1996, 28:788803. 14. De vuyst O, Beauwens R: Ion transport and cystogenesis: The paradigm of autosomal d ominant polycystic kidney disease. Adv Nephrol 1998, (in press). 15. Parfrey PS, Barrett BJ: Hypertension in autosomal dominant polycystic kidney disease. Curr Opin Nephrol Hypertens 1995, 4:460464. 16. Gabow PA: Autosomal dominant polycysti c kidney disease. N Engl J Med 1993, 329:332342. 17. Torres WE, Wilson DM, Hatter y RR, Segura JW: Renal stone disease in autosomal dominant polycystic kidney dis ease. Am J Kidney Dis 1993, 22:513519. 18. Choukroun G, Itakura Y, Albouze G, et al.: Factors influencing progression of renal failure in autosomal dominant poly cystic kidney disease. J Am Soc Nephrol 1995, 6:16341642. 19. Schievink WI, Torre s VE, Wiebers DO, Huston J III: Intracranial arterial dolichoectasia in autosoma l dominant polycystic kidney disease. J Am Soc Nephrol 1997, 8:12981303. 20. Torr a R, Nicolau C, Badenas C, et al.: Ultrasonographic study of pancreatic cysts in autosomal dominant polycystic kidney disease. Clin Nephrol 1997, 47:1922. 21. Sc hievink WI, Huston J III, Torres VA, Marsh WR: Intracranial cysts in autosomal d ominant polycystic kidney disease. J Neurosurg 1995, 83:10041007. 22. Gabow PA: A

utosomal dominant polycystic kidney diseasemore than a renal disease. Am J Kidney Dis 1990, 16:403413. 23. Schievink WI, Torres VE: Spinal meningeal diverticula i n autosomal dominant polycystic kidney disease. Lancet 1997, 349:12231224. 24. Ha teboer N, Dijk M, Torra R, et al.: Phenotype PKD2 vs. PKD1; results from the Eur opean concerted action. J Am Soc Nephrol 1997, 8:373A. 25. Chauveau D, Pirson Y, Le Moine A, et al.: Extrarenal manifestations in autosomal dominant polycystic kidney disease. Adv Nephrol 1997, 26:265289. 26. Torres VE: Polycystic liver dise ase. In Polycystic Kidney Disease. Edited by Watson ML, Torres VE. Oxford: Oxfor d University Press; 1996:500529. 27. Pirson Y, Chauveau D: Intracranial aneurysms in autosomal dominant polycystic kidney disease. In Polycystic Kidney Disease. Edited by Watson ML, Torres VE. Oxford:Oxford University Press; 1996:530547. 28. Ravine D, Gibson RN, Walker RG, et al.: Evaluation of ultrasonographic diagnosti c criteria for autosomal dominant polycystic kidney disease 1. Lancet 1994, 343: 824827. 29. Pirson Y, Christophe JL, Goffin E: Outcome of renal replacement thera py in autosomal dominant polycystic kidney diseases. Nephrol Dial Transplant 199 6, 11 (suppl. 6):2428.

Toxic Nephropathies Jean-Louis Vanherweghem T ubular interstitial structures of the kidney are particularly vulnerable in face of toxic compounds. High concentration of the toxics in de medulla as well as m edullary hypoxia and renal hypoperfusion could explain this particularity. Clini cal nephrotoxicity involves toxins of diverse origin. The culprits are often reg istered and non registered drugs either prescribed or purchased over the counter . Other major causes result from occupational and industrial exposures. Sometime s, the identification of the nephrotoxin requires astuteness and long investigat ions especially in cases of environmental toxins or prolonged intake of unregula ted drugs or natural products. A correct diagnosis of the causes is, however, th e key for future prevention of renal diseases. The diagnosis of chronic interstit ial nephritis of unknown origin should, therefore, no longer be used. CHAPTER 10

10.2 Tubulointerstitial Disease Exposure to Nephrotoxins TOXIC CAUSES OF CHRONIC TUBULOINTERSTITIAL RENAL DISEASES Metals (Environmental or Occupational Exposure) Lead Cadmium Drugs or Additives (Use, Misuse, or Abuse) Lithium Germanium Analgesics Cyclosporine Mesalazine Fun gus and Plant Toxins (Environmental or Iatrogenic Exposure) Ochratoxins Aristolo chic acids FIGURE 10-1 Chronic exposure to drugs, occupational hazards, or environmental to xins can lead to chronic interstitial renal diseases. The following are the majo r causes of chronic interstitial renal diseases: occupational exposure to heavy metals; abuse of over-the-counter analgesics; misuse of germanium; chronic intak e of mesalazine for intestinal disorders, lithium for depression, and cyclospori ne in renal and nonrenal diseases; and environmental or iatrogenic exposure to f ungus or plant nephrotoxins (ochratoxins, aristolochic acids). Exposure to Metals 30 Odds ratio (95% confidence intervals) 25 20 15 10 5 0 Mercury Tin Chromium Co pper Odds ratio Mercury Tin Chromium Copper Lead Cadmium 5130 3720 2770 2540 211 0 2200 Lead C1 > 1020 1220 1210 1160 1230 900 Cadmium C1 < 25,700 11,300 6330 55 30 4360 8250 FIGURE 10-2 Occupational exposure to metals and risks for chronic renal failure. Comparison of the occupational histories of 272 patients with chronic renal fai lure with those of a matched control group having normal renal function has show n an increased risk of chronic renal failure after exposure to mercury, tin, chr omium, copper, and lead. In this study the increased risk with exposure to cadmi um was not statistically significant. Squares indicate odds ratios; circles indi cate CIs. (Adapted from Nuyts and coworkers [1]; with permission.)

Toxic Nephropathies 10.3 Lead nephropathy CAUSES OF LEAD NEPHROPATHY CLINICAL MANIFESTATIONS OF LEAD NEPHROPATHY Gout Arterial hypertension Renal failure (interstitial type) Environmental Eating paint from lead-painted furniture, woodwork, and toys in ch ildren Lead-contaminated flour Home lead-contaminated drinking water from lead p ipes Drinking of moonshine whiskey Occupational Lead-producing plants: lead smel ters, battery plants FIGURE 10-3 Lead nephropathy associated with environmental and occupational expo sure. Epidemiologic observations have established the relationship between lead exposure and renal failure in association with children eating lead paint in the ir homes, chronic ingestion of leadcontaminated flour, lead-loaded drinking wate r in homes, and drinking of illegal moonshine whiskey [2,3]. Occupational exposu re in lead-producing industries also has been associated with a higher incidence of renal dysfunction. FIGURE 10-4 Gout and hypertension are the major clinical manifestations of lead nephropathy. The prominent feature of early hyperuricemia in lead nephropathy ma y explain the confusion between lead nephropathy and gout nephropathy. Lead urin ary excretion after ethylenediamine tetraacetic acid (EDTA)lead mobilization test ing may help with the correct diagnosis [3]. Days 1 2 3 8 AM EDTA 1 g IM 8 PM 1g IM Urinary collection Lead, mg FIGURE 10-5 Ethylenediamine tetraacetic acid (EDTA)lead mobilization test in lead nephropathy. EDTA (calcium disodium acetate) for detecting lead nephropathy. Th is test consists of a 24-hour urinary lead excretion over 3 consecutive days aft er administration of 2 g of EDTA by intramuscular route on the first day in divi ded doses 12 hours apart. Persons without excessive lead exposure excrete less t han 0.6 mg of lead during the day after receiving 2 g of EDTA parenterally. In t he presence of renal failure, the excretion is delayed; however, the cumulative total remains less than 0.6 mg over 3 days (From Batuman and coworkers [3]; with permission.) Excessive lead exposure: No < 0.6 Yes >0.6 Creatinine clearance, mL/min 120 100 I II 1500

IV 60 40 20 III IV V Lead, mg/72 h 80 1000 III 500 I II V 0 Blood pressure N Gout A + B 0 FIGURE 10-6 Ethylenediamine tetraacetic acid (EDTA) lead mobilization test in chr onic renal failure of uncertain origin (AC). In a study of 296 patients without h istory of lead exposure, the results of this test were abnormal in 15.4% (II) of patients with hypertension and normal renal function and in 56.1% of patients w ith renal failure of uncertain origin (in 44.1% of the patients without associat ed gout (III) and in 68.7% of the patients with associated gout (IV), respective ly). (Continued on next page)

10.4 Tubulointerstitial Disease FIGURE 10-6 (Continued) The EDTAlead mobilization test was normal in normotensive subjects with normal renal function and in patients with chronic renal failure (I) of well-known origin (V). (Adapted from Sanchez-Fructuoso and coworkers [4]. ) Patients with abnormal test results, % IV 50 III II C 0 Cadmium nephropathy 110 105 100 95 90 85 80 75 70 5 Glomerular filtration rate, mL/min/1.73 m2 FIGURE 10-7 Decrease in renal function after 25-year exposure to cadmium (Cd). I n workers exposed to cadmium for an average time of 25 years, a progressive decr ease in renal function occurs during a 5-year follow-up period, despite removal from cadmium exposure 10 years earlier. On average, the glomerular filtration ra te was shown to be decreased to 31 mL/min/1.73 m2 after 5 years instead of the e xpected age-related value of 5 mL/min/1.73 m2. (Adapted from Roels and coworkers [5].) Expected values Cd exposure 6 8 9 7 10 11 Removal from Cd exposure, y Graph values I NEP CC16 RBP 2-m 43 16 80 73 II 53 17 122 112 III 50 25 132 102 IV 76 124 594 834 800 Creatinine, g/g 600 200 NEP CC16 RBP 2m *P < 0.05 * * * 834 * 594 FIGURE 10-8 Tubular markers in cadmium workers. Impairment of renal proximal tub ular epithelium induced by cadmium can be documented by an increase in urinary e xcretion of urinary neutral endopeptidase 24.11 (NEP), an enzyme of the proximal tubule brush borders, as well as by an increase in microproteinuria: Clara cell protein (CC16), retinol-binding protein (RBP) and 2-microglobulin ( 2-m). The d ata were obtained from 106 healthy persons working in cadmium smelting plants. T hese markers could be used for the screening of cadmium workers. (Adapted from N ortier and coworkers [6].) 0 I I Creatinine clearance, mL/min Urinary Cd, g/g/creatinine 103 0.55 II II 103 1.34 III 90* 3.28* III IV 79* 8.45* IV

Toxic Nephropathies 10.5 Lithium nephropathy LITHIUM NEPHROTOXICITY Reversible polyuria and polydipsia Persistent nephrogenic diabetes insipidus Inc omplete distal tubular acidosis Chronic renal failure (chronic interstitial fibr osis) FIGURE 10-9 Lithium acts both distally and proximally to antidiuretic hormoneindu ced generation of cyclic adenosine monophosphatase. Polyuria and polydipsia can occur in up to 40% of patients on lithium therapy and are considered harmless an d reversible. However, nephrogenic diabetes insipidus may persist months after l ithium has been discontinued [7]. Lithium also induces an impairment of distal u rinary acidification. Chronic renal failure secondary to chronic interstitial fi brosis may appear in up to 21% of patients on maintenance lithium therapy for mo re than 15 years [8]. However, these observations are still a matter of debate [ 7]. FIGURE 10-10 (see Color Plate) Lithium nephropathy. A 22-year-old female patient was on maintenance lithium therapy (lithium carbonate 750 mg/d) for 5 years. Sh e presented with polyuria (6500 mL/d) and moderate renal failure (creatinine cle arance, 60 mL/min). Proteinuria was not present, and the urinary sediment was un remarkable. A renal biopsy showed focal interstitial fibrosis with scarce inflam matory cell infiltrate, tubular atrophy, and characteristic dilated tubule (micr ocyst formation). Half of the glomeruli (not shown) were sclerotic. (Magnificati on 125, periodic acidSchiff reaction.) Germanium nephropathy CIRCUMSTANCES OF CHRONIC RENAL FAILURE SECONDARY TO GERMANIUM SUPPLEMENTS FIGURE 10-11 Germanium (atomic number, 32; atomic weight, 72.59) is contained in soil, plants, and animals as a trace metal. It is widely used in the industrial fields because of its semiconductive capacity. The increased use of natural rem edies and trace elements to protect, improve, or restore the health has lead reg ular supplementation with germanium salts either through food addition or by the means of elixirs and capsules. The chronic supplementation by germanium salts w as at the origin of the development of chronic renal failure secondary to a tubu lointerstitial nephritis [912]. Ge-dioxyde elixir, food additives, or capsules (used to improve health in normal persons [Japan]) Ge-lactate-citrate (used to rebuild the immune system) in pati ents with HIV infection (Switzerland) Ge-lactate-citrate (used to improve health ) in patients with cancer (the Netherlands) Ge-dioxyde elixir (used to restore h ealth) in patients with chronic hepatitis (Japan)

10.6 Tubulointerstitial Disease A FIGURE 10-12 Light microscopy of renal tissue in a patient with chronic renal fa ilure secondary to the chronic intake of germanium, showing focal tubular atroph y and focal interstitial lymphocyte infiltration. A, Hematoxylin and eosin stain . (Magnification 162.) B Renal tubular epithelial cells show numerous dark small inclusions. B, Periodic acidSchiff reaction. (Magnification, 350). (From Hess and coworkers [12]; with pe rmission). Exposure to Analgesics Normal papilla Swollen Forniceal erosion Detachment Calcification FIGURE 10-13 Analgesic nephropathy and papillary necrosis. The characteristic fe ature of analgesic nephropathy is the papillary necrosis process that begins wit h swollen papillae and continues with forniceal erosion, detachment, and calcifi cation of necrotic papillae. FIGURE 10-14 Pathology of analgesic nephropathy. Ne phrectomy showing a kidney reduced in size with necrosed and calcified papillae.

Toxic Nephropathies 10.7 CLINICAL FEATURES OF ANALGESIC NEPHROPATHY Daily consumption of analgesic mixtures Women Headache Gastrointestinal disturba nces Urinary tract infection Papillary necrosis (clinical) Papillary calcificati ons (computed tomography scan) 100% 80% 80% 3540% 3048% 20% 65% FIGURE y. The alyx), defect 10-15 Radiologic appearance of papillary necrosis in analgesic nephropath pyelogram was obtained by pyelostomy. It shows a swollen papilla (upper c forniceal erosions (middle calyx), and detachment of papilla, or filling (lower calyx).

FIGURE 10-16 Classic analgesic nephropathy is a slowly progressive disease resul ting from the daily consumption over several years of mixtures containing analge sics usually combined with caffeine, codeine, or both. Caffeine and codeine crea te psychological dependence. Most cases of analgesic nephropathy occur in women. In 80% of the cases, analgesics were taken for persistent headache. Gastrointes tinal complaints are also frequent, as are urinary tract infections. Evidence of clinical papillary necrosis (fever and pain) is present in 20% of cases. Calcif ications of papillae (detected by computed tomography scan) are present in 65% o f persons who abuse analgesics [13]. FIGURE 10-17 Worldwide epidemiology of anal gesic nephropathy. The frequency of analgesic nephropathy in patients with end-s tage renal diseases (ESRD) varies greatly within and among countries [1416]. The highest prevalence rates of end-stage renal disease from analgesic nephropathy o ccur in South Africa (22%), Switzerland and Australia (20%), Belgium (18%), and Germany (15%). In Belgium, the prevalence is 36% in the north and 10% in the sou th. In Great Britain, the rate is 1% nationwide; in Scotland it is 26%. In Unite d States, the rate is 5% nationwide, 13% in North Carolina, and 3% in Washington , DC. In Canada, the rate is 6% nationwide. EPIDEMIOLOGY OF ANALGESIC NEPHROPATHY AMONG ESRD PATIENTS Australia Belgium Canada Germany South Africa Switzerland United Kingdom United States 20% 18% 6% 15% 22% 20% 1% 5% 25 20 15 % 10 5 0 Prevalence (EDTA, 1989) Analgesic nephropathy Unknown cause FIGURE 10-18 Prevalence of analgesic nephropathy versus nephropathy with unknown cause. Crossnational comparisons in Europe indicate that the proportion of case s of end-stage renal disease attributed to analgesics varies considerably; howev er, it is inversely proportional to unknown causes. These findings suggest an un derestimation of the prevalence of analgesic nephropathy in several countries, p robably owing to the lack of well-defined criteria for diagnosis [13,15]. EDTAEur opean Dialysis and Transplant Association. (From Elseviers and coworkers [13]; w ith permission). any Bel giu m stri a rlan ds nce itze rlan d

al Ital Por tug rm Au Sw F.R . Ne the Ge Fra Spa in y

10.8 Tubulointerstitial Disease has been replaced with acetaminophen in analgesia mixtures without significant c hanges in the cause of analgesic nephropathy in some countries [15]. A, The risk factor for end-stage renal disease of unknown cause is increased in relationshi p to the cumulative intake of acetaminophen as well as nonsteroidal anti-inflamm atory drugs but not to aspirin. Moreover, mixtures containing several analgesic compounds were shown to be more nephrotoxic than are simple drugs. B, In Belgium , the prevalence of analgesic nephropathy in 1991 was strongly correlated with s ales of analgesic mixtures in 1983. Rscoefficient of correlation. (A, Adapted fro m Perneger and coworkers [17]; B, adapted from Elseviers and De Broe [18]; with permission). Pills taken in lifetime < 5000 5000 1983 sales of mixtures containing two analgesic components 3000 Rs = 0.86 P< 0.001 Belgium 2000 Odds ratio, 95% confidence intervals 10.0 1000 5.0 0 0 40 30 10 20 1991 prevalence of analgesic nephropathy, % 50 1.0 0 A Acetaminiophen Aspirin B FIGURE 10-19 Risk of analgesic nephropathy associated with specific types of ana lgesics. The initial reports of analgesic nephropathy chiefly concerned phenacet in mixtures. Phenacetin Renal volume Right kidney A RA RV RA Left kidney A Indentations Papillary calcifications SP B B Decreased: A + B < 103 mm (males) < 96 mm (females) 0 12

35 Bumpy contours >5 A B C D. PERCENTAGES OF SENSITIVITY AND SPECIFICITY Criteria Decrease in renal size Bumpy contours Papillary calcifications Sensitivity, % 95 50 87 Specificity, % 10 90 97 FIGURE 10-20 High performance of computed tomography (CT) scan for diagnosing an algesic nephropathy. Three criteria may be used to diagnose analgesic nephropath y by CT scan: decrease in renal size, measured by the sum of both sides of the r ectangle enclosing the kidney at the level of the renal vessels (A); indentation s counted at the level at which most indentations are present (more than three a re qualified of bumpy contours) (B); and papillary calcifications (C). Percentag es of sensitivity and specificity are given for the three criteria (D). Example of papillary calcifications on CT scan (E). RA renal artery; RVrenal vein; SPspine. (Adapted from Elseviers and De Broe [19]; with permission). E

Toxic Nephropathies 10.9 HONCOCH3 NCOCH3 O OH OC2H5 O O OH N-hydroxyp-ocetophenetidine HNCOCH3 OH [OH] OC2H5 OC2H5 OC2H5 OC2H5 N-hydroxyp-p henetidine H 2N OH O H OC2H5 p-nitrosophenetidine OH NH2 HNCOCH3 NH2 HNOH NO FIGURE 10-21 Malignancies of the urinary tract and their association with analge sic nephropathy. Malignancies of the renal pelvis and ureters were reported in u p to 9% of patients with analgesic nephropathy. This high prevalence can be expl ained by the appearance of carcinogenic substances in the major pathways of the metabolism of phenacetin. Probable carcinogenic substances are indicated by a pl us sign. Phenacetin (p-ocetophenetidine) HNCOCH3 NH2 OC2H5 OH N-acetyl-p-amino- 2-hydroxyphenol (NAPA) phenetidine OC2H5 Arene oxide OC2H5 NIH shift FIGURE 10-22 Malignant uroepithelial tumors of the upper urinary tract in patien ts with analgesic nephropathy. A, Pyelogram showing a filling defect, indicating a tumor of the renal pelvis. B, Retrograde pyelography showing a long malignant stricture of the ureter, causing ureteral dilation and hydronephrosis. (Courtes y of W Lornoy, MD, OL Vrouwziekenhuis, MD.) A B

10.10 Tubulointerstitial Disease Exposure to Cyclosporine Cyclosporine toxicity Cyclosporine Cyclosporine Intestinal absorption 2530% Inact ive metabolites Cyclosporine induced hypertension Acute effects Sympathetic nervous system Endothelium Thromboxane Endothelin Chronic effects Liver cytochrome P450 Cytosol calcium Inhibition Ketoconazole Verapamil Diltiazem Erythromycin Renal vasoconstruction Sodium chloride retention Hypertension Chronic renal failure FIGURE 10-23 Toxicity of cyclosporine. Cyclosporine is a neutral fungal hydropho bic 11-amino acid cyclic polypeptide. Cyclosporine is metabolized by hepatic cyt ochrome P450 to multiple less active and less toxic metabolites. Drugs that inhi bit cytochrome P450 enzymes such as ketoconazole, verapamil, diltiazem, and eryt hromycin increase the concentration of cyclosporine and may thus precipitate ren al side effects [20,21]. FIGURE 10-24 Cyclosporine and hypertension. Hypertension can develop in 10% to 8 0% of patients treated with cyclosporine, depending on dosage and length of the exposure. Cyclosporine increases cytosol calcium and, thus, enhances arteriolar smooth muscle responsiveness to vasoconstrictive stimuli. Vasoconstrictive effec ts of cyclosporine also are mediated by enhanced thromboxane action, sympathetic nerve stimulation, and release of endothelin. Renal vasoconstriction results in salt retention and hypertension. In chronic exposure to cyclosporine, hypertens ion also is a part of cyclosporine-induced chronic renal failure [22]. Mechanisms of cyclosporine renal injury Cyclosporine Renin Sustained vasoconstriction FIGURE 10-25 Pathogenesis of cyclosporine nephropathy. Chronic administration of cyclosporine may induce sustained renal vasoconstriction. Impairment of renal b lood flow leads to tubulointerstitial fibrosis. Cyclosporine increases the recru itment of renin-containing cells along the afferent arteriole. Hyperplasia of th e juxtaglomerular apparatus increases angiotensin II levels that, in turn, stimu late tumor growth factor- (TGF- ) secretion, resulting in interstitial fibrosis [20]. Angiotensin II Renal ischemia Interstitial fibrosis TGF-

Toxic Nephropathies 10.11 100 Glomerular filtration rate, % of normal values 80 60 40 20 0 0 CyA, 7.5 mg/kg 100 Glomerular filtration rate, % of normal values 80 60 40 20 0 8 Weeks 0 CyA, 9.3 mg/kg 100 Glomerular filtration rate, % of normal values 80 60 40 20 0 0 CyA, 10 to 6 mg/kg A Psoriasis B 13 Months Autoimmune diseases C 36 Months Cardiac transplantations 100 Glomerular filtration rate, % of normal values 80 60 40 20 0 0 CyA, 5 mg/kg 24 Months Uveitis D FIGURE 10-26 Cyclosporine (CyA) nephrotoxicity in nonrenal diseases. A, Patients treated with cyclosporine (7.5 mg/kg) for psoriasis experienced a median decrea se to 84% of the initial values in the glomerular filtration rate after 8 weeks of therapy. B, Of patients treated with cyclosporine (9.3 mg/kg) for autoimmune diseases, 21% showed cyclosporine nephropathy on biopsy, with a decrease to 60% of the initial values in renal function. C, Patients with cardiac transplantatio n treated with high doses of cyclosporine (10 to 6 mg/kg) developed a reduction to 57% of the initial values in renal function 36 months after transplantation. Patients treated with azathioprine did not show any reduction in renal function. D, Patients receiving cyclosporine (5 mg/kg) for uveitis for 2 years showed a d ecrease in glomerular filtration rate to 65% of the initial values. (Panel A ada pted from Ellis and coworkers [23]; panel B adapted from Feutren and Mihatsch [2 4]; panel C adapted from Myers and Newton [25]; and panel D adapted from Deray a nd coworkers [26].) A FIGURE 10-27 Morphology of cyclosporine nephropathy on renal biopsy of a patient with cardiac transplantation. Two different types of lesions are seen in cyclos porine nephropathy. A, Arteriolopathy: Hyalin, paucicellular thickening of the i ntima with focal wall necrosis results in narrowing of the vascular lumen (magni fication 300 B periodic acidSchiff reaction). B, A striped form of interstitial fibrosis charact

erized by irregularly distributed areas of stripes of interstitial fibrosis and tubular atrophy in the renal cortex. Tubules in other areas were normal (magnifi cation x 100 periodic acidSchiff reaction).

10.12 Tubulointerstitial Disease Exposure to Aminosalicylic Acid 10.6 10 Seerum creatinine, mg/dL 8 6 4 2 0 IBD diagnosis 1.1 Renal biopsy 32 mg/d Renal biopsy Hemodialysis Methyl- 16 mg/d prednisolone C.P. man born January 19, 1971 4.9 4.2 4.0 3.9 Oral Pentasa 500 mg/d, 3 x per day v2 2 De , 1994 c2 De , 1994 c2 De 2, 199 c3 1, 4 Jan 1994 6, 1 995 199 1 199 2 Ma Feb A B FIGURE 10-28 Aminosalicylic acid and chronic tubulointerstitial nephritis. A, A 36-year-old man suffering from Crohn's disease exhibited severe renal failure afte r 23 months of treatment with 5-aminosalicylic acid (5-ASA, or Pentasa, Hoechst Marion Roussel, Kansas City, MO). B, The first renal biopsy showing widening and massive cellular infiltration of the interstitium, tubular atrophy, and relativ e spacing of glomeruli. C, The second renal biopsy 8 months, after discontinuati on of the drug and moderate improvement of the renal function, again showing imp ortant cellular infiltration Ma of the interstitium tubular atrophy, and fibrosis. Several atrophic tubules are surrounded by one or more layers of -smooth muscle actin positive cells. The pat ient had normal renal function on beginning treatment with 5-ASA. After 5 years of 5-ASA therapy, the patient demonstrated severe impaired renal function. The a ssociation between the use of 5-ASA and development of chronic tubulointerstitia l nephritis in patients with inflammatory bowel disease (IBD) has gained recogni tion in recent years [27,28]. (Courtesy of ME De Broe, MD.) No C Ma y1 , 19 96 De c1 , 19 96 t 3,

rch Oc rch 23, 199 4 2, 1 994

Toxic Nephropathies 10.13 Exposure to Ochratoxins Ochratoxin A COOH CH2- CH-NH-COCI Contamination of cereals Chronic nephropathy i n pigs Endemic Balkan nephropathy Chronic interstitial nephritis in Tunisia Chro nic interstitial nephritis in France (?) OH O CH3 FIGURE 10-29 Ochratoxin nephropathy. Ochratoxin A is a mycotoxin produced by var ious species of Aspergillus and Penicillium. Ochratoxins contaminate foods (main ly cereals) for humans as well as for cattle. Ochratoxins are mutagenic, oncogen ic, and nephrotoxic. Ochratoxins are responsible for chronic nephropathy in pigs and also may be the cause of endemic Balkan nephropathy and some chronic inters titial nephropathies seen in North Africa and France [29]. Austria Slovenia R. Sava R. Danube Hungary CLINICAL FEATURES OF BALKAN NEPHROPATHY Croatia R. S ava Slavonski Brod Romania Oravita Turn Severin Belgrade Lazarevac Paracin Nis Bneljina Bosnia and Herezgovina Sarajevo R. D Mikhaylovgrad Vratsa anu be Yugoslavia Italy Macedonia Albania Greece Sofia Residence in an endemic area Occupational history of farming Progressive renal f ailure Microproteinuria of tubular type Unremarkable urinary sediment Small and shrunken kidneys Associated urothelial tumors Bulgaria FIGURE 10-31 Clinical features in Balkan nephropathy. Balkan nephropathy is char acterized by progressive renal failure in residents (generally farmers) living i n endemic areas for over 10 years. The urinary sediment is unremarkable and no p roteinuria is seen, except for a microproteinuria of tubular type. The kidneys a re small and shrunken. Urothelial cancers are frequently associated with Balkan

nephropathy [29,30]. FIGURE 10-30 Endemic Balkan nephropathy. Endemic nephropathy is encountered in s ome well-defined areas of the Balkans. Distribution (dark areas) is along the af fluents of the Danube, in a few areas on the plains and low hills owing to high humidity and rainfall. (From Stefanovic and Polenakovic [30]; with permission.)

10.14 Tubulointerstitial Disease A FIGURE 10-32 Pathology of Balkan nephropathy. Balkan nephropathy is characterize d by pure interstitial fibrosis with marked tubular atrophy (A) and by B hyperplasia of the myocythial cells with narrowing of the lumen of the vessel (B ) (From Stefanovic and M. Polenakovic [30]; with permission). FIGURE 10-33 Patho logy of ochratoxin nephropathy. In addition to interstitial fibrosis, large hype rchromatic nuclei in tubular epithelial cells are shown by the arrow (interstiti al caryomegalic nephropathy). (Masson trichrome stain, magnification x 160.) The renal biopsy was obtained from a woman from France who had renal failure (creat inine clearance 40 mL/min) without significant proteinuria and urinary sediment abnormalities. Ochratoxin levels were 367 and 1810 ng/mL, respectively, in the p atient's blood and urine. (From Godin and coworkers [29].) Cereal samples contaminated by ochratoxin, % Number of urothelial cancers per million inhabitants 12.8 80 70 60 50 40 30 20 10 0 74.2 10 1.6 0 Endemic Nonendemic Areas of Balkan nephropathy 3.2 Endemic Nonendemic Areas of Balkan nephropathy FIGURE 10-34 Balkan nephropathy and ochratoxin A in food. A survey of homeproduc ed foodstuffs in the Balkans has revealed that contamination with ochratoxin A i s more frequent in areas in which endemic nephropathy is prevalent (endemic area s) than in areas in which nephropathy is absent. (Adapted from Krogh and coworke rs [31].) FIGURE 10-35 Balkan nephropathy and urothelial cancers. Urothelial cancers appea r as a frequent complication of Balkan nephropathy. An increased prevalence of u pper tract urothelial tumors is described in inhabitants of areas in which Balka n nephropathy is endemic. (Adapted from Godin and coworkers [29].)

Toxic Nephropathies 10.15 Exposure to Chinese Herbs Release of Chinese herb (so-called Stephania tetrandra) on Belgian market Chinese herb nephropathy (number of new cases) 40 90 31 92 24 32 30 20 10 1 1 15 7 5 FIGURE 10-36 Epidemiology of Chinese herbs nephropathy. Chinese herbs nephropath y was described for the first time in Belgium in 1993 [32]. A peak incidence of new cases of women with rapidly progressive interstitial nephritis in Brussels d uring 1992 lead to suspicion of a new cause of renal disease. The relationship b etween this new renal disease and the recent introduction of Chinese herbs (name ly, Stephania tetrandra) in a slimming regimen was established [32]. The withdra wal from the market of this herb has decreased the incidence of interstitial nep hritis in Brussels, Belgium. 0 1989 1990 1991 1992 1993 Year 1994 1995 1996 A. CHINESE HERBAL MEDICINE Chinese Name Han fang-ji Guang fang-ji Western name Stephania tetrandra Aristolochia fang chi Chemical Marker Tetrandrine Aristolochic acid 30 Chinese herbs (Number of batches) 30 FIGURE 10-37 Role of Aristolochia in Chinese herbs nephropathy. Stephania tetran dra was the Chinese herb chronologically associated with the development of Chin ese herbs nephropathy. However, tetrandrine, the alkaloid characterizing Stephan ia tetrandra was not found in the capsules taken by the patients. In fact, confu sion between Stephania tetrandra and Aristolochia fang chi was done in the deliv ery of Chinese herbs in Belgium [33]. Chinese characters and the pingin name of Stephania tetrandra (Han fang-ji) are identical to that of Aristolochia fang chi (Guang fang-ji). Investigations conducted on batches of Stephania tetrandra pow ders distributed in Belgium have shown that most of them contained aristolochic acids (characteristic of Aristolochia) and not tetrandrine (From Vanhaelen and c oworkers [33] and P Daenens, Katholiek Universiteit Leuven, Belgium, report of e xpertise 1996.) 20 10 5

7 4 0 B +A, +T +A, T A, +T A, T +A, aristolochic acid present A, aristolochic acid absent +T, tetrandrine present T, tetrandine absent

10.16 Tubulointerstitial Disease FIGURE 10-38 DNA aristolochic acid adducts in kidney tissues of patients with Ch inese herbs nephropathy. The role of Aristolochia in the pathogenesis of Chinese herbs nephropathy was confirmed by the demonstration of DNA aristolochic acid a dducts (a biomarker of aristolochic acids exposure) in renal tissue of patients with Chinese herbs nephropathy, whereas these adducts were absent in the renal t issue of control cases. (Adapted from Schmeiser and coworkers [34].) DNA ADDUCTS FORMED BY ARISTOLOCHIC ACID IN RENAL TISSUE Chinese Herb Nephropathy (n = 5) 0.75.3 per 107 nucleotides Controls (n = 6) 0 CLINICAL FEATURES OF CHINESE HERB NEPHROPATHY Rapidly progressive renal failure Microproteinuria of tubular type Unremarkable urinary sediment Small and shrunken kidneys Valvular hear diseases (dexfenfluram ine-associated therapy), 30% Associated urothelial cancers FIGURE 10-39 The clinical features of Chinese herbs nephropathy are characterize d by rapidly progressive renal failure without both urinary sediment abnormaliti es and proteinuria except for a microproteinuria of tubular type. The kidneys ar e small and shrunken. Vascular heart diseases are associated in 30% of cases (pr obably owing to dexfenfluramine administered with the Chinese herbs for slimming purposes) [35]. Some cases of associated urothelial cancers also are described [36,37]. FIGURE 10-40 Photographic image of the pathology of Chinese herbs nephropathy. C hinese herbs nephropathy is characterized by a large reduction in kidney volume. Moreover, an associated tumor of the lower ureter is shown. A FIGURE 10-41 (see Color Plate) Pathology of Chinese herb nephropathy. The major pathologic lesion consists of extensive interstitial fibrosis with atrophy and l oss of the tubules, predominantly located in superficial cortex [38,39]. A, A lo w-power view of transition between superficial cortex (left) and deep cortex (ri ght) shows an B extensive interstitial fibrosis with relative sparing of glomeruli. (Masson tric hrome stain, magnification 50.) B, A normal glomerulus surrounded by a paucicell ular interstitial fibrosis and atrophic tubules. (Masson's trichrome stain, magnif ication 300.)

Toxic Nephropathies 10.17 50 40 30 20 10 0 Controls ug/24 h NEP 40 log ug/24 h 30 20 10 0 CC16 5 log ug/24 h 4 3 2 1 0 B2m A Normal Renal End-stage renal function failure renal disease After exposure to Ch inese herbs Controls B Normal Renal End-stage renal function failure renal disease After exposure to Ch inese herbs Controls C Normal Renal End-stage renal function failure renal disease After exposure to Ch inese herbs 5 log ug/24 h 4 3 2 1 0 RBP FIGURE 10-42 AD, Microproteinuria and neutral endopeptidase enzymuria in Chinese herbs nephropathy. Proximal tubular injury in Chinese herbs nephropathy is demon strated by a significant increase in urinary excretion of microproteins (Clara c ell protein, CC16; 2-microglobulin [ 2-m] and retinol binding protein [RBP]) as well as a decrease in urinary excretion of neutral endopeptidase (NEP) a marker of the brush border tubular mass. (Adapted from Nortier and coworkers [40].) D Controls Normal Renal End-stage renal function failure renal disease After expos ure to Chinese herbs FIGURE 10-43 Chinese herbs nephropathy and renal pelvic carcinoma. Urothelial ca ncers are associated with Chinese herbs nephropathy [36,37]. Shown is a filling defect (arrow) in the renal pelvis in an antegrade pyelogram obtained from a pat ient with Chinese herbs nephropathy and hematuria. (From Vanherweghem and cowork ers [37]; with permission).

10.18 Tubulointerstitial Disease A FIGURE 10-44 Pathology of urothelial tumors associated with Chinese herbs nephro pathy. Microscopic pattern is shown of a lower urothelial tumor obtained by uret eronephrectomy of a native kidney in a patients with transplantation who has Chi nese herbs nephropathy (the macroscopic appearance of the nephrectomy B is shown in Fig. 10-40). A, Part of the urothelial proliferation. Plurifocal thi ckening of the urothelium is present. (Hematoxylin and eosin stain x 50.) B, In situ transitional cell carcinoma with high mitotic rate. (Magnification x 400 pe riodic acid Schiff reaction.) 0.7 1/P creatinine ratio 0.6 0.5 0.4 0.3 0.2 0.1 6 3 0 3 6 Months 9 12 Controls, n = 23 Steroids, n = 12 TOXIC CHRONIC INTERSTITIAL NEPHROPATHIES WITH UROTHELIAL CANCERS Analgesic nephropathy (phenetidin compounds) Balkan nephropathy (ochratoxins) Ch inese herbs nephropathy (aristolochic acids) FIGURE 10-45 Effects of steroids on the evolution of renal failure in Chinese he rbs nephropathy. Steroid therapy was shown to decrease the evolution of renal fa ilure in a subgroup of patients with Chinese herbs nephropathy [41]. The evoluti on is shown of the 1/P creatinine ratio of patients with Chinese herbs nephropat hy, 12 of whom were treated with steroids as compared with 23 not treated with s teroids (control group). In the control group the 1/P creatinine curve was limit ed to 6 months of follow-up because at 12 months, 17 of the 23 patients were on renal replacement therapy. (From Vanherweghem and coworkers [41]; with permissio n.) FIGURE 10-46 Of interest is the association between chronic renal interstitial f ibrosis and urothelial cancers. This association appears, at least, in three chr onic toxic nephropathies: analgesic nephropathy, Balkan nephropathy, and Chinese herbs nephropathy. This association indicates that nephrotoxins promoting inter stitial fibrosis (analgesics, ochratoxins, and aristolochic acids) also may be o ncogenic substances.

Toxic Nephropathies 10.19 References 1. 2. Nuyts GD, Van Vlem E, Thys J, et al.: New occupational risk factors for ch ronic renal failure. Lancet 1995, 346:711. Nuyts GD, Daelemans RA, Jorens PG, et al.: Does lead play a role in the development of chronic renal disease? Nephrol Dial Transplant 1991, 6:307315. Batuman V, Maesaka JK, Haddad B, et al.: The role of lead in gout nephropathy. N Engl J Med 1981, 304:520523. Sanchez-Fructuoso AI , Torralbo A, Arroyo M, et al.: Occult lead intoxication as a cause of hypertens ion and renal failure. Nephrol Dial Transplant 1996, 11:17751780. Roels HA, Lauwe rys RR, Buchet JP, et al.: Health significance of cadmium induced renal dysfunct ion: a five year follow up. Br J Ind Med 1989, 46:755764. Nortier J, Bernard A, R oels H, et al.: Urinary neutral endopeptidase in workers exposed to cadmium: int eraction with cigarette smoking. Occup Environ Med 1997, 54:432436. Walker RG: Li thium nephrotoxicity. Kidney Int 1993, 44(suppl 42):S93S98. 22. Luke RG: Mechanis m of cyclosporine-induced hypertension. Am J Hypertens 1991, 4:468-471. 23. Elli s CN, Fradin MS, Messana JM, et al.: Cyclosporine for plaquetype psoriasis. N En gl J Med 1991, 324:277284. 24. Feutren G, Mihatsch MJ: Risk factors for cyclospor ine-induced nephropathy in patients with autoimmune diseases. N Engl J Med 1992, 326: 16541660. 25. Myers BD, Newton L: Cyclosporin induced chronic nephropathy: an obliterative renal injury. J Am Soc Nephrol 1991, 2:S45S52. 26. Deray G, Benhm ida M, Le Hoang P, et al. Renal function and blood pressure in patients receivin g long-term, low-dose cyclosporine therapy for idiopathic autoimmune uveitis. An n Intern Med 1992, 117:578583. 27. World MJ, Stevens PE, Ashton MA, Rainford DJ: Mesalazine-associated interstitial nephritis. Nephrol Dial Transplant 1996, 11:6 14621. 28. De Broe ME, Stolear JC, Nouwen EJ, Elseviers MM: 5-Aminosalicylic acid (5-ASA) and chronic tubulointerstitial nephritis in patients with chronic infla mmatory bowel disease: Is there a link? Nephrol Dial Transplant 1997; 12:18391841 . 29. Godin M, Fillastre JP, Simon P, et al.: L'ochratoxine est-elle nphrotoxique c hez l'homme ? In Actualits Nphrologiques. Edited by Brentano JL, Bach JF, Kreis H, G runfeld JP. Paris: FlammarionMedecine Sciences; 1996:225250. 30. Stefanovic V, Pol enakovic MH: Balkan nephropathy: kidney disease beyond the Balkans? Am J Nephrol 1991, 11:111. 31. Krogh P, Hald B, Plestina R, Ceovic S: Balkan (endemic) nephro pathy and foodborn ochratoxin A: preliminary results of a survey of foodstuffs. Acta Path Microbiol Scand Sect B 1977, 85:238240. 32. Vanherweghem JL, Depierreux M, Tielemans C, et al.: Rapidly progressive interstitial renal fibrosis in youn g women: association with slimming regimen including Chinese herbs. Lancet 1993, 341:387391. 33. Vanhaelen M, Vanhaelen-Fastre R, But P, Vanherweghem JL: Identif ication of aristolochic acid in Chinese herbs. Lancet 1994, 343:174. 34. Schmeis er HH, Bieler CA, Wiessler M, et al.: Detection of DNAadducts formed by aristolo chic acid in renal tissue from patients with Chinese herbs nephropathy. Cancer R es 1996, 56:20252028. 35. Vanherweghem JL: Association of valvular heart disease with Chinese herbs nephropathy. Lancet 1997, 350:1858. 36. Cosijns JP, Jadoul M, Squifflet JP: Urothelial malignancy in nephropathy due to Chinese herbs. Lancet 1994, 344:118. 37. Vanherweghem JL, Tielemans C, Simon J, Depierreux M: Chinese herbs nephropathy and renal pelvic carcinoma. Nephrol Dial Transplant 1995, 10: 270273. 38. Depierreux M, Van Damme B, Vanden Houte K, Vanherweghem JL: Pathologi c aspects of a newly described nephropathy related to the prolonged use of Chine se herbs. Am J Kidney Dis 1994, 24:172180. 39. Cosijns JP, Jadoul M, Squifflet JP et al.: Chinese herbs nephropathy: a clue to Balkan endemic nephropathy? Kidney Int 1994, 45:16801688. 40. Nortier JL, Deschodt-Lankman MM, Simon S, et al. Prox imal tubular injury in Chinese herbs nephropathy: monitoring by neutral endopept idase enzymuria. Kidney Int 1997, 51:288293. 41. Vanherweghem JL, Abramowicz D, T ielemans C, Depierreux M: Effects of steroids on the progression of renal failur e in chronic interstitial renal fibrosis: a pilot study in Chinese herbs nephrop athy. Am J Kidney Dis 1996, 27:209215. 3. 4.

5. 6. 7. 8. Bendz H, Aurell M, Balldin J, et al.: Kidney damage in long-term lithium patient s: a cross-sectional study of patients with 15 years or more on lithium. Nephrol Dial Transplant 1994, 9:12501254. 9. Sanai T, Okuda S, Onoyama K, et al.: German ium dioxide-induced nephropathy: a new type of renal disease. Nephron 1990, 54:5 360. 10. Van Der Spoel JI, Stricker BH, Esseveld MR, Schipper MEI: Dangers of die tary germanium supplements. Lancet 1990, 336:117. 11. Takeuchi A, Yoshizawa N, O shima S, et al.: Nephrotoxicity of germanium compounds: report of a case and rev iew of the literature. Nephron 1992, 60:436442. 12. Hess B, Raisin J, Zimmermann A, et al.: Tubulointerstitial nephropathy persisting 20 months after discontinua tion of chronic intake of germanium lactate citrate. Am J Kidney Dis 1993, 21:54 8552. 13. Elseviers MM, Bosteels V, Cambier P, et al.: Diagnostic criteria of analgesi c nephropathy in patients with end-stage renal failure: results of the Belgian s tudy. Nephrol Dial Transplant 1992, 7:479486. 14. Drukker W, Schwarz A, Vanherweg hem JL: Analgesic nephropathy: an underestimated cause of end-stage renal diseas e. Int J Artif Organs 1986, 9:216243. 15. Klag MJ, Whelton PK, Perneger TV: Analg esics and chronic renal disease. Curr Opinion Nephrol Hypertens 1996, 5:236241. 1 6. Vanherweghem JL, Even-Adin D: Epidemiology of analgesic nephropathy in Belgiu m. Clin Nephrol 1982, 17:129133. 17. Perneger TV, Whelton PK, Klag MJ: Risk of ki dney failure associated with the use of acetaminophen, aspirin, and nonsteroidal anti-inflammatory drugs. N Engl J Med 1994, 331:16751679. 18. Elseviers MM, De B roe ME: Analgesic nephropathy in Belgium is related to the sales of particular a nalgesic mixtures. Nephrol Dial Transplant 1994, 9:4146. 19. Elseviers MM, De Sch epper A, Corthouts R, et al.: High diagnostic performance of CT scan for analges ic nephropathy in patients with incipient to severe renal failure. Kidney Int 19 95, 48:13161323. 20. Shihab FS: Cyclosporine nephropathy: pathophysiology and cli nical impact. Sem Nephrol 1996, 16:536547. 21. Bennett WM, De Mattos A, Meyer MM, et al.: Chronic cyclosporine nephropathy: The Achilles' heel of immunosuppressive therapy. Kidney Int 1996, 50:10891100.

Metabolic Causes of Tubulointerstitial Disease Steven J. Scheinman A variety of metabolic conditions produce disease of the renal interstitium and tu bular epithelium. In many cases, disease reflects the unique functional features of the nephron, in which the ionic composition, pH, and concentration of both t he tubular and interstitial fluid range widely beyond the narrow confines seen i n other tissues. Recent genetic discoveries have offered new insights into the m olecular basis of some of these conditions, and have raised new questions. This chapter discusses nephrocalcinosis, the relatively nonspecific result of a varie ty of hypercalcemic and hypercalciuric states, as well as the renal consequences of hyperoxaluria, hypokalemia, and hyperuricemia. CHAPTER 11

11.2 Tubulointerstitial Disease FIGURE 11-1 The recent discovery of the calcium-sensing receptor and increased u nderstanding of its expression along the nephron have provided explanations for many of the known effects of hypercalcemia to cause clinical disturbances in ren al tubular function [1]. In the parathyroid gland the calcium-sensing receptor a llows the cell to sense extracellular levels of calcium and transduce that signa l to regulate parathyroid hormone production and release. In the nephron, expres sion of the calcium receptor can be detected on the apical surface of cells of t he papillary collecting duct, where calcium inhibits antidiuretic hormone action . Thus, hypercalcemia impairs urinary concentration and leads to isotonic polyur ia. The most intense expression of the calcium receptor is in the thick ascendin g limb of the loop of Henle, particularly the cortical portion, where the calciu m receptor protein is located on the basolateral side of the cells; this explain s the known effects of hypercalcemia in inhibiting reabsorption of calcium, magn esium, and sodium chloride in the thick ascending limb [2]. In addition, hyperca lcemia causes hypercalciuria through an increased filtered calcium load and supp ression of parathyroid hormone release with a consequent reduction in calcium re absorption. Cacalcium; Mgmagnesium; NaClsodium chloride. Hypercalcemia inhibits reabsorption of NaCl, Ca, and Mg Hypercalcemia inhibits reabsorption of water RENAL EFFECTS OF CALCIUM Hypercalcemia Collecting duct Resistance to vasopressin, leading to isotonic pol yuria Thick ascending limb of the loop of Henle Impaired sodium chloride reabsor ption, leading to modest salt wasting Inhibition of calcium transport, leading t o hypercalciuria Inhibition of magnesium transport, leading to hypomagnesemia Re nal vasculature Arteriolar vasoconstriction Reduction in ultrafiltration coeffic ient Hypercalciuria Microscopic hematuria Nephrocalcinosis Impaired urinary acid ification FIGURE 11-2 Hypercalcemia leads to renal vasoconstriction and a reduction in the glomerular filtration rate. However, no expression of the calcium-sensing recep tor has been reported so far in renal vascular or glomerular tissue. Calcium rec eptor expression is present in the proximal convoluted tubule, on the basolatera l side of cells of the distal convoluted tubule, and on the basolateral side of macula densa cells. Functional correlates of calcium receptor expression at thes e sites are not yet clear [3]. Hypercalciuria leads to microscopic hematuria and , in fact, is the most common cause of microscopic hematuria in children. The me chanism is presumed to involve microcrystallization of calcium salts in the tubu lar lumen. Conflicting effects of calcium on urinary acidification have been rep orted in clinical settings in which other factors, such as parathyroid hormone l evels, may explain the observations. whether or not it is the result of renal tu bular acidosis, Nephrocalcinosis often is associated with impaired urinary acidi fication, whether or not it is the result of renal tubular acidosis.

Metabolic Causes of Tubulointerstitial Disease 11.3 CAUSES OF NEPHROCALCINOSIS Medullary (total) Primary hyperparathyroidism Distal renal tubular acidosis Medu llary sponge kidney Idiopathic hypercalciuria Dent's disease Milk-alkali syndrome Oxalosis Hypomagnesemia-hypercalciuria Sarcoidosis Renal papillary necrosis Hype rvitaminosis D Other* Undiscovered causes Cortical (total) 97.6 32.4 19.5 11.3 5 .9 4.3 3.2 3.2 1.6 1.6 1.6 1.6 4.0 6.7 2.4 Adapted from Wrong [3]; with permission. * Other causes include Bartter syndrome, idiopathic Fanconi syndrome, hypothyFIGURE 11-3 Nephrocalcinosis represents calcification of the renal parenchyma. I t is primarily medullary in most cases except in dystrophic calcification associ ated with inflammatory, toxic, or ischemic disease. Nephrocalcinosis can be seen in association with chronic or severe hypercalcemia or in a variety of hypercal ciuric states. The spectrum of causes of nephrocalcinosis is described by Wrong [3]. The numbers represent the percentage of the total of 375 patients. It is li kely that the case mix is affected to some extent by Wrong's interests in, eg, ren al tubular acidosis (RTA) and Dent's disease, but this is by far the largest publi shed series. As in other studies, the most important causes of nephrocalcinosis are primary hyperparathyroidism, distal RTA, and medullary sponge kidney. The pr imary factor predisposing patients to renal calcification in many of these condi tions is hypercalciuria, as occurs in idiopathic hypercalciuria, Dent's disease, m ilk-alkali syndrome, sarcoidosis, hypervitaminosis D, and often in distal RTA. I n distal RTA and milk-alkali syndrome, relative or absolute urinary alkalinity p romote precipitation of calcium phosphate crystals in the tubular lumena, and hy pocitraturia is an important contributing factor in distal RTA. Causes of cortic al nephrocalcinosis in this study included acute cortical necrosis, chronic glom erulonephritis, and chronic pyelonephritis. roidism, and severe acute tubular necrosis. Impaired urinary acidification Alkaline urine Systemic acidosis Hypercalciuria Hypokalemia Decreased urinary citrate excretion Reduced renal tubular calcium reabsorption Resorption of bone mineral Hypercalciuria CaPO4 precipitation FIGURE 11-4 Nephrocalcinosis in type I (distal) renal tubular acidosis. Nephroca lcinosis and nephrolithiasis are common complications in distal renal tubular ac idosis (RTA-1). Several factors contribute to the pathogenesis. The most importa nt of these factors are a reduction in urinary excretion of citrate and a persis tently alkaline urine. Citrate inhibits the growth of calcium stones; its excret ion is reduced in RTA-1 as a result of both systemic acidosis and hypokalemia. The high urine pH favors precipitation o f calcium phosphate (CaPO4). Thus, RTA-1 should be suspected in any patient with pure calcium phosphate stones [4]. Systemic acidosis also promotes hypercalciur ia, although not all patients with RTA-1 have excessive urinary calcium excretio

n [5]. Hypercalciuria results from resorption of bone mineral and the consequent increased filtered load of calcium as acidosis leads to consumption of bone buf fers. Acidosis also has a direct effect of inhibiting renal tubular calcium reab sorption. Conversely, nephrocalcinosis from other causes can impair urinary acid ification and lead to RTA in some patients. The mainstay of therapy for RTA-1 is potassium citrate, which corrects acidosis, replaces potassium, restores urinar y citrate excretion, and reduces urinary loss of calcium [5]. (From Buckalew [5] ; with permission.)

11.4 Tubulointerstitial Disease Epithelial cell of the thick ascending limb of the loop of Henle Lumen Na+ 2Cl K+ ROMK Blood NKCC2 ClC-Kb K+ Na+ ATP K+ FIGURE 11-5 Bartter syndrome. Bartter syndrome is a hereditary renal functional disorder characterized by hypokalemic metabolic alkalosis, renal salt wasting wi th normal or low blood pressure, polyuria, and hypercalciuria. Other features in clude juxtaglomerular hyperplasia, secondary hyperreninemia and hyperaldosteroni sm, and excessive urinary excretion of prostaglandin E. It often has been noted that patients with Bartter syndrome appear as if they were chronically exposed t o loop diuretics; in fact, the major differential diagnosis is with diuretic abu se. Bartter syndrome often presents with growth retardation in children, and nep hrocalcinosis is common. Bartter syndrome is inherited as an autosomal recessive trait. The speculation that this syndrome could be explained by impaired reabso rption in the loop of Henle has now been confirmed by molecular studies. R.P. Li fton's group [68] identified loss-offunction mutations in three genes encoding diff erent proteins, each involved in the coordinated transport of salt in the thick ascending limb of the loop of Henle. In this nephron segment, sodium chloride is transported into the cell together with potassium by the bumetamide-inhibitible sodium-potassium-2 c hloride cotransporter (NKCC2). Recycling of potassium back to the lumen through an apical potassium channel (ROMK) allows an adequate supply of potassium for op timal activity of the NKCC2. Chloride exits the basolateral side of the cell thr ough a voltage-gated chloride channel (ClC-Kb), and sodium is expelled separatel y by the sodium-potassium adenosine triphosphatase cotransporter. Inactivating m utations in NKCC2, ROMK, and ClC-Kb have been identified in patients with Bartte r syndrome [68]. Approximately 20% of filtered calcium is reabsorbed in the thick ascending limb, and inactivation of any of these three transport proteins can l ead to hypercalciuria. Nephrocalcinosis occurs in almost all patients with mutat ions in NKCC2 or ROMK, but it is less common in patients with a mutation in the basolateral chloride channel ClC-Kb, even though patients with chloride-channel mutations currently make up the largest reported group [8]. This interesting obs ervation is unexplained at present. In addition, a significant number of patient s with Bartter syndrome have been found to have normal coding sequences for all three of these genes, indicating that mutations in other gene(s) may explain Bar tter syndrome in some patients. In contrast, the Gitelman variant of Bartter syn drome is associated with hypocalciuria. In this respect these patients resemble people treated with thiazide diuretics. In fact, mutations have been found in th e thiazide-sensitive sodium chloride cotransporter of the distal tubule [9]. Hyp omagnesemia is common and often severe, and patients with Gitelman syndrome do n ot develop nephrocalcinosis. ATPadenosine triphosphate. (From Simon and coworkers [8]; with permission.) FIGURE 11-7 Noncontrast abdominal radiograph in a 24-yea r-old man with X-linked nephrolithiasis (Dent's disease). The patient had recurren t calcium nephrolithiasis beginning in childhood and developed end-stage renal d isease requiring dialysis at 40 years of age. Extensive medullary calcinosis is evident.

FIGURE 11-6 Nephrocalcinosis. Ultrasound image of right kidney in a patient with primary hyperparathyroidism. Echogenicity of the renal cortex is comparable to that of the adjacent liver. The dense nephrocalcinosis is entirely medullary. (C ourtesy of Robert Botash, MD.)

Metabolic Causes of Tubulointerstitial Disease 11.5 X-LINKED NEPHROLITHIASIS (DENT'S DISEASE) Males who are affected Low molecular weight proteinuria Other defects in proximal tubular function Hype rcalciuria Nephrocalcinosis Calcium stones Renal failure Rickets Extreme Variabl e Occurs early in most Nearly all have it Common but not universal Common but no t universal Present in some Females who are carriers Absent, mild, or moderate Uncommon Present in half Rare Uncommon Rare Not report ed FIGURE 11-8 Syndromes of X-linked nephrolithiasis have been reported under vario us names, including Dent's disease in the United Kingdom, X-linked recessive hypop hosphatemic rickets in Italy and France, and a syndrome of low molecular weight (LMW) proteinuria with hypercalciuria and nephrocalcinosis in Japanese schoolchi ldren. Mutations in a gene encoding a voltage-gated chloride channel (ClC-5) are present in all of these syndromes, establishing that they represent variants of one disease [10]. The disease occurs most often in boys, with microscopic hemat uria, proteinuria, and hypercalciuria. Many but not all have recurrent nephrolit hiasis from an early age. Affected males excrete extremely large quantities of L MW proteins, particularly 2microglobulin and retinol-binding protein. Other defe cts of proximal tubular function, including hypophosphatemia, aminoaciduria, gly cosuria, or hypokalemia, occur variably and often intermittently. Many affected males have mild to moderate polyuria and nocturia, and they often exhibit this s ymptom on presentation. Urinary acidification is usually normal, and patients do not have acidosis in the absence of advanced renal insufficiency. Nephrocalcino sis is common by the teenage years, and often earlier. Renal failure is common a nd often progresses to end-stage renal disease by the fourth or fifth decade, al though some patients escape it. Renal biopsy documents a nonspecific pattern of interstitial fibrosis and tubular atrophy, with glomerular sclerosis that is pro bably secondary [11]. Rickets occurs early in childhood in some patients but is absent in most patient s with X-linked nephrolithiasis (Dent's disease). In a few families, all affected males have had rickets. In other families, rickets is present in only one of sev eral males sharing the same mutation. At present, the variability of this featur e and other features of the disease is unexplained and may reflect dietary or en vironmental factors or the participation of other genes in the expression of the phenotype. Females who are carriers often have mild to moderate LMW proteinuria . This abnormality can be used clinically as a screening test, but LMW protein e xcretion will not be abnormal in all heterozygous females. Approximately half of women who are carriers have hypercalciuria, but other biochemical abnormalities are rare. Although symptomatic nephrolithiasis and even renal insufficiency hav e been reported in female carriers, they are very uncommon. The gene for ClC-5 t hat is mutated in X-linked nephrolithiasis (Dent's disease) is expressed in the en dosomal vacuoles of the proximal tubule; it appears to be important in acidifica tion of the endosome. Thus, defective endosomal function would explain the LMW p roteinuria. The mechanism of hypercalcinuria remains unexplained at present. Thi s gene belongs to the family of voltagegated chloride channels that includes ClC -Kb, one of the gene mutations in some patients with Bartter syndrome. To date, 32 mutations have been reported in 40 families, and nearly all are unique [11].

11.6 Tubulointerstitial Disease HYPEROXALURIA Type Primary (genetic): PH1 Mechanism Functional deficiency of AGT Clinical consequences Nephrolithiasis Nephrocalcinosis and progressive renal failure Systemic oxalosis (kidneys, bones, cartilage, teeth, eyes, peripheral nerves, central nervous sys tem, heart, vessels, bone marrow) Nephrolithiasis Increased risk of nephrolithia sis Nephrolithiasis Nephrocalcinosis Systemic oxalosis (rarely) Nephrolithiasis Tubular obstruction by crystals leading to acute renal failure Nephrolithiasis PH2 Secondary: Dietary Enteric Functional deficiency of DGDH Sources include for example spinach, s, peanuts, chocolate, and tea Enhanced oxalate absorption because oxalate solubility, bile salt malabsorption, and altered gut flora tory bowel disease and bowel resection) Ascorbate Ethylene glycol, erol, xylitol, methoxyflurane Cofactor for AGT Metabolism from excess of precursors Pyridoxine deficiency FIGURE 11-9 Oxalate is a metabolic end-product of limited solubility in physiolo gic solution. Thus, the organism is highly dependent on urinary excretion, which involves net secretion. Normal urine is supersaturated with respect to calcium oxalate. Crystallization is prevented by a number of endogenous inhibitors, incl uding citrate. A mild excess of oxalate load, as occurs with excessive dietary i ntake, contributes to nephrolithiasis. A more severe oxalate overload, as in typ e 1 primary hyperoxaluria, can lead to organ damage through tissue deposition of calcium oxalate and possibly through the toxic effects of glyoxalate [12]. Two types of primary hyperoxaluria (PH) have been identified (Fig. 11-10), of which type 1 (PH1) is much more common. PH1 results from absolute or functional defici ency of the liver-specific enzyme alanine:glyoxalate aminotransferase (AGT). Thi s deficiency leads to calcium oxalate nephrolithiasis in childhood, with nephroc alcinosis and progressive renal failure. Because the kidney is the main excretor y route for oxalate, in the face of excessive oxalate production even mild degre es of renal insufficiency can lead to systemic deposition of oxalate in a wide v ariety of tissues. It is interesting that the liver itself is spared from calciu m oxalate deposition. Clinical consequences include heart block and cardiomyopat hy, severe peripheral vascular insufficiency and calcinosis cutis, and bone pain and fractures. Many of these conditions are exacerbated by the effects of end-s tage renal disease. In contrast, PH2 is much more rare than is PH1. Patients wit h PH2 have recurrent nephrolithiasis. Nephrocalcinosis, renal failure, and syste mic oxalosis have not been reported in PH2. The metabolic defect in PH2 appears to be a functional deficiency of D-glycerate dehydrogenase (DGDH) [12]. Secondar y causes of hyperoxaluria include dietary excess, enteric hyperabsorption, and e nhanced endogenous production resulting from either exposure to metabolic precursors of oxalate or pyridoxine deficiency . Normally, dietary sources of oxalate account for only approximately 10% of uri nary oxalate. Restriction of dietary oxalate can be effective in some patients w ith kidney stones who are hyperoxaluric, but even conscientious adherence to die tary restriction is disappointing in many patients who may have mild metabolic h yperoxaluria, an entity that probably exists but is poorly understood. Intestina rhubarb, beet of increased (eg, inflamma glycine, glyc

l absorption of oxalate can be enhanced markedly in patients with bowel disease, particularly inflammatory bowel disease or after extensive bowel resection or j ejunoileal bypass. In this setting, several mechanisms have been described inclu ding a) enhanced oxalate solubility as a consequence of binding of calcium to fa tty acids in patients with fat malabsorption; b) a direct effect of malabsorbed bile salts to enhance absorption of oxalate by intestinal mucosa, and c) altered gut flora with reduction in the population of oxalate-metabolizing bacteria [4, 12]. Because of the important role of the colon in absorbing oxalate, ileostomy abolishes enteric hyperoxaluria [4]. Excessive endogenous production of oxalate occurs in patients ingesting large quantities of ascorbic acid, which may increa se the risk of nephrolithiasis. In the setting of acute exposure to large quanti ties of metabolic precursors, such as ingestion of ethylene glycol or administra tion of glycine or methoxyflurane, tubular obstruction by calcium oxalate crysta ls can lead to acute renal failure. Pyridoxine deficiency is associated with inc reased oxalate excretion clinically in humans and experimentally in animals; it can contribute to mild hyperoxaluria. In all patients with primary hyperoxaluria , a trial of pyridoxine therapy should be given, because some patients will have a beneficial response.

Metabolic Causes of Tubulointerstitial Disease 11.7 Primary hyproxaluria metabolism Peroxisome Glycolate DGDH Glycine AGT Block in P H1 Oxalate Oxalate Glyoxylate Cytosol Glycolate Block in PH2 Glycine FIGURE 11-10 Metabolic events in the primary hyperoxalurias. Primary hyperoxalur ia type 1 (PH1) results from functional deficiency of the peroxisomal enzyme ala nine:glyoxalate aminotransferase (AGT). PH2 results from a deficiency of the cyt osolic enzyme d-glycerate dehydrogenase (DGDH), which also functions as glyoxala te reductase. This figure presents a simplified illustration of the metabolic consequences of these defects. Both diseases are inherited as autosomal recessiv e traits. In PH1, much clinical, biochemical, and molecular heterogeneity exists . Liver AGT catalytic activity is absent in approximately two thirds of patients with PH1. It is detectable in the remaining third, however, in whom the enzyme is targeted to the mitochondria rather than peroxisomes. Absence of peroxisomal AGT activity leads to impaired transamination of glyoxalate to glycine, with exc essive production of oxalate and, usually, glycolate. In PH2, deficiency of cyto solic DGDH results in overproduction of oxalate and glycine. Mild cases of PH1, without nephrocalcinosis or systemic oxalosis, resemble PH2 clinically, but the two usually can be distinguished by measurement of urinary glycolate and glycine . Assay of AGT activity in liver biopsy specimens can be diagnostic in PH1 even when renal failure prevents analysis of urinary excretion. The gene encoding AGT has been localized to chromosome 2q37.3 and has been cloned and sequenced. Muta tions in this gene have been identified in patients with absent enzymatic activi ty, abnormal enzyme targeting to mitochondria, aggregation of AGT within peroxis omes, and absence of both enzymatic activity and immunoreactivity. However, muta tions have not been identified in all patients with PH1 who have been studied, a nd molecular diagnosis is not yet routinely available [12]. (Adapted from Danpur e and Purdue [12].) A FIGURE 11-11 Sequential biopsies of a transplanted kidney documenting progressiv e recurrence of renal oxalosis. This patient with primary hyperoxaluria type I r eceived renal transplantation, without liver transplantation, at 24 years of age . Panels AD show tissue stained with hematoxylin B and eosin. Panels AC show specimens viewed by polarization microscopy, all at the same low-power magnification, from biopsies taken after transplantation within the first year (A), third year (B), (Continued on next page)

11.8 Tubulointerstitial Disease C D radial array of oxalate crystals and phagocytosis of small crystals by multinucl eated giant cells (E). Conservative treatment of PH1 is of limited efficacy. Die tary restriction has little effect on the course of the disease. High-dose pyrid oxine should be tried in all patients, but many patients do not respond. Strateg ies to prevent calcium oxalate stone formation include a high fluid intake (reco mmended in all patients), magnesium oxide (because magnesium increases the solub ility of calcium oxalate salts), and inorganic phosphate. Lithotripsy or surgery may be necessary but do not alter the progression of nephrocalcinosis [12,13]. Hemodialysis is superior to peritoneal dialysis in its ability to remove oxalate , but neither one is able to maintain a rate of oxalate removal sufficient to ke ep up with the production rate in patients with PH1. Once end-stage renal diseas e develops, hemodialysis does not prevent the progression of systemic oxalosis. In some patients, renal transplantation accompanied by an aggressive program of management has been followed by a good outcome for years [14]. However, oxalosis often recurs in the transplanted kidney, particularly if any degree of renal in sufficiency develops for any reason. In recent years, liver transplantation has been used with success, with or without renal transplantation, and offers the pr ospect of definitive cure. Results of liver transplantation are best in patients who have not yet developed significant renal insufficiency [12]. (Courtesy of P aul Shanley, MD.) Multinucleated giant cells Ox Oxalate crystals Ox Ox Ox Ox Ox Ox E FIGURE 11-11 (Continued) and fifth year (C), following renal transplantation. De position of oxalate crystals became progressively more severe with time, and the kidney failed after 5 years. Panel D illustrates a higher-power magnification, without polarization, of the biopsy at 5 years, showing a

Metabolic Causes of Tubulointerstitial Disease 11.9 URIC ACID AND RENAL DISEASE Disease Uric acid nephrolithiasis Acute uric acid nephropathy Clinical setting Hyperuricosuria Cytotoxic chemotherapy for leukemia or lymphoma; occasionally sp ontaneous Gout or hyperuricemia in the setting of hypertension, preexisting rena l disease, advanced age, vascular disease, inflammatory reaction, and chronic ex posure to lead Autosomal dominant inheritance Features Uric acid nephrolithiasis Calcium nephrolithiasis Intratubular obstruction by ur ic acid crystals in acidic urine Intrarenal tophi; sodium urate crystals in inte rstitium with accompanying destructive inflammatory reaction Therapeutic issues Allopurinol; alkalinize urine Allopurinol Prevention with allopurinol, fluids, a nd alkalinization Acute dialysis as indicated Hemodialysis for renal failure Chronic gouty nephropathy Familial hyperuricemic nephropathy Interstitial fibrosis, chronic inflammation; crystals are rare No consensus regarding allopurinol FIGURE 11-12 Uric acid contributes to the risk of kidney stones in several ways. Pure uric acid stones occur in patients with hyperuricosuria, particularly when the urine is acidic. Thus, therapy involves both allopurinol and alkalinization with potassium alkali salts. Hyperuricosuria also promotes calcium oxalate ston e formation. In these patients, calcium nephrolithiasis can be prevented by ther apy with allopurinol. The mechanism may involve heterogenous nucleation of calci um oxalate by uric acid microcrystals, binding of endogenous inhibitors of calci um crystallization, or salting out of calcium oxalate by urate [4]. Acute uric aci d nephropathy occurs most often in the setting of brisk cell lysis from cytotoxi c therapy or radiation for myeloproliferative or lymphoproliferative disorders o r other tumors highly responsive to therapy. Uric acid nephropathy can uncommonl y occur spontaneously in malignancies or other states of high uric acid producti on. Examples are infants with the Lesch-Nyhan syndrome who have excessive uric a cid production resulting from deficiency of hypoxanthine-guanine phosphoribosylt ransferase deficiency and, rarely, adults with gout who become volume-contracted and whose urine is concentrated and acidic. The mechanism involves intratubular obstruction by crystals of uric acid in the setting of an acute overwhelming lo ad of uric acid, particularly in acidic urine. In recent years, the widespread u se of an effective prophylactic regimen for chemotherapy has made acute uric aci d nephropathy much less common [15]. This regimen includes preparation of the pa tient with high-dose allopurinol, volume-expanding the patient to maintain a dil ute urine, and alkaline diuresis. In patients whose tumor lysis leads to hyperph osphatemia, however, it is important to discontinue urinary alkalinization or el se calcium phosphate precipitation may occur. Occasionally, patients will develo p renal failure despite these measures. In such patients, hemodialysis is prefer able to peritoneal dialysis because of the higher clearance rates for uric acid. Frequent hemodialy sis, even multiple times per day, may be necessary to prevent extreme hyperurice

mia and facilitate recovery of renal function. A modification of continuous arte riovenous hemodialysis has recently been reported to be effective in management of these patients [16]. Chronic gouty nephropathy is a term referring to deposit ion of sodium urate crystals in the renal interstitium, with an accompanying des tructive inflammatory reaction. As a specific entity with intrarenal tophi, gout y nephropathy appears to have become uncommon. It appears clear that long-standi ng hyperuricemia alone is not sufficient to cause this condition in most patient s, and that renal failure in patients with hyperuricemia or gout is almost alway s accompanied by other predisposing conditions, particularly hypertension or exp osure to lead [17]. Familial hyperuricemic nephropathy is an entity that now has been reported in over 40 kindreds. It is characterized by recurrent gout, often occurring in youth and even childhood; hyperuricemia; and renal failure. Histop athology reveals interstitial inflammation and fibrosis, almost always without e vidence of urate crystal deposition, although this has been found in two patient s. In contrast to gouty nephropathy, hypertension usually is absent until renal failure is advanced. The hyperuricemia appears to reflect decreased renal excret ion of urate rather than overproduction of urate. Although hyperuricemia precede s and is disproportionate to any degree of renal failure, the role, if any, that uric acid plays in the pathogenesis of the renal failure remains unclear. These is no consensus among authors regarding the potential value of allopurinol in t his disease. The inheritance follows an autosomal dominant pattern, but, beyond this, the genetics of the disease are not understood [18,19].

11.10 Tubulointerstitial Disease References 1. Hebert SC: Extracellular calcium-sensing receptor: implications for calcium a nd magnesium handling in the kidney. Kidney Int 1996, 50:21292139. 2. Riccardi D, Hall A, Xu J, et al.: Localization of the extracellular Ca2+ (polyvalent) catio n-sensing receptor in kidney. Am J Physiol (Renal Fluid Electrolyte Physiol), 19 98, in press. 3. Wrong OM: Nephrocalcinosis. In The Oxford Textbook of Clinical Nephrology. Edited by Davison AM, et al. London: Oxford University Press; 1997:1 3781396. 4. Coe FL, Parks JH, Asplin JR: The pathogenesis and treatment of kidney stones. N Engl J Med 1992, 327:11411152. 5. Buckalew VM: Nephrolithiasis in rena l tubular acidosis. J Urol 1989, 141:731737. 6. Simon DB, Karet FE, Hamdan JM, et al.: Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nature Genet 1996, 13:183188. 7. Simon DB, Karet FE, Rodriguez-Soriano J, et al.: Genetic heterogeneity of Bartte r's syndrome revealed by mutations in the K+ channel, ROMK. Nature Genet 1996, 14: 152156. 8. Simon DB, Bindra RS, Mansfield TA, et al.: Mutations in the chloride c hannel gene, CLCNKB, cause Bartter's syndrome type III. Nature Genet 1997, 17:17117 8. 9. Simon DB, Nelson-Williams C, Bia MJ, et al.: Gitelman's variant of Bartter's s yndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazid e-sensitive Na-Cl cotransporter. Nature Genet 1996, 12:2430. 10. Lloyd SE, Pearce SHS, Fisher SE, et al.: A common molecular basis for three inherited kidney sto ne diseases. Nature 1996, 379:445449. 11. Scheinman SJ: X-linked hypercalciuric n ephrolithiasis: clinical syndromes and chloride channel mutations. Kidney Int 19 98, 53:317. 12. Danpure CJ, Purdue PE: Primay hyperoxaluria. In The Metabolic and Molecular Bases of Inherited Disease, edn 6. Edited by Scriver CR, et al. New Y ork: McGraw-Hill; 1995:23852424. 13. Scheinman JI: Primary hyperoxaluria. Miner E lectrolyte Metab 1994, 20:340351. 14. Katz A, Freese D, Danpure CJ, et al.: Succe ss of kidney transplantation in oxalosis is unrelated to residual hepatic enzyme activity. Kidney Int 1992, 42:14081411. 15. Razis E, Arlin ZA, Ahmed T, et al.: Incidence and treatment of tumor lysis syndrome in patients with acute leukemia. Acta Haematol 1994, 91:171174. 16. Pichette V, Leblanc M, Bonnardeaux A, et al.: High dialysate flow rate continuous arteriovenous hemodialysis: a new approach for the treatment of acute renal failure and tumor lysis syndrome. Am J Kidney D is 1994, 23:591596. 17. Beck LH: Requiem for gouty nephropathy. Kidney Int 1986, 30:280287. 18. Puig JG, Miranda ME, Mateos FA, et al. Hereditary nephropathy asso ciated with hyperuricemia and gout. Arch Intern Med 1993, 153:357365. 19. Reiter L, Brown MA, Edmonds J: Familial hyperuricemic nephropathy. Am J Kidney Dis 1995 , 25:235241.

Renal Tubular Disorders Lisa M. Guay-Woodford I nherited renal tubular disorders involve a variety of defects in renal tubular t ransport processes and their regulation. These disorders generally are transmitt ed as single gene defects (Mendelian traits), and they provide a unique resource to dissect the complex molecular mechanisms involved in tubular solute transpor t. An integrated approach using the tools of molecular genetics, molecular biolo gy, and physiology has been applied in the 1990s to identify defects in transpor ters, channels, receptors, and enzymes involved in epithelial transport. These i nvestigations have added substantial insight into the molecular mechanisms invol ved in renal solute transport and the molecular pathogenesis of inherited renal tubular disorders. This chapter focuses on the inherited renal tubular disorders , highlights their molecular defects, and discusses models to explain their unde rlying pathogenesis. CHAPTER 12

12.2 Tubulointerstitial Disease Overview of Renal Tubular Disorders OVERVIEW OF RENAL TUBULAR DISORDERS INHERITED AS MENDELIAN TRAITS Inherited disorder Renal glucosuria Glucose-galactose malabsorption syndrome Acidic aminoaciduria C ystinuria Lysinuric protein intolerance Hartnup disease Blue diaper syndrome Neu tral aminoacidurias: Methioninuria Iminoglycinuria Glycinuria Hereditary hypopho sphatemic rickets with hypercalciuria X-linked hypophosphatemic rickets Inherite d Fanconi's syndrome isolated disorder Inherited Fanconi's syndrome associated with inborn errors of metabolism Carbonic anhydrase II deficiency Distal renal tubula r acidosis Bartter-like syndromes: Antenatal Bartter variant Classic Bartter var iant Gitelman's syndrome Pseudohypoparathyroidism: Type Ia Type Ib Low-renin hyper tension: Glucocorticoid-remedial aldosteronism Liddle's syndrome Apparent mineralo corticoid excess Pseudohypoaldosteronism: Type 1 Type 2 (Gordon's syndrome) Nephro genic diabetes insipidus: X-linked Autosomal Urolithiases: Cystinuria Dent's disea se X-linked recessive nephrolithiasis X-linked recessive hypophosphatemic ricket s Hereditary renal hypouricemia Transmission mode ?AR, AD AR AR AR AR ? AR AR Defective protein Sodium-glucose transporter 2 Sodium-glucose transporter 1 Sodium-potassiumdepende nt glutamate transporter Apical cystine-dibasic amino acid transporter Basolater al dibasic amino acid transporter ? Kidney-specific tryptophan transporter ? FIGURE 12-1 Inherited renal tubular disorders generally are transmitted as autos omal dominant, autosomal recessive, X-linked dominant, or X-linked recessive tra its. For many of these disorders, the identification of the disease-susceptibili ty gene and its associated defective protein product has begun to provide insigh t into the molecular pathogenesis of the disorder. AR X-linked dominant AR and AD AR AR AR AD AR AR AR AD ? AD AD AR AR and AD AD X -linked recessive AR and AD AR X-linked X-linked X-linked AR ? Sodium-phosphate cotransporter Phosphate-regulating with endopeptidase feature s on the X chromosome ? Carbonic anhydrase type II ? Basolateral anion exchanger (AE1) NKCC2, ROMK, ClC-K2 ClC-K2b NCCT Guanine nucleotidebinding protein Chimeric gene (11 -hydroxylase and aldosterone synthase) and subunits of the sod ium channel 11- -hydroxysteroid dehydrogenase and subunits of the sodium channel ? Arginine vasopressin 2 receptor Aquaporin 2 water channel Apical cystinedibasi c amino acid transporter Renal chloride channel (ClC-5) Renal chloride channel ( ClC-5) Renal chloride channel (ClC-5) ? Urate transporter ADautosomal dominant; ARautosomal recessive; ClC-K2renal chloride channel; NCCTthiaz ide-sensitive cotransporter; NKCC2bumetanide-sensitive cotransporter; ROMKinwardly rectified.

Renal Tubular Disorders 12.3 Renal Glucosuria 400 Observed curve Threshold Tmax 200 Glucose reabsorption, mg/min 1.73m2 0 0 400 Normal Type B renal glucosuria 200 400 600 200 Type A renal glucosuria 0 0 200 400 600 Filtered glucose load, mg/min 1.73m2 FIGURE 12-2 Physiology and pathophysiology of glucose titration curves. Under no rmal physiologic conditions, filtered glucose is almost entirely reabsorbed in t he proximal tubule by way of two distinct sodiumcoupled glucose transport system s. In the S1 and S2 segments, bulk reabsorption of glucose load occurs by way of a kidney-specific high-capacity transporter, the sodium-glucose transporter-2 ( SGLT2) [1]. The residual glucose is removed from the filtrate in the S3 segment by way of the high-affinity sodium-glucose transporter-1 (SGLT1) [2]. This trans porter also is present in the small intestine. As are all membrane transport sys tems, glucose transporters are saturable. The top panel shows that increasing th e glucose concentration in the tubular fluid accelerates the transport rate of t he glucose transporters until a maximal rate is achieved. The term threshold app lies to the point that glucose first appears in the urine. The maximal overall r ate of glucose transport by the proximal tubule SGLT1 and SGLT2 is termed the Tm ax. Glucose is detected in urine either when the filtered load is increased (as in diabetes mellitus) or, as shown in the bottom panel, when a defect occurs in tubular reabsorption (as in renal glucosuria). Kinetic studies have demonstrated two types of glucosuria caused by either reduced maximal transport velocity (ty pe A) or reduced affinity of the transporter for glucose (type B) [3]. Mutations in the gene encoding SGLT1 cause glucose-galactose malabsorption syndrome, a se vere autosomal recessive intestinal disorder associated with mild renal glucosur ia (type B). Defects in SGLT2 result in a comparatively more severe renal glucos uria (type A). However, this disorder is clinically benign. Among members of the basolateral glucose transporter (GLUT) family, only GLUT1 and GLUT2 are relevan t to renal physiology [4]. Clinical disorders associated with mutations in the g enes encoding these transporters have yet to be described. (From Morris and Ives [5]; with permission.)

12.4 Tubulointerstitial Disease Aminoacidurias CLASSIFICATION OF INHERITED AMINOACIDURIAS Major categories Acidic amino acids Basic amino acids and cystine Forms Acidic aminoaciduria Cystinuria Lysinuric protein intolerance Isolated cystinuri a Lysinuria Hartnup disease Blue diaper syndrome Iminoglycinuria Glycinuria Meth ioninuria OMIM number* 222730 220100, 600918, 104614 222690, 222700, 601872 238200 234500, 260650 21100 0 242600 138500 Amino acids involved Glutamate, aspartate Cystine, lysine, arginine, ornithine Lysine, arginine, orni thine Cystine Lysine Alanine, asparagine, glutamine, histidine, isoleucine, leuc ine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine Tryptophan G lycine, proline, hydroxyproline Glycine Methionine Neutral amino acids *OMIMOnline Mendelian Inheritance in Man (accessible at http://www3.ncbi.nlm.nih. gov/omin/). FIGURE 12-3 Over 95% of the filtered amino acid load is normally reabsorbed in t he proximal tubule. The term aminoaciduria is applied when more than 5% of the f iltered load is detected in the urine. Aminoaciduria can occur in the context of metabolic defects, which elevate plasma amino acid concentrations and thus incr ease the glomerular filtered load. Aminoaciduria can be a feature of generalized proximal tubular dysfunction caused by toxic nephropathies or Fanconi's syndrome. In addition, aminoaciduria can arise from genetic defects in one of the several amino acid transport systems in the proximal tubule. Three distinct groups of i nherited aminoacidurias are distinguished based on the net charge of the target amino acids at neutral pH: acidic (negative charge), basic (positive charge), an d neutral (no charge) [5]. Acidic aminoaciduria involves the transport of glutam ate and aspartate and results from a defect in the high-affinity sodiumpotassiumd ependent glutamate transporter [6]. It is a clinically benign disorder. Four syn dromes caused by defects in the transport of basic amino acids or cystine have b een described: cystinuria, lysinuric protein intolerance, isolated cystinuria, a nd isolated lysinuria. Cystine actually is a neutral amino acid that shares a common carrier with the d ibasic amino acids lysine, arginine, and ornithine. The transport of all four am ino acids is disrupted in cystinuria. The rarer disorder, lysinuric protein into lerance, results from defects in the basolateral transport of dibasic amino acid s but not cystine. Increased intracelluar concentrations of lysine, arginine, an d ornithine are associated with disturbances in the urea cycle and consequent hy perammonemia [7]. Disorders involving the transport of neutral amino acids inclu de Hartnup disease, blue diaper syndrome, methioninuria, iminoglycinuria, and gl ycinuria. Several neutral amino acid transporters have been cloned and character ized. Clinical data suggest that Hartnup disease involves a neutral amino acid t ransport system in both the kidney and intestine, whereas blue diaper syndrome i nvolves a kidney-specific tryptophan transporter [5]. Methioninuria appears to i nvolve a separate methionine transport system in the proximal tubule. Case repor ts describe seizures, mental retardation, and episodic hyperventilation in affec

ted patients [8]. The pathophysiologic basis for this phenotype is unclear. Imin oglycinuria and glycinuria are clinically benign disorders.

Renal Tubular Disorders 12.5 ROSENBERG CLASSIFICATION OF CYSTINURIAS Category I Heterozygote Homozygote II Heterozygote Homozygote III Heterozygote Homozygote Excess excretion of cystine and basic amino acids Cystinuria, basic aminoacidur ia, cystine stones None Excess excretion of cystine and basic amino acids Cystin uria, basic aminoaciduria, cystine stones Basic amino acids only No abnormality Cystinuria, basic aminoaciduria, cystine stones Cystinine, basic amino acids Phenotype Intestinal transport defect From Morris and Ives [5]; with permission. FIGURE 12-4 In this autosomal recessive disorder the apical transport of cystine and the dibasic amino acids is defective. Differences in the urinary excretion of cystine in obligate heterozygotes and intestinal amino acid transport studies in homozygotes have provided the basis for defining three distinct phenotypes o f cystinuria [9]. Genetic studies have identified mutations in the gene (SCL3A1) encoding a high-affinity transporter for cystine and the dibasic amino acids in patients with type I cystinuria [10,11]. In patients with type III cystinuria, SCL3A1 was excluded as the disease-causing gene [12]. A second cystinuria-suscep tibility gene recently has been mapped to chromosome 19 [13]. FIGURE 12-5 Urinary cystine crystals. Excessive urinary excretion of cystine (25 0 to 1000 mg/d of cystine/g of creatinine) coupled with its poor solubility in u rine causes cystine precipitation with the formation of characteristic urinary c rystals and urinary tract calculi. Stone formation often causes urinary tract ob struction and the associated problems of renal colic, infection, and even renal failure. The treatment objective is to reduce urinary cystine concentration or t o increase its solubility. High fluid intake (to keep the urinary cystine concen tration below the solubility threshold of 250 mg/L) and urinary alkalization are the mainstays of therapy. For those patients refractory to conservative managem ent, treatment with sulfhydryl-containing drugs, such as D-penicillamine, mercap topropionylglycine, and even captopril can be efficacious [14,15].

12.6 Tubulointerstitial Disease Renal Hypophosphatemic Rickets INHERITED FORMS OF HYPOPHOSPHATEMIC RICKETS Disorder X-linked hypophosphatemic rickets Hereditary hypophosphatemic rickets with hyper calciuria Vitamin D Low, low normal Elevated Parathyroid hormone Normal, high normal Low, low normal Serum calcium Low, normal Normal Urinary calcium Elevated Elevated Treatment Calciferol, phosphate supplementation Phosphate supplementation Vitamin D1,25-dihydroxy-vitamin D3 FIGURE 12-6 Several inherited disorders have been described that result in isola ted renal phosphate wasting. These disorders include X-linked hypophosphatemic r ickets (HYP), hereditary hypophosphatemic rickets with hypercalciuria (HHRH), hy pophosphatemic bone disease (HBD), autosomal dominant hypophosphatemic rickets ( ADHR), autosomal recessive hypophosphatemic rickets (ARHR), and X-linked recessi ve hypophosphatemic rickets (XLRH). These inherited disorders share two common f eatures: persistent hypophosphatemia caused by decreased renal tubular phosphate (Pi) reabsorption (expressed as decreased ratio of plasma concentration at whic h maximal phosphate reabsorption occurs [TmP] to glomerular filtration rate [GFR ], [TmP/GFR], a normogram derivative of the fractional excretion of Pi); and associated metabolic bone disease, eg, rickets in children or osteomala cia in adults [5]. These disorders can be distinguished on the basis of the rena l hormonal response to hypophosphatemia, the biochemical profile, and responsive ness to therapy. In addition, the rare disorder XLRH is associated with nephroli thiasis. The clinical features of the two most common disorders HYP and HHRH are contrasted here. Whereas both disorders have defects in renal Pi reabsorption, the renal hormonal response to hypophosphatemia is impaired in HYP but not in HH RH. Indeed, in children with HHRH, phosphate supplementation alone can improve g rowth rates, resolve the radiologic evidence of rickets, and correct all biochem ical abnormalities except the reduced TmP GFR [5]. ized by growth impairment in children, metabolic bone disease, phosphaturia, and abnormal bioactivation of vi tamin D [16]. Cell culture, parabiosis, and transplantation experiments have dem onstrated that the defect in HYP is not intrinsic to the kidney but involves a c irculating humoral factor other than parathyroid hormone [16,17]. Phosphate is t ransported across the luminal membrane of the proximal tubule by a sodium-phosph ate cotransporter (NaPi). This transporter is regulated by multiple hormones. Am ong these is a putative phosphaturic factor that has been designated phosphatoni n [18]. It is postulated that phosphatonin inhibits Pi reabsorption by way of th e sodium-coupled phosphate cotransporter, and it depresses serum 1,25-dihydroxyvitamin D3 production by inhibiting 1- -hydroxlase activity and stimulating 24-h ydroxylase activity. Positional cloning studies in families with HYP have identi fied a gene, designated PEX (phosphate-regulating gene with homologies to endope

ptidases on the X chromosome), that is mutated in patients with X-linked hypopho sphatemia [19]. PEX, a neutral endopeptidase, presumably inactivates phosphatoni n. Defective PEX activity would lead to decreased phosphatonin degradation, with excessive phosphaturia and deranged vitamin D metabolism. A similar scenario as sociated with increased phosphatonin production has been proposed as the basis f or oncogenic hypophosphatemic osteomalacia, an acquired disorder manifested in p atients with tumors of mesenchymal origin [17]. Na+sodium ion; K+potassium ion. PEX (endopeptidase) Phosphatonin Degradation Na + ATP 3Na+ 2K+ 1a-hdroxlse ADP Pi 25-Vitamin D Lumen 1,25-Vitamin D Interstitium FIGURE 12-7 Proposed pathogenesis of X-linked hypophosphatemic rickets (HYP). HY P, the most common defect in renal phosphate (Pi) transport, is transmitted as a n X-linked dominant trait. The disorder is character-

Renal Tubular Disorders 12.7 Fanconi's Syndrome INHERITED FANCONI'S SYNDROME Disorder Idiopathic Cystinosis Hepatorenal tyrosinemia (tyrosinemia type I) Hereditary fr uctose intolerance Galactosemia Glycogen storage disease type I Wilson's disease O culocerebrorenal (Lowe's) syndrome Vitamin-Ddependent rickets OMIM number* 227700, 227800 219800, 219900, 219750 276700 229600 230400 232200 277900 309000 264700 FIGURE 12-8 Fanconi's syndrome is characterized by two components: generalized dys function of the proximal tubule, leading to impaired net reabsorption of bicarbo nate, phosphate, urate, glucose, and amino acids; and vitamin Dresistant metaboli c bone disease [20]. The clinical manifestations in patients with either the her editary or acquired form of Fanconi's syndrome include polyuria, dehydration, hypo kalemia, acidosis, and osteomalacia (in adults) or impaired growth and rickets ( in children). Inherited Fanconi's syndrome occurs either as an idiopathic disorder or in association with various inborn errors of metabolism. *OMIMOnline Mendelian Inheritance in Man (accessible at http://www3.ncbi.nlm.nih. gov/omin/). From Morris and Ives [5]; with permission. Na (1) Na+ S (4) Na+ ATP 3Na+ (2) 2K+ ADP (3) ADP H+ ATP ATP Lumen Interstitium FIGURE 12-9 Proposed pathogenic model for Fanconi's syndrome. The underlying patho genesis of Fanconi's syndrome has yet to be determined. It is likely, however, tha t the various Mendelian diseases associated with Fanconi's syndrome cause a global disruption in sodiumcoupled transport syste ms rather than a disturbance in specific transporters. Bergeron and coworkers [2 0] have proposed a pathophysiologic model that involves the intracellular gradie nts of sodium, adenosine triphosphate (ATP), and adenosine diphosphate (ADP). A transepithelial sodium gradient is established in the proximal tubule cell by so dium (Na) entry through Na-solute cotransport systems (Na-S) (1) and Na exit thr ough the sodium-potassium adenosine triphosphatase (Na-K ATPase) (2). This Na gr adient drives the net uptake of cotransported solutes. A small decrease in the a ctivity of the Na-K ATPase cotransporter may translate into a proportionally lar ger increment in the Na concentration close to the luminal membrane, thus decrea sing the driving force that energizes all Na-solute cotransport systems. Concomi tantly, reciprocal ATP and ADP gradients are established in the cell by the acti vity of membrane bound ATPases (Na-K ATPase (2) and hydrogen-ATPase (3)) and mit ochondrial (4) ATP synthesis. A small reduction in mitochondrial rephosphorylati on of ADP may result in a juxtamembranous accumulation of ADP and a reciprocal d ecrease in ATP, altering the ADP-ATP ratio and downregulating pump activities. T herefore, a relatively small mitochondrial defect may be amplified by the effect s on the intracellular sodium gradients and ADP-ATP gradients and may lead to a global inhibition of Na-coupled transport. H+hydrogen ion.

12.8 Tubulointerstitial Disease Renal Tubular Acidoses INHERITED RENAL TUBULAR ACIDOSES Disorder Isolated proximal RTA Carbonic anhydrase II deficiency Isolated distal RTA Dista l RTA with sensorineural deafness Transmission mode Autosomal recessive Autosomal recessive Autosomal dominant Autosomal recessive RTArenal tubular acidosis. FIGURE 12-10 Renal tubular acidosis (RTA) is characterized by hyperchloremic met abolic acidosis caused by abnormalities in renal acidification, eg, decreased tu bular reabsorption of bicarbonate or reduced urinary excretion of ammonium (NH4+ ). RTA can result from a number of disease processes involving either inherited or acquired defects. In addition, RTA may develop from an isolated defect in tub ular transport; may involve multiple tubular transport abnormalities, eg, Fancon i's syndrome; or may be associated with a systemic disease process. Isolated proxi mal RTA (type II) is rare, and most cases of proximal RTA occur in the context o f Fanconi's syndrome. Inherited forms of classic distal RTA (type I) are transmitt ed as both autosomal dominant and autosomal recessive traits. Inherited disorder s in which RTA is the major clinical manifestation are summarized. and water to hydrogen ions (H+) and bicarbonate (HCO-3) [21]. A least two isoenzymes of carbo nic anhydrase are expressed in the kidney and play critical roles in urinary aci dification. In the proximal tubule, bicarbonate reabsorption is accomplished by the combined action of both luminal carbonic anhydrase type IV (CA4) and cytosol ic carbonic anhydrase type II (CA2), the luminal sodium-hydrogen exchanger, and the basolateral sodium-bicarbonate exchanger. Impaired bicarbonate reabsorption in the proximal tubule is the underlying defect in type II or proximal RTA. In t he distal nephron, carbonic anhydrase type II is expressed in the intercalated c ells of the cortical collecting duct. There carbonic anhydrase type II plays a c ritical role in catalyzing the condensation of hydroxy ions, generated by the pr oton-translocating H+adenosine triphosphatase (H+ ATPase), with carbon dioxide t o form bicarbonate. In carbonic anhydrase type II deficiency, the increase in in tracellular pH impairs the activity of the proton-translocating H-ATPase. Carbon ic anhydrase inhibitors (eg, acetazolamide) act as weak diuretics by blocking bi carbonate reabsorption. Cl-chloride ion; H2CO3carbonic acid; K+potassium ion; Na+sod ium ion. Proximal tubule Distal tubule: a intercalated cell Cl Interstitium Na+ HCO3 K+ CO2 + H2O Cl HCO3 CA2 HCO3

 H2CO3 CA2 CO2 OH H+ H+ K+ Na+ HCO3 Na+ H + H2CO3 CA4 CO2 H+ K+ H+ Lumen HCO3 FIGURE 12-11 Carbonic anhydrase II deficiency. Carbonic anhydrase II deficiency is an autosomal recessive disorder characterized by renal tubular acidosis (RTA) , with both proximal and distal components, osteopetrosis, and cerebral calcific ation. Carbonic anhydrase catalyzes the reversible hydration of carbon dioxide ( CO2), and thereby accelerates the conversion of carbon dioxide

Renal Tubular Disorders Cl 12.9 Cortical collecting duct Principal cell K+ Cl HCO3 a intercalated cell CA2 CO2 K+ OH Lumen Na+ K+ H+ K+ Cl H+ Outer medullary collecting duct Principal cell K+ Cl HCO3 a intercalated cell K+ Lumen + H 2O H+ K+ H+ FIGURE 12-12 Distal renal tubular acidosis (RTA). The collecting duct is the pri

ncipal site of distal tubule acidification, where the final 5% to 10% of the fil tered bicarbonate load is reabsorbed and the hydrogen ions (H+) generated from dietary protein catabolism are secrete d. The distal nephron is composed of several distinct segments, eg, the connecti ng tubule, cortical collecting duct, and medullary collecting duct. The tubular epithelia within these segments are composed of two cell types: principal cells that transport sodium, potassium, and water; and intercalated cells that secrete hydrogen ions and bicarbonate (HCO-3) [22]. Urinary acidification in the distal nephron depends on several factors: an impermeant luminal membrane capable of s ustaining large pH gradients; a lumen-negative potential difference in the corti cal collecting duct that supports both hydrogen and potassium ion (K+) secretion ; and secretion of hydrogen ions by the intercalated cells of the cortical and m edullary collecting ducts at a rate sufficient to regenerate the bicarbonate con sumed by metabolic protons [22]. Abnormalities in any of these processes could r esult in a distal acidification defect. Recent studies in families with isolated autosomal dominant distal RTA have identified defects in the basolateral chlori debicarbonate exchanger, AE1 [23,24]. Defects in various components of the H+-ad enosine triphosphatase (H+ ATPase) and subunits of the H+-K+ ATPase (H+\K+ ATPas e) also have been proposed as the basis for other hereditary forms of distal RTA . CA2cytosolic carbonic anhydrase type II; Cl-chloride ion; CO2carbon dioxide; Na+so dium ion; OH-hydroxy ions. Bartter-like Syndromes CLINICAL FEATURES DISTINGUISHING BARTTER-LIKE SYNDROMES Classic Bartter's syndrome Infancy, early childhood +/++ +/++ Rare Low in 20% Normal to high +/High +/Feature Age at presentation Prematurity, polyhydramnios Delayed growth Delayed cognitive development Polyuria, polydipsia Tetany Serum magnesium Urinary calcium excreti on Nephrocalcinosis Urine prostaglandin excretion Clinical response to indometha cin Gitelman's syndrome Childhood, adolescence + ++ Low in about 100% Low Normal Antenatal Bartter's syndrome In utero, infancy ++ +++ + +++ Low-normal to normal Very high ++ Very high Often life-saving FIGURE 12-13 Familial hypokalemic, hypochloremic metabolic alkalosis, or Bartter's syndrome, is not a single disorder but rather a set of closely related disorder s. These Bartter-like syndromes share many of the same physiologic derangements but differ with regard to the age of onset, presenting symptoms, magnitude of ur inary potassium and prostaglandin excretion, and extent of urinary calcium excre tion. At least three clinical phenotypes have been distinguished: classic Bartte r's syndrome, the antenatal hypercalciuric variant (also called hyperprostaglandin E syndrome), and hypocalciuric-hypomagnesemic Gitelman's syndrome [25]. From Guay-Woodford [25]; with permission.

12.10 Tubulointerstitial Disease FIGURE 12-14 Transport systems involved in transepithelial sodium-chloride trans port in the thick ascending limb (TAL). Clinical data suggest that the primary d efect in the antenatal and classic Bartter syndrome variants involves impaired s odium chloride transport in the TAL. Under normal physiologic conditions, sodium chloride is transported across the apical membrane by way of the bumetanide-sen sitive sodium-potassium-2chloride (Na-K-2Cl) cotransporter (NKCC2). This electro neutral transporter is driven by the low intracellular sodium and chloride conce ntrations generated by the sodium-potassium pump and the basolateral chloride ch annels and potassium-chloride cotransporter. In addition, apical potassium recyc ling by way of the low-conductance potassium channel (ROMK) ensures the efficien t functioning of the Na-K-2Cl cotransporter. The activity of the ROMK channel, i n turn, is regulated by a number of cell messengers, eg, calcium (Ca2+) and aden osine triphosphate (ATP), as well as by the calcium-sensing receptor (CaR), pros taglandin EP3 receptor, and vasopressin receptor (V2R) by way of cAMP-dependent pathways and arachidonic acid (AA) metabolites, eg, 20-hydroxy-eicosatetraenoic acid (20-HETE). The positive transluminal voltage (Vte) drives the paracellular reabsorption of calcium ions and magnesium ions (Mg2+) [25]. cAMPcyclic adenosine monophosphate; PGE2 prostaglandin E2; PKAprotein kinase A. FIGURE 12-15 Proposed pathogenic model for the antenatal and classic variants of Bartter's syndrome. Gen etic studies have identified mutations in the genes encoding the bumetanide-sens itive sodium-potassium-2chloride cotransporter (NKCC2), luminal ATPregulated pota ssium channel (ROMK), and kidney-specific chloride channel (ClC-K2). These findi ngs support the theory of a primary defect in thick ascending limb (TAL) sodiumchloride (Na-Cl) reabsorption in, at least, subsets of patients with the antenat al or classic variants of Bartter's syndrome. In the proposed model the potential interrelationships of the complex set of pathophysiologic phenomena are illustra ted. The resulting clinical manifestations are highlighted in boxes [25]. Ca2+ ca lcium ion; H+hydrogen ion; K+potassium ion; Mg2+magnesium ion; PGE2 prostaglandin E2 . Lumen AA Na+ K+ 2Cl 20 HETE K+ Ca2+ ATP ATP Stimulatory Inhibitory cAMP Cl 3Na+ Interstitium Ca2+ sensing receptor 2K+ K+ Cl V2R EP3 PGE2 Vte + Ca2+ Mg2+ Gene defect Pathophysiology Defective NKCC2 Defective ROMK Defective CIC-Kb Defective NaCl transport in TAL Volume contraction - Renin - Angiotensin II (AII) - Na Cl delivery to the distal nephron Voltage-driven paracellular reabsorption of Ca2+ and Mg2+ - Kallikrein - Aldosterone - H+ and K+ secretion

Hypercalciuria Hypermagnesuria Normotension Blunted vascular response to AII and norepinephrine - PGE2 Metabolic alkalosis Hypokalemia Impaired vasopressinstimulated urinary concentration Hyposthenuria - Urinary prostaglandins - Bone reabsorption Fever

Renal Tubular Disorders 12.11 Gene defect Pathophysiologic model Defective NCCT DefectiveHypercalciuria in DCT NaCl transport ? Na+-dependent Mg2+ reabsorption in DCT Volume contraction - Renin - Angiotensin II (AII) - Aldosterone - NaCl delivery to the distal nephron Cl efflux mediates cell hyperpolarization - H+ and K+ secretion Metabolic alkalosis hypokalemia - Ca2+ reabsorption Hypocalciuria Hypermagnesuria FIGURE 12-16 Proposed pathogenic model for Gitelman's syndrome. The electrolyte di sturbances evident in Gitelman's syndrome also are observed with administration of thiazide diuretics, which inhibit the sodium-chloride (Na-Cl) cotransporter in the distal convoluted tubule (DCT). In families with Gitelman's syndrome, genetic studies have identified defects in the gene encoding the thiazidesensitive cotra nsporter (NCCT) protein. The proposed pathogenic model is predicated on loss of function of the NCCT protein and, thus, most closely applies to those patients w ho inherit Gitelman's syndrome as an autosomal recessive trait. Given that the phy siologic features of this syndrome are virtually indistinguishable in familial a nd sporadic cases, it may be reasonable to propose the same pathogenesis for all patients with Gitelman's syndrome. However, it is important to caution that evide nce for NCCT mutations in sporadic cases has not yet been established [25]. Ca2+c alcium ion; Cl-chloride ion; H+hydrogen ion; K+potassium ion; Mg2+magnesium ion; Na+s odium ion. Pseudohypoparathyroidism CLINICAL SUBTYPES OF PSEUDOHYPOPARATHYROIDISM Disorder Pseudohypoparathyroidism type Ia Pseudohypoparathyroidism type Ib Pathophysiology Defect in guanine nucleotidebinding protein Resistance to parathyroid hormone, no rmal guanine nucleotidebinding protein activity ? Defect in parathyroid hormone r eceptor Skeletal anomalies Yes No Associated endocrinopathies Yes No FIGURE 12-17 Pseudohypoparathyroidism applies to a heterogeneous group of heredi tary disorders whose common feature is resistance to parathyroid hormone (PTH).

Affected patients are hypocalcemic and hyperphosphatemic, despite elevated plasm a PTH levels. Hypocalcemia and hyperphophatemia result from the combined effects of defective PTHmediated calcium reabsorption in the distal convoluted tubule a nd reduced formation of 1,25-dihydroxy-vitamin D3. The latter leads to defects i n renal phosphate excretion, calcium mobilization from bone, and gastrointestina l calcium reabsorption. Differences in clinical features and urinary cyclic aden osine monophosphate response to infused PTH provide the basis for distinguishing three distinct subtypes of pseudohypoparathyroidism (type Ia, type Ib, and type II) [26]. Pseudohypoparathyroidism type Ia (Albright's hereditary osteodystrophy) is associa ted with a myriad of physical abnormalities and resistance to multiple adenylate cyclasecoupled hormones, most notably thyrotropin and gonadotropin [27]. The mol ecular defect in a guanine nucleotidebinding protein (Gs) blocks the coupling of PTH and other hormone receptors to adenylate cyclase. The molecular defect has n ot been identified in type Ib, although specific resistance to PTH suggests a de fect in the PTH receptor. Oral supplementation with 1,25 dihydroxy-vitamin D3 an d, if necessary, oral calcium, is used to correct the hypocalcemia and minimize PTH-induced bone disease [26]. Pseudohypoparathroidism type II may be an acquire d disease.

12.12 Tubulointerstitial Disease Disorders of Aldosterone-Regulated Transport (A) GRA chimeric gene Aldosterone synthetase 11-OHase Unequal crossover Aldosterone synthetase Chimeric gene 11-OHase (B) Amiloride-sensitive Na+ channel Na+ Na+ K+ Aldosterone (A) MR K+ channel (A) GRA (B) Liddle's (C) AME Cortisol (C) Degradation FIGURE 12-18 Aldosterone-regulated transport in the cortical collecting duct and defects causing low-renin hypertension. The mineralocorticoid aldosterone regul ates electrolyte excretion and intravascular volume by way of its action in the principal cells of the cortical collecting duct. The binding of aldosterone to i ts nuclear receptor (MR) leads directly or indirectly to increased activity of t he apical sodium (Na) channel and the basolateral sodium-potassium adenosine triphosphatase (Na-K ATPase). Sod ium moves from the lumen into the cell and down its electrochemical gradient, th us generating a lumen-negative transepithelial voltage that drives potassium sec retion from the principal cells and hydrogen secretion from the intercalated cel ls. The type I mineralocorticoid receptor (MR) is nonspecific and can bind both aldosterone and cortisol, but not cortisone. The selective receptor specificity for aldosterone is mediated by the kidney isoform of the enzyme, 11- -hydroxyste roid dehydrogenase, which oxidizes intracellular cortisol to its metabolite cort isone. Three hypertensive syndromes, glucocorticoid-remedial aldosteronism (GRA) , Liddle's syndrome, and apparent mineralocorticoid excess (AME), share a common c linical phenotype that is characterized by normal physical examinations, hypokal emia, and very low plasma renin activity. The molecular defect in GRA derives fr om an unequal crossover event between two adjacent genes encoding 11- -hydroxyla se and aldosterone synthase (A). The resulting chimeric gene duplication fuses t he regulatory elements of 11- -hydroxylase and the coding sequence of aldosteron e synthase. Consequently, aldosterone is ectopically synthesized in the adrenal zona fasciculata and its synthesis regulated by adrenocorticotropic hormone rath er than its physiologically normal secretagogue, angiotensin II [28]. Activating mutations in the and regulatory subunits of the epithelial sodium channel (B) a re responsible for Liddle's syndrome [29]. Deficiency of the kidney type 2 isozyme of 11- -hydroxysteroid dehydrogenase (C) can render type I MR responsive to cor tisol and produce the syndrome of apparent mineralocorticoid excess [30]. Inhibi tors of this enzyme (eg, licorice) also can produce an acquired form of apparent mineralocorticoid excess. Medical management of these disorders focuses on diet ary sodium restriction, blocking the sodium channel with the potassium-sparing d iuretics triamterene and amiloride, downregulating the ectopic aldosterone synth esis with glucocorticoids (GRA), or blocking the MR using the competitive antago nist spironolactone (GRA and AME).

Renal Tubular Disorders 12.13 Low-renin hypertension + Family history Family history Abnormal PE Serum K+ Virilization High-normal Gordon's syndrome Urinary steroid profile: Diagnosis: TH180x0F THAD GRA Low-normal 11b-hydroxyase deficiency Neglig ible urinary aldosterone Liddle's syndrome Hypogonadism Normal PE Low serum K+ 17a-hdroxlse deficiency THF + alloTHF THE AME FIGURE 12-19 Algorithm for evaluating patients with lowrenin hypertension. Gluco corticoid-remedial aldosteronism (GRA), Liddle's syndrome, and apparent mineraloco rticoid excess (AME) can be distinguished from one another by characteristic uri nary steroid profiles [31]. K+potassium ion; PEphysical examination; TH18oxoF/THADr atio of urinary 18-oxotetrahydrocortisol (TH18oxoF) to urinary tetrahydroaldoste rone (normal: 00.4; GRA patients: >1); THF + alloTHF/THEratio of the combined urin ary tetrahydrocortisol and allotetrahydrocortisol to urinary tetrahydrocortisone (normal: <1.3; AME patients: 510-fold higher). CLINICAL SUBTYPES OF PSEUDOHYPOALDOSTERONISM Disorder Pseudohypoaldosteronism type I Autosomal recessive Clinical features Dehydration, severe neonatal salt wasting, hyperkalemia, metabolic acidosis Elev ated plasma renin activity Severity of electrolyte abnormalities may diminish af ter infancy Mild salt wasting Hypertension, hyperkalemia, mild hyperchloremic me tabolic acidosis Undetectable plasma renin activity Treatment Sodium chloride supplementation Ion-binding resin; dialysis Autosomal dominant Pseudohypoaldosteronism type II (Gordon's syndrome) Thiazide diuretics FIGURE 12-20 Mineralocorticoid resistance with hyperkalemia (pseudohypoaldostero nism) includes at least three clinical subtypes, two of which are hereditary dis orders. Pseudohypoaldosteronism type I (PHA1) is characterized by severe neonata l salt wasting, hyperkalemia, and metabolic acidosis. The diagnosis is supported by elevated plasma renin and plasma aldosterone concentrations. Life-saving interventions include aggressive sodium chloride supplementation and treatment with ion-binding resins or dialysi s to reduce the hyperkalemia. This autosomal recessive form of PHA1 results from inactivating mutations in the or subunits of the epithelial sodium channel [32] . A milder form of PHA1 with autosomal dominant inheritance also has been descri bed; however, the molecular defect remains unexplained [33]. Adolescents or adul ts with hyperkalemic, hyperchloremic metabolic acidosis, low-normal renin and al dosterone levels, and hypertension have been recently described and classified a s having pseudohypoaldosteronism type II (PHA2) or Gordon's syndrome [34]. Phenoty pically, this disorder is the mirror image of Gitelman's syndrome; however, the th

iazidesensitive cotransporter (NCCT) has been excluded as a candidate gene [35].

12.14 Tubulointerstitial Disease Nephrogenic Diabetes Insipidus 1200 1000 Urine osmolality, mOsm/kg 800 600 400 200 0 0 1 2 3 4 5 Plasma AVP, pg /mL 10 15 NDI Primary polydipsia Pituitary diabetes insipidus FIGURE 12-21 The relationship between urine osmolality and plasma arginine vasop ressin (AVP). Nephrogenic diabetes insipidus (NDI) is characterized by renal tub ular unresponsiveness to the antidiuretic hormone AVP or its antidiuretic analog ue 1-desamino-8-D-arginine vasopressin (DDAVP). In both the congenital and acqui red forms of this disorder the clinical picture is dominated by polyuria, polydi psia, and hyposthenuria despite often elevated AVP levels [17]. (From Robertson et al. [36]; with permission.) Physiologic X-linked NDI V2R Pathophysiologic ADH V2R AQP3 AQP2 H 2O AQP3 AQP2 H 2O AQP4 AQP4 AQP2 +ADH V2R cAMP AQP4 Interstitium Lumen AQP3 ATP H 2O Autosomal recessive NDI V2R AQP2 AQP3 ATP cAMP AQP4 H 2O Interstitium Lumen FIGURE 12-22 Pathogenic model for nephrogenic diabetes insipidus (NDI). The prin ciple cell of the inner medullary collecting duct is the site where fine tuning of the final urinary composition and volume occurs. As shown, the binding of arginine vasopressin (AVP) to the vasopr essin V2 receptor (V2R) stimulates a series of cyclic adenosine monophosphate (cA MP) mediated events that results in the fusion of cytoplasmic vesicles carrying water channel proteins (aquaporin-2 [AQP2]), with the apical membrane, thereby i ncreasing the water permeability of this membrane. Water exits the cell through the basolateral water channels AQP3 and AQP4. In the absence of AVP, water chann els are retrieved into cytoplasmic vesicles and the water permeability of the ap ical membrane returns to its baseline low rate [37]. Genetic studies have identi fied mutations in two proteins involved in this water transport process, the V2 receptor and AQP2 water channels. Most patients (>90%) inherit NDI as an X-linke d recessive trait. In these patients, defects in the V2 receptor have been ident

ified. In the remaining patients, the disease is transmitted as either an autoso mal recessive or autosomal dominant trait involving mutations in the AQP2 gene [ 38,39]. ADH antidiuretic hormone; ATPadenosine triphosphate.

Renal Tubular Disorders 12.15 Urolithiases INHERITED CAUSES OF UROLITHIASES Disorder Cystinuria Dent's disease X-linked recessive nephrolithiasis X-linked recessive hy pophosphatemic rickets Hereditary renal hypouricemia Hypoxanthine-guanine phosph oribosyltransferase deficiency Xanthinuria Primary hyperoxaluria Stone characteristics Cystine Calcium-containing Calcium-containing Calcium-containing Uric acid, calc ium oxalate Uric acid Xanthine Calcium oxalate Treatment High fluid intake, urinary alkalization Sulfhydryl-containing drugs High fluid i ntake, urinary alkalization High fluid intake, urinary alkalization High fluid i ntake, urinary alkalization High fluid intake, urinary alkalization Allopurinol High fluid intake, urinary alkalization Allopurinol High fluid intake, dietary p urine restriction High fluid intake, dietary oxalate restriction Magnesium oxide , inorganic phosphates FIGURE 12-23 Urolithiases are a common urinary tract abnormality, afflicting 12% of men and 5% of women in North America and Europe [40]. Renal stone formation is most commonly associated with hypercalciuria. Perhaps in as many as 45% of th ese patients, there seems to be a familial predisposition. In comparison, a grou p of relatively rare disorders exists, each of which is transmitted as a Mendeli an trait and causes a variety of different crystal nephropathies. The most commo n of these disorders is cystinuria, which involves defective cystine and dibasic amino acid transport in the proximal tubule. Cystinuria is the leading single ge ne cause of inheritable urolithiasis in both children and adults [41,42]. Three Mendelian disorders, Dent's disease, X-linked recessive nephrolithiasis, and X-lin ked recessive hypophosphatemic rickets cause hypercalciuric urolithiasis. These disorders involve a functional loss of the renal chloride channel ClC-5 [43]. Th e common molecular basis for these three inherited kidney stone diseases has led to speculation that ClC-5 also may be involved in other renal tubular disorders associated with kidney stones. Hereditary renal hypouricemia is an inborn error of renal tubular transport that appears to involve urate reabsorption in the pr oximal tubule [16]. In addition to renal transport deficiencies, defects in meta bolic enzymes also can cause urolithiases. Inherited defects in the purine salva ge enzymes hypoxanthine-guanine phosphoribosyltransferase (HPRT) and adenine pho sphoribosyltransferase (APRT) or in the catabolic enzyme xanthine dehydrogenase (XDH) all can lead to stone formation [44]. Finally, defective enzymes in the ox alate metabolic pathway result in hyperoxaluria, oxalate stone formation, and co nsequent loss of renal function [45]. Acknowledgment The author thanks Dr. David G. Warnock for critically reviewing this manuscript. References 1. Wells R, Kanai Y, Pajor A, et al.: The cloning of a human cDNA with similarit y to the sodium/glucose cotransporter. Am J Physiol 1992, 263:F459F465. 2. Hedige r M, Coady M, Ikeda T, Wright E: Expression cloning and cDNA sequencing of the N a/glucose co-transporter. Nature 1987, 330:379381. 3. Woolf L, Goodwin B, Phelps C: Tm-limited renal tubular reabsorption and the genetics of renal glycosuria. J Theor Biol 1966, 11:1021. 4. Meuckler M: Facilitative glucose transporters. Euro J Biochem 1994, 219:713725. 5. Morris JR, Ives HE: Inherited disorders of the re nal tubule. In The Kidney. Edited by Brenner B, Rector F. Philadelphia: WB Saund

ers, 1996:17641827. 6. Kanai Y, Hediger M: Primary structure and functional chara cterization of a high affinity glutamate transporter. Nature 1992, 360:467471. 7. Oynagi K, Sogawa H, Minawi R,et al.: The mechanism of hyperammonemia in congeni tal lysinuria. J Pediatr 1979, 94:255. 8. Smith A, Strang L: An inborn error of metabolism with the urinary excretion of -hydroxybutric acid and phenyl-pyruvic acid. Arch Dis Child 1958, 33:109. 9. Rosenberg LE, Downing S, Durant JL, Segal S: Cystinuria: biochemical evidence for three genetically distinct diseases. J C lin Invest 1966, 45:365371. 10. Pras E, Arber N, Aksentijevich I, et al.: Localiz ation of a gene causing cystinuria to chromosome 2p. Nature Genet 1994, 6:415419. 11. Calonge MJ, Gasparini P, Chillaron J, et al.: Cystinuria caused by mutation s in rBAT, a gene involved in the transport of cystine. Nature Genet 1994, 6:4204 25. 12. Calonge M, Volpini V, Bisceglia L, et al.: Genetic heterogeneity in cyst inuria: the SLC3A1 gene is linked to type I but not to type III cystinuria. Proc Am Acad Sci USA 1995, 92:96679671.

12.16 Tubulointerstitial Disease 30. White P, Mune T, Rogerson F, et al.: 11- -hydroxysteroid dehydrogenase and i ts role in the syndrome of apparent mineralocorticoid excess. Pediatr Res 1997, 41:2529. 31. Yiu V, Dluhy R, Lifton R, Guay-Woodford L: Low peripheral plasma ren in activity as a critical marker in pediatric hypertension. Pediatr Nephrol 1997 , 11:343346. 32. Chang S, Grunder S, Hanukoglu A, et al.: Mutations in subunits o f the epithelial sodium channel cause salt wasting with hyperkalemic acidosis, p seudohypoaldosteronism type 1. Nature Genet 1996, 12:248253. 33. Kuhle U: Pseudoh ypoaldosteronism: mutation found, problem solved? Mol Cell Endocrinol 1997, 133: 7780. 34. Gordon R: Syndrome of hypertension and hyperkalemia with normal glomeru lar filtration rate. Hypertension 1986, 8:93102. 35. Mansfield T, Simon D, Farfel Z, et al.: Multilocus linkage of familial hyperkalaemia and hypertension, pseud ohypoaldosteronism type II, to chromosomes 1q31-42 and 17p11-q2. Nature Genet 19 97, 16:202205. 36. Robertson GL, et al: Development and clinical application of a new method for the radioimmunoassay of arginine vasopressin in human plasma. J Clin Invest 1973, 52:23402352. 37. Bichet D, Osche A, Rosenthal W: Congenital nep hrogenic diabetes insipidus. JASN 1997, 12:19511958. 38. van Lieburg A, Verdijk M , Knoers N, et al.: Patients with autosomal recessive nephrogenic diabetes insip idus homozygous for mutations in the aquaporin 2 water channel gene. Am J Hum Ge net 1994, 55:648652. 39. Bichet D, Arthus M-F, Lonergan M, et al.: Autosomal domi nant and autosomal recessive nephrogenic diabetes insipidus: novel mutations in the AQP2 gene. J Am Soc Nephrol 1995, 6:717A. 40. Coe F, Parks J, Asplin J: The pathogenesis and treatment of kidney stones. N Engl J Med 1992, 327:11411152. 41. Segal S, Thier S: Cystinuria. In The Metabolic and Molecular Bases of Inherited Diseases. Edited by Scriver CH, Beaudet AL, Sly WS, Valle D. York: McGraw-Hill; 1995:35813602. 42. Polinsky MS, Kaiser BA, Baluarte HJ: Urolithiasis in childhoo d. Pediatr Clin North Am 1987, 34:683710. 43. Lloyd S, Pearce S, Fisher S, et al. : A common molecular basis for three inherited kidney stone diseases. Nature 199 6, 379:445449. 44. Cameron J, Moro F, Simmonds H: Gout, uric acid and purine meta bolism in paediatric nephrology. Pediatr Nephrol 1993, 7:105118. 45. Danpure C, P urdue P: Primary Hyperoxaluria. In The Metabolic and Molecular Bases of Inherite d Diseases. Edited by Scriver CH, Beaudet AL, Sly WS, Valle D. New York: McGrawHill; 1995:23852424. 13. Wartenfeld R, Golomb E, Katz G, Bale S, et al.: Molecular analysis of cystin uria in Libyan Jews: exclusion of the SLC3A1 gene and mapping a new locus on 19q . Am J Med Genet 1997, 60:617624. 14. Stephens AD: Cystinuria and its treatment: 25 years' experience at St. Bartholomew's Hospital. J Inherited Metab Dis 1989, 12:1 97209. 15. Perazella M, Buller G: Successful treatment of cystinuria with captopr il. Am J Kidney Dis 1993, 21:504507. 16. Grieff M: New insights into X-linked hyp ophosphatemia. Curr Opin Nephrol Hypertens 1997, 6:1519. 17. Robertson GL: Vasopr essin in osmotic regulation in man. Annu Rev Med 1974, 25:315. 18. Econs M, Drez ner M: Tumor-induced osteomalacia: unveiling a new hormone. N Engl J Med 1994, 3 30:16791681. 19. The HYP Consortium: A gene (PEX) with homologies to endopeptidas es is mutated in patients with X-linked hypophosphatemic rickets. Nature Genet 1 995, 11:130136. 20. Bergeron M, Gougoux A, Vinay P: The renal Fanconi syndrome. I n The Metabolic and Molecular Bases of Inherited Diseases. Edited by Scriver CH, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill, 1995:36913704. 21. Sly W, Hu P: The carbonic anhydrase II deficiency syndrome: osteopetrosis with renal tubu lar acidosis and cerebral calcification. In The Metabolic and Molecular Bases of Inherited Diseases. Edited by Scriver CH, Beaudet AL, Sly WS, Valle D. New York : McGraw-Hill; 1965:35813602. 22. Bastani B, Gluck S: New insights into the patho genesis of distal renal tubular acidosis. Miner Electrolyte Metab 1996, 22:396409 . 23. Bruce L, Cope D, Jones G, et al.: Familial distal renal tubular acidosis i s associated with mutations in the red cell anion exchanger (band 3, AE1) gene. J Clin Invest 1997, 100:16931707. 24. Jarolim P, Shayakul C, Prabakaran D, et al. : Autosomal dominant distal renal tubular acidosis is associated in three famili es with heterozygosity for the R589H mutation in the AE1 (band 3) Cl-/HCO-3 exch

anger. J Biol Chem, 1998, 273:63806388. 25. Guay-Woodford L: Bartter syndrome: un raveling the pathophysiologic enigma. Am J Med, 1998, 105:151161. 26. Spiegel A, Weinstein L: Pseudohypoparathyroidism. In The Metabolic and Molecular Bases of I nherited Diseases. Edited by Scriver CH, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill; 1995:30733085. 27. Van Dop C: Pseudohypoparathyroidism: clinical and molecular aspects. Semin Nephrol 1989, 9:168178. 28. Lifton RP, Dluhy RG, Powers M., et al.: A chimaeric 11- -hydroxylase aldosterone synthase gene causes gluco corticoid-remediable aldosteronism and human hypertension. Nature 1992, 355:26226 5. 29. Shimkets RA, Warnock DG, Bositis CM, et al.: Liddle's syndrome: heritable h uman hypertension caused by mutations in the subunit of the epithelial sodium ch annel. Cell 1994, 79:407414.

The Kidney in Blood Pressure Regulation L. Gabriel Navar L. Lee Hamm D espite extensive animal and clinical experimentation, the mechanisms responsible for the normal regulation of arterial pressure and development of essential or primary hypertension remain unclear. One basic concept was championed by Guyton and other authors [14]: the long-term regulation of arterial pressure is intimate ly linked to the ability of the kidneys to excrete sufficient sodium chloride to maintain normal sodium balance, extracellular fluid volume, and blood volume at normotensive arterial pressures. Therefore, it is not surprising that renal dis ease is the most common cause of secondary hypertension. Furthermore, derangemen ts in renal function from subtle to overt are probably involved in the pathogene sis of most if not all cases of essential hypertension [5]. Evidence of generali zed microvascular disease may be causative of both hypertension and progressive renal insufficiency [5,6]. The interactions are complex because the kidneys are a major target for the detrimental consequences of uncontrolled hypertension. Wh en hypertension is left untreated, positive feedback interactions may occur that lead progressively to greater hypertension and additional renal injury. These i nteractions culminate in malignant hypertension, stroke, other sequelae, and dea th [7]. In normal persons, an increased intake of sodium chloride leads to appro priate adjustments in the activity of various humoral, neural, and paracrine mec hanisms. These mechanisms alter systemic and renal hemodynamics and increase sod ium excretion without increasing arterial pressure [3,8]. Regardless of the init iating factor, decreases in sodium excretory capability in the face of normal or increased sodium intake lead to chronic increases in extracellular fluid volume and blood volume. These increases can result in hypertension. When the derangem ents also include increased levels of humoral or neural factors that directly ca use vascular smooth muscle constriction, these effects increase peripheral vascu lar resistance or decrease vascular capacitance. Under these conditions the effe cts of subtle increases in blood volume are compounded because of increases in t he blood volume relative to CHAPTER 1

1.2 Hypertension and the Kidney extrinsic influences and intrarenal derangements can lead to reduced sodium excr etory capability. Many factors also exist that alter cardiac output, total perip heral resistance, and cardiovascular capacitance. Accordingly, hypertension is a multifactorial dysfunctional process that can be caused by a myriad of differen t conditions. These conditions range from stimulatory influences that inappropri ately enhance tubular sodium reabsorption to overt renal pathology, involving se vere reductions in filtering capacity by the renal glomeruli and associated mark ed reductions in sodium excretory capability. An understanding of the normal mec hanisms regulating sodium balance and how derangements lead to altered sodium ho meostasis and hypertension provides the basis for a rational approach to the tre atment of hypertension. the capacitance, often referred to as the effective blood volume. Through the me chanism of pressure natriuresis, however, the increases in arterial pressure inc rease renal sodium excretion, allowing restoration of sodium balance but at the expense of persistent elevations in arterial pressure [9]. In support of this ov erall concept, various studies have demonstrated strong relationships between ki dney disease and the incidence of hypertension. In addition, transplantation stu dies have shown that normotensive recipients from genetically hypertensive donor s have a higher likelihood of developing hypertension after transplantation [10] . This unifying concept has helped delineate the cardinal role of the kidneys in the normal regulation of arterial pressure as well as in the pathophysiology of hypertension. Many different 160 Aortic pressure, mm Hg Arterial pressure, mm Hg Isolated systolic hypertension (61 y) 120 80 Aortic blood flow, mL/s 400 0 Normotensive (56 y) 200 180 160 140 120 100 80 60 40 20 C A B HEMODYNAMIC DETERMINANTS For any vascular bed: Arterial pressure gradient Blood flow = Vascular resistanc e For total circulation averaged over time: Blood flow = cardiac output Therefor e, Arterial pressure - right atrial pressure Cardiac output = Total peripheral r esistance and: Mean arterial pressure = Cardiac output total peripheral resistan ce PP = 72 mm Hg PP = 40 mm Hg PP = 30 mm Hg A B 500

600 700 800 900 Arterial volume, mL FIGURE 1-1 Aortic distensibility. The cyclical pumping nature of the heart place s a heavy demand on the distensible characteristics of the aortic tree. A, Durin g systole, the aortic tree is rapidly filled in a fraction of a second, distendi ng it and increasing the hydraulic pressure. B, The distensibility characteristi cs of the arterial tree determine the pulse pressure (PP) in response to a speci fic stroke volume. The normal relationship is shown in curve A, and arrows desig nate the PP. A highly distensible arterial tree, as depicted in curve B, can acc ommodate the stroke volume with a smaller PP. Pathophysiologic processes and agi ng lead to decreases in aortic distensibility. These decreases lead to marked in creases in PP and overall mean arterial pressure for any given arterial volume, as shown in curve C. Decreased distensibility is partly responsible for the isol ated systolic hypertension often found in elderly persons. Recordings of actual aortic pressure and flow profiles in persons with normotension and systolic hype rtension are shown in panel A [11,12]. (Panel B Adapted from Vari and Navar [4] and Panel A from Nichols et al. [12].) FIGURE 1-2 Hemodynamic determinants of arterial pressure. During the diastolic p hase of the cardiac cycle, the elastic recoil characteristics of the arterial tr ee provide the kinetic energy that allows a continuous delivery of blood flow to the tissues. Blood flow is dependent on the arterial pressure gradient and tota l peripheral resistance. Under normal conditions the right atrial pressure is ne ar zero, and thus the arterial pressure is the pressure gradient. These relation ships apply for any instant in time and to timeintegrated averages when the mean pressure is used. The time-integrated average blood flow is the cardiac output that is normally 5 to 6 L/min for an adult of average weight (70 to 75 kg).

The Kidney in Blood Pressure Regulation 1.3 Dietary Insensible losses Urinary intake (skin, respiration, fecal) excretion + Net sodium and fluid balance ECF volume Arterial pressure Blood volume Interstitial fluid volume Arterial baroreflexes Atrial reflexes Renin-angiotensin-aldosterone Adrenal cate cholamines Vasopressin Natriuretic peptides Endothelial factors: nitric oxide, e ndothelin kallikrein-kinin system Prostaglandins and other eicosanoids (Autoregu lation) Total peripheral resistance Neurohumoral systems Mean circulatory pressure Venous return Cardiac output Cardiovascular capacitance Heart rate and contractility FIGURE 1-3 Volume determinants of arterial pressure. The two major determinants of arterial pressure, cardiac output and total peripheral resistance, are regula ted by a combination of short- and long-term mechanisms. Rapidly adjusting mecha nisms regulate peripheral vascular resistance, cardiovascular capacitance, and c ardiac performance. These mechanisms include the neural and humoral mechanisms l isted. On a long-term basis, cardiac output is determined by venous return, whic h is regulated primarily by the mean circulatory pressure. The mean circulatory pressure depends on blood volume and overall cardiovascular capacitance. Blood v olume is closely linked to extracellular fluid (ECF) volume and sodium balance, which are dependent on the integration of net intake and net losses [13]. (Adapt ed from Navar [3].) NaCl intake Antidiuretic hormone release If increased Concentrated urine: Increased free water reabsorption Thirst: Increased water in take 6 5 Blood volume, L 4 3 2 0 10 Edema Na+ and Cl Quantity of Extracellular concentrations fluid volume = NaCl in ECF in ECF volume + If decreased NaCl losses (urine insensible) Antidiuretic hormone inhibition

Decreased water intake Increased salt intake Dilute urine: Increased solute-free water excretion A B 15 Extracellular fluid volume, L 20 FIGURE 1-4 A, Relationship between net sodium balance and extracellular fluid (E CF) volume. Sodium balance is intimately linked to volume balance because of pow erful mechanisms that tightly regulate plasma and ECF osmolality. Sodium and its accompanying anions constitute the major contributors to ECF osmolality. The in tegration of sodium intake and losses establishes the net amount of sodium in th e body, which is compartmentalized primarily in the ECF volume. The quotient of these two parameters (sodium and volume) determines the sodium concentration and , thus, the osmolality. Osmolality is subject to very tight regulation by vasopr essin and other mechanisms. In particular, vasopressin is a very powerful regula tor of plasma osmolality; however, it achieves this regulation primarily by regu lating the relative solute-free water retention or excretion by the kidney [1315] . The important point is that the osmolality is rapidly regulated by adjusting t he ECF volume to the total solute present. Corrections of excesses in extracellu lar fluid volume involve more complex interactions that regulate the sodium excr etion rate. B, Relationship between the ECF volume and blood volume. Under normal conditions a consistent relationship exists between the total ECF volume and blood volume. This relationship is consistent as long as the plasma protein concentration and , thus, the colloid osmotic pressure are regulated appropriately and the microva sculature maintains its integrity in limiting protein leak into the interstitial compartment. The shaded area represents the normal operating range [13]. A chro nic increase in the total quantity of sodium chloride in the body leads to a chr onic increase in ECF volume, part of which is proportionately distributed to the blood volume compartment. When accumulation is excessive, disproportionate dist ribution to the interstitium may lead to edema. Chronic increases in blood volum e increase mean circulatory pressure (see Fig. 1-3) and lead to an increase in a rterial pressure. Therefore, the mechanisms regulating sodium balance are primar ily responsible for the chronic regulation of arterial pressure. (Panel B adapte d from Guyton and Hall [13].)

1.4 Hypertension and the Kidney Intrarenal Mechanisms Regulating Sodium Balance 6 Sodium excretion, normal 5 4 3 2 1 0 60 80 100 120 140 160 Renal arterial pres sure, mm Hg 180 200 Normal sodium intake Reduced 1 3 Elevated sodium intake 2 4 High sodium intake N ormal sodium intake Low sodium intake B A 5 C FIGURE 1-5 Arterial pressure and sodium excretion. In principle, sodium balance can be regulated by altering sodium intake or excretion by the kidney. However, intake is dependent on dietary preferences and usually is excessive because of t he abundant salt content of most foods. Therefore, regulation of sodium balance is achieved primarily by altering urinary sodium excretion. It is therefore of m ajor significance that, for any given set of conditions and neurohumoral environ ment, acute elevations in arterial pressure produce natriuresis, whereas reductions in arterial pressure cause antinatriuresis [9]. This phenomenon of pr essure natriuresis serves a critical role linking arterial pressure to sodium ba lance. Representative relationships between arterial pressure and sodium excreti on under conditions of normal, high, and low sodium intake are shown. When renal function is normal and responsive to sodium regulatory mechanisms, steady state sodium excretion rates are adjusted to match the intakes. These adjustments occ ur with minimal alterations in arterial pressure, as exemplified by going from p oint 1 on curve A to point 2 on curve B. Similarly, reductions in sodium intake stimulate sodiumretaining mechanisms that prevent serious losses, as exemplified by point 3 on curve C. When the regulatory mechanisms are operating appropriate ly, the kidneys have a large capability to rapidly adjust the slope of the press ure natriuresis relationship. In doing so, the kidneys readily handle sodium cha llenges with minimal long-term changes in extracellular fluid (ECF) volume or ar terial pressure. In contrast, when the kidney cannot readjust its pressure natri uresis curve or when it inadequately resets the relationship, the results are so dium retention, expansion of ECF volume, and increased arterial pressure. Failur e to appropriately reset the pressure natriuresis is illustrated by point 4 on c urve A and point 5 on curve C. When this occurs the increased arterial pressure directly influences sodium excretion, allowing balance between intake and excret ion to be reestablished but at higher arterial pressures. (Adapted from Navar [3 ].) Filtered sodium load, mol/min/g 150 100 50 0 100 Low Normal High Fractional sodium reabsorption, % 98 96 94 92 8 FIGURE 1-6 Intrarenal responses to changes in arterial pressure at different lev els of sodium intake. The renal autoregulation mechanism maintains the glomerula r filtration rate (GFR) during changes in arterial pressure, GFR, and filtered s odium load. These values do not change significantly during changes in arterial pressure or sodium intake [3,16]. Therefore, the changes in sodium excretion in

response to arterial pressure alterations are due primarily to changes in tubula r fractional reabsorption. Normal fractional sodium reabsorption is very high, r anging from 98% to 99%; however, it is reduced by increased sodium chloride inta ke to effect the large increases in the sodium excretion rate. These responses d emonstrate the importance of tubular reabsorptive mechanisms in modulating the s lope of the pressure natriuresis relationship. (Adapted from Navar and Majid [9] .) Fractional sodium excretion, % 6 4 2 0 75 100 125 150 175 Renal arterial pressure, mm Hg

The Kidney in Blood Pressure Regulation 1.5 RA pa=25 pB<1 PB=20 Pg=60 pe=37 EFP=9 GFR=Kf EFP pi=8 Pi=6 Tubular reabsorption Pc=20 RE pc=37 PCU=Kr ERP 15 25 RV FIGURE 1-7 Hemodynamic mechanisms regulating sodium excretion. Many different ne urohumoral mechanisms, paracrine factors, and drugs exist that can influence sod ium excretion and the pressure natriuresis relationship. These modulators may in fluence sodium excretion by altering changes in filtered load or changes in tubu lar reabsorption. Filtered load depends primarily on hemodynamic mechanisms that regulate the forces operating at the glomerulus. As shown, the glomerular filtr ation rate (GFR) is determined by the filtration coefficient (Kf) and the effect ive filtration pressure (EFP). The EFP is a distributed force determined by the glomerular pressure (Pg), the pressure in Bowman's space (PB), and the plasma coll oid osmotic pressure within the glomerular capillaries (p). The p increases progre ssively along the length of the glomerular capillaries as protein-free fluid is filtered such that filtra tion is greatest in the early segments of the glomerular capillaries, as designa ted by the large arrow. The glomerular forces, EFP, and blood flow are regulated by mechanisms that control the vascular smooth muscle tone of the afferent and efferent arterioles and of the intraglomerular mesangial cells. The filtration c oefficient also is subject to regulation by neural, humoral, and paracrine influ ences [17]. Changes in tubular reabsorption can result from alterations of vario us processes governing both active and passive transport along the nephron segme nts. Peritubular capillary uptake (PCU) of the tubular reabsorbate is mediated b y the net colloid osmotic pressure gradient (pc - pi). As a result of the filtration of protein-free filtrate, the plasma colloid osmotic pressure entering the peri tubular capillaries is markedly increased. Thus, the colloid osmotic gradient ex ceeds the outwardly directed hydrostatic pressure gradient (Pc - Pi). Appropriat e responses of one or more of these modulating mechanisms allow the kidneys to r espond rapidly and efficiently to changes in sodium chloride intake [3,17]. pBcoo id osmotic pressure in Bowman's space; pacooid osmotic pressure in initial parts o f glomerular cappillaries; pecooid osmotic pressure in terminal segments of glom erular capillaries; RAresistance of preglomerular arterioles; REefferent resistanc e; RVvenous resistance. (Adapted from Navar [3].) 0.6 0.4 0.2 0 20 15 10 5 0 5 RE RA Renal blood flow, mL/ming

Vascular resistance, mm Hgming/mL FIGURE 1-8 Renal autoregulatory mechanism. Because the glomerular filtration rat e (GFR) is so responsive to changes in the glomerular forces, highly efficient m echanisms have been developed to maintain a stable intrarenal hemodynamic enviro nment [16]. These powerful mechanisms adjust vascular smooth muscle tone in resp onse to various extrinsic disturbances. During changes in arterial pressure, ren al blood flow and the GFR are autoregulated with high efficiency as a consequenc e of adjustments in the vascular resistance of the preglomerular arterioles. Alt hough efferent resistance also can be regulated by other mechanisms, it does not participate significantly over most of the autoregulatory range. The GFR, filte red sodium load, and the intrarenal pressures are maintained stable in the face of various extrarenal disturbances by the autoregulatory mechanism. (Adapted fro m Navar [3].) Glomerular filtration rate, mL/ming 4 3 2 1 0 0 50 100 150 200 Renal arterial pressure, mm Hg

1.6 Arterial pressure Hypertension and the Kidney Plasma colloid Proximal tubular osmotic pressure and loop of Henle reabsorption Macula densa Glomerulotubular balance Collection pipette Wax blocking pipette Perfusion pipette Early distal tubule: flow-related changes in fluid composition Proximal tubule Glomerular pressure and plasma flow Glomerular filtration rate Proximal to distal tubule flow Distal tubule Preglomerular resistance Vascular effector (afferent arteriole) Macula densa: Sensor mechanism Transmitter A B vasoconstriction, whereas decreases in flow cause afferent vasodilation [16,18 ,19]. Blocking flow to the distal tubule or interrupting the feedback loop atten uates the autoregulatory efficiency of the glomerular filtration rate (GFR), glo merular pressure, and renal blood flow. B, Individual tubules can be blocked and perfused downstream, while collections are made or pressure measured in an earl y tubular segment. C, When the tubule is perfused at increased flows, the glomer ular pressure and GFR of that nephron decrease. The shaded area in the normal re lationship represents the normal operating level of the TGF mechanism. This mech anism helps stabilize the filtered load and the solute and sodium load to the di stal nephron segment. The responsiveness of the TGF mechanism is modulated by ch anges in sodium intake and in extracellular fluid (ECF) volume status. At high s odium intake and ECF volume expansion the sensitivity of the TGF mechanism is lo w, thus allowing greater spillover of salt to the distal nephron. During low sod ium intake and other conditions associated with ECF volume contraction, the sens itivity of the TGF mechanism is markedly increased to minimize spillover into th e distal nephron and maximize sodium retention. The hormonal and paracrine mecha nisms responsible for regulating TGF sensitivity are discussed subsequently. The myogenic mechanism is intrinsic to the vessel wall and responds to changes in w all tension to regulate vascular smooth muscle tone. Preglomerular arteries and afferent arterioles but not efferent arterioles exhibit myogenic responses to ch anges in wall tension [16,20]. The residual autoregulatory capacity that exists during blockade of the tubuloglomerular feedback mechanism indicates that the my ogenic mechanism contributes about half to the autoregulatory efficiency of the renal vasculature. (Figure adapted from Navar [3].) 40 30 Single nephron GFR, nL/min High sodium intake, ECF volume expansion 20 Normal 10

Low sodium intake Decreased ECF volume 0 0 10 C 20 30 Late proximal perfusion rate, nL/min 40 FIGURE 1-9 Tubuloglomerular feedback (TGF) and myogenic mechanisms. Two mechanis ms are responsible for efficient renal autoregulation: the TGF and myogenic mech anisms. The TGF mechanism is explained here. A, Increases in distal tubular flow past the macula densa generate signals from the macula densa cells to the affer ent arterioles to elicit

The Kidney in Blood Pressure Regulation Agents that increase cytosolic calcium: Angiotensin II, vasopressin, epinephrine (a), TXA2, leukotrienes, adenosine (A1), ATP, norepinephrine, endothelin VoltageR eceptoroperated operated channel 2+ Ca channel 2+ Ca 1.7 Chloride channel_ Cl + Calcium-activated potassium channel K+ Agents that increase cAMP (or cGMP): Epinephrine (b), PTH, PGI2, PGE2, ANP, dopami ne, nitric oxide, adenosine (A2) Ca2+ Ca2+ R Gq PLC Phosphoinositides Ca2+ DAG + IP3 Ca2+ SR PKC Calmodulin Ca2+-Cal MLCK A ctive MLCK MLC Phosphorylated MLCK (inactive) PKA cAMP cAMP Na+ Gi Gs Ad Cy R Phosphorylated MLC Actin Tension development Smooth muscle cell FIGURE 1-10 Cellular mechanisms of vascular smooth muscle contraction. The vascu lar resistances of different arteriolar segments are ultimately regulated by the contractile tone of the corresponding vascular smooth muscle cells. Shown are t he various membrane activation mechanisms and signal transduction events leading to a change in cytosolic calcium ions (Ca2+), cyclic AMP (cAMP), and phosphoryl ation of myosin light chain kinase. Many of the circulating hormones and paracri ne factors that increase or decrease vascular smooth muscle tone are identified. Ad Cyadenylate cyclase; ANPatrial natriuretic protein; Calcalm odulin; cGMPcyclic GMP; DAG1,2-diacylglycerol; Gq, Gi, GsG proteins; IP3inositol 1,4 ,5-triphosphate; MLCmyosin light chain; MLCKmyosin light chain kinase; PGE2prostagl andin E2; PGI2prostaglandin I2; PKAprotein kinase A; PKCprotein kinase C; PLCphospho lipase C; PTHparathyroid hormone; Rreceptor; SRsarcoplasmic reticulum; TXA2 thrombo xane A2. (Adapted from Navar et al. [16].) FIGURE 1-11 Differential activating mechanisms in afferent and efferent arteriol es. The relative contributions of the activation pathways are different in affer ent and efferent arterioles. Increases in cytosolic Ca2+ in afferent arterioles appear to be primarily by calcium ion (Ca2+) entry by way of receptor- and volta ge-dependent Ca2+ channels. The efferent arterioles are less dependent on voltag e-dependent Ca2+ channels. These differential mechanisms in the renal vasculatur e are exemplified by comparing the afferent and efferent arteriolar responses to angiotensin II before and after treatment with Ca2+ channel blockers. A, These experiments were done using the juxtamedullary nephron preparation that allows d irect visualization of the renal microcirculation [21]. AAafferent arteriole; ArAa rcuate artery; PCperitubular capillaries; Vvein; VRvasa recta. (Continued on next p age) A

1.8 Hypertension and the Kidney FIGURE 1-11 (Continued) B, Both afferent and efferent arterioles constrict in re sponse to angiotensin II [22]. Ca2+ channel blockers, dilate only the afferent a rterioles and prevents the afferent vasoconstriction responses to angiotensin II . In contrast, Ca2+ channel blockers do not significantly vasodilate efferent ar terioles and do not block the vasoconstrictor effects of angiotensin II. Thus, a fferent and efferent arterioles can be differentially regulated by various hormo nes and paracrine agents. (Panel A from Casellas and Navar [21]; panel B from Na var et al. [23].) 30 25 Diameter, Afferent arteriole Efferent arteriole 20 15 10 Control Ca2+ channel blockers 0.1 nM 10 nM 0.1 nM 10 nM B Control Angiotensin II Control Angiotensin II Smooth muscle cell Vasodilation Vasoconstriction EDHF NO PGI 2 Relaxing factors TXA2 EDCF PGF2a Endothelin Constricting factors ACE Angiotensin II Endothelial cell Angiotensin I Shear stress Bradykinin Platelet activating ATP-A DP Serotonin Leukotrienes factor Acetylcholine Thrombin Insulin Histamine FIGURE 1-12 Endothelial-derived factors. In addition to serving as a diffusion b arrier, the endothelial cells lining the vasculature participate actively in the regulation of vascular function. They do so by responding to various circulatin g hormones and physical stimuli and releasing paracrine agents that alter vascular smooth muscle tone and influence tubular tr ansport function. (Examples are shown.) Angiotensinconverting enzyme (ACE) is pr esent on endothelial cells and converts angiotensin I to angiotensin II. Nitric oxide is formed by nitric oxide synthase, which cleaves nitric oxide from L-argi nine. Nitric oxide diffuses from the endothelial cells to activate soluble guany late cyclase and increases cyclic GMP (cGMP) levels in vascular smooth muscle ce lls, thus causing vasodilation. Agents that can stimulate nitric oxide are shown . The relative amounts of the various factors released by endothelial cells depe

nd on the physiologic circumstances and pathophysiologic status. Thus, endotheli al cells can exert vasodilator or vasoconstrictor effects. At least one major in fluence participating in the normal regulation of vascular tone is nitric oxide. EDCFendothelial derived constrictor factor; EDHFendothelial derived hyperpolarizi ng factor; PGF2 prostaglandin F2 ; PGI2prostaglandin I2; TXA2 thromboxane A2. (Adap ted from Navar et al. [16].) Renal arterial pressure normal Shear stress Endothelial nitric oxide release Diffusion to tubules Vascular dilation but counteracted by autoregulation 3 2 1 Control NOS inhibition Epithelial cGMP Decreased sodium reabsorption Sodium excretion 50 75 100 125 150 Renal arterial pressure, mm Hg FIGURE 1-13 Nitric oxide in mediation of pressure natriuresis. Several recent st udies have demonstrated that nitric oxide also directly affects tubular sodium t ransport and may be an important mediator of the changes induced by arterial pre ssure in sodium excretion, as described in Figure 1-5 [9,24]. Increases in arter iolar shear stress caused by increases in arterial pressure stimulate production of nitric oxide. Nitric oxide may exert direct effects to inhibit tubule sodium reabsorptive mechanisms and may elicit vasodilatory actions. Nitric oxide incre ases intracellular cyclic GMP (cGMP) in tubular cells, which leads to a reduced reabsorption rate through cGMP-sensitive sodium entry pathways [24,25]. When for mation of nitric oxide is blocked by agents that prevent nitric oxide synthase a ctivity, sodium excretion is reduced and the pressure natriuresis relationship i s markedly suppressed. Thus, nitric oxide may exert a critical role in the regul ation of arterial pressure by influencing vascular tone throughout the cardiovas cular system and by serving as a mediator of the changes induced by the arterial pressure in tubular sodium reabsorption. (Adapted from Navar [3].) Sodium excretion,

The Kidney in Blood Pressure Regulation 1.9 PCT 60% DCT 7% CCD PST 2% 3% TALH 30% OMCD DLH ALH IMCD < 1% Filtered NA+ load = Plasma Na Glomerular filtration rate = 140 mEq/L 0.120 L/min = 16.8 mEq/min 1440 min/d = 24,192 mEq/min Urinary Na+ excretion = 200 mEq /d Fractional Na excretion = 0.83% Fractional Na reabsorption = 99.17% FIGURE 1-14 Tubular transport processes. Sodium excretion is the difference betw een the very high filtered load and net tubular reabsorption rate such that, und er normal conditions less than 1% of the filtered sodium load is excreted. The p ercentage of reabsorption of the filtered load occurring in each nephron segment is shown. The end result is that normally less than 1% of the filtered load is excreted; however, the exact excretion rate can be changed by many mechanisms. D espite the lesser absolute sodium reabsorption in the distal nephron segments, t he latter segments are critical for final regulation of sodium excretion. Theref ore, any factor that changes the delicate balance existing between the hemodynam ically determined filtered load and the tubular reabsorption rate can lead to ma rked alterations in sodium excretion. ALHthin ascending limb of the loop of Henle ; CCDcortical collecting duct; DCTdistal convoluted tubule; DLHthin descending limb of the loop of Henle; IMCDinner medullary collecting duct; OMCDouter medullary co llecting duct; PCTproximal convoluted tubule; PSTproximal straight tubule; TALHthic k ascending limb of the loop of Henle. Peritubular capillary Lateral intercellular P space p () Na K Na Active transcellular [K ] + Na K K Cells Paracellular (passive) Na+ () [Na+] Tubule lumen FIGURE 1-15 Proximal tubule reabsorptive mechanisms. The proximal tubule is resp

onsible for reabsorption of 60% to 70% of the filtered load of sodium. Reabsorpt ion is accomplished by a combination of both active and passive transport mechan isms that reabsorb sodium and other solutes from the lumen into the lateral spac es and interstitial compartment. The major driving force for this reabsorption i s the basolateral sodium-potassium ATPase (Na+-K+ ATPase) that transports Na+ ou t of the proximal tubule cells in exchange for K+. As in most cells, this mainta ins a low intracellular Na+ concentration and a high intracellular K+ concentrat ion. The low intracellular Na+ concentration, along with the negative intracellu lar electrical potential, creates the electrochemical gradient that drives most of the apical transport mechanisms. In the late proximal tubule, a lumen to inte rstitial chloride concentration gradient drives additional net solute transport. The net solute transport establishes a small osmotic imbalance that drives tran stubular water flow through both transcellular and paracellular pathways. In the tubule, water and solutes are reabsorbed isotonically (water and solute in equi valent proportions). The reabsorbed solutes and water are then further reabsorbe d from the lateral and interstitial spaces into the peritubular capillaries by t he colloid osmotic pressure, which establishes a predominant reabsorptive force as discussed in Figure 1-7. Ptranscapillary hydrostatic pressure gradient; ptransca iary colloid osmotic pressure gradient.

1.10 Hypertension and the Kidney pathways across the apical membrane may include a coupled sodium chloride entry step or chloride anion exchange that is coupled with sodium-hydrogen exchange. M ajor transport pathways at the basolateral membrane include the ubiquitous and p reeminent sodium-potassium ATPase (Na+-K+ ATPase) that creates the major driving force. The other major pathway is a sodium-bicarbonate transport system that tr ansports the equivalent of one sodium ion coupled with the equivalent of three b icarbonate ions (HCO-3). Because this transporter transports two net charges out the electrically negative cell, membrane voltage partially drives this transpor t pathway. A basolateral sodium-calcium exchanger is important in regulating cel l calcium. Not shown are several other pathways that predominantly transport pro tons or other ions and organic substrates. Several major regulatory factors are listed. Lumen Proximal tubule cells Regulation of reabsorption _ Na+ Glucose ATP 3Na+ 2 K+ Na+ _ HCO3 CO3 Ca2+ ADP Na+ H+ Anion _ _ Stimulation Angiotensin II Adrenergic agents or increased renal nerve activity I ncreased luminal flow or solute delivery Increased filtration fraction Inhibitio n Volume expansion (via increased backleak) Atrial natriuretic peptide Dopamine Increased interstitial pressure Cl _ 3Na+ FIGURE 1-16 Major transport pathways across proximal tubule cells. At the apical membrane, sodium is transported in conjunction with organic solutes (such as gl ucose, amino acids, and citrate) and inorganic anions (such as phosphate and sul fate). The major mechanism for sodium entry into the cells is sodium-hydrogen ex change (the isoform NHE3). Chloride transport Lumen Furosemide Cell _ K+ or NH4+ +10mv K+ Na+ H+ 2ClNa Thick ascending limb cells ATP ADP CI _ Regulation of reabsorbtion Stimulation Antidiuretic hormone 3Na+ b-adreneric agen ts 2 K+ Mineralocorticoids Inhibition Hypertonicity Prostaglandin E2 Acidosis Ca lcium

FIGURE 1-17 Sodium transport mechanisms in the thick ascending limb of the loop of Henle. The major sodium chloride reabsorptive mechanism in the thick ascendin g limb at the apical membrane is the sodiumpotassium-chloride cotransporter. Thi s electroneutral transporter is inhibited by furosemide and other loop diuretics and is stimulated by a variety of factors. Potassium is recycled across the api cal membrane into the lumen, creating a positive voltage in the lumen. An apical sodium-hydrogen exchanger also exists that may function to reabsorb some sodium bicarbonate. The sodium-potassium ATPase (Na+-K+ ATPase) at the basolateral mem brane again is the driving force. The basolateral chloride channel and possibly other chloride cotransporters are important in mediating chloride efflux across the basolateral membrane. Sodium and chloride are reabsorbed without water in th is segment because water is impermeable across the apical membrane of the thick ascending limb. Thus, the tubular fluid osmolality in this nephron segment is hy potonic.

The Kidney in Blood Pressure Regulation 1.11 Thiazides _ Na _ Cl Na+ Amiloride _ Distal tubule and connecting tubule cells ATP 3Na+ 2 K+ ADP FIGURE 1-18 Mechanisms of sodium chloride reabsorption in the distal tubule. The distal convoluted tubule and subsequent connecting tubule have a variety of sod ium transport mechanisms. The distal tubule has predominantly a sodium chloride cotransporter, which is inhibited by thiazide diuretics. In the connecting tubul e, sodium channels and a sodium-hydrogen exchange mechanism also are present. Am iloride inhibits sodium channel activity. Again the sodium-potassium ATPase (Na+ -K+ ATPase) on the basolateral membrane provides most of the driving force for s odium reabsorption. Na+ H+ Collecting duct principal cell Lumen Cell ATP Regulation of reabsorbtion Stimulation Aldosterone 3Na+ Antidiuretic hormone 2 K+ Inhibition Prostaglandins Nitric oxide Atrial natriuretic peptide Bradykin in Na+_ 2CI K+ (IMCD) Na+ _ Amiloride K+ ADP FIGURE 1-19 Mechanism of sodium chloride reabsorption in collecting duct cells. Sodium transport in the collecting duct is mainly via amiloridesensitive sodium channels in the apical membrane. Some evidence for other mechanisms such as an e lectroneutral sodium-chloride cotransport mechanism and a different sodium chann el also has been reported. Again, the basolateral sodium-potassium ATPase (Na+-K + ATPase) creates the driving force for overall sodium transport. There are some differences between the cortical collecting duct and the deeper inner medullary collecting duct (IMCD). In the cortical collecting duct, sodium transport occur s in the predominant principal cell type interspersed between acid-base transpor ting intercalated cells. The principal cell also is an important site of potassi um secretion by way of apical potassium channels and water transport via antidiu retic sensitive water channels. Regulation of sodium channels may involve either insertion (from subapical compartments) or activation of preexisting sodium cha nnels.

1.12 Hypertension and the Kidney Systemic Factors Regulating Arterial Pressure and Sodium Excretion Medulla NTS Baroreceptor firing rate, impulses/s Normal I Resetting Glossopharyngeal nerve Afferents Carotid sinus Efferents NA DN P Bulbospinal pathway epinephrine 100 Arterial pressure, mm Hg Arterial pressure Vagus nerve Atrial receptors Aortic arch Heart rate Preganglionic sympathetics (acetylcholine) Postganglionic Sympathetics Vascular smooth muscle TPR Norepinephrine Kidney RBF GFR -Reabsorption Na+ excretion Adrenal medulla Epinephrine FIGURE 1-20 Neural and sympathetic influences. The neural reflexes serve as the principal mechanisms for the rapid regulation of arterial pressure. The neural r eflexes also exert a long-term role by influencing sodium excretion. The pathway s and effectors of the arterial baroreflex and atrial pressure-volume reflex are depicted. The arrows indicate increased or decreased activity in response to an acute reduction in arterial pressure which is sensed by the baroreceptors in th e aortic arch and carotid sinus. The insert depicts the relationship between the arterial blood pressure and baroreflex primary afferent firing rate. At the nor mal level of mean arterial pressure of approximately 100 mm Hg, the sensitivity ( I/ P) is set at the maximum level. After chronic resetting of the baroreceptor s, the peak sensitivity and threshold of activation are shifted to a higher leve l of arterial pressure. The cardiovascular reflexes involve high-pressure arteri al receptors in the aortic arch and carotid sinus and low-pressure atrial recept ors. In response to decreases in arterial pressure or vascular volume, increased sympathetic stimulation participates in shortterm control of arterial pressure. This increased stimulation does so by enhancing cardiac performance and stimulating vascular smooth muscle tone, leading to increased total peripheral resistance and decreased capacitance. The direct effects of the sympathetic nervous system on kidney function lead to dec reased sodium excretion caused by decreases in filtered load and increases in tu bular reabsorption [26]. The decreases in the glomerular filtration rate (GFR) a nd filtered sodium load are due to increases in both afferent and efferent arter iolar resistances and to decreases in the filtration coefficient (see Fig. 1-7). Sympathetic activation also enhances proximal sodium reabsorption by stimulatin g the sodium-hydrogen (Na+-H+) exchanger mechanism (see Fig. 1-16) and by increa

sing the net chloride reabsorption by the thick ascending limb of the loop of He nle. The indirect effects include stimulation of renin secretion and angiotensin II formation, which, as discussed next, also stimulates tubular reabsorption. Ic hange in impulse firing; Pchange in pressure; DNdorsal motor nucleus; NAnucleus amb iguous; NTSnucleus tractus solitarii; RBFrenal blood flow; TPRtotal peripheral resi stance. (Adapted from Vari and Navar [4].)

The Kidney in Blood Pressure Regulation 1.13 Angiotensinogen Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Val-Tyr-Ser-R Renin NaCl intake Arterial pressure ECF volume Stress trauma Angiotensin I Asp-Arg-Val -Tyr-Ile-His-Pro-Phe-His-Leu Angiotensinconverting enzyme, chymase (heart) Angio tensin II Juxtaglomerular apparatus Cytosolic Ca2+ cAMP Renin release Asp-Arg-Va l-Tyr-Ile-His-Pro-Phe Angiotensinases Macula densa mechanism Baroreceptor mechanism Sympathetic nervous system Metabolites Angiotensin (17) Angiotensin (28) Angiotensin (38) Inactive fragments AT1, AT2, AT? Receptor binding and Biologic actions FIGURE 1-21 Renin-angiotensin system. The renin-angiotensin system serves as one of the most powerful regulators of arterial pressure and sodium balance. In res ponse to various stimuli that compromise blood volume, extracellular fluid (ECF) volume, or arterial pressureor those associated with stress and traumathree major mechanisms are activated. These mechanisms stimulate renin release by the cells of the juxtaglomerular apparatus that act on angiotensinogen to form angiotensi n I. Angiotensinogen is an 2 globulin formed primarily in the liver and to a les ser extent by the kidney. Angiotensin I is a decapeptide that is rapidly convert ed by angiotensin-converting enzyme (ACE) and to a lesser extent by chymase (in the heart) to angiotensin II, an octapeptide. Recent studies have indicated that other angiotensin metabolites such as angiotensin (28), angiotensin (17), and ang iotensin (38) have biologic actions. Angiotensin II and/or active metabolites Adrenal cortex Kidney Intestine Central nervous system Peripheral nervous system Vascular smooth muscle Heart Growth factors Aldosterone Distal nephron reabsorption Vasoconstriction transport effects Adrenergic facilitation Sympathetic discharge Thirst, salt appetite Vasopressin release Water reabsorption Vasoconstriction Contractility Proliferation Proximal and distal sodium + water Reabsorption by intestine Maintain or increas e extracellular fluid volume Total peripheral resistance

Cardiac output Hypertrophy FIGURE 1-22 Multiple actions of angiotensin. Angiotensin II and some of the othe r angiotensin II metabolites have a myriad of actions on many different vascular beds and organ systems. Angiotensin II exerts short- and long-term actions, inc luding vasoconstriction and stimulation of aldosterone release. Angiotensin II a lso interacts with the sympathetic nervous system by facilitating adrenergic transmi ssion and has long-term actions on vascular smooth muscle proliferation by inter acting with growth factors. Angiotensin II exerts several important effects on t he kidney that contribute to sodium conservation. (Adapted from Navar [3].)

1.14 Hypertension and the Kidney Enhance proximal tubular reabsorption PT BS Decrease Kf GC FIGURE 1-23 Angiotensin II actions on renal hemodynamics. Systemic and intrarena l angiotensin II exert powerful vasoconstrictive actions on the kidney to decrea se renal blood flow and sodium excretion. At the level of the glomerulus, angiot ensin II is a vasoconstrictor of both afferent (AA) and efferent arterioles (EA) and decreases the filtration coefficient Kf. Angiotensin II also directly inhib its renin release by the juxtaglomerular apparatus. Increased intrarenal angiote nsin II also is responsible for the increased sensitivity of the tubuloglomerula r feedback mechanism that occurs with decreased sodium chloride intake (see Fig. 1-9) [17,27,28]. BSBowman's space; GCglomerular capillaries; PCperitubular capillari es; PTproximal tubule; TALthick ascending limb; TGFtubuloglomerular feedback mechan ism. (Adapted from Arendshorst and Navar [17].) EA Inhibit renin release PC Efferent arteriolar vasoconstriction Afferent arteriolar vasoconstriction TAL Increased sensitivity of TGF mechanism AA Angiotensin Angiotensin G PLA _ + cAMP _ + H+ Tubule lumen Na+ HCO3 Na+ _ K+ Na+ FIGURE 1-24 Angiotensin II actions on tubular transport. Angiotensin II receptor s are located on both the luminal and basolateral membranes of the proximal and distal nephron segments. The proximal effect has been studied most extensively. Activation of angiotensin II-AT1 receptors leads to increased activities of the

sodium-hydrogen (Na+-H+) exchanger and the sodium-bicarbonate (Na+-HCO-3) cotran sporter. These increased activities lead to augmented volume reabsorption. Highe r angiotensin II concentrations can inhibit the tubular sodium reabsorption rate ; however, the main physiologic role of angiotensin II is to enhance the reabsor ption rate [28]. cAMPcyclic AMP; GG protein; PLAphospholipase A. (Adapted from Mitc hell and Navar [28].)

The Kidney in Blood Pressure Regulation 1.15 A. SYNERGISTIC RENAL ACTIONS OF ANGIOTENSIN II Enhancement of proximal reabsorption rate Stimulation of apical amiloride-sensit ive Na-H exchanger Stimulation of basolateral Na-HCO3 cotransporter Sustained ch anges in distal volume and sodium delivery Increased sensitivity of afferent art eriole to signals from macula densa cells Reabsorption 60 Proximal SNGFR Glomerular pressure, mm Hg 55 50 45 40 35 30 0 Distal delivery Proximal reabsorption 60 SNGFR Glomerular pressure, mm Hg 55 50 45 40 35 30 0 B 10 20 30 End proximal fluid flow, nL/min 40 Distal delivery C 10 20 30 End proximal fluid flow, nL/min 40 FIGURE 1-25 AC, Synergistic effects of angiotensin II on proximal reabsorption an d tubuloglomerular feedback mechanisms. The actions of angiotensin II on proxima l nephron reabsorption and the ability of angiotensin II to enhance the sensitiv ity of the tubuloglomerular feedback (TGF) mechanism prevent a compensatory incr ease in glomerular filtration rate caused by the reduced distal tubular flow. Th ese actions allow elevated angiotensin II levels to exert a sustained reduction in sodium delivery to the distal nephron segment. This effect is shown here by t he shift of operating levels to a lower proximal fluid flow under the influence of elevated angiotensin II [27]. The effects of angiotensin II to enhance TGF se nsitivity allow the glomerular pressure (GP) and nephron filtration rate to be m aintained at a reduced distal volume delivery rate that would occur as a consequ ence of the angiotensin II effects on reabsorption. SNGFRsingle nephron glomerula r filtration rate. (Panels B and C adapted from Mitchell et al. [27].) FIGURE 126 Effects of aldosterone on distal nephron sodium reabsorption. A, Mechanism of action of aldosterone. Angiotensin II also is a very powerful regulator of aldo sterone release by the adrenal gland. The increased aldosterone levels synergize with the direct effects of angiotensin II to enhance distal tubule sodium reabs orption. Aldosterone increases sodium reabsorption and potassium secretion in th e distal segments of the nephron by binding to the cytoplasmic mineralocorticoid receptor (MR). On binding, the receptor complex migrates to the nucleus where i t induces transcription of a variety of messenger RNAs (mRNAs). The mRNAs encode for proteins that stimulate sodium reabsorption by increasing sodium-potassium ATPase (Na+-K+ ATPase) protein and activity at basolateral membranes, increasing mitochondrial ATP formation, and increasing the sodium and potassium channels a t the luminal membrane [29]. Growing evidence also exists for nongenomic actions of aldosterone to activate sodium entry pathways such as the amiloride-sensitiv e sodium channel [30]. (Continued on next page) Lumen

Principal cell Mitochondria ATP Na+ Proteins mRNA ADP 3Na+ 2 K+ K+ Nucleus MR Aldosterone _ Spironolactone A

1.16 14 12 Filtered sodium remaining, % 10 8 6 4 2 0 0 Hypertension and the Kidney FIGURE 1-26 (Continued) B, The net effect of aldosterone is to stimulate sodium reabsorption along the distal nephron segment, decreasing the remaining sodium t o only 2% or 3% of the filtered load. The direct action of aldosterone can be bl ocked by drugs such as spironolactone that bind directly to the mineralocorticoi d receptor. Aldosterone blockade Normal 20 B 40 60 Distal nephron length, % 80 100 Lumen Principal cell Mitochondria ATP Na+ 3Na+ 2 K+ Proteins ADP mRNA MR Nucleus Cortisone K+ Aldosterone Cortisol II-b_OHSD defect or glycyrrhizic acid or carbenoxolone FIGURE 1-27 Syndrome of apparent mineralocorticoid excess and hypertension. Aldo sterone increases sodium reabsorption and potassium secretion in the distal segm ents of the nephron by binding to the cytoplasmic mineralocorticoid receptor (MR ). Cortisol, the glucocorticoid that circulates in plasma at much higher concent rations than does aldosterone, also binds to MR. However, cortisol normally is p revented from this by the action of 11- -hydroxysteroid dehydrogenase (11-OHSD), which metabolizes cortisol to cortisone in mineralocorticoid-sensitive cells. A deficiency or defect in this enzyme has been found to be responsible for a rare form of hypertension in persons with the hereditary syndrome of apparent minera locorticoid excess. In these persons, cortisol binds to the MR receptor, causing sodium retention and hypertension [31]. This enzyme also is blocked by glycyrrh izic acid (in some forms of licorice) and carbenoxolone. The diuretic spironolac tone acting by way of inhibition of MR is able to block this excessive action of cortisol on the MR receptor. Lumen Principal cell

Mitochondria ATP Na+ Proteins mRNA ADP 3Na+ 2K+ Primary hyperaldosteronism Adrenal enzymatic disorder Adenoma Glucortic oid-remediable aldosteronism Aldosterone K+ Nucleus MR FIGURE 1-28 Hyperaldosteronism and glucocorticoid-remediable aldosteronism. Hype rtension can result from increased aldosterone or from increases in other closel y related steroids derived from abnormal adrenal metabolism (11- -hydroxylase de ficiency and 17- hydroxylase deficiency). The most common cause is an aldosteron e-producing adenoma; bilateral hyperplasia of the adrenal zona glomerulosa is th e next most common cause. In glucocorticoid-remediable aldosteronism, a DNA cros sover mutation results in a chimeric gene in which aldosterone production is reg ulated by adrenocorticotropic hormone (ACTH). Increases in aldosterone also can result secondarily from any state of increased renin such as renal artery stenos is, which leads to increased circulating concentrations of angiotensin II and st imulation of aldosterone release [31]. MRmineralocorticoid receptor; mRNAmessenger RNA.

The Kidney in Blood Pressure Regulation 1.17 Lumen Cell Liddle's syndrome d d Na+ pp pp pp ATP ADP K+ b b 3Na+ 2 K+ a a Liddles syndrome FIGURE 1-29 Excess epithelial sodium channel activity in Liddle's syndrome. The ep ithelial sodium channel responsible for sodium reabsorption in much of the dista l portions of the nephron is a complex of three homologous subunits, , , and eac h with two membrane-spanning domains. Liddle's syndrome, an autosomal dominant dis order causing low renin-aldosterone hypertension often with hypokalemia, results from mutated or subunits. These mutations increase the sodium reabsorptive rate by way of these channels by keeping them open longer, increasing sodium channel density on the membranes, or both. The specific problem appears to reside with proline (P)-rich domains in the carboxyl terminal region of or that are involved in regulation of the channel membrane localization or activity. The net result is excess sodium reabsorption and a reduced capability to increase sodium excret ion in response to volume expansion [31,32]. Extracellular fluid volume Blood volume Na Cl Intrathoracic blood volume Atrial stretch receptors Gitleman's syndrome Na+ Sodium excretion Aldosterone Renin Tubular sodium reabsorption Atrial natriuretic peptide B L Na+2Cl _ Cl K+ K+ Pseudohypoaldosteronism Vascular resistance Vasodilation

Bartter's syndrome FIGURE 1-30 Syndromes of diminished sodium reabsorption and hypotension. Recentl y, a variety of syndromes associated with salt wasting, and usually hypotension, have been attributed to specific molecular defects in the distal nephron. Bartt er's syndrome, which usually is accompanied by metabolic alkalosis and hypokalemia , has been found to be associated with at least three separate defects (the thre e transporters shown) in the thick ascending limb. These defects are at the leve l of the sodium-potassium-2chloride (Na+-K+-2Cl-) cotransporter, apical potassiu m channel, and basolateral chloride channel (see Fig. 1-17). Malfunction in any of these three proteins results in diminished sodium chloride reabsorption simil ar to that occurring with administration of loop diuretics. Gitelman's syndrome, w hich was originally described as a variant of Bartter's syndrome, represents a def ect in the sodium chloride cotransport mechanism in the distal tubule. Pseudohyp oaldosteronism results from a defect in the apical sodium channels in the collec ting ducts. In contrast to Bartter's and Gitelman's syndromes, hyperkalemia may be p resent. These rare disorders illustrate that defects in sodium chloride reabsorp tive mechanisms can result in abnormally low blood pressure as a consequence of excessive sodium excretion in the urine. Although these conditions are rare, sim ilar but more subtle defects of the heterozygous state may contribute to protect ion from hypertension in some persons [31]. Bbasolateral side; Llumen of tubule. FIGURE 1-31 Atrial natriuretic peptide (ANP). In response to increased intravasc ular volume, atrial distention stimulates the release of ANP from the atrial gra nules where the precursor is stored. Extracellular fluid volume expansion is ass ociated with increased ANP levels, whereas reductions in vascular volume and deh ydration elicit decreases in plasma ANP levels. ANP participates in arterial pre ssure regulation by sensing the degree of vascular volume expansion and exerting direct vasodilator actions and natriuretic effects. ANP has been shown to marke dly increase the slope of the pressure natriuresis relationship (see Figs. 1-5 a nd 1-6). The vasorelaxant and transport actions are mediated by stimulation of m embrane-bound guanylate cyclase, leading to increased cyclic GMP levels. ANP als o inhibits renin release, which reduces circulating angiotensin II levels [3335]. Related peptides, such as brain natriuretic peptides, have similar effects on s odium excretion and renin release [36].

1.18 Hypertension and the Kidney States of volume depletion and hypoperfusion stimulate prostaglandin synthesis [ 16,17,38]. The vasodilator prostaglandins attenuate the influence of vasoconstri ctor substances during activation of the renin-angiotensin system, sympathetic n ervous system, or both [33]. These prostaglandins also have transport effects on renal tubules through activation of distinct prostaglandin receptors [40]. In s ome pathophysiologic conditions, enhanced production of TXA2 and other vasoconst rictor prostanoids may occur. The vasoconstriction induced by TXA2 appears to be mediated primarily by calcium influx [17,40]. Leukotrienes are hydroperoxy fatt y acid products of 5-hydroperoxyeicosatetraenoic acid (HPETE) that are synthesiz ed by way of the lipoxygenase pathway. Leukotrienes are released in inflammatory and immunologic reactions and have been shown to stimulate renin release. The c ytochrome P450 monooxygenases produce several vasoactive agents [16,37,41,42] us ually referred to as EETs and hydroxy-eicosatetraenoic acids (HETEs). These subs tances exert actions on vascular smooth muscle and epithelial tissues [16,41,42] . (Adapted from Navar [3].) Membrane phospholipids Phospholipase A2 COOH Arachidonic acid Cytochrome P450 monooxygenases EETs (vasodilation ) HETEs (vaso constriction) Cyclooxygenase Endoperoxides Lipoxygenases HPETEs Leukotrienes (vasoconstriction) PGI2/PGE2 (vasodilation, natriuresis) TXA2/PGH2 (vasoconstriction) HETEs Lipoxins FIGURE 1-32 Arachidonic acid metabolites. Several eicosanoids (arachidonic acid metabolites) are released locally and exert both vasoconstrictor and vasodilator effects as well as effects on tubular transport [16,37]. Phospholipase A2 catal yzes formation of arachidonic acid (an unsaturated 20-carbon fatty acid) from me mbrane phospholipids. The cyclooxygenase pathway and various prostaglandin synth etases are responsible for the formation of endoperoxides (PGH2), prostaglandins E2 (PGE2) and I2 (PGI2), and thromboxane (TXA2) [38,39]. Kallikrein-kinin system Low molecular weight kininogen Tissue kallikrein Bradyki nin Kininase I Des Arg-bradykinin Kininase II (ACE) NEP Kinin degradation produc ts B2-receptor Endothelium-dependent Nitric oxide PGE2 Vasodilation natriuresis High molecular weight kininogen Plasma kallikrein B1-receptor FIGURE 1-33 Kallikrein-kinin system. Plasma and tissue kallikreins are functiona lly different serine protease enzymes that act on kininogens (inactive 2 glycopr oteins) to form the biologically active kinins (bradykinin and lysyl-bradykinin [kallidin]). Kidney kallikrein and kininogen are localized in the distal convolu ted and cortical collecting tubules. Release of kallikrein into the tubular flui d and interstitium can be stimulated by prostaglandins, mineralocorticoids, angi otensin II, and diuretics. B1 and B2 are the two major bradykinin receptors that exert most of the vascular actions. Although glomerulus and distal nephron segm ents contain both B1 and B2 receptors, most of the renal vascular and tubular ef fects appear to be mediated by B2-receptor activation [16,17,43,44]. Bradykinin

and kallidin elicit vasodilation and stimulate nitric oxide, prostaglandin E2 (P GE2) and I2 (PGI2), and renin release [45,46]. Kinins are inactivated by the sam e enzyme that converts angiotensin I to angiotensin II, angiotensin-converting e nzyme (ACE). The kallikrein-kinin system is stimulated by sodium depletion, indi cating it serves as a mechanism to dampen or offset the effects of enhanced angi otensin II levels [47,48]. Des Arg bradykinin; NEPneutral endopeptidase.

The Kidney in Blood Pressure Regulation 1.19 10 Plasma vasopressin, pg/mL 8 6 4 2 0 260 Decreased ECF volume Normal ECF volume Increased ECF volume 280 300 320 Plasma osmolality, mOsm/kg 340 FIGURE 1-34 Vasopressin. Vasopressin is synthesized by the paraventricular and s upraoptic nuclei of the hypothalamus. Vasopressin is stored in the posterior pit uitary gland and released in response to osmotic or volume-dependent barorecepto r stimuli, or both. Atrial filling inhibits vasopressin release. Increases in pl asma osmolality increase vasopressin release; however, the relationship is shift ed by the status of extracellular fluid (ECF) volume, with decreases in the ECF volume increasing the sensitivity of the relationship. Stress and trauma also in crease vasopressin release [15]. Therefore, when ECF volume and blood volume are diminished, vasopressin is released to help guard against additional losses of body fluids. (Adapted from Navar [8].) Collecting duct principal cell Plasma membrane ATP cAMP + PPi Protein kinase A GTP Tubule lumen Adenylate cyclase GTP Ga G Ga G V2 Circulating vasopressin GDP H 2O Aquaporin 2 water channels Aquaporin 2 FIGURE 1-35 Vasopressin receptors. Vasopressin exerts its cellular actions throu gh two major receptors. Activation of V1 receptors leads to vascular smooth musc le constriction and increases peripheral resistance. Vasopressin stimulates inos itol 1,4,5-triphosphate and calcium ion (Ca2+) mobilization from cytosolic store s and also increases Ca2+ entry from extracellular stores as shown in Figure 1-1 0. The vasoconstrictive action of vasopressin helps increase total peripheral re sistance and reduces medullary blood flow, which enhances the concentrating abil ity of the kidney. V2 receptors are located primarily on the basolateral side of the principal cells in the collecting duct segment. Vasopressin activates heter otrimeric G proteins that activate adenylate cyclase, thus increasing cyclic AMP levels. Cyclic AMP (cAMP) activates protein kinase A, which increases the densi ty of water channels in the luminal membrane. Water channels (aquaporin proteins ) reside in subapical vesicles and on activation fuse with the apical membrane. Thus, vasopressin markedly increases the water permeability of the collecting du ct and allows conservation of fluid and excretion of a concentrated urine. An in tact vasopressin system is essential for the normal regulation of urine concentr ation by the kidney that, in turn, is the major mechanism for coupling the solut e to solvent ratio (osmolality) of the extracellular fluid. As discussed in Figu

re 1-4, this tight coupling allows the confluence of homeostatic mechanisms regu lating sodium balance with those regulating extracellular fluid volume. G and Gpr oteins; PPi inorganic pyrophosphate. (Adapted from Vari and Navar [4].)

1.20 Hypertension and the Kidney Hypertensinogenic Process Initial increase in vascular resistance Neurogenic or humoral stimuli Vasoconstr ictor effects Renal volume retention Effective blood volume Initial increase in volume Volume Cardiac output Tissue blood flow Autoregulatory resistance adjustments Capacitance Increased vascular resistance Increased arterial blood pressure FIGURE 1-36 Overview of mechanisms mediating hypertension. From a pathophysiolog ic perspective, the development of hypertension requires either a sustained abso lute or relative overexpansion of the blood volume, reduction of the capacitance of the cardiovascular system, or both [4,49,50]. One type of hypertension is du e primarily to overexpansion of either the actual or the effective blood volume compartment. In such a condition of volume-dependent hypertension, either one or more of the physiologic mechanisms described in this chapter fails to respond appropriately to intravascular expansion or some pathophysiologic pr ocess causes excess production of one or more sodium-retaining factors such as m ineralocorticoids or angiotensin II [51,52]. Through mechanisms delineated earli er, overexpansion leads to increased cardiac output that results in overperfusio n of tissues; the resultant autoregulatory-induced increases in peripheral resis tance contribute further to an increase in total peripheral resistance and eleva ted arterial pressure [2,53,54]. Hypertension also can be initiated by excess va soconstrictor influences that directly increase peripheral resistance, decrease cardiovascular capacitance, or both. Examples of this type of hypertension are e nhanced activation of the sympathetic nervous system and overproduction of catec holamines such as that occurring with a pheochromocytoma [45,54,55]. When hypert ension caused by a vasoconstrictor influence persists, however, it must also exe rt significant renal vasoconstrictor and sodium-retaining actions. Without a ren al effect the elevated arterial pressure would cause pressure natriuresis, leadi ng to a compensatory reduction in extracellular fluid volume and intravascular v olume. Thus, the elevated systemic arterial pressure would not be sustained [2,8 ,54]. Derangements that activate both a vasoconstrictor system and produce sodiu m-retaining effects, such as inappropriate elevations in the activity of the ren in-angiotensin-aldosterone system, lead to an even more powerful hypertensinogen ic mechanism that is not easily counteracted [27]. These dual mechanisms are why the reninangiotensin system has such a critical role in the cause of many forms of hypertension, leaving only the option to increase arterial pressure and elic it a pressure natriuresis. (Adapted from Navar [3].) 180 Mean arterial pressure, mm Hg 160 140 120 100 80 14 12 10 8 6 4 2 0 Aldosterone Renal perfusion pressure Reduce renal perfusion pressure Angiotensin II + Aldosterone Angiotensin II + Aldosterone Aldosterone 0 1 2 3 4 Reduced renal pressure, d 5 FIGURE 1-37 Predominance of the renin-angiotensin-aldosterone mechanisms. Collec

tively, the various mechanisms discussed provide overlapping influences responsi ble for the highly efficient regulation of sodium balance, extracellular fluid ( ECF) volume, blood volume, and arterial pressure. Nevertheless, the synergistic actions of the renin-angiotensin-aldosterone system on both vasoconstrictor as w ell as sodium-retaining mechanisms exert a particularly powerful influence that is not easily counteracted. In a recent study by Seeliger and coworkers [56], re nal perfusion pressure was lowered to 90 to 95 mm Hg. The angiotensin II and ald osterone levels were not allowed to decrease and were fixed at normal levels by continuous infusions. The results demonstrated that all compensatory mechanisms (such as increased release of atrial natriuretic peptide and reduced activity of the sympathetic system) could not overcome the hypertensinogenic influence of m aintained aldosterone or aldosterone plus angiotensin II as long as renal perfus ion pressure was not allowed to increase. Thus, under conditions of increased ac tivity of the renin-angiotensin system, an increased renal arterial pressure see ms essential to reestablish sodium balance. In conclusion, regardless of the spe cific intrarenal mechanism involved, the net effect of a long-term hypertensinog enic derangement is a reduced capability for sodium excretion at normotensive ar terial pressures that cannot be completely compensated by other neural, humoral, or paracrine mechanisms, leaving only the option to increase arterial pressure and elicit a pressure natriuresis. (Adapted from Seeliger et al. [56].) Cumulative sodium balance, mmol/kg BW

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1.22 Hypertension and the Kidney 53. Coleman TG, Guyton AC: Hypertension caused by salt loading in the dog. Circ Res 1969, XXV:153160. 54. Guyton AC, Hall JE, Coleman TG, et al.: The dominant ro le of the kidneys in long-term arterial pressure regulation in normal and hypert ensive states. In Hypertension: Pathophysiology, Diagnosis, and Management, edn 2. Edited by Laragh JH, Brenner BM. New York: Raven Press; 1995, 78:13111326. 55. Julius S, Nesbitt S: Sympathetic overactivity in hypertension: a moving target. Am J Hypertens 1996, 9:113S120S. 56. Seeliger E, Boemke W, Corea M, et al.: Mech anisms compensating Na and water retention induced by long-term reduction of ren al perfusion pressure. Am J Physiol (Regulat Integrative Comp Physiol 42) 1997, 273:R646R654. 48. Siragy HM: Evidence that intrarenal bradykinin plays a role in regulation of renal function. Am J Physiol (Endocrinol Metab28) 1993, 265:E648E654. 49. Ploth DW, Navar LG: Physiologic control of arterial blood pressure and mechanisms of h ypertension. In Clinical Approaches to High Blood Pressure in the Young. Edited by Kotchen TA, Kotchen JM. Boston: John Wright, PSG; 1983:2378. 50. Guyton AC, Ma nning RA, Normon RA, et al.: Current concepts and perspectives of renal volume r egulation in relationship to hypertension. J Hypertens 1986, 4(suppl 4):S49S56. 5 1. DeWardener HE: The primary role of the kidney and salt intake in the aetiolog y of essential hypertension: part II. Clin Sci 1990, 79:289297. 52. Hamlyn JM, Bl austein MP: Sodium chloride, extracellular fluid volume, and blood pressure regu lation. Am J Physiol (Renal Fluid Electrolyte Physiol 20) 1986, 251:F563F575.

Renal Parenchymal Disease and Hypertension Stephen C. Textor H ypertension and parenchymal disease of the kidney are closely interrelated. Most primary renal diseases eventually disturb sodium and volume control sufficientl y to produce clinical hypertension. Both on theoretical and practical grounds, m any authors argue that any sustained elevation of blood pressure depends ultimat ely on disturbed renal sodium excretion, ie, altered pressure natriuresis. Hence , some investigators argue that a clinical state of hypertension represents de f acto evidence of disturbed (or reset) renal function even before changes in glomer ular filtration can be measured. Many renal insults further induce inappropriate activation of vasoactive systems such as the renin-angiotensin system, adrenerg ic sympathetic nerve traffic, and endothelin. These mechanisms may both enhance vasoconstriction and act as mediators of additional tissue injury by altering th e activity of inflammatory cytokines and promoters of interstitial fibrosis. Art erial hypertension itself accelerates many forms of renal disease and hastens th e progression to advanced renal failure. Recent studies have firmly established the importance of blood pressure reduction as a means to slow the progression of many forms of renal parenchymal injury, particularly those characterized by mas sive proteinuria. Over the long term, damage to the heart and cardiovascular sys tem resulting from hypertension represents the major causes of morbidity and mor tality for patients with end-stage renal disease. Here are illustrated the roles of renal parenchymal disease in sustaining hypertension and of arterial pressur e reduction in slowing the progression of renal injury. As discussed, parenchyma l renal disease may refer to either unilateral (uncommon) or bilateral condition s. CHAPTER 2

2.2 Hypertension and the Kidney FIGURE 2-1 Forms of unilateral renal parenchymal diseases related to hypertensio n. Many unilateral abnormalities, such as congenital malformations, renal agenes is, reflux nephropathy, and stone disease, do not commonly produce hypertension. However, some unilateral lesions can produce blood pressure elevation. Data for each of these are based primarily on demonstrating unilateral secretion of reni n and resolution with unilateral nephrectomy. It should be emphasized that unila teral renal disease does not reduce the overall glomerular filtration rate beyon d that expected in patients with a solitary kidney. It follows that additional r eductions in the glomerular filtration rate must reflect bilateral renal injury. FORMS OF UNILATERAL RENAL PARENCHYMAL DISEASE RELATED TO HYPERTENSION Renal artery stenosis Atherosclerosis and fibromuscular lesions (Chapter X) Smal l vessel disease Vasculitis Atheroembolic renal infarction Thrombosis and infarc tion Traumatic injury Renal fracture Perirenal fibrosis (Page kidney) Radiation in jury Arteriovenous malformation or fistulas Other diseases Renal carcinoma Enlar ging renal cyst Multiple renal cysts Renin-secreting tumors (rare) FIGURE 2-2 Angiogram and nephrogram of a persistent fractured kidney. The kidney damage shown here produced hypertension in a young woman 2 years after a motor vehicle accident. Measurement of renal vein renins confirmed unilateral producti on of renin from the affected side. Blood pressure control was achieved with blo ckade of the renin-angiotensin system using an angiotensin II receptor antagonis t (losartan). Many traumatic injuries to the kidney produce temporary hypertensi on when a border of viable but underperfused renal tissue remains. Prevalence of Hypertension in Chronic Renal Disease 80 Prevalence of hypertension, % 70 60 50 40 30 20 10 0 CIN APKD MCN IgA MGN DN MPGN FSGN FIGURE 2-3 Prevalence of hypertension in chronic renal parenchymal disease. Most forms of renal disease are associated with hypertension. This association is mo st evident with glomerular diseases, including diabetic nephropathy (DN) and mem branoproliferative glomerulonephritis (MPGN), in which 70% to 80% of patients ar e affected. Minimal change nephropathy (MCN) is a notable exception. Tubulointer stitial disorders such as analgesic nephropathy, medullary cystic diseases, and chronic reflux nephropathies are less commonly affected. APKDadult-onset polycyst ic kidney disease; CINchronic interstitial nephritis; FSGNfocal segmental glomerul onephritis; MGN membranous glomerulonephritis. (Data from Smith and Dunn [1].)

Renal Parenchymal Disease and Hypertension 2.3 100 90 Mean GFR=39 mL/min/1.73 m2 *n=255 patients Mean GFR=18.5 mL/min/1.73 m2 80 70 60 % 50 40 30 20 10 0 MDRD: Study B* MDRD: Study A NHANES estimates FIGURE 2-4 Prevalence of hypertension requiring therapy as a function of the deg ree of chronic renal failure in the Modification of Diet in Renal Disease (MDRD) trial on progressive renal failure. The mean age of these patients was 52 years , with glomerular disease (25%) and polycystic disease (24%) being the most comm on renal diagnoses in this trial. In Study B, more than 90% of patients were tre ated with antihypertensive agents, including diuretics, to achieve an overall av erage blood pressure of 133/81 mm Hg. In general, the more severe the level of r enal dysfunction, the more antihypertensive therapy is required to achieve accep table blood pressures. Patients with glomerular filtration rates (GRFs) below 10 mL/min were hypertensive in 95% of cases. NHANESNational Health and Nutrition Ex amination Survey. (Data from Klahr and coworkers [2].) US Population 80 Prevalence of hypertension, % 70 60 50 40 30 20 10 0 Acute GN Acute IN Early Late FIGURE 2-5 Hypertension in acute renal disease. Acute renal failure is defined a s transient increases in serum creatinine above 5.0 mg/dL. During the course of acute renal failure, worsening of preexisting levels or newly detected hypertens ion (>140/90 mm Hg) is common and almost universally observed in patients with a cute glomerulonephritis (GN). Many of these patients have lower pressures as the course of acute renal injury subsides, although residual abnormalities in renal function and sediment may remain. Blood pressure returns to normal in some but not all of these patients. Overall, 39% of patients with acute renal failure dev elop new hypertension. INinterstitial nephritis. (Adapted from RodriguezIturbe an d coworkers [3]; with permission.) FIGURE 2-6 (see Color Plate) Micrograph of an onion skin lesion from a patient w ith malignant hypertension.

2.4 Hypertension and the Kidney Pathophysiology of Hypertension in Renal Disease x FIGURE 2-7 Pathophysiologic mechanisms related to hypertension in parenchymal re nal disease: schematic view of candidate mechanisms. The balance between cardiac output and systemic vascular resistance determines blood pressure. Numerous stu dies suggest that cardiac output is normal or elevated, whereas overall extracel lular fluid volume is expanded in most patients with chronic renal failure. Syst emic vascular resistance is inappropriately elevated relative to cardiac output, reflecting a net shift in vascular control toward vasoconstricting mechanisms. Several mechanisms affecting vascular tone are disturbed in patients with chroni c renal failure, including increased adrenergic tone and activation of the renin angiotensin system, endothelin, and vasoactive prostaglandins. An additional fea ture in some disorders appears to depend on reduced vasodilation, such as in imp aired production of nitric oxide. Blood pressure = Cardiac output Systemic vascular resistance Increased extracellular fluid volume Decreased glomerular filtration rate Impair ed sodium excretion Increased renal nerve activity Ineffective natriuresis, eg, atrial natriuretic peptide resistance Increased contraction Increased adrenergic activation Increased vasoconstriction Increased adrenergic stimuli Inappropriate renin-endo thelin release Increased endothelin-derived contracting factor Increased thrombo xane Decreased vasodilation Decreased prostacyclin Decreased nitric oxide 7 Intake and output of water and salt (x normal) Intake and output of water and salt (x normal) 6 5 4 3 Normal D 7 kid G o ld ne blat t ys Al do ste ron e-s tim ula ted 6 5 4 3 2 1 0 Normal intake Low intake A H B High intake E s se n hyp tial erte nsio n Normal High intake F G 2 1 0 0 50 Normal intake Low intake

A C B ss ma al ren of ss D Lo C E A 100 150 Arterial pressure, mm Hg 200 0 50 B 100 150 Arterial pressure, mm Hg 200 FIGURE 2-8 A, The relationship between renal artery perfusion pressure and sodiu m excretion (which defines pressure natriuresis) has been the subject of extensive research. Essential hypertension is characterized by higher renal perfusion pre ssures required to achieve daily sodium balance. B, Distortion of this relations hip routinely occurs in patients with parenchymal renal disease, illustrated her e as loss of renal mass. Similar effects are observed in conditions with disturbed h ormonal effects on sodium excretion (aldosterone-stimulated kidneys) or reduced renal blood flow as a result of an arterial stenosis (Goldblatt kidneys). In all o f these instances, higher arterial pressures are required to maintain sodium bal ance.

Renal Parenchymal Disease and Hypertension 200 Percentage of body weight, kg Total blood volume, mL/cm 130 Hemodialysis 2.5 40 Cumulative daily sodium intake 0 Cumulative urinary sodium loss 126 35 400 Sodium, mEq 800 122 30 118 F 10.0 S S M T W TH Days F S S M Sodium losses during hemodialysis or ultrafiltration Net sodium loss 1200 1600 Plasma renin activity, mg/mL/h 5.0 Uremic control subjects Total net loss of sodium=1741 mEq F S S M T B W TH F Days S S M T Blood pressure, mm Hg 180

Captopril, 25 mg 140 A 100 FIGURE 2-9 Sodium expansion in chronic renal failure. The degree of sodium expan sion in patients with chronic renal failure can be difficult to ascertain. A, Sh own are data regarding body weight, plasma renin activity, and blood pressure (before and after administration of an ACE inhibito r) over 11 days of vigorous fluid ultrafiltration. Sequential steps were underta ken to achieve net negative sodium and volume losses by means of restricting sod ium intake (10 mEq/d) and initiating ultrafiltration to achieve several liters o f negative balance with each treatment. A negative balance of nearly 1700 mEq wa s required before evidence of achieving dry weight was observed, specifically a reduction of blood pressure. Measured levels of plasma renin activity gradually increased during sodium removal, and blood pressure became dependent on the reni n-angiotensin system, as defined by a reduction in blood pressure after administ ration of the angiotensin-converting enzyme inhibitor captopril. Achieving adequ ate reduction of both extracellular fluid volume and sodium is essential to sati sfactory control of blood pressure in patients with renal failure. B, Daily and cumulative sodium balance. Plasma renin Cumulative sodium balance, mEq activity, ng/mL/hr Blood pressure, mm Hg Angiotensin II inhibitor, g/kg/min 5 10 50 100 10 10 Saline infusion L40 200 150 100 200 FIGURE 2-10 Interaction between sodium balance and angiotensin-dependence in mal ignant hypertension. Studies in a patient with renal dysfunction and accelerated hypertension during blockade of the renin-angiotensin system using Sar-1-ala-8angiotensin II demonstrate the interaction between angiotensin and sodium. Reduc tion of blood pressure induced by the angiotensin II antagonist was reversed dur ing saline infusion with a positive sodium balance and reduction in circulating plasma renin activity. Administration of a loop diuretic (L40 [furosemide], 40 m g intravenously) induced net sodium losses, restimulated plasma renin activity, and restored sensitivity to the angiotensin II antagonist. Such observations fur ther establish the reciprocal relationship between the sodium status and activat ion of the renin-angiotensin system [5]. (From Brunner and coworkers [5]; with p ermission.) 100 0 100 50 0 0 1 11 35 38 41 Hours 65 67

2.6 Hypertension and the Kidney FIGURE 2-11 A, Sympathetic neural activation in chronic renal disease. Adrenergi c activity is disturbed in chronic renal failure and may participate in the deve lopment of hypertension. Microneurographic studies in patients undergoing hemodi alysis demonstrate enhanced neural traffic (panel A) that relates closely to per ipheral vascular tone [6]. Studies in patients in whom native kidneys are remove d by nephrectomy demonstrate normal levels of neural traffic, suggesting that af ferent stimuli from the kidney modulate central adrenergic outflow. B, Delayed o nset hypertension in denervated rats. Panel B shows evidence from experimental s tudies in denervated animals subjected to deoxycorticosteronesalt hypertension. T he role of the renal nerves in modifying the development of hypertension is supp orted by studies of renal denervation that show a delayed onset of hypertension, although no alteration in the final level of blood pressure was achieved. NSnot significant. (Panel A from Converse and coworkers [6]; with permission. Panel B from Katholi and coworkers [7]; with permission.) 15 s Normal person Hemodialysis, bilateral nephrectomy Hemodialysis, no nephrectomy Neurogram Electrocardiogram A 3s 200 Systolic blood pressure, mm Hg 190 180 170 160 150 140 130 120 110 NS Sham Renal denervated NS <0.01 <0.001 <0.001 <0.01 <0.05 <0.05 <0.05 NS 0 B 5 10 15 20 25 30 Deoxycorticosterone acetatesalt administration, d 35

Renal Parenchymal Disease and Hypertension 2.7 MAJOR CANDIDATE MECHANISMS THAT MAY ELEVATE PERIPHERAL VASCULAR RESISTANCE IN RE NAL PARENCHYMAL DISEASE Increased vasoconstrictors Renin-angiotensin system Endothelin Prostanoids: thromboxane Arginine vasopressi n Endogenous digitalis-like substance: ouabain (?) Impaired or relatively inadequate vasodilators Nitric oxide: inadequate compensation Vasodilator prostaglandins: prostacyclin 2 Natriuretic peptides: atrial natriuretic peptide Kallikrein-kinin system FIGURE 2-12 Major candidate mechanisms that may elevate peripheral vascular resi stance in renal parenchymal disease. Some data support each of these pathways, a lthough rarely does one mechanism predominate. Experimental studies suggest that endothelin-1 may magnify interstitial fibrosis and contribute to hypertension i n some models; however, rarely is the effect major [8,9]. Most levels of vasodil ators, including nitric oxide, prostacyclin, and atrial natriuretic peptide, are normal or elevated in patients with renal disease. The vasodilators appear to b uffer the vasoconstrictive actions of angiotensin II, which may be increased abr uptly if the vasodilator is removed, as occurs with inhibition of cyclo-oxygenas e with the use of nonsteroidal antiinflammatory drugs. Sham-operated rats Rats with renal mass reduction 80 Urinary endothelin, ng/d 60 40 Urinary endothelin excretion, pg/d Mean SEM *P<0.01 vs pretransplantation P<0.01 vs normal subjects 200 160 120 80 40 0 Horizontal bars=mean values P<0.01 vs basal * * * 20 0 Normal A Pretransplantation 12 mo 24 mo B Basal

Day 45 Basal Day 45 FIGURE 2-13 Urinary endothelin in renal disease. A, Urinary endothelin levels in patients with cyclosporine-induced renal dysfunction and hypertension before an d after liver transplantation. These patients had near-normal kidney function be fore liver transplantation, after which their glomerular filtration rates decrea sed from 85 to 55 mL/min, on average. These data underscore the observation that the kidney itself is a rich source of vasoactive materials and that renal excre tion of substances such as endothelin is independent of circulating blood levels [10]. Endothelin has properties that both facilitate vasoconstriction and enhan ce mitogenic and fibrogenic responses, perhaps accelerating interstitial fibrosi s in the kidney. Early withdrawal of cyclosporine leads to reversal of a diminished glomerular filtration rate. With time, however, these changes lose th e feature of reversibility [11]. B, Renal ablation. Urinary endothelin levels in rats exposed to reduced renal mass achieved by 5/6 nephrectomy. As in humans, p lasma levels of endothelin were dissociated from urinary levels, and injected en dothelin was not excreted. These results suggest that urinary levels were of ren al origin. These studies further support the concept that the diminished nephron number elicits production of potent vasoactive and inflammatory materials that may accelerate irreversible parenchymal injury. (Panel A from Textor and coworke rs [10]; with permission. Data in panel B from Benigni and coworkers [12].)

2.8 Hypertension and the Kidney Renal parenchymal disease PHARMACOLOGIC AGENTS THAT COMMONLY AGGRAVATE OR INDUCE HYPERTENSION IN PARENCHYM AL RENAL DISEASE Increased cytokine Increased growth factors Cellular proliferation Corticosteroi ds Cyclosporine Erythropoietin Nonsteroidal anti-inflammatory drugs Decreased afferent resistance Decreased efferent resistance Impaired autoregulat ion Increased angiotensin Increased norepinephrine Increased endothelin Systemic hyp ertension Other agents Over-the-counter sympathomimetic agents, eg, phenylpropanolamine Supplements con taining ephedrine Oral contraceptives (less common with low-dose forms) Amphetam ines and stimulants, eg, methylphenidate hydrochloride and cocaine Increased glomerular pressure Increased glomerular volume Increased glomerular pressure FIGURE 2-14 Mechanisms of glomerular injury in hypertension and progressive rena l failure. This schematic diagram summarizes the general mechanisms by which dis turbances linked to elevated arterial pressure in patients with parenchymal rena l disease may lead to further tissue injury. Hemodynamic changes lead to increas ed glomerular perfusion pressures, whereas local activation of growth factors, a ngiotensin, and probably several other factors both worsen peripheral resistance and increase tissue fibrotic mechanisms. (From Smith and Dunn [1].) FIGURE 2-15 Many pharmacologic agents affect blood pressure levels or the effect iveness of antihypertensive therapy. Shown here are several agents that commonly lead to worsening hypertension and are likely to be administered to patients wi th renal disease. Mean arterial pressure, mL/min Blood pressure, mm Hg 160 150 140 130 120 110 * * 120 90 60 30 1 min * * * Control 10 g LNAME 50 g LNAME Heart rate, bpm 280 240 200 L-NAME L-Arginine

Renal plasma flow, mL/min 4.0 3.0 2.0 1.0 1.2 1.0 0.8 Control 60' 120' * * * * * * * * Results=meansstandard error *P<0.05 compared with controls A 100 mg kg-1 300 mg kg-1 * * FIGURE 2-16 Increase in arterial pressure induced by inhibition of nitric oxide. A, Intra-arterial pressure in rabbits during N-nitro-L-arginine methyl ester (L -NAME) infusion. B, Decrease in renal plasma flow and glomerular filtration rate in the blood pressures of rats during nitric oxide inhibition. (Continued on ne xt page) Glomerular filtration rate, mL/min * B 180'

Renal Parenchymal Disease and Hypertension 2.9 21 Urinary sodium excretion, Eq/min 19 17 15 13 11 9 140 Urinary flow rate, mL/mi n 120 100 80 Control 10 g/kg/min L NAME 50 g/kg/min L NAME * * * Results=meansstandard error *P<0.05 compared with controls * FIGURE 2-16 (Continued) C, Urine flow rate and urinary sodium excretion over tim e. Inhibition of nitric oxide synthesis from L-arginine by a competitive substra te such as L-NAME produces dose-dependent and widespread vasoconstriction, leadi ng to an increase in blood pressure [13]. Within specific regional beds such as the kidney, inhibition of nitric oxide produces a decrease in renal plasma flow, diminished glomerular filtration, and sodium retention [14]. The magnitude of t hese changes in normal animals and humans suggests that tonic nitric oxide produ ction is a major endothelial buffering mechanism preserving vascular tone. The d egree to which renal parenchymal disease alters the production of nitric oxide i s not known precisely. In some situations, such as nephrotoxicity associated wit h cyclosporine administration, endothelial production of nitric oxide appears to be substantially impaired [15]. (Panel A from Rees and coworkers [13]; with per mission. Panel B from Lahera and coworkers [14]; with permission.) * 60 C Control 60' 120' 180' Clinical Features of Hypertension in Renal Disease A. HYPERTENSION IN PARENCHYMAL RENAL DISEASE: CLINICAL MANIFESTATIONS OF HYPERTE NSIVE DISEASE Cardiovascular disease Myocardial infarction Congestive heart failure Atherosclerotic vascular disease Claudication and limb ischemia Aneurysm 100 90 80 70 60 50 40 30 20 10 0 Cardiac Vascular Infection Other Central nervous system Stroke Intracerebral hemorrhage Progressive renal injury End-stage renal disease Increased proteinuria B FIGURE 2-17 A and B, Major target organ manifestations of hypertension produci ng cardiovascular morbidity and mortality in patients with renal disease. More t han half of deaths are related to cardiovascular disease in both patients on dia

lysis and transplantation recipients. These observations underscore the major ri sk for cardiovascular morbidity and mortality associated with hypertension in th e population with chronic renal failure. (From Whitworth [16]; with permission.) Percentage of total Transplantation Dialysis

2.10 Hypertension and the Kidney Blood pressure Left ventricular hypertrophy Congestive heart failure Percentage of total 40 35 30 25 20 15 10 5 Blood pressure Death: Congestive heart failure Overall mortality A FIGURE 2-18 Based on average blood pressure values, a strong direct relationsh ip was found between arterial pressure and left ventricular hypertrophy, left ve ntricular chamber dilation (by echocardiography), and systolic dysfunction in pa tients undergoing dialysis for end-stage renal disease. After prolonged follow-u p, blood pressures fell with the onset of congestive heart failure and manifest coronary artery disease. With the onset of cardiac failure, there appeared to be an inverse relationship between arterial pressure and mortality. From the outse t, the strongest predictor of congestive heart failure was elevated blood pressu re. (Adapted from Foley and coworkers [17].) B 0 Left ventricular Systolic Left ventricular chamber dilation dysfunction hypert rophy 250 Awake: 156/101 mm Hg Nocturnal: 167/100 mm Hg 200 Blood pressure values Heart rate 150 140 100 90 50 MMMM Rx F d MMMM Fd ZZZZZ Rx RxZZZ ZZZZZZZZZZZZZZZZZZ MMMM 0 0.0 10a 12n 2p 4p 6p 8p 10p 12m Real time data 2a 4a 6a 8a FIGURE 2-19 Around-the-clock ambulatory blood pressure monitoring in a patient w ith renal disease. Loss of diurnal blood pressure patterns have been implicated in increased rates of target organ injury in patients with hypertension. In norm al persons with essential hypertension, nocturnal pressures decreased by at leas t 10% and were associated with a decrease in heart rate. Several conditions have been associated with a loss of the nocturnal decrease in pressure, particularly chronic steroid administration and chronic renal failure. Such a loss in normal circadian rhythm, in particular loss of the nocturnal decrease in blood pressur e is more commonly associated with left ventricular hypertrophy and lacunar stro kes (manifested as enhanced T-2 signals in magnetic resonance images) and increa sed rates of microalbuminuria. Data from a single subject with end-stage renal d isease studied with are depicted here. Blood pressure, mm Hg

Renal Parenchymal Disease and Hypertension 2.11 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 May 1979 Feb 1982 Nov 1984 Aug 1987 May 1990 Date Jan 1993 Oct 1995 Jul 1998 A FIGURE 2-20 (see Color Plate) Hypertension accelerates the rate of progressive r enal failure in patients with parenchymal renal disease. A, Photomicrograph of m alignant phase hypertension. Regardless of the cause of renal disease, untreated hypertension leads to more rapid loss of remaining nephrons and decline in glom erular filtration rates. A striking example of pressure-related injury may be ob served in patients with malignant phase hypertension. This image is an open biop sy specimen obtained from a patient with papilledema, an expanding aortic aneury sm, and B blood pressure level at approximately 240/130 mm Hg. The biopsy specimen shows t he following features of malignant nephrosclerosis: these patients develop vascu lar and glomerular injury, which can progress to irreversible renal failure. Bef ore the introduction of antihypertensive drug therapy, patients with malignant p hase hypertension routinely proceeded to uremia. Effective antihypertensive ther apy can slow or reverse this trend in some but not all patients. B, Progressive renal failure in malignant hypertension over 8 years. 1/Creatinine 0.12 0.10 Proportion with ESRD 0.08 0.06 165<SBP180 n=11,912 men P<0.001 100 SBP>180 White=300,645 Black=20,222 83.1 Incidence per 100,000 person-years, % 80 N=332,544 men 60 40 27.34 26.18 14.22 5.41 9.1 37.21 32.37 0.04 0.02 SBP165 20 5.43 15.83 0.00 0 1 2 0 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Years from beginning therapy to ESRD <11 7 A

B 117123 124130 131140 Systolic blood pressure, mm Hg >140 FIGURE 2-21 Blood pressure levels and rates of end-stage renal disease (ESRD). A , Line graph showing Kaplan-Meier estimates of ESRD rates; 15-year follow-up. B, Age-adjusted 16-year incidence of all-cause ESRD in men in the Multiple Risk Fa ctor Intervention Trial (MRFIT). Largescale epidemiologic studies indicate a pro gressive increase in the risk for developing ESRD as a function of systolic bloo d pressure levels. Follow-up of nearly 12,000 male veterans in the United States established that systolic blood pressure above 165 mm Hg at the initial visit w as predictive of progressively higher risk of ESRD over a 15-year follow-up period [18]. Similarly, follow-up studies after 16 years of more than 300,000 men in MRFIT demonstrated a progressive increase in the risk for ESRD, m ost pronounced in blacks [19]. These data suggest that blood pressure levels pre dict future renal disease. However, it remains uncertain whether benign essentia l hypertension itself induces a primary renal lesion (hypertensive renal disease nephrosclerosis) or acts as a catalyst in patients with other primary renal dis ease, otherwise not detected at initial screening. SBPsystolic blood pressure. (P anel A from Perry and coworkers [18]; with permission.)

2.12 50 Hypertension and the Kidney 0 Ccr, mL/min 40 30 20 4 mL/mmol-1 3 2 1 400 200 Days 0 +200 +400 Chronic glomerulonephritis: Rates of progression over time decrease after reduct ion of BP from 149/102 mm Hg to treated level, 136/90 mm Hg. 0 3 6 Protein excretion, g/d 00.25 1.03.0 0.251 3.0 Study A: mean GFR: 39 mL/min/1.73 m2 N =585: range: 2555 mL/min Decrease in glomerular filtration rate, mL/min/y 3 6 9 9 12 15 18 107 12 15 Cr-1/s, 18 86 92 98 Mean follow-up MAP, mm Hg FIGURE 2-22 Rates of progression in glomeruloneophritis. The decrease in glomeru lar filtration rate is illustrated. The rates of decline decreased considerably with administration of antihypertensive drug therapy. Among other mechanisms, th e decrease in arterial pressure lowers transcapillary filtration pressures at th e level of the glomerulus [20]. This effect is correlated with a reduction in pr oteinuria and slower development of both glomerulosclerosis and interstitial fib rosis. A distinctive feature of many glomerular diseases is the massive proteinu ria and nephron loss associated with high single-nephron glomerular filtration, partially attributable to afferent arteriolar vasodilation. The appearance of wo rsening proteinuria (>3 g/d) is related to progressive renal injury and developm ent of renal failure. Reduction of arterial pressure can decrease urinary protei n excretion and slow the progression of renal injury. Ccrcreatinine clearance rat e; Cr-1/sreciprocal creatinine, expressed as 1/creatinine. (From Bergstrom and co workers [20]; with permission.) FIGURE 2-23 Blood pressure, proteinuria, and the rate of renal disease progressi on: results from the Modification of Diet in Renal Disease (MDRD) trial. Shown a re rates of decrease of glomerular filtration rate (GFR) for patients enrolled i n the MDRD trial, depending on level of achieved treated blood pressure during t he trial [21]. A component of this trial included strict versus conventional blo od pressure control. The term strict was defined as target mean arterial pressur e (MAP) of under 92 mm Hg. The term conventional was defined as MAP of under 107 mm Hg. The rate of decline in GFR increased at higher levels of achieved MAP in patients with significant proteinuria (>3.0 g/d). No such relationship was evid ent over the duration of this trial (mean, 2.2 years) for patients with less sev ere proteinuria. These data emphasize the importance of blood pressure in determ ining disease progression in patients with proteinuric nondiabetic renal disease . No distinction was made in this study regarding the relative benefits of speci fic antihypertensive agents. (From Peterson and coworkers [21]; with permission. )

Effects of Antihypertensive Therapy on Renal Disease Progression FIGURE 2-24 Blood pressure and rate of progressive renal failure. Rates of disea se progression (defined as the slope of 1/creatinine) were determined in 86 pati ents who reached end-stage renal disease and dialytic therapy. The rates of prog ression were defined between mean creatinine levels of 3.8 mg/dL (start) and 11. 4 mg/dL (end) over a mean duration of 33 months [22]. Brazy and coworkers [22] d emonstrated that the slope of disease progression appeared to be related to the range of achieved diastolic blood pressure during this interval. Hence, these au thors argue that more intensive antihypertensive therapy may delay the need for replacement therapy in patients with end-stage renal disease. As noted in the Mo dification of Diet in Renal Disease trial, such benefits are most apparent in pa tients with proteinuria over a shorter follow-up period. (From Brazy and coworke rs [22]; with permission.) Slope of 1/creatinine vs time, dL/mg mo 0.006 0.008 0.010 0.012 0 8590 7085 9096 96113 Range of diastolic blood pressure (mm for each quartile of the population

Renal Parenchymal Disease and Hypertension 2.13 CLASSES OF ANTIHYPERTENSIVE AGENTS USED IN TREATMENT OF CHRONIC RENAL DISEASE Diuretics: Thiazide class Loop diuretics Potassium-sparing agents Adrenergic inh ibitors Peripheral agents, eg, guanethidine Central -agonists, eg, clonidine, me thyldopa, and guanfacine -Blocking agents, eg, doxazosin -Blocking agents Combin ed - blocking agents, eg, labetalol Vasodilators Hydralazine Minoxidil Classes o f calcium-channel blocking agents Verapamil Diltiazem Dihydropyridine Angiotensi n-converting enzyme inhibitors Angiotensin receptor blockers FIGURE 2-25 The current classification of agents applied for chronic treatment o f hypertension as summarized in the report by the Joint National Committee on Pr evention, Detection, Evaluation and Treatment of High Blood Pressure [23]. Atten tion must be given to drug accumulation and limitations of individual drug effic acy as glomerular filtration rates decrease in chronic renal disease. Potassium levels may increase during administration of potassium-sparing agents and medica tions that inhibit the renin-angiotensin system, especially in patients with imp aired renal function [24]. 60 55 GFR, mL/min/1.73 m2/y 50 45 40 35 30 25 6 0 6 12 18 4 Conventional Strict n=87 patients Bars=95% confidence intervals for GFR estimate s Rate of change in GFR, mL/min/1.73 m2/y 3 2 Mean SEM 1 0 1 2 3 A 24 30 Time, mo 36 42 48 B Strict Conventional Blood pressure control group FIGURE 2-26 Strict blood pressure control and progression of hypertensive nephro sclerosis. Whether vigorous blood pressure reduction reduces progression of earl y parenchymal renal disease in blacks with nephrosclerosis is not yet certain. A and B, A randomized prospective trial comparing strict (panel A) blood pressure control (defined as diastolic blood pressure [DBP] <80 mm Hg) with conventional (panel B) levels of diastolic control between 85 and 95 mm Hg for more than 3 y ears could not identify a reduction in rates of disease progression [25]. Of pat ients, 68 of 87 were black. Rates of progression in

these patients were low. It should be emphasized that entry criteria excluded pa tients with diabetes and massive proteinuria. Initial studies from the African A merican Study of Kidney Disease trial confirm that biopsy findings in most patie nts with clinical features of hypertension were considered consistent with prima ry hypertensive disease [26]. Whether lower than normal levels of blood pressure in these patients will prevent progression to end-stage renal disease over long er time periods remains to be determined. GFRglomerular filtration rate. (From To to and coworkers [25]; with permission.)

2.14 100 90 80 Patients who died or needed dialysis or transplantation, % 70 60 50 40 30 20 10 0 0.0 Hypertension and the Kidney FIGURE 2-27 Angiotensin-converting enzyme (ACE) inhibitors and chronic renal dis ease. Progression of type I diabetic nephropathy to renal failure was reduced in the ACE inhibitor arm of a trial comparing conventional antihypertensive therap y with a regimen containing the ACE inhibitor captopril. All patients in this tr ial had significant proteinuria (>500 mg/d). The most striking effect of the ACE inhibitor regimen was seen in patients with higher serum creatinine levels (>1. 5 mg/dL) as shown in the top two lines. It should be noted that calcium channel blocking drugs were excluded from this trial and the ACE inhibitor arm had somew hat lower arterial pressures during treatment. These data offer support to the c oncept that ACE inhibition lowers intraglomerular pressures, reduces proteinuria , and delays the progression of diabetic nephropathy by more mechanisms than can be explained by pressure reduction alone. (Data from Lewis and coworkers [27].) P=0.002 P=0.14 0.5 1.0 44 52 148 152 1.5 40 51 146 150 Creatinine 1.5 mg/dL Placebo 49 48 Captopril 53 53 Creatinine <1.5 mg/dL Placebo 153 150 Captopril 154 154 2.0 2.5 Years of follow-up 33 48 138 147 23 36 98 104 3.0 16 25 84 78 3.5 7 17 52 47 4.0 1 8 25 29 2.6 Benazepril: n=583 patients; creatinine=1.54.0 Placebo 2.6 Benazepril: n=583 patients; creatinine=1.54.0 Placebo 117 2.4 239 2.4 137 262 2.2 2.2 2.0

2.0 A 0 1 Years 2 3 B 0 1 Years 2 3 FIGURE 2-28 Angiotensin-converting enzyme (ACE) inhibition in nondiabetic renal disease. A and B, Shown here are serum creatinine levels from the 12-month (pane l A) and 36-month (panel B) cohorts followed in the benazepril trial. In this tr ial, 583 patients were randomized to therapy with or without benazepril [28]. Sl ight reductions in the rates of increase in creatinine and of stop points in the ACE inhibitor group occurred; however, these reductions were modest. Whereas th ese data support a role for ACE inhibition, the results are considerably less convin cing than are those for diabetic nephropathy. These results argue that some grou ps may not experience major benefit from ACE inhibition over the short term. Pre liminary reports from recent studies limited to patients with proteinuria sugges t that rates of progression were substantially reduced by treatment with ramipri l [29]. (From Maschio and coworkers [28]; with permission.)

Renal Parenchymal Disease and Hypertension 2.15 CONCLUSIONS AND RECOMMENDATIONS OF THE SIXTH REPORT OF THE JOINT NATIONAL COMMIT TEE ON PREVENTION, DETECTION, EVALUATION AND TREATMENT OF HIGH BLOOD PRESSURE, 1 997 1. Hypertension may result from renal disease that reduces functioning nephrons. 2. Evidence shows a clear relationship between high blood pressure and end-stag e renal disease. 3. Blood pressure should be controlled to 130/85 mm Hg (<125/75 mm Hg) in patients with proteinuria in excess of 1 g/24 h. 4. Angiotensin-conver ting enzyme inhibitors work well to lower blood pressure and slow progression of renal failure. FIGURE 2-29 Conclusions and Recommendations of the Sixth Report of the Joint Nat ional Committee (JNC) on Prevention, Detection, Evaluation and Treatment of High Blood, 1997 [23]. The JNC Committee has emphasized the importance of vigorous b lood pressure control with any agents needed, rather than specific classes of me dication. Angiotensin-converting enzyme inhibitors in proteinuric disease are th e exception. References 1. Smith MC, Dunn MJ: Hypertension in renal parenchymal disease. In Hypertension : Pathophysiology, Diagnosis and Management. Edited by Laragh JH, Brenner BM. Ne w York: Raven Press; 1995:20812102. 2. Klahr S, Levey AS, Beck GJ, et al.: The ef fects of dietary protein restriction and blood-pressure control on the progressi on of chronic renal disease. N Engl J Med 1994, 330:877884. 3 Rodriguez-Iturbe B, Baggio B, Colina-Chouriao J, et al.: Studies on the renin-aldosterone system in the acute nephritic syndrome. Kidnet Int 1981, 445453 4. Curtiss JJ, Luke RG, Du stan HP, et al.: Remission of essential hypertension after renal transplantation . N Engl J Med 1983, 309:10091015. 5. Brunner HR, Gavras H, Laragh JH: Specific i nhibition of the reninangiotensin system: a key to understanding blood pressure regulation. Prog Cardiovasc Dis 1974; 17:8798. 6. Converse RL, Jacobsen TN, Toto RD, et al.: Sympathetic overactivity in patients with chronic renal failure. N E ngl J Med1992, 327:19121918. 7. Katholi RE, Nafilan AJ, Oparil S: Importance of r enal sympathetic tone in the development of DOCA-salt hypertension in the rat. H ypertension 1980, 2:266273. 8. Benigni A, Zoja C, Cornay D, et al.: A specific en dothelin subtype A receptor antagonist protects against injury in renal disease progression. Kidney Int 1993, 44:440444. 9. Levin ER: Mechanisms of disease: endo thelins. N Engl J Med 1995, 333:356363. 10. Textor SC, Burnett JC, Romero JC, et al.: Urinary endothelin and renal vasoconstriction with cyclosporine or FK506 af ter liver transplantation. Kidney Int 1995, 47:14261433. 11. Sandborn WJ, Hay JE, Porayko MK, et al.: Cyclosporine withdrawal for nephrotoxicity in liver transpl ant recipients does not result in sustained improvement in kidney function and c auses cellular and ductopenic rejection. Hepatology 1994, 19:925932. 12. Benigni A, Perico N, Gaspari F, et al.: Increased renal endothelin production in rats wi th renal mass reduction. Am J Physiol 1991, 260:F331F339. 13. Rees DD, Palmer RMJ , Moncada S: Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci U S A 1989, 86:33753378. 14. Lahera V, Salom MG, Mi randa-Guardiola F, et al.: Effects of N-nitroL-arginine methyl ester on renal fu nction and blood pressure. Am J Physiol 1991, 261:F1033F1037. 15. Gaston RS, Schl essinger SD, Sanders PW, et al.: Cyclosporine inhibits the renal response to L-a rginine in human kidney transplant recipients. J Am Soc Nephrol 1995, 5:14261433. 16. Whitworth JA: Renal parenchymal disease and hypertension. In Clinical Hyper tension. Edited by Robertson JIS. Amsterdam: Elsevier, 1992:326350. 17. Foley RN, Parfrey PS, Harnett JD, et al.: Impact of hypertension on cardiomyopathy, morbi dity and mortality in end-stage renal disease. Kidney Int 1996, 49:13791385. 18. Perry HM, Miller JP, Fornoff JR, et al.: Early predictors of 15-year end-stage r enal disease in hypertensive patients. Hypertension 1995, 25(part 1):587594. 19. Klag MJ, Whelton PK, Randall BL, et al.: End-stage renal disease in African-Amer

ican and White men. JAMA 1997, 277:12931298. 20. Bergstrom J, Alvestrand A, Bucht H, Guttierrez A: Progression of chronic renal failure in man is retarded with m ore frequent clinical follow-ups and better blood pressure control. Clin Nephrol 1986, 25:16. 21. Peterson JC, Adler S, Burkart JM, et al.: Blood pressure contro l, proteinuria and the progression of renal disease. Ann Intern Med 1995; 123:75 4762. 22. Brazy PC, Stead WW, Fitzwilliam JF: Progression of renal insufficiency: role of blood pressure. Kidney Int 1989, 35:670674. 23. JNC Committee: Sixth Rep ort of the Joint National Committee on Prevention, Detection, Evaluation and Tre atment of High Blood Pressure. Bethesda, MD: National Institutes of Health Publi cation; 1997. 24. Textor SC: Renal failure related to ACE inhibitors. Semin Neph rol 1997, 17:6776. 25. Toto RD, Mitchell HC, Smith RD, et al.: Strict blood pressur e control and progression of renal disease in hypertensive nephrosclerosis. Kidn ey Int 1995, 48:851859. 26. Fogo A, Breyer JA, Smith MC, et al.: Accuracy of the diagnosis of hypertensive nephrosclerosis in African-Americans: a report from th e African American Study of Kidney Disease (ASSK) trial. Kidney Int 1997; 51:2442 52. 27. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensinconv erting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993, 329:14561462 . 28. Maschio G, Alberti D, Janin G, et al.: Effect of the angiotensin-convertin g enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med 1996, 334:939945. 29. Ruggenenti P, Perna A, Mosconi M, et al.: The angiotensin converting enzyme inhibitor ramipril slows the rate of GFR decline and the progression to end-stage renal failure in proteinuric, non-diabetic chro nic renal diseases [abstract]. J Am Soc Nephrol 1997, 8:147A. 30. Giatras I, Lau J, Levey AS: Effect of angiotensin-converting enzyme inhibitors on the progress ion of non-diabetic renal disease: a metaanalysis of randomized trials. Ann Inte rn Med 1997, 127:345.

Renovascular Hypertension and Ischemic Nephropathy Marc A. Pohl T he major issues in approaching patients with renal artery stenosis relate to the role of renal artery stenosis in the management of hypertension, ie, renovascula r hypertension, and to the potential for vascular compromise of renal function, i e, ischemic nephropathy. Ever since the original Goldblatt experiment in 1934, whe rein experimental hypertension was produced by renal artery clamping, countless investigators and clinicians have been intrigued by the relationship between ren al artery stenosis and hypertension. Much discussion has focused on the pathophy siology of renovascular hypertension, the renin angiotensin system, diagnostic t ests to detect presumed renovascular hypertension, and the relative merits of su rgical renal revascularization (SR), percutaneous transluminal renal angioplasty (PTRA), and drug therapy in managing patients with renal artery stenosis and hy pertension. Hemodynamically significant renal artery stenosis, when bilateral or affecting the artery to a solitary functioning kidney, can also lead to a reduc tion in kidney function (ischemic nephropathy). This untoward observation may be reversed by interventive maneuvers, eg, surgical renal revascularization, PTRA, or renal artery stenting. The syndrome of ischemic renal disease or ischemic nephr opathy now looms as an important clinical condition and has attracted the fascina tion of nephrologists, vascular surgeons, and interventional cardiologists and r adiologists. The detection of renal artery stenosis in a patient with hypertensi on usually evokes the assumption that the hypertension is due to the renal arter y stenosis. However, renal artery stenosis is not synonymous with renovascular hy pertension. On the basis of autopsy studies and clinical angiographic correlation s, high-grade atherosclerotic renal artery stenosis (ASO-RAS) in patients with m ild blood pressure elevation or in patients with normal arterial pressure is wel l recognized. The vast majority of patients with ASO-RAS who have hypertension h ave essential hypertension, not renovascular hypertension. These hypertensive pa tients with ASO-RAS are rarely cured of their hypertension by interventive proce dures that either bypass or CHAPTER 3

3.2 Hypertension and the Kidney chronic subcapsular hematoma, and unilateral ureteral obstruction may also be as sociated with hypertension that is relieved when the affected kidney is removed. These clinical analogues of the experimental Page kidney reflect the syndrome o f renovascular hypertension (RVHT), but without main renal artery stenosis. Taka yasu's arteritis and atheroembolic renal disease are additional examples of RVHT w ithout main renal artery stenosis. Accordingly, the anatomic presence of renal a rtery stenosis should not be equated with renovascular hypertension and the synd rome of RVHT need not reflect renal artery stenosis. This chapter reviews the ty pes of renal arterial disease associated with RVHT, the pathophysiology of RVHT, clinical features and diagnostic approaches to renal artery stenosis and RVHT, evolving concepts regarding ischemic nephropathy, and management considerations in patients with renal artery stenosis, presumed RVHT, and ischemic renal diseas e. dilate the stenotic lesion. Thus, it is critical to distinguish between the anat omic presence of renal artery stenosis, in which a stenotic lesion is present bu t not necessarily causing hypertension, and the syndrome of renovascular hyperte nsion in which significant arterial stenosis is present and sufficient to produc e renal tissue ischemia and initiate a pathophysiologic sequence of events leadi ng to elevated arterial pressure. In the final analysis, proof that a patient ha s the entity of renovascular hypertension rests with the demonstration that the hy pertension, presumed to be renovascular, can be eliminated or substantially amelio rated following removal of the stenosis by surgical or endovascular intervention , or by removing the kidney distal to the stenosis. Although the great majority of patients diagnosed as having renovascular hypertension have this syndrome bec ause of main renal artery stenosis, hypertension following unilateral renal trau ma, CLASSIFICATION OF RENAL ARTERY DISEASE Disease Atherosclerosis Fibrous dysplasia Medial (30%) Perimedial (5%) Intimal (5%) *Per cent of renal artery lesions. Incidence, %* 6080 2040 FIGURE 3-1 Classification of renal artery disease. Two main types of renal arter ial lesions form the anatomic basis for renal artery stenosis. Atherosclerotic r enal artery disease (ASO-RAD) is the most common cause of renal artery disease, accounting for 60% to 80% of all renal artery lesions. The fibrous dysplasias ar e the other major category of renal artery disease, and as a group account for 2 0% to 40% of renal artery lesions. Arterial aneurysm and arteriovenous malformat ion are rarer types of renal artery disease. A B FIGURE 3-2 Angiographic examples of atherosclerotic renal artery disease (ASO-RA D). A, Aortogram demonstrating severe nonostial atherosclerotic renal artery dis ease of the left main renal artery. B, Intra-arterial digital subtraction aortog ram showing severe proximal right renal artery stenosis (ostial lesion) and mode rately severe narrowing of the left renal artery due to atherosclerosis. Atherosclerotic renal artery disease is typically associated with atheroscleroti c changes of the abdominal aorta (see panel B). ASORAD predominantly affects men and women in the fifth to seventh decades of life but is uncommon in women unde

r the age of 50. Anatomically, the majority of these patients demonstrate athero sclerotic plaques located in the proximal third of the main renal artery. In the majority of cases (70% to 80%), the obstructing lesion is an aortic plaque inva ding the renal artery ostium (ostial lesion). Twenty to 30 percent of patients w ith ASORAD demonstrate atherosclerotic narrowing 1 to 3 cm beyond the takeoff of the renal artery (nonostial lesion). Nonostial lesions are technically more ame nable to percutaneous transluminal renal angioplasty (PTRA) than ostial ASO-RAD lesions, which are technically difficult to dilate and have a high restenosis ra te after PTRA. Renal artery stenting has gained wide acceptance for ostial lesio ns. Endovascular intervention for nonostial lesions includes both PTRA and stent s. Surgical renal revascularization is used for both ostial and nonostial ASO-RA D lesions. (From Pohl [1]; with permission.)

Renovascular Hypertension and Ischemic Nephropathy 3.3 NATURAL HISTORY OF ATHEROSCLEROTIC RENOVASCULAR DISEASE: REPORTS OF SERIAL ANGIO GRAMS First author Wollenweber Meaney Dean Schreiber Tollefson Total Year 1968 1968 1981 1984 1991 Months of follow-up, n/n 12/88 6/120 6/102 12/60 15/180 Patients, n 30 39 35 85 48 237 Progression, n (%) 21 (70) 14 (36) 10 (29) 37 (44) 34 (71) 116 (49) Total occlusion NA 3 (8) 4 (11) 14 (I6) 7 (15) 28 (14) FIGURE 3-3 Natural history of atherosclerotic renovascular disease. Retrospectiv e studies, based on serial renal angiograms, suggest that atherosclerotic renal artery disease (ASO-RAD) is a progressive disorder. This figure summarizes retro spective series on the natural history of ASO-RAD. A large series from the Cleve land Clinic in nonoperated patients indicated progression of renal artery obstru ction in 44%; progression to total occlusion occurred in 16% of these patients. Reduction in ipsilateral renal size is associated with angiographic evidence of progression in contrast to patients with nonprogressive (angiographically) ASO-R AD. Zierler and coworkers have prospectively studied the progression of ASO-RAD by sequential duplex ultrasonography. The cumulative incidence of progession of lesions with less than 60% reduction in lu men diameter progressing to more than 60% reduction in lumen diameter was 30% at 1 year, 44% at 2 years, and 48% at 3 years. Progression to total occlusion occu rred only in arteries with a baseline reduction in lumen diameter of more than 6 0%. The cumulative incidence of progression to total occlusion in patients with baseline stenosis of 60% or greater was 4% at 1 year, 4% at 2 years, and 7% at 3 years. Blood pressure control and serum creatinine were not predictors of progr ession. The risk of renal parenchymal atrophy over time in kidneys with ASO-RAD has also been described. (Table adapted from Rimmer and Gennari [2]; with permis sion.) the second most common type of fibrous dysplasia, accounting for 10% to 2 5% of fibrous renal artery lesions. This lesion also occurs predominantly in wom en, is diagnosed between the ages of 15 and 30, is frequently bilateral and high ly stenotic, and may progress to total arterial occlusion. These patients should undergo surgical renal revascularization to relieve hypertension and to avoid l oss of renal function. Intimal fibroplasia and medial hyperplasia (usually indis tinguishable angiographically) are not common, accounting for only 5% to 10% of fibrous renal artery lesions. Intimal fibroplasia occurs primarily in children a nd adolescents. Medial hyperplasia is found predominantly in adolescents; angiog raphically it appears as a smooth linear stenosis that may extend into the prima ry renal artery branches. Medial hyperplasia, like intimal fibroplasia, is a pro gressive lesion and is associated with ipsilateral renal atrophy. Surgical renal revascularization is recommended for patients with either intimal fibroplasia o r medial hyperplasia to avoid lifelong antihypertensive therapy and to avert ren al atrophy.

FREQUENCY AND NATURAL HISTORY OF FIBROUS RENAL ARTERY DISEASES Lesion Intimal fibroplasia and medial hyperplasia Perimedial fibroplasia Medial fibropl asia Frequency, %* 10 1025 7085 Risk of progression ++++ ++++ ++ Threat to renal function ++++ ++++ *Frequency relates to frequency of only the fibrous renal artery diseases. FIGURE 3-4 Frequency and natural history of fibrous renal artery diseases. There are four types of fibrous renal artery disease (fibrous dysplasias): medial fib roplasia, perimedial fibroplasia, intimal fibroplasia, and medial hyperplasia. A lthough the true incidence of these specific types of fibrous renal artery disea se is not clearly defined, medial fibroplasia is the most common, estimated to a ccount for 70% to 85% of fibrous renal artery disease. The majority of patients with medial fibroplasia are almost exclusively women who are diagnosed between t he ages of 25 to 50 years. Although medial fibroplasia progresses to higher degr ees of stenosis in about one third of cases, complete arterial occlusion or isch emic atrophy of the involved kidney is rare. Intervention on this type of fibros is dysplasia is for relief of hypertension because the threat of progressive med ial fibroplasia to renal function is negligible. Perimedial fibroplasia is

3.4 Hypertension and the Kidney FIGURE 3-5 Arteriogram and schematic diagrams of medial fibroplasia. A, Right re nal arteriogram demonstrating weblike stenosis with interposed segments of dilat ation (large beads) typical of medial fibroplasia (string of beads lesion). B, Sch ematic diagram of medial fibroplasia. The lesion of medial fibroplasia character istically affects the distal half of the main renal artery, frequently extending into the branches, is often bilateral, and angiographically gives the appearanc e of multiple aneurysms (string of beads). Histologically, this beaded lesion is c haracterized by areas of proliferation of fibroblasts of the media surrounded by fibrous connective tissue (stenosis) alternating with areas of medial thinning (aneurysms). Inspection of the renal angiogram in panel A indicates that the wid th of areas of aneurysmal dilatation is wider than the nonaffected proximal rena l artery, an angiographic clue to medial fibroplasia. (Panel A from Pohl [1]; wi th permission.) FIGURE 3-6 Arteriogram and schematic diagram of perimedial fibro plasia. A, Selective right renal arteriogram shows a tight stenosis in the mid p ortion of the renal artery with a small string of beads appearance, typical of p erimedial fibroplasia. B, Schematic diagram of perimedial fibroplasia. Perimedia l fibroplasia, accounting for 10% to 25% of the fibrous renal artery diseases, i s also observed almost exclusively in women. The stenotic lesion occurs in the m id and distal main renal artery or branches and may be bilateral. Angiographical ly, serial stenoses are observed with small beads, which are smaller in diameter than the unaffected portion of the renal artery. This highly stenotic lesion ma y progress to total occlusion; collateral blood vessels and renal atrophy on the involved side are frequently observed. Pathologically, the outer layer of the m edia varies in thickness and is densely fibrotic, producing a severe reduction i n lumen diameter (panel B). Renal artery dissection and/or thrombosis are common . (Panel A from Pohl [1]; with permission.) B A A B

Renovascular Hypertension and Ischemic Nephropathy 3.5 A B FIGURE 3-7 Arteriogram and schematic diagram of intimal fibroplasia. A, Selectiv e right renal arteriogram demonstrating a localized, highly stenotic, smooth les ion involving the distal renal artery, from intimal fibroplasia. B, Schematic di agram of intimal fibroplasia. Intimal fibroplasia occurs primarily in children a nd adolescents and angiographically gives the appearance of a localized, highly stenotic, smooth lesion, with poststenotic dilatation. It may occur in the proxi mal portion of the renal artery as well as in the mid and distal portions of the renal artery, is progressive, and is occasionally associated with dissection or renal infarction. Pathologically, idiopathic intimal fibroplasia is due to a pr oliferation of the intimal lining of the arterial wall. Intimal fibroplasia of t he renal artery may also occur as an event secondary to atherosclerosis or as a reactive intimal fibroplasia consequent to an inciting event such as prior endar terectomy or balloon angioplasty. (Panel A from Pohl [1]; with permission.) kidn ey beyond the stenosis are relatively common with ASO-RAD, but ischemic atrophy of the kidney ipsilateral to the medial fibroplasia lesion is rare. Surgical int ervention or pecutaneous transluminal renal angioplasty (PTRA) typically produce good cure rates for the hypertension in medial fibroplasia and these lesions ar e technically quite amenable to PTRA. In contrast, ASO-RAD is, technically, much less amenable to PTRA (particularly ostial lesions), and surgical intervention or PTRA produce mediocre-to-poor cure rates of the hypertension. ASO-RAD and med ial fibroplasia may cause hypertension and when the hypertension is cured or mar kedly improved following intervention, the patient may be viewed as having renova scular hypertension. This sequence of events is far more likely to occur in patie nts with medial fibroplasia than in patients with ASO-RAD. ASO-RAD and medial fi broplasia involve both main renal arteries in approximately 30% to 40% of patien ts. ATHEROSCLEROTIC RENAL ARTERY DISEASE VERSUS MEDIAL FIBROPLASIA Atherosclerotic Men and women Age >5055 y Total occlusion common Ischemic atrophy common Surgical intervention or angioplasty: Mediocre cure rates of the hypertension Less amena ble to PTRA Medial fibroplasia Women Age 2040 y Total occlusion rare Ischemic atrophy rare Surgical intervention or angioplasty: Good cure rates of the hypertension More amenable to PTRA FIGURE 3-8 A comparison of atherosclerotic renal artery disease and medial fibro plasia. The most common types of renal artery disease (atherosclerotic renal art ery disease [ASO-RAD] and medial fibroplasia) are compared here. In general, ASO -RAD is observed in men and women older than 50 to 55 years of age, whereas medi al fibroplasia is observed primarily in younger white women. Total occlusion of the renal artery and, hence, atrophy of the

3.6 Hypertension and the Kidney Pathophysiology of Renovascular Hypertension This diagram shows the classic model of two-kidney, one clip (2K,1C) Goldblatt h ypertension, wherein one renal artery is constricted and the contralateral kidne y is left intact. In the presence of hemodynamically sufficient unilateral renal artery stenosis, the kidney distal to the stenosis is rendered ischemic, activa ting the renin angiotensin system, and producing high levels of angiotensin II, causing a vasoconstrictor type of hypertension. Numerous studies have established the causal relationship between angiotensin IImediated vasoconstriction and hyper tension in the early phase of this experimental model. In addition, the high lev els of angiotensin II stimulate the adrenal cortex to elaborate larger amounts o f aldosterone such that the stenotic kidney demonstrates sodium retention. This se condary aldosteronism also produces hypokalemia. The degree of renal artery sten osis necessary to produce hemodynamically significant reductions in perfusion, t riggering renal ischemia and activation of the renin angiotensin system, general ly does not occur until a reduction of 80% or more in both lumen diameter and cr oss-sectional area of the renal artery takes place. Lesser degrees of renal arte ry constriction do not initiate this sequence of events. This model of 2K,1C Gol dblatt hypertension implies that the contralateral (nonaffected) kidney is prese nt, and that its renal artery is not hemodynamically significantly narrowed. As illustrated, the contralateral kidney demonstrates suppressed renin production and undergoes a pressure natriuresis, presumably because of angiotensin IIinitiated vasoconstriction and sodium retention, leading to systemic elevation of blood pr essure that then results in suppression of renin release and enhanced excretion of sodium (pressure natriuresis) by the contralateral kidney. Stenotic kidney Contralateral kidney Supressed renin Pressure natriuresis Ischemia Renin Angiotensin II Vasoconstriction Aldosterone Intrarenal hemodynamics Sodium retention FIGURE 3-9 Schematic representation of renovascular hypertension. Renovascular h ypertension may be defined as the secondary elevation of blood pressure produced by any of a variety of conditions that interfere with the arterial circulation to kidney tissue and cause renal ischemia. Almost always, renovascular hypertens ion is caused by obstruction of the renal artery or its branches, and demonstrat ion of causality between the renal artery lesion and the hypertension is essenti al to this definition.

Renovascular Hypertension and Ischemic Nephropathy 3.7 Clip Blood pressure I Phase II III Renin Change in blood pressure on removing clip FIGURE 3-10 Sequential phases in two-kidney, one-clip (2K,1C) experimental renov ascular hypertension. The schematic representation of renovascular hypertension depicted in Figure 3-9 is an oversimplification. In fact, the course of experime ntal 2K,1C hypertension may be divided into three sequential phases. In phase I, renal ischemia and activation of the renin angiotensin system are of fundamenta l importance, and in this early phase of experimental hypertension, the blood pr essure elevation is renin- or angiotensin IIdependent. Acute administration of an giotensin II antagonists, administration of angiotensin-converting enzyme (ACE) inhibitors, removal of the renal artery stenosis (ie, removal of the clip in the experimental animal or removal of the stenotic kidney) promptly normalizes blood pressure. Several days after renal artery clamping, renin levels fall, but blood pressure remains elevated. This second phase of experimental 2K,1C hypertension may be viewed as a pathophysiologic transition phase that, depending on the exp erimental model and species, may last from a few days to several weeks. During t his transition phase (phase II), salt and water retention are observed as a cons equence of the effect of hypoperfusion of the stenotic kidney; augmented proximal tubular reabsorption of sodium and water and angiotensin IIind uced stimulation of aldosterone secretion contribute to this sodium and water re tention. In addition, the high levels of angiotensin II stimulate thirst, which further augments expansion of the extracellular fluid volume. The expanded extra cellular fluid volume results in a progressive suppression of peripheral renin a ctivity. During this transition phase, the hypertension is still responsive to r emoval of the unilateral renal artery stenosis, to angiotensin II blockade, or u nilateral nephrectomy, although these maneuvers do not normalize the blood press ure as promptly and consistently as in the acute phase. After several weeks, a c hronic phase (phase III) ensues wherein unclipping the renal artery of the exper imental animal does not lower the blood pressure. This failure of unclipping to lo wer the blood pressure in this chronic phase (III) of 2K,1C hypertension is due to widespread arteriolar damage to the contralateral kidney, consequent to prolong ed exposure to high blood pressure and high levels of angiotensin II. In this ch ronic phase of 2K,1C renovascular hypertension, extracellular fluid volume expan sion and systemic vasoconstriction are the main pathophysiologic abnormalities. The pressure natriuresis of the contralateral kidney blunts the extracellular flui d volume expansion caused by the stenotic kidney; but as the contralateral kidney suffers vascular damage from extended exposure to elevated arterial pressure, it s excretory function diminishes and extracellular fluid volume expansion persist s. In this third phase of experimental 2K,1C hypertension, acute blockade of the renin angiotensin system fails to lower blood pressure. Sodium depletion may am eliorate the hypertension but does not normalize it. The clinical surrogate of p hase III experimental 2K,1C hypertension is duration of hypertension. Widespread clinical experience indicates that major improvements in blood pressure control or cure of the hypertension following renal revascularization or even removal o f the kidney ipsilateral to the renal artery stenosis are rarely observed in pat ients with a long duration (ie, >5 years) of hypertension. (Adapted from Brown a nd coworkers [3]; with permission.) FIGURE 3-11 Schematic representation of two

types of experimental hypertension. The discussion so far of the pathophysiology of renovascular hypertension has focused on the two-kidney, one-clip model of r enovascular hypertension (two-kidney hypertension), wherein the artery to the contr alateral kidney is patent and the contralateral nonaffected kidney is present. Elev ated peripheral renin activity, normal plasma volume, and hypokalemia are typica lly associated with the elevated arterial pressure. There is another type of reno vascular hypertension known as one-kidney hypertension, wherein in the experimental model, one renal artery is constricted and the contralateral kidney is removed. Although there is an initial increase in renin release responsible for the earl y rise in blood pressure in one-kidney hypertension as in two-kidney hypertension, t he absence of an unclipped contralateral kidney allows for sodium retention earl y in the course of this one-kidney, one-clip (1K,1C) model. Renin levels are sup pressed to normal levels in conjunction with high blood pressure which is mainta ined by salt and water retention. Thus, extracellular fluid volume expansion is a prime feature of one-kidney hypertension. Two-kidney hypertension One-kidney hypertension Blood pressure Renin High Volume Normal Blood pressure Renin Normal Volume High

3.8 Hypertension and the Kidney FIGURE 3-12 Lesions producing the syndrome of renovascular hypertension. A, Twokidney hypertension. The most common clinical counterpart to two-kidney hypertensi on is unilateral renal artery stenosis due to either atherosclerotic or fibrous renal artery disease. Unilateral renal trauma, with development of a calcified f ibrous capsule surrounding the injured kidney causing compression of the renal p arenchyma, may produce renovascular hypertension; this clinical situation is ana logous to the experimental Page kidney, wherein cellophane wrapping of one of tw o kidneys causes hypertension, which is relieved by removal of the wrapped kidne y. B, One-kidney hypertension. Clinical counterparts of experimental one-kidney, one-clip (one kidney) hypertension include renal artery stenosis to a solitary fu nctioning kidney, bilateral renal arterial stenosis, aortic coarctation, Takayas u's arteritis, fulminant polyarteritis nodosa, atheroembolic renal disease, and re nal artery stenosis in a transplanted kidney. In some parts of the world, eg, Ch ina and India, Takayasu's arteritis is a frequent cause of renovascular hypertensi on. A. LESIONS PRODUCING THE SYNDROME OF RENOVASCULAR HYPERTENSION (TWO-KIDNEY HYPERT ENSION)* Unilateral atherosclerotic renal arterial disease Unilateral fibrous renal arter y disease Renal artery aneurysm Arterial embolus Arteriovenous fistula (congenit al and traumatic) Segmental arterial occlusion (traumatic) Pheochromocytoma comp ressing renal artery Unilateral perirenal hematoma or subcapsular hematoma (comp ressing renal parenchyma) *Implies contralateral (nonaffected) kidney present. B. LESIONS PRODUCING THE SYNDROME OF RENOVASCULAR HYPERTENSION (ONE-KIDNEY HYPERT ENSION)* Stenosis to a solitary functioning kidney Bilateral renal arterial stenosis Aort ic coarctation Vasculitis (polyarteritis nodosa and Takayasu's arteritis) Atheroem bolic disease *Implies total renal mass ischemic. STEPS IN MAKING THE DIAGNOSIS OF RENOVASCULAR HYPERTENSION 1. Demonstration of renal arterial stenosis by angiography 2. Determination of p athophysiologic significance of the stenotic lesion 3. Cure of the hypertension by intervention, ie, revascularization, percutaneous transluminal angioplasty, n ephrectomy FIGURE 3-13 Steps in making the diagnosis of renovascular hypertension (RVHT). W ith the exception of oral contraceptive use and alcohol ingestion, RVHT is the m ost common cause of potentially remediable secondary hypertension. RVHT is estim ated to occur with a prevalence of 1% to 15%. Some hypertension referral clinics have estimated a prevalence of RVHT as high as 15%, whereas other prevalence da ta suggest that less than 1% to 2% of the hypertensive population has RVHT. Although elderly atherosclerotic hypertensive individuals often have atheroscler otic renal artery disease, their hypertension is usually essential hypertension, not RVHT. On balance, the prevalence of RVHT in the general hypertensive popula tion is probably no more than 2% to 3%. The particular appeal of diagnosing RVHT centers around its potential curability by an interventive maneuver such as sur gical revascularization, percutaneous transluminal renal angioplasty (PTRA), or renal artery stenting. Whether or not to use these interventions for the goal of improving blood pressure depends on the likelihood such intervention will impro ve the blood pressure. The overwhelming majority of patients with RVHT will have this syndrome because of main renal artery stenosis. Therefore, the first step in making the diagnosis of RVHT is to demonstrate renal artery stenosis by one o f several imaging procedures and, eventually, by angiography. The second step in establishing the probability that the renal artery stenosis is instrumental in promoting hypertension is to determine the pathophysiologic significance of the

stenotic lesion. Finally, the hypertension, presumed to be renovascular in origi n, is proven to be RVHT when the elevated blood pressure is cured or markedly am eliorated by an interventive maneuver such as surgical revascularization, PTRA, renal artery stent, or nephrectomy.

Renovascular Hypertension and Ischemic Nephropathy 3.9 DIAGNOSIS OF RENAL ARTERIAL STENOSIS Clinical clues Age of onset of hypertension <30 y or >55 y Abrupt onset of hypertension Acceler ation of previously well-controlled hypertension Hypertension refractory to an a ppropriate three-drug regimen Accelerated retinopathy Systolic-diastolic abdomin al bruit Evidence of generalized atherosclerosis obliterans Malignant hypertensi on Flash pulmonary edema Acute renal failure with use of angiotensin-converting enzyme inhibitors or angiotensin II receptor-blockers Diagnostic tests Duplex ultrasonography Radionuclide renography Captopril renography Captopril pr ovocation test Intravenous digital subtraction angiography Rapid sequence IVP Ma gnetic resonance angiography Spiral CT angiography CO2 angiography Conventional (contrast) angiography FIGURE 3-14 Diagnosis of renal artery stenosis. Clinical clues suggesting renal artery stenosis, some of which suggest that the stenosis is the cause of the hyp ertension, are listed on the left. The well-documented age of onset of hypertens ion in an individual under the age of 30 or over age 55 years, particularly if t he hypertension is severe and requiring three antihypertensive drugs, is a stron g clinical clue to renal artery stenosis and predicts that the stenosis is causi ng the hypertension. The patient with a long history of mild hypertension, easil y controlled with one or two drugs, who, particularly in older age, develops sev ere and refractory hypertension, is likely to have developed atherosclerotic ren al artery stenosis as a contributor to underlying longstanding essential hypertension. Grade III hypertensive retinopathy, maligna nt hypertension, and flash pulmonary edema all suggest renal artery stenosis wit h or without renovascular hypertension. The observation of a diastolic bruit in the abdomen of a young white women suggests fibrous renal artery disease and, fu rther, is a reliable clinical clue that the hypertension will be helped substant ially by surgical renal revascularization or percutaneous transluminal renal ang ioplasty. The diagnostic tests listed along the right side are used mainly to de tect renal artery stenosis (ie, the anatomic presence of disease). Captopril ren ography is also used to predict physiologic significance of the stenotic lesion. The popularity of these diagnostic tests in detecting renal artery stenosis var ies from institution to institution; correlations with percent stenosis by compa rative angiography are widely variable. A substantial fall in blood pressure fol lowing initiation of an angiotensin-converting enzyme inhibitor or angiotensin I I receptor blocker suggests RVHT. With the exception of a diastolic abdominal br uit and accelerated retinopathy, no clear-cut physical findings definitely discr iminate patients with RVHT from the larger pool of patients with essential hyper tension. FIGURE 3-15 Renal duplex ultrasound for diagnosis of renal artery stenosis. Dupl ex ultrasound scanning of the renal arteries is a noninvasive screening test for the detection of renal artery stenosis. It combines direct visualization of the renal arteries (B-mode imaging) with measurement of various hemodynamic factors in the main renal arteries and within the kidney (Doppler), thus providing both an anatomic and functional assessment. Unlike other noninvasive screening tests (eg, captopril renography), duplex ultrasonography does not require patients to discontinue any antihypertensive medications before the test. The study should be performed while the patient is fasting. The white arrow indicates the aorta a nd the black arrow the left renal artery, which is stenotic. Doppler scans (bott om) measure the corresponding peak systolic velocities in the aorta and in the r enal artery. The peak systolic velocity in the left renal artery was 400 cm/s, a

nd the peak systolic velocity in the aorta was 75 cm/s. Therefore, the renalaort ic ratio was 5.3, consistent with a 60% to 99% left renal artery stenosis. (From Hoffman and coworkers [4]; with permission.)

3.10 Hypertension and the Kidney FIGURE 3-16 Comparison of duplex ultrasound with arteriography. A total of 102 c onsecutive patients with both duplex ultrasound scanning of the renal arteries a nd renal arteriography were prospectively studied. All patients in this study ha d difficult-to-control hypertension, unexplained azotemia, or associated periphe ral vascular disease, giving them a high pretest likelihood of renovascular hype rtension. Sixty-two of 63 arteries that showed less than 60% stenosis by formal arteriography, were identified by duplex ultrasound scanning. Twenty-two of 23 a rteries with total occlusion on arteriography were correctly identified by duple x ultrasound. Thirty-one of 32 arteries with 60% to 79% stenosis using arteriogr aphy were identified as having 60% to 99% stenosis on duplex ultrasound and 67 o f 69 arteries with 80% to 99% stenosis on arteriography were detected to have 60 % to 99% stenosis on ultrasound. A current limitation of duplex ultrasound is th e inability to consistently distinguish between more than and less than 80% sten osis (considered to be the magnitude of stenosis required for hemodynamic signif icance of the lesion). Nevertheless, duplex ultrasound is currently highly sensi tive and specific in patients with a high likelihood of renovascular disease in detecting patients with more or less than 60% renal artery stenosis. Accessory r enal arteries are difficult to identify by ultrasound and remain a limitation of this test. (Adapted from Olin and coworkers [5]; with permission.) renogram not only suggest the anatomic presence of renal artery stenosis but also imply that the stenosis is instrumental in producing the hypertension. Reductions of lumen diameter of less than 70% to 80% generally do not initiate renal ischemia or ac tivation of the renin angiotensin system; thus, before recommending a renal reva scularization procedure, severe renal artery stenosis (>75% reduction in lumen d iameter) should be observed on the renal angiogram. A lateralizing renal vein re nin ratio (a comparison of renin harvested from the renal vein ipsilateral to th e renal artery stenosis with the renin level from renal vein of the contralatera l kidney), particularly when renin production from the contralateral kidney is s uppressed, suggests that an intervention on the renal artery stenosis will cure or markedly ameliorate the hypertension in about 90% of cases. Conversely, cure or marked improvement in blood pressure following renal revascularization has be en reported in nearly 50% of cases in the absence of lateralizing renal vein ren ins. Hypokalemia, in the absence of diuretic therapy, strongly suggests that the hypertension is renovascular in origin, consequent to secondary aldosteronism. The sensitivity of an IVP in detecting unilateral RVHT is relatively poor (about 75%) and the overall sensitivity in detecting patients with bilateral renal art ery disease is only about 60%. Because RVHT has a low prevalence in the general population, a negative IVP provides strong evidence (98% to 99% certainty) again st RVHT. COMPARISON OF DUPLEX ULTRASOUND WITH ARTERIOGRAPHY Percent stenosis by arteriogram 059 62 1 0 63 6079 0 31 1 32 8099 1 67 1 69 100 1 0 22 23 Total 64 99 24 187 Percent stenosis by ultrasound 059 6099 100 Total Sensitivity, 0.98. Specificity, 0.98. Positive predictive value, 0.99. Negative predictive value, 0.97. DETERMINATION OF PATHOPHYSIOLOGIC SIGNIFICANCE OF THE STENOTIC LESION Duration of hypertension <35 y Appearance of lesion on angiogram (>75% stenosis) Systolic-diastolic bruit in abdomen Renal vein renin ratio >1.5 Positive captopr il provocation test or captopril renogram Abnormal rapid sequence IVP Hypokalemi a FIGURE 3-17 Determination of pathophysiologic significance of the stenotic lesio

n. The second step in making the diagnosis of renovascular hypertension (RVHT) i s to determine the pathophysiologic significance of the stenotic lesion demonstr ated by angiography. The likelihood of cure of the hypertension by an interventi ve maneuver is greatly enhanced when one or more of the items listed here are pr esent. A positive captopril provocation test, abnormal rapid sequence intravenou s pyelogram (IVP), or positive captopril

Renovascular Hypertension and Ischemic Nephropathy 3.11 RENIN CRITERIA FOR CAPTOPRIL TEST THAT DISTINGUISH PATIENTS WITH RVHT FROM THOSE WITH ESSENTIAL HYPERTENSION Stimulated PRA of 12 ng/mL/h or more Absolute increase in PRA of 10 ng/mL/h or m ore Percent increase in PRA Increase in PRA of 150% if baseline PRA >3 ng/mL/h I ncrease in PRA of 400% if baseline PRA <3 ng/mL/h FIGURE 3-18 The captopril test: renin criteria that distinguish patients with re novascular hypertension from those with essential hypertension. The captopril pr ovocation test evolved because the casual measurement of peripheral plasma renin activity (PRA) has been of little value as a diagnostic screening test for renovascular hypertension (RVHT). The n otion that patients with high PRA, even in the face of high urinary sodium excre tion, might turn out to have RVHT has not been supported by numerous clinical ob servations. However, the short-term (60- to 90-minute) response of blood pressur e and PRA to an oral dose (25 to 50 mg) of captopril has gained recent popularit y as a screening test for presumed RVHT. Preparation of patients for this test i s vital; ideally patients should discontinue their antihypertensive medications, maintain a diet adequate in salt, and have good renal function. A baseline bloo d pressure and PRA are obtained after which captopril is administered; 60 minute s after captopril administration, a postcaptopril PRA is obtained along with repea t measurements of blood pressure. Early reports with this test indicated a high sensitivity and specificity (95% to 100%) in identifying RVHT if all three of th e renin criteria listed here were met. Subsequent reports have not been as encou raging such that the overall sensitivity of this captopril test is only about 70 %, with a specificity of approximately 85%. (Adapted from Muller and coworkers [ 6]; with permission.) 1.0 1.0 0.8 Relative acidity Relative acidity Bladder Right kidney Left kidney 0.8 0.6 0.6 0.4 0.4 0.2 0.2 Bladder Right kidney Left kidney 0 0 8 16 0 24 Time, min 32 40 48 A

B 0 8 16 24 Time, min 32 40 48 FIGURE 3-19 Captopril renography. A, TcDPTA time-activity curves during baseline . B, TcDPTA time-activity curves after captopril administration. These curves re present a captopril renogram in a patient with unilateral left renal artery sten osis. This diagnostic test has been used to screen for renal artery stenosis and to predict renovascular hypertension. Captopril renography appears to be highly sensitive and specific for detecting physiologically significant renal artery s tenosis. Scintigrams and time-activity curves should both be analyzed to assess renal perfusion, function, and size. If the renogram following captopril adminis tration is abnormal (panel B, demonstrating delayed time to maximal activity and retention of the radionuclide in the right kidney), another renogram may be obt ained without captopril for comparison. The diagnosis of renal artery stenosis i s based on asymmetry of renal size and function and on specific, captoprilinduced changes i n the renogram, including delayed time to maximal activity (11 minutes), signific ant asymmetry of the peak of each kidney, marked cortical retention of the radio nuclide, and marked reduction in the calculated glomerular filtration rate of th e kidney ipsilateral to the stenosis. One must interpret the clinical and renogr aphic data with caution, as protocols are complex and diagnostic criteria are no t well standardized. Nevertheless, captopril renography appears to be an improve ment over the captopril provocation test, with many reports indicating sensitivi ty and specificity from 80% to 95% in predicting an improvement in blood pressur e following intervention. (Adapted from Nally and coworkers [7]; with permission .)

3.12 Hypertension and the Kidney now available to detect renal artery stenosis and several tests designed to pred ict the physiologic significance of the stenotic lesion, the index of clinical s uspicion for RVHT remains the focal point of the work-up for RVHT. A brief durat ion of moderately severe hypertension is the most important clue directing subse quent work-up for RVHT. If the index of clinical suspicion (see Fig. 3-14) is hi gh, it is reasonable to proceed directly to formal renal arteriography with rena l vein renin determination. Alternatively, in patients highly suspected to have RVHT, a captopril renogram followed by a renal arteriogram may be recommended. S trong arguments against RVHT include 1) long duration (more than 5 years) of hyp ertension, 2) old age, 3) generalized atherosclerosis, 4) increased serum creati nine, and 5) a normal serum potassium concentration. For these patients, particu larly if the blood pressure is only minimally elevated or easily controlled with one or two antihypertensive medications, further work-up for RVHT is not indica ted. (Adapted from Mann and Pickering [8]; with permission.) Suggested work-up for renovascular hypertension Index of clinical suspicion Low (<1%) Low PRA Normal or high Moderate (5%15%) High (>25%) ? Captopril test, or captopril renogram, or stimulated renal vein renins, or (?) d uplex ultrasound No further work-up Negative Positive Arteriogram + renal vein renins FIGURE 3-20 Suggested work-up for renovascular hypertension. Because the prevale nce of renovascular hypertension (RVHT) among hypertensive persons in general is approximately 2% or less, widespread screening for renovascular disease is not justified. Despite the proliferation of diagnostic tests Ischemic Nephropathy FIGURE 3-21 Aortogram in a 62-year-old white woman demonstrating subtotal occlus ion of the left main renal artery supplying an atrophic left kidney and high-gra de ostial stenosis of the proximal right renal artery from atherosclerosis. This patient presented in 1977 with a recent appearance of hypertension and a blood pressure of 170/115 mm Hg. Three years previously, when diagnosed with polycythe mia vera, an IVP was normal. She was followed closely between 1974 and 1977 by h er physician and was always normotensive until the hypertension suddenly appeare d. A repeat rapid sequence IVP demonstrated a reduction in the size of the left kidney from 14 cm in height (1974) to 11.5 cm in height (1977). The serum creati nine was 2.6 mg/dL. The renal arteriogram shown here indicates high-grade bilate ral renal artery stenosis with the left kidney measuring 11.5 cm in height, and the right kidney measuring 14.5 cm in height. Renal vein renins were obtained an d lateralized strongly to the smaller left kidney. The blood pressure was well c

ontrolled with inderal and chlorthalidone. Right aortorenal reimplantation was u ndertaken solely to preserve renal function. Postoperatively the serum creatinin e fell to 1.5 mg/dL and remained at this level for the next 13 years. Blood pres sure continued to require antihypertensive medication, but was controlled to nor mal levels with inderal and chlorthalidone.

Renovascular Hypertension and Ischemic Nephropathy 3.13 12.0 11.0 10.0 9.0 8.0 Serum creatinine, mg/dL 7.0 6.0 Pt. 3 Pt. 8 Pt. 7 5.0 Pt. 6 A 4.0 3.0 2.0 1.0 0 Admission Medical therapy Surgery or angioplasty Pt. 2 Pt. 1 Pt. 4 Pt. 3 FIGURE 3-22 Effects of medical therapy and surgery or angioplasty on serum creat inine levels. This figure describes eight patients hospitalized because of sever e hypertension and renal insufficiency. With medical management of the hypertens ion (antihypertensive drug therapy), four of the eight patients developed substa ntial worsening of their renal function as measured by serum creatinine; three o f these four patients demonstrated improvement following surgery or angioplasty. The other four patients (patients one to four) did not demonstrate a worsening serum creatinine level with medical therapy; but three of these four patients sh owed improved renal function following surgery or angioplasty. (Adapted from Yin g and coworkers [9]; with permission.) B FIGURE 3-23 Improved renal function demonstrated by intravenous pyelography foll owing left renal revascularization. A, preoperative IVP (5-minute film) in a 65year-old white man with a 15-year history of hypertension; serum creatinine 2.6 mg/dL. Note poorly functioning left kidney, which measured 11.5 cm in height. B, post operative IVP (5-minute film) obtained following left aortorenal saphenous vein bypass grafting to the left kidney. Note the prompt function and increased height (14.0 cm) of the revascularized left kidney versus the preoperative IVP. (From Novick and Pohl [10]; with permission.) The clinical story of the patient in Figure 3-21, the benefits of surgical renal revascularization or pecutaneous transluminal renal angioplasty (Fig. 3-22), and the radiographic evidence of im proved renal function after renal revascularization (Fig. 3-23) are examples of ischemic nephropathy. Two definitions of ischemic nephropathy are suggested here in: 1) clinically significant reduction in renal function due to compromise of t he renal circulation; and 2) clinically significant reduction in glomerular filt ration rate due to hemodynamically significant obstruction to renal blood flow, or renal failure due to renal artery occlusive disease.

3.14 Hypertension and the Kidney FIGURE 3-24 Atherosclerotic renal artery stenosis in patients with generalized a therosclerosis obliterans and in patients with coronary artery disease (CAD). At herosclerotic renal artery stenosis is common in older patients with and without hypertension simply as a consequence of generalized atherosclerosis obliterans. Approximately 40% of consecutively studied patients undergoing arteriography fo r routine evaluation of abdominal aortic aneurysm, aorto-occlusive disease, or l ower extremity occlusive disease have associated renal artery stenosis (more tha n 50% unilateral renal artery stenosis) and nearly 30% of patients undergoing co ronary angiography may have incidentally detected unilateral renal artery stenos is. Approximately 4% to 13% of patients with CAD or peripheral vascular disease have more than 75% bilateral renal artery stenosis. Correlations of hypercholest erolemia and cigarette smoking with renal artery atherosclerosis are not unequiv ocally clear, but they probably represent risk factors for renal artery atherosc lerosis just as they represent risk factors for atherosclerosis in other vascula r beds. (Adapted from Olin and coworkers [11]; with permission.) ATHEROSCLEROTIC RENAL ARTERY STENOSIS IN 395 PATIENTS WITH GENERALIZED ATHEROSCL EROSIS OBLITERANS AND IN PATIENTS WITH CORONARY ARTERY DISEASE Patients, n Abdominal aortic aneurysm Aorto-occlusive disease Lower extremity disease Suspec ted renal artery stenosis Coronary artery disease 109 21 189 76 76 817 Percent of patients with >50% stenosis 38 33 39* 70 29 20 *50% in diabetic patients. Data from Vetrovec and coworkers [12]. Data from Hardin g [13]. CLINICAL PRESENTATIONS OF ISCHEMIC RENAL DISEASE Acute renal failure, frequently precipitated by a reduction in blood pressure (i e, angiotensin-converting enzyme inhibitors plus diuretics) Progressive azotemia in a hypertensive patient with known renal artery stenosis treated medically Pr ogressive azotemia in a patient (usually elderly) with refractory hypertension U nexplained progressive azotemia in an elderly patient Hypertension and azotemia in a renal transplant patient FIGURE 3-25 Clinical presentations of ischemic renal disease. The clinical prese ntation of a patient likely to develop renal failure from atherosclerotic ischem ic renal disease is that of an older (more than 50 years) individual demonstrati ng progressive azotemia in conjunction with antihypertensive drug therapy, risk factors for generalized atherosclerosis obliterans, known renal artery disease, refractory hypertension, and generalized atherosclerosis. Acute renal failure pr ecipitated by a reduction in blood pressure below a critical perfusion pressure, a nd particularly with the use of angiotensin convertingenzyme inhibitors (ACEI) o r angiotensin II receptor blockers plus diuretics, strongly suggests severe intr arenal ischemia from arteriolar nephrosclerosis and/or severe main renal artery stenosis. Unexplained progressive azotemia in an elderly patient with clinical s igns of vascular disease with minimal proteinuria and a bland urinary sediment a lso suggest ischemic nephropathy. (Adapted from Jacobson [14]; with permission.)

Renovascular Hypertension and Ischemic Nephropathy 3.15 A B FIGURE 3-26 Mild stenosis (less than 50%) due to atherosclerotic disease of the left main renal artery (panel A) that has progressed to high-grade (75% to 99%) stenosis on a later arteriogram (panel B). Underlying the concept of renal revas cularization for preservation of renal function is the notion that atherosclerot ic renal artery disease (ASO-RAD) is a progressive disorder. The sequential angi ograms in Figures 3-26 and 3-27 show angiographic progression of ASO-RAD over ti me. In patients demonstrating progressive renal artery stenosis by serial angiog raphy, a decrease in kidney function as measured by serum creatinine and a decre ase in ipsilateral kidney size correlate significantly with progressive occlusiv e disease. Patients demonstrating more than 75% stenosis of a renal artery are a t highest risk for progression to complete occlusion. (From Novick [15]; with pe rmission.) A FIGURE 3-27 A, Normal right main renal artery and minimal atherosclerotic irregu larity of left main renal artery on initial (1974) aortogram. B, Repeat aortogra phy (1978) showed progression to moderate B stenosis of the right main renal artery (arrow) and total occlusion of left main renal artery (arrow). (From Schreiber and coworkers [16]; with permission.)

3.16 Hypertension and the Kidney entire renal functioning mass is not threatened by large vessel occlusive diseas e. Clinical clues to the high-risk patient are similar to the clinical presentat ions of ischemic renal disease shown in Figure 3-25. Nearly 75% of adults with a unilateral small kidney have sustained this renal atrophy due to large vessel o cclusive disease from atherosclerosis. One third of these patients with a unilat eral small kidney have high-grade stenosis of the artery involving the contralat eral normalsized kidney. Flash pulmonary edema is another clue to bilateral reno vascular disease or high-grade stenosis involving a solitary functioning kidney. These patients, usually hypertensive and with documented coronary artery diseas e and underlying hypertensive heart disease, present with the abrupt onset of pu lmonary edema. Left ventricular ejection fractions in these patients are not ser iously impaired. Flash pulmonary edema is associated with atherosclerotic renal artery disease and may occur with or without severe hypertension. Renal revascul arization to preserve kidney function or to prevent life-threatening flash pulmo nary edema may be considered in patients with high-grade arterial stenosis to a solitary kidney or high-grade bilateral renal artery stenosis. Pecutaneous trans luminal renal angioplasty (PTRA), renal artery stenting, or surgical renal revas cularization may be employed. Patients with chronic total renal artery occlusion bilaterally or in a solitary functioning kidney are candidates for surgical ren al revascularization, but are not candidates (from a technical standpoint) for P TRA or renal artery stents. potential for salvable renal function. Clinical clue s suggesting renal viability include 1) kidney size greater than 9 cm (pole-topo le length) by laminography (tomography); 2) some function of the kidney on eithe r urogram or renal flow scan; 3) filling of distal renal arteries (by collateral s) angiographically, when the main renal artery is totally occluded proximally ( see Fig. 3-30); and 4) well-preserved glomeruli with minimal interstitial scarri ng (see Fig. 3-31) on renal biopsy. Patients with moderately severe azotemia, eg , serum creatinine more than 3-4 mg/dL, are likely to have severe renal parenchy mal scarring (see Fig. 3-32), which renders improvement in renal function follow ing renal revascularization unlikely. Exceptions to this observation are cases o f total main renal artery occlusion wherein kidney viability is maintained via c ollateral circulation (see Figure 3-30). A kidney biopsy may guide subsequent de cision making regarding renal revascularization for the goal of improving kidney function. FIGURE 3-30 This abdominal aortogram reveals complete occlusion of th e left main renal artery (panel A) with filling of the distal renal artery branc hes from collateral supply on delayed films (panel B). The observation of collat eral circulation when the main renal artery is totally occluded proximally sugge sts viable renal parenchyma. (From Novick and Pohl [10]; with permission.) CLINICAL CLUES TO BILATERAL ATHEROSCLEROTIC RENOVASCULAR DISEASE Generalized atherosclerosis obliterans Presumed renovascular hypertension Unilat eral small kidney Unexplained azotemia Deterioration in renal function with BP r eduction and/or ACE inhibitor therapy Flash pulmonary edema FIGURE 3-28 Clinical clues to bilateral atherosclerotic renovascular disease. Th e patient at highest risk for developing renal insufficiency from renal artery s tenosis (ischemic nephropathy) has sufficient arterial stenosis to threaten the entire renal functioning mass. These highrisk patients have high-grade (more tha n 75%) arterial stenosis to a solitary functioning kidney or high-grade (more th an 75%) bilateral renal artery stenosis. Patients with two functioning kidneys w ith only unilateral renal artery stenosis are not at significant risk for develo ping renal insufficiency because the PREDICTORS OF KIDNEY SALVAGEABILITY Kidney size >9 cm (laminography) Function on either urogram or renal flow scan F illing of distal renal arteries (by collaterals) angiographically, with total pr

oximal occlusion Glomerular histology on renal biopsy FIGURE 3-29 Predictors of kidney salvageability. In evaluating patients as candi dates for renal revascularization to preserve or improve renal function, some de termination should be made of the A B

Renovascular Hypertension and Ischemic Nephropathy 3.17 FIGURE 3-31 Renal biopsy of a solitary left kidney in a 67-year-old woman who ha d been anuric and on chronic dialysis for 9 months. The biopsy shows hypoperfuse d retracted glomeruli consistent with ischemia. There is no evidence of active g lomerular proliferation or glomerular sclerosis. Note intact tubular basement me mbranes and negligible interstitial scarring. Left renal revascularization resul ted in recovery of renal function and discontinuance of dialysis with improvemen t in serum creatinine to 2.0 mg/dL. (From Novick [15]; with permission.) FIGURE 3-32 Pathologic specimen of kidney beyond a main renal artery occlusion i n a patient with severe bilateral renal artery stenosis and a serum creatinine o f 4.5 mg/dL. The biopsy demonstrates glomerular sclerosis, tubular atrophy, and interstitial fibrosis. The magnitude of glomerular and interstitial scarring pre dict irreversible loss of kidney viability. (From Pohl [1]; with permission.) FIGURE 3-33 Severe atherosclerosis involving the abdominal aorta, renal, and ili ac arteries. This abdominal aortogram demonstrates a ragged aorta, total occlusi on of the right main renal artery, and subtotal occlusion of the proximal left m ain renal artery. Such patients are at high-risk for atheroembolic renal disease following aortography, selective renal arteriography, pecutaneous transluminal renal angioplasty, renal artery stenting, or surgical renal revascularization. FIGURE 3-34 (see Color Plate) Purple toe syndrome reflecting peripheral atheroembo lic disease in the patient in Figure 3-33 (ragged aorta), following an abdominal aortogram.

3.18 Hypertension and the Kidney FIGURE 3-35 Pathologic specimen of kidney demonstrating atheroembolic renal dise ase (AERD). Microemboli of atheromatous material are readily identified by the c haracteristic appearance of cholesterol crystal inclusions that appear in a bico nvex needle-shaped form. In routine paraffin-embedded histologic sections, the c holesterol is not seen because the methods used in preparing sections dissolve t he crystals; the characteristic biconvex clefts in the glomeruli (or blood vesse ls) persist, allowing easy identification. Several patterns of renal failure in patients with AERD are recognized: 1) insult (eg, abdominal aortogram) leads to end-stage renal disease (ESRD) over weeks to months; 2) insult leads to chronic stable renal insufficiency; 3) multiple insults (repeated angiographic procedure s) lead to a step-wise rise in serum creatinine eventuating in end-stage renal f ailure; and 4) insult leading to ESRD over several weeks to months with recovery of some renal function allowing for discontinuance of dialysis. FIGURE 3-36 Ren al biopsy demonstrating severe arteriolar nephrosclerosis. Arteriolar nephroscle rosis is intimately associated with hypertension. The histology of the kidney in arteriolar nephrosclerosis shows considerable variation in intensity and extent of the arteriolar lesions. Thickening of the vessel wall, edema of the smooth m uscle cells, hypertrophy of the smooth muscle cells, and hyaline degeneration of the vessel wall may be apparent depending on the severity of the nephrosclerosi s. In addition to the vascular lesions of arteriolar nephrosclerosis there are a bnormalities of glomeruli, tubules, and interstitial areas that are believed to be secondary to the ischemia that results from arteriolar insufficiency. Arterio lar nephrosclerosis is observed in patients with longstanding hypertension; the more severe the hypertension, the more severe the arteriolar nephrosclerosis. Ar teriolar nephrosclerosis may also be seen in elderly normotensive individuals an d is frequently observed in elderly patients with generalized atherosclerosis or essential hypertension. FIGURE 3-37 Schematic representation of ischemic nephro pathy. Patients with atherosclerotic renal artery disease (ASO-RAD) often have c oexisting renal parenchymal disease with varying degrees of nephrosclerosis (sma ll vessel disease) or atheroembolic renal disease. Whether or not the renal insu fficiency is solely attributable to renal artery stenosis, nephrosclerosis, or a theroembolic renal disease is difficult to determine. The term ischemic nephropat hy is more complex than being simply due to atherosclerotic renal artery stenosis . In addition, in the azotemic patient with ASORAD, one should exclude other pot ential or contributing causes of renal insufficiency such as obstructive uropath y, primary glomerular disease (suggested by heavy proteinuria), drug-related ren al insufficiency (eg, nonsteroidal anti-inflammatory drugs), and uncontrolled bl ood pressure. Atherosclerosis Nephrosclerosis Atheroembolism

Renovascular Hypertension and Ischemic Nephropathy 4% Miscellaneous 3.19 11% Other 12% CGN 36% DM 29% High blood pressure 5% Urology 3% Cyst FIGURE 3-38 Distribution of endstage renal disease diagnoses. Atherosclerotic re nal artery disease (ASORAD) has been claimed to contribute to the ESRD populatio n. This diagram from the US Renal Data System Coordinating Center 1994 report in dicates that 29% of calendar year 1991 incident patients entered ESRD programs b ecause of hypertension (HBP). No renovascular disease diagnosis is listed. Crude e stimates of the percentage of patients entering ESRD programs because of ASO-RAD range from 1.7% to 15%. Precise bases for making these estimates are both uncle ar and confounded by the high likelihood of coexisting arteriolar nephrosclerosi s, type II diabetic nephropathy, and atheroembolic renal disease. ASO-RAD as a m ajor contributor to the ESRD population is probably small on a percentage basis, occupying some portion of the ESRD diagnosis hypertension (HBP). For dialysis-dep endent patients with ASO-RAD, predictors of recovery of renal function following renal revascularization and allowing for discontinuance of dialysis (temporary or permanent) include 1) bilateral (vs unilateral) renal artery stenosis, 2) a r elatively fast rate of decline of estimated glomerular filtration rate (less tha n 6 months) prior to initiation of dialysis; and 3) mild-tomoderate arteriolar n ephrosclerosis angiographically. Treatment of Renovascular Hypertension and Ischemic Nephropathy TREATMENT OPTIONS FOR RENOVASCULAR HYPERTENSION AND ISCHEMIC NEPHROPATHY Pharmacologic antihypertensive therapy PTRA Renal artery stents Surgical renal r evascularization FIGURE 3-39 Treatment options for renovascular hypertension and ischemic nephrop athy. The main goals in the treatment of renovascular hypertension or ischemic n ephropathy are to control the blood pressure, to prevent target organ complicati ons, and to avoid the loss of renal function. Although the issue of renal functi on may be viewed as mutually exclusive from the issue of blood pressure control, uncontrolled hypertension may hasten a decline in renal function, and renal ins ufficiency may produce worsening hypertension. Even in the presence of excellent blood pressure control, progressive arterial stenosis might worsen renal ischem ia and promote renal atrophy and fibrosis. Therapeutic options include pharmacol ogic antihypertensive therapy, percutaneous transluminal renal angioplasty (PTRA ), renal artery stents, and surgical renal revascularization. Pharmacologic anti hypertensive therapy is covered in more detail separately in this Atlas. FIGURE 3-40 Comorbidity in patients undergoing renovascular surgery. Patients presentin g for renovascular surgery or endovascular renal revascularization are at high-r isk for complications during intervention because of age, and frequently associa ted coronary, cerebrovascular, or peripheral vascular disease. As the population ages, the percentage of patients being considered for interventive maneuvers on the renal artery has increased significantly. Approximately 30% of patients cur rently undergoing interventive approaches to renal artery disease have angina, o r have had a previous myocardial infarction. Congestive heart failure, cerebrova scular disease (eg, carotid artery stenosis), diabetes mellitus, and claudicatio n are frequent comorbid conditions in these patients. Their aortas are often lad en with extensive atherosclerotic plaque (Fig. 3-33), making angiographic invest igation or endovascular renal revascularization hazardous. (Adapted from Hallet

and coworkers [17]; with permission.) INCREASING COMORBIDITY IN PATIENTS UNDERGOING RENOVASCULAR SURGERY Comorbidity, % Condition Angina Prior MI CHF Cerebrovascular disease Diabetes Claudication *P <0.001. 19701980 21.4 16.3 12.2 11.2 7.1 35.7 19801993 29.9 27.0 23.7* 24.8* 18.1* 56.4*

3.20 Hypertension and the Kidney bypass with saphenous vein grafting is a frequently used surgical approach in pa tients with nondiseased abdominal aortas. Severe atherosclerosis of the abdomina l aorta may render an aortorenal bypass or renal endarterectomy technically diff icult and potentially hazardous to perform. Effective alternate bypass technique s include splenorenal bypass for left renal revascularization, hepatorenal bypas s for right renal revascularization, ileorenal bypass, bench surgery with autotr ansplantation, and use of the supraceliac or lower thoracic aorta (usually less ravaged by atherosclerosis). Simultaneous aortic replacement and renal revascula rization are associated with an increased risk of operative mortality in compari son to renal revascularization alone. Some surgeons advocate unilateral renal re vascularization in patients with bilateral renovascular disease. FIGURE 3-42 Sch ematic diagram of alternate bypass procedures. A, Hepatorenal bypass to right ki dney. B, Splenorenal bypass to left kidney. C, Ileorenal bypass to left kidney. D, Autotransplantation. DIMINISHED OPERATIVE MORBIDITY AND MORTALITY FOLLOWING SURGICAL REVASCULARIZATIO N FOR ATHEROSCLEROTIC RENOVASCULAR DISEASE Preoperative screening and correction of coronary and carotid artery disease Avo idance of operation on severely diseased aorta Unilateral revascularization in p atients with bilateral renovascular disease FIGURE 3-41 Diminished operative morbidity and mortality following surgical reva scularization for atherosclerotic renovascular disease. Operative morbidity and mortality in patients undergoing surgical revascularization have been minimized by selective screening and/or correction of significant coexisting coronary and/ or carotid artery disease before undertaking elective surgical renal revasculari zation for atherosclerotic renal artery disease. Screening tests for carotid art ery disease include carotid ultrasound and carotid arteriography. Screening test s for coronary artery disease include thallium stress testing, dipyridamole stre ss testing, dobutamine echocardiography, and coronary arteriography. Aortorenal A B C D

Renovascular Hypertension and Ischemic Nephropathy 3.21 A FIGURE 3-43 Percutaneous transluminal renal angioplasty (PTRA) of the renal arte ry. A, High-grade (more than 75%) nonostial atherosclerotic stenosis of the left main renal artery in a patient with a solitary functioning kidney (right renal artery totally occluded). Note gradient of 170 mm Hg across the stenotic lesion. B, Balloon angioplasty of the left main renal artery was successfully performed with reduction in the gradient across the stenotic lesion from 170 mm Hg pre-PT RA to 15 mm Hg post-PTRA. Repeat aortogram 3 years later demonstrated patency of the left renal artery. FIGURE 3-44 High-grade atherosclerotic renal artery sten osis at the ostium of the right main renal artery in a 68-year-old man with a to tally occluded left main renal artery. Several attempts at balloon dilatation we re unsuccessful. Over the subsequent 10 days, severe renal insufficiency develop ed (serum creatinine increasing from 2.0 to 12.0 mg/dL) requiring dialysis. Rena l function never improved and the patient remained on dialysis. B PTRA of the renal artery has emerged as an important interventional modality in the management of patients with renal artery stenosis. PTRA is most successful a nd should be the initial interventive therapeutic maneuver for patients with the medial fibroplasia type of fibrous renal artery disease (eg, Fig.3-5A). Excelle nt technical success rates have also been attained for nonostial atherosclerotic lesions of the main renal artery, as shown here. FIGURE 3-45 Palmaz stent, expanded. Because percutaneous transluminal renal angi oplasty (PTRA) has suboptimal long-term benefits for atherosclerotic ostial rena l artery stenosis, endovascular stenting has gained wide acceptance. Renal arter y stenting may be performed at the time of the diagnostic angiogram, or at some time thereafter, depending on the physician's preference and the risk to the patie nt of repeated angiographic procedures. From a technical standpoint, indications for renal artery stenting include 1) as a primary procedure for ostial atherosc lerotic renal artery disease (ASO-RAD), 2) technical difficulties in conjunction with attempted PTRA, 3) post-PTRA dissection, 4) post-PTRA abrupt occlusion, an d 5) restenosis following PTRA. It is unclear what the long-term patency and res tenosis rates will be for renal artery stenting for ostial disease. Preliminary observations suggest that the 1-year patency rate for stents is approximately tw ice that for PTRA.

3.22 Hypertension and the Kidney FIGURE 3-46 Abdominal aortogram in a 63-year-old male, 6 months following placem ent of a Palmaz stent. Note wide patency of the left main renal artery. A. SURGICAL REVASCULARIZATION VERSUS PTRA FOR ATHEROSCLEROTIC RENAL ARTERY DISEA SE Successful surgical revascularization, % 90 90 B. SURGICAL REVASCULARIZATION VERSUS PTRA FOR FIBROUS RENAL ARTERY DISEASE Successful surgical revascularization, % 90 90 Lesion Nonostial (20%) Ostial (80%) Successful PTRA, % 8090 2530 Lesion Main (50%) Branch (50%) Successful PTRA, % 8090 NA FIGURE 3-47 Surgical revascularization vs percutaneous transluminal renal angiop lasty (PTRA) for renal artery disease. A, Success rates for atherosclerotic rena l artery disease (ASO-RAD). B, Success rates for fibrous renal artery disease. S uccess of either PTRA or surgical renal revascularization is viewed in terms of t echnical success and clinical success. For PTRA, technical success reflects a lumen patency with less than 50% residual stenosis (ie, successful establishment of a patent lumen). For surgical revascularization, technical success is the demonst ration of good blood flow to the revascularized kidney determined during surgery , or postoperatively by DPTA renal scan or other immediate postoperative imaging procedures. Technical success with either PTRA or surgical revascularization is rarely defined by postoperative angiography. Clinical success may be defined as i mproved blood pressure or improvement in kidney function, and/or resolution of f lash pulmonary edema. Technical and clinical successes do not necessarily occur together because technical success may be apparent, but without improvement in b lood pressure or renal function. The percent success for PTRA and surgical revascularization depicted above are est imates, and reflect primarily technical success for both nonostial and ostial lesi ons in ASO-RAD. Technical success rates for surgical revascularization are high, approximating 90%, with little difference in the technical success rates betwee n ostial and nonostial lesions. For PTRA, technical success rates are much highe r for nonostial lesions. There is a high rate of restenosis at 1 year (50% to 70% ) for ostial ASO-RAD, which has promoted the use of renal artery stents for thes e lesions. The success rates of surgical renal revascularization and PTRA for st enosis of the main renal artery in fibrous renal artery disease are comparable, approximately 90%. Hypertension is more predictably improved with surgical revas cularization and PTRA in fibrous renal artery disease in comparison with ASO-RAD . Technical success rates with surgical renal revascularization are high for bra nch fibrous renal artery disease, but long-term technical and clinical success r ates are not available for PTRA of branch lesions due to fibrous dysplasia. NAnot available. (Adapted from Pohl [18]; with permission.)

Renovascular Hypertension and Ischemic Nephropathy 3.23 COMPLICATIONS OF TRANSLUMINAL ANGIOPLASTY OF THE RENAL ARTERIES Contrast-induced ARF (mild or severe) Atheroembolic renal failure Rupture of the renal artery Dissection of the renal artery Thrombotic occlusion of the renal a rtery Occlusion of a branch renal artery Balloon malfunction (may lead to inabil ity to remove balloon) Balloon rupture Puncture site hematoma, hemorrhage, or ve ssel tear Median nerve compression (axillary approach) Renal artery spasm Mortal ity (1%) FACTORS TO CONSIDER IN SELECTION OF TREATMENT FOR PATIENTS WITH RENAL ARTERY DIS EASE Is renal artery disease causing hypertension? Severity of hypertension Specific type of renal artery disease and threat to renal function General medical condit ion of patient Relative efficacy and risk of medical antihypertensive therapy, P TRA, renal artery stenting, surgical revascularization FIGURE 3-48 Complications of transluminal angioplasty of the renal arteries. The more common complications of PTRA are contrast-induced acute renal failure (ARF ) and atheroembolic renal failure. Dissection of the renal artery, occlusion of a branch renal artery, and occasionally thrombotic occlusion of the main renal a rtery may occur. In experienced hands, rupture of the renal artery is rare. Mino r complications relate primarily to the puncture site. When the axillary approac h is used (because of severe iliac and lower abdominal aortic atherosclerosis), median nerve compression may transpire. Some of these complications of percutane ous transluminal renal angioplasty, particularly atheroembolic renal failure and /or contrast-induced acute renal failure (ARF) may also be observed with renal a rtery stent procedures. FIGURE 3-49 Selection of treatment for patients with renal artery disease. In se lecting treatment options for patients with renal artery disease, there are seve ral factors to consider: what is the likelihood that the renal artery disease is causing the hypertension? For patients with fibrous renal artery disease the li kelihood is high; for patients with atherosclerotic renal artery disease (ASO-RA D), the likelihood for a cure of hypertension is small. The more severe the hype rtension, the greater the inclination to intervene with either surgery or balloo n angioplasty. For children, adolescents, and younger adults, most of whom will have fibrous renal artery disease, intervention is usually recommended to avoid lifelong antihypertensive therapy. Cardiovascular comorbidity is high for patien ts with ASO-RAD and appropriate caution in approaching these patients is warrant ed, weighing the relative efficacy and risk of medical antihypertensive therapy, percutaneous transluminal renal angioplasty (PTRA), renal artery stenting, and surgical revascularization. Local experience and expertise of the treating physi cians must be considered as well in selection of treatment options for these pat ients. References 1. Pohl MA: Renal artery stenosis, renal vascular hypertension and ischemic neph ropathy. In Diseases of the Kidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown & Co; 1997: 13671427. 2. Rimmer JM, Gennari FJ: Atheroscler otic renovascular disease and progressive renal failure. Ann Intern Med 1993, 11 8:712719. 3. Brown JJ, Davies DL, Morton JJ, et al.: Mechanism of renal hypertens ion. Lancet 1976, 1:12191221. 4. Hoffmann U, Edwards JM, Carter S, et al.: Role o f duplex scanning for the detection of atherosclerotic renal artery disease. Kid ney Int 1991, 39:12321239. 5. Olin JW, Piedmonte MR, Young JR, et al.: The utilit y of duplex ultrasound scanning of the renal arteries for diagnosing significant renal artery stenosis. Ann Intern Med 1995, 122:833838. 6. Muller FB, Sealey JE, Case DB, et al.: The captopril test for identifying renovascular disease in hyp

ertensive patients. Am J Med 1986, 80:633644. 7. Nally JV, Olin JW , Lammert MD: Advances in noninvasive screening for renovascular hypertension disease. Cleve C lin J Med 1994, 61:328336. 8. Mann SJ, Pickering TG: Detection of renovascular hy pertension: state of the art: 1992. Ann Intern Med 1992, 117:845853. 9. Ying CY, Tifft CP, Gavras H, Chobanian AV: Renal revascularization in the azotemic hypert ensive patient resistant to therapy. N Engl J Med 1984, 311:10701075. 10. Novick AC, Pohl MA: Atherosclerotic renal artery occlusion extending into branches: suc cessful revascularization in situ with a branched saphenous vein graft. J Urol 1 979, 122:240242. 11. Olin JW, Melia M, Young JR, et al.: Prevalence of atheroscle rotic renal artery stenosis in patients with atherosclerosis elsewhere. Am J Med 1990, 88:46N51N. 12. Vetrovec GW, Landwehr DM, Edwards VL: Incidence of renal ar tery stenosis in hypertensive patients undergoing coronary angiography. J Interv ent Cardiol 1989, 2:6976. 13. Harding MB, Smith LR, Himmelstein SI, et al.: Renal artery stenosis: prevalence and associated risk factors in patients undergoing routine cardiac catheterization. J Am Soc Nephrol 1992, 2:16081616. 14. Jacobson HR: Ischemic renal disease: an overlooked clinical entity? [clinical conference] . Kidney Int 1988, 34:729743. 15. Novick AC: Patient selection for intervention t o preserve renal function in ischemic renal disease. In Renovascular Disease. Ed ited by Novick AC, Scoble J, Hamilton G. London: WB Saunders; 1996:323335. 16. Sc hreiber MJ, Pohl MA, Novick AC: The natural history of atherosclerotic and fibro us renal artery disease. Urol Clin North Am 1984, 11:383392. 17. Hallett JW Jr, T extor SC, Kos PB, et al.: Advanced renovascular hypertension and renal insuffici ency: trends in medical comorbidity and surgical approach from 1970 to 1993. J V asc Surg 1995, 21:750759. 18. Pohl MA: Renovascular hypertension: An internist's po int of view. In Hypertension. Edited by Punzi HA, Flamenbaum W. Mt. Kisco, NY: F utura Publishing Co Inc; 1989:367393.

3.24 Hypertension and the Kidney Selected Bibliography Goldblatt H, Lynch J, Hanzal RF, Summerville WW: Studies on experimental hyperte nsion. I. The production of persistent elevation of systolic blood pressure by m eans of renal ischemia. J Exp Med 1934, 59:347381. Morris GC Jr, DeBakey ME, Cool ey MJ: Surgical treatment of renal failure of renovascular origin. JAMA 1962, 18 2:113116. Novick AC, Ziegelbaum M, Vidt DG, et al.: Trends in surgical revascular ization for renal artery disease: ten years' experience. JAMA 1987, 257:498501. Dus tan HP, Humphries AW, DeWolfe VG, et al.: Normal arterial pressure in patients w ith renal arterial stenosis. JAMA 1964, 187:10281029. Holley KE, Hunt JC, Brown A LJ, et al.: Renal artery stenosis: a clinicalpathological study in normotensive and hypertensive patients. Am J Med 1964, 34:1422. Page IH: The production of per sistent arterial hypertension by cellophane perinephritis. JAMA 1939, 113:2046204 8. McCormack LJ, Poutasse EF, Meaney TF, et al.: A pathologic-arteriographic cor relation of renal arterial disease. Am Heart J 1966, 72:188198. Pohl MA, Novick A C: Natural history of atherosclerotic and fibrous renal artery disease: clinical implications. Am J Kidney Dis 1985, 5:A120A130. Zierler RE, Bergelin RO, Davidso n RC, et al.: A prospective study of disease progression in patients with athero sclerotic renal artery stenosis. Am J Hypertens 1996, 9:10551061. Caps MT, Zierle r RE, Polissar NL, et al.: Risk of atrophy in kidneys with atherosclerotic renal artery stenosis. Kidney Int 1998, 53:735742. Goncharenko V, Gerlock AJ Jr, Shaff MI, Hollifield JW: Progression of renal artery fibromuscular dysplasia in 42 pa tients as seen on angiography. Radiology 1981, 139:4551. Vaughan ED Jr, Carey RM, Ayers CR, et al.: A physiologic definition of blood pressure response to renal revascularization in patients with renovascular hypertension. Kidney Int 1979, 1 5:S83S92. Textor SC: Renovascular hypertension. Curr Opin Nephrol Hyperten 1993, 2:775783. Working Group on Renovascular Hypertension: Detection, evaluation, and treatment of renovascular hypertension. Final report. Arch Intern Med 1987, 147: 820829. Hughes JS, Dove HG, Gifford RW Jr, Feinstein AR: Duration of blood pressu re elevation in accurately predicting surgical cure of renovascular hypertension . Am Heart J 1981, 101:408413. Svetkey LP, Himmelstein SI, Dunnick NR, et al.: Pr ospective analysis of strategies for diagnosing renovascular hypertension. Hyper tension 1989, 14:247257. Setaro JF, Saddler MC, Chen CC, et al.: Simplified capto pril renography in diagnosis and treatment of renal artery stenosis. Hypertensio n 1991, 18:289298. Novick AC, Pohl MA, Schreiber M, et al.: Revascularization for preservation of renal function in patients with atherosclerotic renovascular di sease. J Urol 1983, 129:907912. Gifford RW Jr, McCormack LJ, Poutasse EF: The atr ophic kidney: its role in hypertension. Mayo Clin Proc 1965, 40:834852. Pickering TG, Herman L, Devereux RB, et al.: Recurrent pulmonary oedema in hypertension d ue to bilateral renal artery stenosis: treatment by angioplasty or surgical reva scularisation. Lancet 1988, 2:551552. United States Renal Data System Coordinatin g Center: Incidence and causes of treated ESRD. In The USRDS 1994 Annual Data Re port. Edited by Agodoa LYC, Held PJ, Port FK. Bethesda: USRDS Coordinating Cente r; 1994:4354. Mailloux LU, Napolitano B, Bellucci AG, et al.: Renal vascular dise ase causing end-stage renal disease, incidence, clinical correlates, and outcome s: a 20-year clinical experience. Am J Kidney Dis 1994, 24:622639. Appel RG, Bley er AJ, Reavis S, Hansen KJ: Renovascular disease in older patients beginning ren al replacement therapy. Kidney Int 1995, 48:171176. Hansen KJ, Thomason RB, Crave n TE, et al.: Surgical management of dialysisdependent ischemic nephropathy. J V asc Surg 1995, 21:197209. Hallett JW Jr, Fowl R, O'Brien PC, et al.: Renovascular o perations in patients with chronic renal insufficiency: do the benefits justify the risks? J Vasc Surg 1987, 5:622627. Conlon PJ, Athirakul K, Kovalik E, et al.: Survival in renal vascular disease. J Am Soc Nephrol 1998, 9:252256. Textor SC, McKusick MA, Schirger AA, et al.: Atherosclerotic renovascular disease in patien ts with renal failure. Adv Nephrol Necker Hosp 1997, 27:281295. Novick AC, Straff on RA, Stewart BH, et al.: Diminished operative morbidity and mortality in renal revascularization. JAMA 1981, 246:749753. Khauli RB, Novick AC, Ziegelbaum M: Sp

lenorenal bypass in the treatment of renal artery stenosis: experience with sixt y-nine cases. J Vasc Surg 1985, 2:547551. Chibaro EA, Libertino JA, Novick AC: Us e of the hepatic circulation for renal revascularization. Ann Surg 1984, 199:4064 11. Novick AC, Stewart R: Use of the thoracic aorta for renal revascularization. J Urol 1990, 143:7779. Tarazi RY, Hertzer NR, Beven EG, et al.: Simultaneous aor tic reconstruction and renal revascularization: risk factors and late results in eighty-nine patients. J Vasc Surg 1987, 5:707714. Hollenberg NK: Medical therapy of renovascular hypertension: efficacy and safety of captopril in 269 patients. Cardiovasc Rev Rpts 1983, 4:852879. Pohl MA: Medical management of renovascular hypertension. In Renal Vascular Disease. Edited by Novick AC, Scoble J, Hamilton G. London: WB Saunders; 1996, 339349. Palmaz JC, Kopp DT, Hayashi H, et al.: Nor mal and stenotic renal arteries: Experimental balloon-expandable intraluminal st enting. Radiology 1987, 164:705708. Blum U, Krumme B, Flugel P, et al.: Treatment of ostial renal-artery stenoses with vascular endoprostheses after unsuccessful balloon angioplasty. N Engl J Med 1997, 336:459465. Harden PN, MacLeod MJ, Rodge r RSC, et al.: Effect of renal-artery stenting on progression of renovascular re nal failure. Lancet 1997, 349:11331136. Fiala LA, Jackson MR, Gillespie DL, et al .: Primary stenting of atherosclerotic renal artery ostial stenosis. Ann Vasc Su rg 1998, 12:128133. Canzanello VJ, Millan VG, Spiegel JE, et al.: Percutaneous tr ansluminal renal angioplasty in management of atherosclerotic renovascular hyper tension: results in 100 patients. Hypertension 1989, 13:163172. Plouin PF, Chatel lier G, Darne B, Raynaud A, for the Essai Multicentrique Medicaments vs. Angiopl astie (EMMA) Study Group: Blood pressure outcome of angioplasty in atherosclerot ic renal artery stenosis: a randomized trial. Hypertension 1998, 31:823829. Texto r SC: Revascularization in atherosclerotic renal artery disease [clinical confer ence]. Kidney Int 1998, 53:799811.

Adrenal Causes of Hypertension Myron H. Weinberger T he adrenal gland is involved in the production of a variety of steroid hormones and catecholamines that influence blood pressure. Thus, it is not surprising tha t several adrenal disorders may result in hypertension. Many of these disorders are potentially curable or responsive to specific therapies. Therefore, identify ing adrenal disorders is an important consideration when elevated blood pressure occurs suddenly or in a young person, is severe or difficult to treat, or is as sociated with manifestations suggestive of a secondary form of hypertension. Bec ause these occurrences are relatively rare, it is necessary to have a high index of suspicion and understand the pathophysiology on which the diagnosis and trea tment of these problems is based. Three general forms of hypertension that resul t from excessive production of mineralocorticoids, glucocorticoids, or catechola mines are reviewed in the context of their normal production, metabolism, and fe edback systems. The organization of this chapter provides the background for und erstanding the normal physiology and pathophysiologic changes on which effective screening and diagnosis of adrenal abnormalities are based. Therapeutic options also are briefly considered. Primary aldosteronism, Cushing's syndrome, and pheoc hromocytoma are discussed. CHAPTER 4

4.2 Hypertension and the Kidney Adrenal Hypertension PHYSIOLOGIC MECHANISMS IN ADRENAL HYPERTENSION Disorder Primary aldosteronism Cause Autonomous hypersecretion of aldosterone (hypermineralocorticoidism) Pathophysiology Increased renal sodium and water reabsorption, increased urinary excretion of po tassium and hydrogen ions Increased activation of mineralocorticoid receptor (?) , increased angiotensinogen (renin substrate) concentration Vasoconstriction, in creased heart rate Pressure mechanism Extracellular fluid volume expansion, hypokalemia (?), alkalosis FIGURE 4-1 The causes and pathophysiologies of the three major forms of adrenal hypertension and the proposed mechanisms by which blood pressure elevation resul ts. Cushing's syndrome Hypersecretion of cortisol (hyperglucocorticoidism) Pheochromocytoma Hypersecretion of catecholamines Extracellular fluid volume expansion (?), increased angiotensin II (vasoconstric tion and increased peripheral resistance) Increased peripheral resistance, incre ased cardiac output Histology of the Adrenal Capsule Zona glomerulosa Zona fasciculata Zona reticularis Medulla Normal human suprarenal gland Human suprarenal gland af ter administration of crude ACTH FIGURE 4-2 Histology of the adrenal. A cross section of the normal adrenal befor e (left) and after (right) stimulation with adrenocorticotropic hormone (ACTH) [ 1]. The adrenal is organized into the outer adrenal cortex and the inner adrenal medulla. The outer adrenal cortex is composed of the zona glomerulosa, zona fas ciculata, and zona reticularis. The zona glomerulosa is responsible for producti on of aldosterone and other mineralocorticoids and is chiefly under the control of angiotensin II (see Figs. 4-3 and 4-5). The zona fasciculata and zona reticul aris are influenced primarily by ACTH and produce glucocorticoids and some andro gens (see Figs. 4-3 and 4-19). The adrenal medulla produces catecholamines and i s the major source of epinephrine (in addition to the organ of Zuckerkandl locat ed at the aortic bifurcation) (see Fig. 4-25.)

Adrenal Causes of Hypertension 4.3 Adrenal Steroid Biosynthesis CH3 C=O CH3 C=O OH O HO Pregnenolone HO 17-Hydroxypregnenolone HO Dehydroepiandrosterone 3 b-OH-Dehyrogenase: 5 4 Isomerase CH3 C=O CH3 C=O OH O FIGURE 4-3 Adrenal steroid biosynthesis. The sequence of adrenal steroid biosynt hesis beginning with cholesterol is shown as are the enzymes responsible for pro duction of specific steroids [2]. Note that aldosterone production normally occu rs only in the zona glomerulosa (see Fig. 4-2). (From DeGroot and coworkers [2]; with permission.) 17a-Hydroxylase O Pregnenolone 21-Hydroxylase OH2OH C=O O 17-Hydroxypregnenolone O 4 Androstene 3,17-dione CH2OH C=O OH O 11-Deoxycorticosterone 11b
Hydroxylase CH2OH HO C=O O 11-Deoxycortisol CH2OH HO O C=O OH O Corticosterone Cortisol 18-Hydroxylase 18-OH-Dehrydrogenase CH2OH HO OHC C=O O Aldosterone } Zona glomerulosa only

4.4 Hypertension and the Kidney FIGURE 4-4 Circadian rhythmicity of steroid production and major stimulatory fac tors. Aldosterone and cortisol and their respective major stimulatory factors, p lasma renin activity (PRA) and adrenocorticotropic hormone (ACTH), demonstrate c ircadian rhythms. The lowest values for all of these components are normally see n during the sleep period when the need for active steroid production is minimal . ACTH levels increase early before awakening, stimulating cortisol production i n preparation for the physiologic changes associated with arousal. PRA increases abruptly with the assumption of the upright posture, followed by an increase in aldosterone production and release. Both steroids demonstrate their highest val ues through the morning and early afternoon. Cortisol levels parallel those of A CTH, with a marked decline in the afternoon and evening hours. Aldosterone demon strates a broader peak, reflecting the postural stimulus of PRA. sodium and wate r reabsorption (8) at the expense of increased potassium and hydrogen ion excret ion in the urine. The increase in sodium and volume then increase systemic blood pressure and renal perfusion pressure and sodium content (9), thereby suppressi ng further renin release (10) and angiotensin II production (11). Thus, in contr ast to the normal situation depicted in panel A, the levels of angiotensin II ar e highly suppressed and therefore do not contribute to an increase in systemic b lood pressure (12). In primary aldosteronism, ACTH (13) has a dominant modulator y role in influencing aldosterone production and hypokalemia, resulting from inc reased urinary potassium exchange for sodium, which has a negative effect on ald osterone production (14). ACTH PRA Aldosterone Cortisol Morning 6 AM Noon 6 PM Morning Kidney Perfusion pressure 1 Sodium content 6 Renin 2 -Extracellular fluid volume 8 -So dium reabsorption 4 Aldosterone Zona glomerulosa Adrenal complex 7 Aldosterone -So dium reabsorption Juxtaglomerular apparatus -Perfusion pressure 9 -Sodium content 12 Kidney Juxtaglomerular apparatus Renin 10 -Extracellular fluid volume 5 Angiotensin II Angiotensin II 11 Adrenal complex Zona glomerulosa 14 13 ACTH A Normal K+ ACTH B Primary aldosteronism K+

FIGURE 4-5 Control of mineralocorticoid production. A, Control of aldosterone pr oduction under normal circumstances. A decrease in renal perfusion pressure or t ubular sodium content (1) at the level of the juxtaglomerular apparatus and macu la densa of the kidney triggers renin release (2). Renin acts on its substrate a ngiotensinogen to generate angiotensin I, which is converted rapidly by angioten sin-converting enzyme to angiotensin II. Angiotensin II then induces peripheral vasoconstriction to increase perfusion pressure (6) and acts on the zona glomeru losa of the adrenal cortex (3) (see Fig. 4-2) to stimulate production and releas e of aldosterone (4). Potassium and adrenocorticotropic hormone (ACTH) also play a minor role in aldosterone production in some circumstances. Aldosterone then acts on the cells of the collecting duct of the kidney to promote reabsorption o f sodium (and passively, water) in exchange for potassium and hydrogen ions excr eted in the urine. This increased secretion promotes expansion of extracellular fluid volume and an increase in renal tubular sodium content (5) that further su ppresses renin release, thus closing the feedback loop (servomechanism). B, Abno rmalities present in primary aldosteronism. Autonomous hypersecretion of aldoste rone (7) leads to increased extracellular fluid volume expansion and increased r enal tubular sodium content. These elevated levels are a result of increased ren al

Adrenal Causes of Hypertension 4.5 Aldosteronism TYPES OF PRIMARY ALDOSTERONISM Types Solitary adrenal adenoma Bilateral adrenal hyperplasia Unilateral adrenal hyperp lasia Glucocorticoid-remediable aldosteronism Bilateral solitary adrenal adenoma s Adrenal carcinoma SCREENING TESTS FOR PRIMARY ALDOSTERONISM Test Serum potassium 3.5 mEq/L Plasma renin activity 4 ng/mL/90 min Urinary aldosterone 20 g/d Plasma aldosterone 15 ng/dL Plasma aldosteroneplasma renin activity ratio 15 Plasma aldosteroneplasma renin activity ratio 30 Relative frequency, % 65 30 2 <1 <1 <1 Sensitivity, % 75 >99 70 90 99.8 96 Specificity, % 20 4060 60 60 98 100 FIGURE 4-6 Types of primary aldosteronism. (Data from Weinberger and coworkers [ 3].) FIGURE 4-7 Screening tests for primary aldosteronism. Serum potassium levels ran ge from 3.5 to normal levels of patients with primary aldosteronism. Most hypert ensive patients with hypokalemia have secondary rather than primary aldosteronis m. The plasma aldosterone-to-plasma renin activity (PRA) ratio (disregarding uni ts of measure) is the most sensitive and specific single screening test for prim ary aldosteronism. However, because of laboratory variability, normal ranges mus t be developed for individual laboratory values. A random peripheral blood sampl e can be used to obtain this ratio even while the patient is receiving antihyper tensive medications, when the effects of the medications on PRA and aldosterone are considered. (Data from Weinberger and coworkers [3,4].) LOCALIZING TESTS FOR PRIMARY ALDOSTERONISM Test Adrenal computed tomographic scan Adrenal isotopic scan Adrenal venography Adren al magnetic resonance imaging Adrenal venous blood sampling with adrenocorticotr opic hormone infusion Sensitivity, % 50 50 70 ? >92 Specificity, % 60 65 80 ? >95 FIGURE 4-8 Localizing tests for primary aldosteronism. Adrenal venous blood samp ling with determination of both aldosterone and cortisol concentrations during a drenocorticotropic hormone stimulation provides the most accurate way to identif y unilateral hyperaldosteronism. This approach minimizes artefact owing to episo dic steroid secretion and to permit correction for dilution of adrenal venous bl ood with comparison of values to those in the inferior vena cava. (see Fig. 4-12 ). (Data from Weinberger and coworkers [3].)

A FIGURE 4-9 Normal and abnormal adrenal isotopic scans. A, Normal scan. Increased bilateral uptake of I131-labeled iodo-cholesterol of normal adrenal tissue is s hown above the indicated renal outlines. (Continued on next page)

4.6 Hypertension and the Kidney FIGURE 4-9 (Continued) B, Intense increase in isotopic uptake by the left adrena l (as viewed from the posterior aspect) containing an adenoma. B FIGURE 4-10 Adrenal venography in primary aldosteronism. A, Typical leaflike pat tern of the normal right adrenal venous drainage. B, In contrast, marked distort ion of the normal venous anatomy by a relatively large (3-cmdiameter) adenoma of the left adrenal. Most solitary adenomas responsible for primary aldosteronism are smaller than 1 cm in diameter and thus usually cannot be seen using anatomic visualizing techniques. A B In normal persons the increase in plasma renin activity associated with upright posture results in a marked increase in plasma aldosterone at noon compared with that at 8 AM (see Fig. 4-4). In adenomatous primary aldosteronism, the plasma r enin activity is markedly suppressed and does not increase appreciably with upri ght posture. Moreover, aldosterone production is modulated by adrenocorticotropi c hormone (which decreases from high levels at 8 AM to lower values at noon (see Fig. 4-4). Thus, these patients typically demonstrate lower levels of aldostero ne at noon than they do at 8 AM. In patients with bilateral adrenal hyperplasia, the plasma renin activity tends to be more responsive to upright posture and al dosterone production also is more responsive to the renin-angiotensin system. Th us, postural increases in aldosterone usually are seen. Exceptions to these chan ges occur in both forms of primary aldosteronism, however, making the postural t est less sensitive and specific [3]. 60 Plasma aldosterone, ng/dL 50 40 30 20 10 0 Normal Adenoma Hyperplasia 8 AM Supine Noon Upright 8 AM Supine Noon Upright 8 AM Supine Noon Upright A B C FIGURE 4-11 Changes in plasma aldosterone with upright posture. AC, Depicted are individual data for persons showing temporal and postural changes in plasma aldo sterone concentration in normal persons (panel A), and in patients with primary

aldosteronism owing to a solitary adrenal adenoma (panel B) or to bilateral adre nal hyperplasia (panel C). Blood is sampled at 8 AM, while the patient is recumb ent, and again at noon after 4 hours of ambulation.

Adrenal Causes of Hypertension 4.7 AC TH A C A C A C A C A C A C A Bilateral aldosteronism B Unilateral aldosteronism FIGURE 4-12 Adrenal venous blood sampling during infusion of adrenocorticotropic hormone (ACTH) [3]. A, Bilateral aldosteronism. A schematic representation of t he findings in primary aldosteronism owing to bilateral adrenal hyperplasia is s hown on the left. When blood is sampled from both adrenal veins and the inferior vena cava during ACTH infusion, the aldosterone-to-cortisol ratio is similar in both adrenal effluents and higher than that in the inferior vena cava. In such cases, medical therapy (potassium-sparing diuretic combinations such as hydrochl orothiazide plus triamterene, amiloride, or spirolactone and calcium channel ent ry blockers) usually is effective. B, Unilateral aldosteronism. On the right is depicted the findings in a patient with a unilateral right adrenal lesion. This lesion can be diagnosed by an elevated aldosterone-to-cortisol ratio in right ad renal venous blood compared with that of the left adrenal and the inferior vena cava. Even if the venous effluent cannot be accurately sampled from one side (as judge d by the levels of cortisol during ACTH infusion), when the contralateral adrena l venous effluent has an aldosterone-to-cortisol ratio lower than that in the in ferior vena cava, it can be inferred that the unsampled side is the source of ex cessive aldosterone production (unless there is an ectopic source). In such case s, surgical removal of the solitary adrenal lesion usually results in normalizat ion of blood pressure and the attendant metabolic abnormalities. Medical therapy also is effective but often requires high doses of Aldactone (GD Searle & Co., C hicago) (200 to 800 mg/d), which may be intolerable for some patients because of side effects. Aaldosterone; Ccortisol. AC TH TH AC TH AC

4.8 Hypertension and the Kidney FIGURE 4-13 (see Color Plate) A section of a typical adrenal adenoma in primary aldosteronism pathology. A relatively large (2-cm-diameter) adrenal adenoma with its lipid-rich (bright yellow) content is shown. 180 160 140 120 100 80 60 Father A 160 Blood pressure 140 120 100 80 60 Son 1 Dexamethasone mg 200 100 FIGURE 4-14 Glucocorticoid-remediable aldosteronism. AC, Seen are the effects of dexamethasone and spironolactone on blood pressure in a father (panel A) and two sons, one aged 6 years (panel B) and the other aged 8 years (panel C). Blood pr essure levels are shown before and after treatment with dexamethasone (left) or spironolactone (right) [5]. Note that the maximum blood pressure reduction with dexamethasone required more than 2 weeks of treatment. Similarly, the maximum re sponse to spironolactone was both time- and dose-dependent. Spironolactone B 40 160 140 120 100 80 60 40 Son 2 200 100 200 100 C 0 1 2 3 4 Weeks 5 6 0 2 4 6 Months 8

Adrenal Causes of Hypertension Changes with dexamethasone Plasma cortisol, g/ 100 mL 25 Urinary aldosterone, g/ 24 h 20 15 10 5 25 20 15 10 5 Dexamethasone 4.9 A Plasma renin activity, ng AI/mL- 3hr 1.0 0 1 2 3 4 5 B 50 Plasma aldosterone, ng/100 mL 40 30 20 10 0 1 2 3 4 5 7 6 5 4 3 0.8 0.6 0.4 0.2 0 C 0 1 2 3 4 5 D 0 1 2 Weeks

3 4 5 E 0 1 2 3 4 FIGURE 4-15 Humoral changes in glucocorticoid-remediable aldosteronism with dexa methasone. AE, Depicted are the changes in plasma cortisol (panel A), urinary ald osterone (panel B), plasma renin activity (PRA) (panel C), plasma aldosterone (p anel D), and serum potassium (panel E) before and after dexamethasone administra tion in the patients in Figure 4-14. Note that before dexamethasone administrati on, serum cortisol was in the normal range and was markedly suppressed after tre atment. Urinary aldosterone was completely normal and plasma aldosterone was elevated in only one patient before dexamethasone administration. The diagnosis was made by demonstrating that the plasma aldosterone concentration failed to su ppress normally after intravenous saline infusion (2 L/4 h) [6]. After dexametha sone administration, both plasma and urinary aldosterone levels decreased marked ly (except for one occasion when it is suspected that the patient did not comply with dexamethasone therapy). PRA, which was markedly suppressed before treatmen t, increased with dexamethasone. Note also that serum potassium levels were norm al in two of the three patients before treatment with dexamethasone but increase d with therapy in all three [5]. All of these changes reverted to control baseli ne values when dexamethasone therapy was discontinued. Serum potassium, mEq/L Glomerulosa AII Aldosterone Aldosterone AII Glomerulosa Aldosterone Aldosterone ACTH Cortisol ACTH Chimeric Aldos Cortisol + Aldosterone + 18OH cortisol + 18OXO cortisol Fasciculata Fasciculata

A B FIGURE 4-16 Normal and chimeric aldosterone synthase in glucocorticoid-remedial aldosteronism (GRA). A, Normal relationship between the stimuli and site of adre nal cortical steroid production. Aldosterone synthase normally responds to angio tensin II (AII) in the zona glomerulosa, resulting in aldosterone synthesis and release (see Figs. 4-2 and 4-3). B, In GRA, a chimeric aldosterone synthase gene results from a mutation, which stimulates production of aldosterone and other s teroids from the zona glomerulosa under the control of adrenocorticotropic hormo ne (ACTH) (Fig. 4-17). Thus, when ACTH production is suppressed by steroid admin istration, aldosterone production is reduced.

4.10 Hypertension and the Kidney FIGURE 4-17 Mutation of the (11-OHase) chimeric aldosterone synthase gene [8]. T he unequal crossing over between aldosterone synthase and 11-hydroxylase genes r esulting in the mutated gene responsible for glucocorticoid-remedial aldosteroni sm is described. 11OHase 5' 3' 5' 3' Unequal crossing over 5' 3' 5' 3' 5' 3' 5' Chimeric gene 3' 5' 11OHase 3' Aldosterone synthase Cushing's Syndrome B FIGURE 4-18 (see Color Plate) Physical characteristics of Cushing's syndrome. A, S ide profile of a patient with Cushing's syndrome demonstrating an increased cervic al fat pad (so-called buffalo hump), abdominal obesity, and thin extremities and petechiae (on the wrist). The round (so-called moon) facial appearance, plethor a, and acne cannot be seen readily here. B, Violescent abdominal striae in a pat ient with Cushing's syndrome. Such striae also can be observed on the inner parts of the legs in some patients. A

Adrenal Causes of Hypertension 4.11 Pituitary CRF Pituitary Pituitary () () () ACTH Cortisol ACTH - Cortisol - ACTH - Cortisol Adrenal cortex (zona fasciculata zona reticularis) FIGURE 4-19 Normal pituitary-adrenal axis. Corticotropinreleasing factor (CRF) a cts to stimulate the release of adrenocorticotropic hormone (ACTH) from the ante rior pituitary. ACTH then stimulates the adrenal zona fasciculata and zona retic ularis to synthesize and release cortisol (see Figs. 4-2 and 4-3). The increased levels of cortisol feed back to suppress additional release of ACTH. As shown i n Figure 4-4, ACTH and cortisol have circadian patterns. Adrenal cortex (zona fasciculata zona reticularis) Adrenal cortex (zona fasciculata zona reticularis) FIGURE 4-20 Pituitary Cushing's disease. Pituitary Cushing's disease results from ex cessive production of adrenocorticotropic hormone (ACTH), typically owing to a b enign adenoma. Excess ACTH stimulates both adrenals to produce excessive amounts of cortisol and results in bilateral adrenal hyperplasia. The increased cortiso l production does not suppress ACTH release, however, because the pituitary tumo r is unresponsive to the normal feedback suppression of increased cortisol level s. The diagnosis usually is made by demonstration of elevated levels of ACTH in the face of elevated cortisol levels, particularly in the afternoon or evening, representing loss of the normal circadian rhythm (see Fig. 4-4). Radiographic st udies of the pituitary (computed tomographic scan and magnetic resonance imaging ) will likely demonstrate the source of increased ACTH production. When the pitu itary is the source, surgery and irradiation are therapeutic options. FIGURE 4-21 Adrenal Cushing's syndrome. Adrenal Cushing's syndrome typically is caus ed by a solitary adrenal adenoma (rarely by carcinoma) producing excessive amoun ts of cortisol autonomously. The increased levels of cortisol feed back to suppr ess release of adrenocorticotropic hormone (ACTH) and corticotropin-releasing fa ctor. The finding of very low ACTH levels in the face of elevated cortisol value s and a loss of the circadian pattern of cortisol confirm the diagnosis (see Fig . 4-4). Additional anatomic studies of the adrenal (computed tomographic scan an d magnetic resonance imaging) usually disclose the source of excessive cortisol production. Surgical removal usually is effective.

4.12 Hypertension and the Kidney Cushing's syndrome: ectopic etiology Ectopic Tumor Pituitary SCREENING TESTS FOR CUSHING'S SYNDROME Test Elevated PM serum cortisol Elevated urinary 17-hydroxy corticosteroids Elevated urinary free cortisol () Sensitivity, % 75 >90 >95 Specificity, % 60 60 >95 ACTH ACTH Cortisol FIGURE 4-23 Screening tests for Cushing's syndrome. Whereas elevated evening plasm a cortisol levels typically indicate abnormal circadian rhythm, other factors su ch as stress also can cause increased levels late in the day. Urinary levels of 17-hydroxy corticosteroids may be increased in association with obesity. In such cases, repeat measurement after a period of dexamethasone suppression may be re quired to distinguish this form of increased glucocorticoid excretion from Cushi ng's syndrome. The measurement of urinary-free cortisol is the most sensitive and specific screening test. Adrenal cortex (zona fasciculata zona reticularis) FIGURE 4-22 Ectopic etiology of Cushing's syndrome. Rarely, Cushing's syndrome may b e due to ectopic production of adrenocorticotropic hormone (ACTH) from a maligna nt tumor, often in the lung. In such cases, hypercortisolism is associated with increased levels of ACTH-like peptide; however, no pituitary lesions are found. Patients with ectopic Cushing's syndrome often are wasted and have other manifesta tions of malignancy. the morning hours (see Fig. 4-4). In pituitary Cushing's dise ase and ectopic forms of Cushing's syndrome, elevated values are observed, especia lly in the afternoon and evening. The next step in differentiation is an anatomi c evaluation of the pituitary. When no abnormality is found, the next step is a search for a malignancy, typically in the lung. The finding of low ACTH levels p oints to the adrenal as the source of excessive cortisol production, and anatomi c studies of the adrenal are indicated. CT computed tomography; MRImagnetic resona nce imaging. FIGURE 4-24 Algorithm for differentiation of Cushing's syndrome. The first step in the differentiation of Cushing's syndrome after diagnosing hypercortisolism is me asurement of plasma adrenocorticotropic hormone (ACTH) levels. Typically, these should be reduced after

Adrenal Causes of Hypertension 4.13 Catecholamines FIGURE 4-25 Synthesis, actions, and metabolism of catecholamines. Depicted is th e synthesis of catecholamines in the adrenal medulla [9]. Epinephrine is only pr oduced in the adrenal and the organ of Zuckerkandl at the aortic bifurcation. No repinephrine and dopamine can be produced and released at all other parts of the sympathetic nervous system. The kidney is the primary site of excretion of catecholamines and their metabolites, as noted here. The kidney also can contrib ute catecholamines to the urine. The relative contributions of norepinephrine an d epinephrine to biologic events is noted by the plus signs. BMRbasal metabolic r ate; CNScentral nervous system; NEFAnonesterified fatty acids; VMAvanillylmandelic acid.

4.14 Hypertension and the Kidney Pheochromocytoma Blood pressure taken at 2-min intervals 5-min intervals Calibrate 250 Blood pres sure, mm Hg 200 150 100 0 8:30 PM 240 230 220 210 190 180 170 160 140 130 120 110 90 80 70 60 40 30 20 10 50 10 PM 2 AM 5:00 AM 7:45 AM 9 AM 10 AM 11 AM 12 Noon 1 PM During the attack: Blood pressure, 192/100 mm Hg Pulse 108 Respirations, 24 FIGURE 4-26 Paroxysmal blood pressure pattern in pheochromocytoma. Note the extr eme variability of blood pressure in this patient with pheochromocytoma during a mbulatory blood pressure monitoring [9]. Whereas most levels were within the nor mal range, episodic increases to levels of 200/140 mm Hg were observed. Such paroxys ms can be spontaneous or associated with activity of many sorts. (Adapted from M anger and Gifford [9]; with permission.) FIGURE 4-28 Caf au lait lesions in a pat ient with pheochromocytoma. These light-browncolored (coffeewith-cream-colored) lesions, sometimes seen in patients with pheochromocytoma, usually are larger th an 3 cm in the largest dimension. In this particular patient, neurofibromas also are present and can be seen in profile. FIGURE 4-27 (see Color Plate) Neurofibroma associated with pheochromocytoma. Neu rofibromas are sometimes found in patients with pheochromocytoma. These lesions are soft, fluctuant, and nontender and can appear anywhere on the surface of the skin. These lesions can be seen in profile in Figure 4-28.

Adrenal Causes of Hypertension 4.15 DISORDERS ASSOCIATED WITH PHEOCHROMOCYTOMA Cholelithiasis Renal artery stenosis Neurofibromas Caf au lait lesions Multiple e ndocrine neoplasia, types II and III Von Hippel-Lindau syndrome (hemangioblastom a and angioma) Mucosal neuromas Medullary thyroid carcinoma FIGURE 4-29 Disorders associated with pheochromocytoma. In addition to the neuro fibromas and caf au lait lesions depicted in Figures 4-27 and 4-28, several other associated abnormalities have been reported in patients with pheochromocytoma. (From Ganguly et al. [9]; with permission.) COMMON SYMPTOMS AND FINDINGS IN PHEOCHROMOCYTOMA Patients, % Symptoms Severe headache Perspiration Palpitations, tachycardia Anxiety Tremulou sness Chest, abdominal pain Nausea, vomiting Weakness, fatigue Weight loss Dyspn ea Warmth, heat intolerance Visual disturbances Dizziness, faintness Constipatio n Finding Hypertension: Sustained Paroxysmal Pallor Retinopathy: Grades I and II Grades III and IV Abdominal mass Associated multiple endocrine adenomatosis 82 67 60 45 38 38 35 26 15 15 15 12 7 7 FIGURE 4-30 Common symptoms and findings in pheochromocytoma. Note that severe h ypertensive retinopathy, indicative of intense vasoconstriction, frequently is o bserved. (Adapted from Ganguly et al. [10].) SCREENING AND DIAGNOSTIC TESTS IN PHEOCHROMOCYTOMA Test Elevated 24-h urinary catecholamines, vanillylmandelic acid, homovanillic acid, metanephrines Abnormal clonidine suppression test Elevated urinary sleep norepinep hrine Sensitivity, % 85 75 >99 Specificity, % 80 85 >99 61 24 44 40 53 9 6 FIGURE 4-31 Screening and diagnostic tests in pheochromocytoma. Drugs, incomplet e urine collection, and episodic secretion of catecholamines can influence the t ests based on 24-hour urine collections in a patient with a pheochromocytoma. Th e clonidine suppression test is fraught with false-negative and false-positive r esults that are unacceptably high for the exclusion of this potentially fatal tu mor. The sleep norepinephrine test eliminates the problems of incomplete 24-hour u rine collection because the patient discards all urine before retiring; saves al l urine voided through the sleep period, including the first specimen on arising ; and notes the elapsed (sleep) time [10]. The sleep period is typically a time of basal activity of the sympathetic nervous system, except in patients with phe ochromocytoma (see Fig. 4-32).

4.16 Hypertension and the Kidney FIGURE 4-32 Nocturnal (sleep) urinary norepinephrine. The values for urinary exc retion of norepinephrine are shown for normal persons and patients with essentia l hypertension as mean plus or minus SD [10]. Values for patients with pheochrom ocytoma are indicated by symbols. Note that the scale is logarithmic and the hig hest value for patients with normal or essential hypertension was less than 30 g, whereas the lowest value for a patient with pheochromocytoma was about 75 g. Mos t patients with pheochromocytomas had values an order of magnitude higher than t he highest value for patients with essential hypertension. 1000 Sleep urinary norepinephrine excretion, g 100 Patient I Patient II Patient III Patient IV Patient V Patient VI Maximum for normal Maximum for hypertensive 10 Normal mean + SD Hypertensive mean + SD 0 LOCALIZATION OF PHEOCHROMOCYTOMA Test Abdominal plain radiograph Intravenous pyelogram Adrenal isotopic scan (meta-iod obenzoylguanidine) Adrenal computed tomographic scan Sensitivity, % 40 60 85 >95 Specificity, % 50 75 85 >95 FIGURE 4-34 Intravenous pyelogram in pheochromocytoma. Note the displacement of the left kidney (right) by a suprarenal mass. FIGURE 4-33 Localization of pheochromocytoma. Once the diagnosis of pheochromocy toma has been made it is very important to localize the tumor preoperatively so that the surgeon may remove it with a minimum of physical manipulation. Computed tomographic scan or MRI appears to be the most effective and safest techniques for this purpose [10]. The patient should be treated with -adrenergic blocking a gents for 7 to 10 days before surgery so that the contracted extracellular fluid volume can be expanded by vasodilation.

Adrenal Causes of Hypertension 4.17 A B C FIGURE 4-35 AD, Computed tomographic scans in four patients with pheochromocytoma [10]. The black arrows identify the adrenal tumor in D these four patients. Three patients have left adrenal tumors, and in one patient (panel B) the tumor is on the right adrenal. A FIGURE 4-36 (see Color Plates) A and B, Pathologic appearance of pheochromocytom a before (panel A) and after (panel B) sectioning. This 3.5-cm-diameter B tumor had gross areas of hemorrhage noted by the dark areas visible in the photo graphs.

4.18 Hypertension and the Kidney References 1. 2. 3. Netter FH: Endocrine system and selected metabolic diseases. In Ciba Co llection of Medical Illustrations, vol. 4; 1981:Section III, Plates 5, 26. DeGro ot LJ, et al.: Endocrinology, edn 2. Philadelphia: WB Saunders; 1989:1544. Weinb erger MH, Grim CE, Hollifield JW, et al.: Primary aldosteronism: diagnosis, loca lization and treatment. Ann Intern Med 1979, 90:386395. Weinberger MH, Fineberg N S: The diagnosis of primary aldosteronism and separation of subtypes. Arch Inter n Med 1993, 153:21252129. Grim CE, Weinberger MH: Familial, dexamethasone-suppres sible normokalemic hyperaldosteronism. Pediatrics 1980, 65:597604. Kem DC, Weinbe rger MH, Mayes D, Nugent CA: Saline suppression of plasma aldosterone and plasma renin activity in hypertension. Arch Intern Med 1971, 128:380386. 7: Lifton RP, Dluhy RG, Powers M: Hereditary hypertension caused by chimeric gene duplications and ectopic expression of aldosterone synthase. Nat Genet 1992, 2:6674. 8. Lifto n RP, Dluhy RG, Powers M: A glucocorticoid-remediable aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 19 92, 355:262265. 9. Manger WM, Gifford RW Jr: Pheochromocytoma. New York: Springer -Verlag; 1977:97. 10. Ganguly A, Henry DP, Yune HY, et al.: Diagnosis and locali zation of pheochromocytoma: detection by measurement of urinary norepinephrine d uring sleep, plasma norepinephrine concentration and computed axial tomography ( CT scan). Am J Med 1979, 67:2126. 4. 5. 6.

Insulin Resistance and Hypertension Theodore A. Kotchen R esistance to insulin-stimulated glucose uptake is associated with increased risk for cardiovascular disease [1]. Risk factors for cardiovascular disease tend to cluster within individuals, and insulin resistance may be the link between hype rtension and dyslipidemia. Depending on the populations studied and methodologie s used for defining insulin resistance, approximately 25% to 40% of nonobese non diabetic patients with hypertension are insulin-resistant [2]. Insulin resistanc e also has been observed in genetic and acquired animal models of hypertension. A constellation of insulin resistance, reactive hyperinsulinemia, increased trig lycerides, decreased high-density lipoprotein cholesterol, and hypertension was designated as syndrome X by Reaven in 1988 [3]. Although a number of putative me chanisms have been proposed, it is unclear whether insulin resistance or reactiv e hyperinsulinemia, or both, actually cause hypertension. The recent observation s that insulinsensitizing agents attenuate the development of hypertension lend credence to this hypothesis [4]. As discussed subsequently, however, these agent s may lower blood pressure by different mechanisms. Whatever mechanism may be in volved, the observation that a single agent may have the capacity to both increa se insulin sensitivity and lower blood pressure is potentially of considerable c linical significance. Noninsulin-dependent diabetes mellitus represents an extrem e of insulin resistance. Among diabetics, a two- to threefold increased prevalen ce of hypertension exists. Hypertension is associated with a fourfold increase i n mortality among patients with noninsulin-dependent diabetes, and antihypertensi ve drug therapy has a beneficial impact on both macrovascular and microvascular disease [5]. Despite the potential concern that diuretics may augment insulin re sistance, diabetic patients benefit from antihypertensive therapy with diuretics . The renal protective effect of antihypertensive drugs varies among different c lasses of agents. Angiotensin-converting enzyme inhibitors decrease proteinuria and retard the progression of renal insufficiency in diabetic patients with norm al blood pressure and hypertension. CHAPTER 5

5.2 Hypertension and the Kidney dihydropyridine calcium antagonists accelerate the progression of diabetic nephr opathy, particularly in the short term. Additional studies are required to evalu ate the antihypertensive potential of insulin-sensitizing agents in patients wit h noninsulin-dependent diabetes. This benefit is independent of an effect on blood pressure and may be related sp ecifically to the capacity of these agents to dilate the efferent renal arteriol e. Results of studies evaluating the effects of calcium antagonists on the progr ession of diabetic nephropathy are varied. Some studies suggest that 7.0 5054 y Men Women Total cholesterol, mmol/L 6.5 6.0 5.5 4049 y 4049 y 3039 y 3039 y 2029 y 2029 y B. NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY II 1. Persons with blood pressure >140/90 mm Hg or taking medication for hypertensi on: 40% have cholesterol >240 mg/dL 2. Persons with blood cholesterol >240 mg/dL : 46% have blood pressure >140/90 mm Hg 100 5.0 70 80 90 100 70 80 90 Diastolic blood pressure, mm Hg A FIGURE 5-1 Hyperlipidemia and hypertension. A, Epidemiologic studies document an association between serum cholesterol and blood pressure in men and women. B, B ased on data from the National Health and Nutrition Examination Survey II, persons with hypertension have a high preva lence of hyperlipidemia and vice versa [6]. (Panel A from Bonna and Thelle [7]; with permission.) FIGURE 5-2 Insulin resistance and hypertension. A, Genetic and nutritional factors contribute to insulin resistance and resultant hyperinsulin emia. In addition to obesity and type II diabetes, hyperlipidemia and hypertensi on also may be associated with insulin resistance. Insulin resistance may accoun t for the association of hyperlipidemia with hypertension. B, Insulin resistance is associated with hypertension in a number of clinical and experimental settin gs. (Panel A from Ferrari and Weidmann [8]; with permission.) Epidemiologic + clinical association Hereditary + acquired mechanisms B. HYPERTENSION AND INSULIN RESISTANCE Type II diabetes mellitus Obesity Essential hypertension Salt sensitive (?) Expe rimental hypertension Dahl-salt-sensitive rats Spontaneously hypertensive rats Obesity Insulin-resistance Hyperinsulinemia Glucose tolerance Diabetes type II

Dyslipidemia, hypertension

Insulin Resistance and Hypertension 140 Plasma glucose, mg/100 mL 5.3 FIGURE 5-4 Salt sensitivity. Persons who have salt-sensitive hypertension tend t o be more insulinresistant than are those who are saltresistant. That is, patien ts who are saltsensitive have higher plasma glucose and insulin responses to a g lucose load than do those who are salt-resistant. (From Bigazzi and coworkers [1 0]; with permission.) Hypertensive patients 120 * 80 40 0 60 Control group * 40 20 0 0 30 60 Time, min 90 * 120 FIGURE 5-3 Insulin resistance based on glucose and insulin responses to glucose load. In response to an oral glucose load of 75 g, compared with persons with no rmal blood pressure, patients with hypertension tend to have higher plasma gluco se and insulin levels. These data suggest that patients with hypertension are in sulin resistant. (From Ferrannini and coworkers [9]; with permission.) 10 Glucose, mmol/L 1 mmol/l = 0.0555 mg/dL 8 6 Salt-sensitive Salt-resistant 4 0 800 Insulin, pmol/L 600 400 200 0 0 30 60 90 Time, min 120 150 30 60 90 120 150 Plasma insulin, U/mL * * 1 pmol/L = 7.175 U/mL 16 14 12 10 Count 8 6 4 2 0 0 2 4 6 8 10 12 14 M value at clamp, mg/kg/min Hypertensive subjects Control subjects FIGURE 5-5 Insulin sensitivity. Insulin sensitivity also may be assessed using t he euglycemic insulin clamp technique. The frequency distribution for insulin-me diated glucose disposal during euglycemic insulin clamping (M value) differs in persons with normal blood pressure and those with hypertension. The percentage o f persons with hypertension considered insulin-resistant depends on the definiti on of insulin resistance. In this study, 27% of patients with hypertension were classified as being insulin-resistant based on an M value over two SDs above the mean for persons with normal blood pressure. (From Lind and coworkers [2]; with

permission.) SYNDROME X AND ASSOCIATED CONDITIONS Hypertension Hyperinsulinemia Increased triglycerides Decreased high-density lip oprotein cholesterol Increased low-density lipoprotein cholesterol Decreased pla sminogen activator Increased plasminogen activator inhibitor Increased blood vis cosity Increased uric acid Increased fibrinogen (?) FIGURE 5-6 As originally defined, syndrome X includes hypertension, hyperinsulin emia, increased plasma triglycerides, and decreased HDL cholesterol. The syndrom e also may be associated with clustering of additional cardiovascular disease ri sk factors.

5.4 Hypertension and the Kidney FIGURE 5-7 Hypertension associated with insulin resistance. It is unclear whethe r hyperinsulinemia associated with insulin resistance causes hypertension, altho ugh a number of potential mechanisms have been proposed. Obesity Nutrition Genetic predisposition Compensatory hyperinsulinemia Resistance to insulin-stimulated glucose uptake Increased a1 adrenegic receptors Hyperglycemia Hyperlipidemia Increased sympathetic nervous system activity Vascular growth Antinatriuresis Impaired endotheliumdependent vasodilation Hypercholesterolemia (low-density lipoprotein, lipoprotein (a)) Endothelial injury Increased endothelial superoxide anion production Increased degradation of nitric oxide FIGURE 5-8 Metabolic consequences of insulin resistance. These consequences also may affect peripheral vascular resistance. Hypercholesterolemia may result in v ascular endothelial injury and, hence, impaired vasodilation. High glucose Decreased nitric oxide production Protein kinase C activation Incre ased sodium-hydrogen antiport activity FIGURE 5-9 Results of high glucose concentrations. High glucose concentrations m ay inhibit nitric oxide production and alter ion transport in vascular smooth mu scle cells, favoring vasoconstriction. Impaired endothelium-dependent vasodilation Sulfonylureas R1 R2 Biguanides Thiazolidinediones R1 SO2 NH C NH R2 N C NH C NH2 NH NH

R1 O CH2 O S O NH CH2 O S C1 O C NH CH2CH2 SO2 NH C NH O Glyburide H 3C H 3C N N C NH C NH2 NH Metformin NH Pioglitazone CH3CH2 CH2CH2 O O NH FIGURE 5-10 Effects of chemically distinct oral hypoglycemic agents on blood pre ssure. Sulfonylureas stimulate endogenous insulin secretion and do not lower blo od pressure. In contrast, biguanides and thiazolidinediones increase insulin sen sitivity without stimulating endogenous insulin secretion, and drugs in these cl asses lower blood pressure. 160 Systolic blood pressure, mm Hg Control Pioglitazone 140 120 100 80 0 2 4 6 8 10 FIGURE 5-11 Pioglitazone in the treatment of hypertension in rats. A, Systolic b lood pressures in Dahl-salt-sensitive rats treated with either vehicle or piogli tazone (a thiazolidinedione) for 3 weeks. Pioglitazone attenuated development of hypertension in this animal model. Weight gain did not differ in the two groups . (Continued on next page) A 12 Day 14 16 18 20 22

Insulin Resistance and Hypertension 5.5 B. HEMODYNAMIC MEASUREMENTS IN DAHL-SALT-SENSITIVE RATS Mean intra-arterial pressure, mm Hg Control group Group treated with pioglitazone 129 1 121 3* MODELS IN WHICH THIAZOLIDINEDIONES LOWER BLOOD PRESSURE Dahl-S rat 1-Kidney, 1-clip rat Obese Zucker rat Fructose-fed rat L-NNAtreated ra t SHR Obese rhesus monkey Watanabe hyperlipidemic rabbit Obese human Cardiac index, mL/min/100 g 51.4 1.6 59.11.7* Total peripheral resistance, mm Hg/mL/min/100 g 2.50 0.07 2.07 0.07* *P<0.05 FIGURE 5-11 (Continued) B, Direct intra-arterial pressure and cardiac index (the rmodilution) in these same chronically instrumented, conscious pioglitazone-trea ted and control rats. Compared with control animals, rats treated with pioglitaz one had lower mean arterial pressure, higher cardiac index, and lower total peri pheral resistance. Thus, attenuation of hypertension by pioglitazone is due to a reduction of peripheral resistance. (From Dubey and coworkers [11]; with permis sion.) FIGURE 5-12 Thiazolidinediones lower blood pressure in several models of experim ental hypertension and in obese humans. FIGURE 5-13 Agents that increase insulin sensitivity, decrease plasma lipid concentrations, and lower blood pressure in animal models and preliminary studies in humans. AGENTS THAT INCREASE INSULIN SENSITIVITY, DECREASE PLASMA LIPID CONCENTRATIONS, AND LOWER BLOOD PRESSURE IN ANIMAL MODELS AND PRELIMINARY STUDIES IN HUMANS Thiazolidinediones Metformin Spontaneously hypertensive rats Humans (?) Vanadyl sulfate Spontaneously hypertensive rats Fructose-fed rats Etomoxir Spontaneously hypertensive rats Clofibrate Dahl-salt-sensitive rats Fenfluramine derivatives Fructose-fed rats Humans Lovastatin/pravastatin Dahl-salt-sensitive rats Spontan eously hypertensive rats Human (?) 200 Mean arterial pressure, mm Hg 180 160 140 120 100 80 Clofibrate Vehicle Clof ibrate Vehicle Dahl-S Dahl-R EFFECT OF CHOLESTEROL REDUCTION ON BLOOD PRESSURE RESPONSE TO MENTAL STRESS IN P ATIENTS WITH NORMAL BLOOD PRESSURE AND HIGH CHOLESTEROL Systolic blood pressure Baseline Placebo group Group treated with lovastatin 122 119 Diastolic blood pressure Baseline 69 67 Stress 141 133* Stress 78 75 FIGURE 5-14 Clofibrate in prevention of hypertension in rats. Clofibrate prevent s the development of hypertension in Dahl salt-sensitive rats. This agent does n

ot affect blood pressure in Dahl salt-resistant rats. (From Roman and coworkers [12]; with permission.) FIGURE 5-15 In humans with normal blood pressure who have high serum cholesterol concentrations, treatment with lovastatin lowers serum cholesterol and attenuat es the systolic blood pressure response to mathematics-induced stress. (From Sun g and coworkers [13]; with permission.)

5.6 Hypertension and the Kidney FIGURE 5-16 Insulin-sensitizing and lipid-lowering agents may lower blood pressu re by a number of different mechanisms. Different agents may act through differe nt mechanisms. ANTIHYPERTENSIVE MECHANISMS OF INSULIN-SENSITIZING AGENTS Block agonist-induced calcium ion entry into vascular smooth muscle cells Inhibi t agonist-mediated vasoconstriction Inhibit growth of vascular smooth muscle cel ls Augment endothelium-dependent vasodilation Direct effect Metabolic effect Nat riuresis Increase 20-hydroxy-eicosatetraenoic acid production Increase renal med ullary blood flow 1.05 1.00 Intracellular [Ca2+]i R172 #18 + 20 ng/mL PDGF 0.95 0.90 Intracellular [Ca2+]i 0.85 0.80 0.75 0.70 0.65 0.60 R172 #3141 + 2 ug/mL ciglitazone + 20 ng/mL PDGF Arginine vasopressin 350 300 [Ca2+]i(nM) 250 200 150 100 50 0 (286) (290) (73) (59) 0.95 0.90 0.85 0.80 0.75 0.70 0.65 0 100 200 300 400 500 600 700 800 Control Metformin * * P<0.05 * 0 100 200 300 400 500 600 700 800 Basal 450 400 Peak Thrombin (213) (231) Delta A Time, s B Time, s FIGURE 5-17 Use of ciglitazone to abolish calcium concentration elevation. Cigli tazone, a thiazolidinedione, abolishes agonist-stimulated sustained elevations o f intracellular calcium concentrations. Shown are time-dependent plots of change s in intracellular calcium (in arbitrary units; [Ca2+]i) induced by platelet-der

ived growth factor (PDGF) in human gliobastoma cells with and without preincubat ion with ciglitazone. A, Addition of PDGF to control cells is indicated by the v ertical line. B, An identical experiment conducted on cells pretreated with cigl itazone. The capacity of this agent to shorten the duration of agonist-stimulate d increases in intracellular calcium may result in attenuation of both growth of vascular smooth muscle cells and vasoconstriction. (From Pershadsingh and cowor kers [14]; with permission.) 350 300 [Ca2+]i(nM) 250 200 150 100 50 0 Basal (286) (290) * * P<0.05 * Peak Delta FIGURE 5-18 Use of metformin to attenuate intracellular calcium concentration el evation. Metformin is a biguanide that attenuates agonist-stimulated increases o f intracellular calcium concentrations in vascular smooth muscle. (From Bhalla a nd coworkers [15]; with permission.)

Insulin Resistance and Hypertension 28 24 Cell number (x104) 20 16 12 8 4 0 0 2 4 6 8 10 Days in culture 12 14 Insulin + pioglitazone 0.4% FCS Insulin Insulin + pioglitazone (days 06) 5.7 FIGURE 5-19 Effect of pioglitazone on insulin-induced proliferation of arterial smooth muscle cells. Inhibition of insulin-stimulated vascular hyperplasia and h ypertrophy is one potential mechanism by which insulin-sensitizing and lipid-low ering agents may decrease peripheral resistance. Two kinds of evidence suggest t hat thiazolidinediones inhibit the growth of vascular smooth muscle cells in vit ro. Shown here, pioglitazone inhibits insulin-stimulated proliferation of vascul ar smooth muscle cells. Pioglitazone also inhibits 3H-thymidine incorporation in vascular smooth muscle cells (Fig. 5-19). FCSfetal calf serum. (From Dubey and c oworkers [11]; with permission.) 120 H-Thymidine incorporation, % of control 100 80 60 40 20 0 0.001 Insulin = 1 mU/mL EGF = 100 mg/mL 5% FCS FIGURE 5-20 Effect of pioglitazone on 3H-thymidine incorporation in vascular smo oth muscle cells. 3H-thymidine incorporation is stimulated by insulin, fetal cal f serum (FCS), and epidermal growth factor (EGF). Pioglitazone inhibits 3H-thymi dine incorporation stimulated by each of these mitogens. Similar observations ha ve been made with pravastatin and lovastatin. (From Dubey and coworkers [11]; wi th permission.) 3 0.01 0.1 1 10 100 Pioglitazone concentration, uM 50 Percent of change 40 30 20 10 0 0 Control Pioglitazone 50 Percent of change 40 30 20 10 0 Control Pioglitazone FIGURE 5-21 Decreases in mean arterial pressure in rats treated with pioglitazon e and control Dahl-salt-sensitive rats in response to graded infusions of norepi nephrine and angiotensin II. In vivo, pressor responses to norepinephrine and an giotensin are II attenuated in Dahl-salt-sensitive rats treated with pioglitazon e [16]. (From Kotchen and coworkers [16]; with permission.) 100 200 300 400 500 Norepinephrine, ng/kg/min 0 100 200 300 400 500 Angiotensin II, ng/kg/min

Norepinephrine x 108 (log M) 3 * 2 1 FIGURE 5-22 Half-maximal values for norepinephrine-induced contraction in aortic strips preincubated with insulin, pioglitazone, or both. In vitro, pressor resp onsiveness of aortic strips to norepinephrine-induced contraction is inhibited b y preincubation with insulin plus pioglitazone [16]. The half-maximal value is i ncreased for strips incubated with insulin plus pioglitazone (ie, higher concent rations of norepinephrine are required to achieve half-maximal contraction) but not in strips incubated with insulin alone or pioglitazone alone. 0 Control Insulin Pioglitazone Insulin + pioglitazone

5.8 Hypertension and the Kidney Substance P Bradykinin Acetylcholine B Sodium P Gq protein M nitroprusside Endot helium Gi protein Nitric oxide L-arginine synthase Nitric oxide EDRF-nitric oxid e Smooth muscle FIGURE 5-23 Impaired endothelium-dependent vascular relaxation and insulin resis tance. Insulin resistance is associated with impaired endothelium-dependent vasc ular relaxation, which is a defect that may be corrected by insulin-sensitizing agents. One approach to evaluating vascular endothelial function is to measure v ascular relaxation in response to acetylcholine. EDRFendothelium derived relaxing factor. Acetylcholine x 107 (log M) 5 4 Protein, pmol/min/mg 3 2 1 0 Control Insulin Pioglitazone Insulin + pioglita zone * 60 50 40 30 20 10 0 20-Hydroxy-eicosotetraenoic acid * P<0.05 Control, n = 9 Clofibrate, n = 12 * (+) 2 Cl + Na + K K + * Na K Ca2 Mg2 AA PLA 20-HETE K + + + + + R PLC 3 Na + All bradykinin vasopressin + Ca2 * Cortex Outer medulla Liver 2K Cl + FIGURE 5-24 Half-maximal values for acetylcholineinduced vasodilation in aortic strips preincubated with insulin, pioglitazone, or both. In the presence of insu lin, pioglitazone augments endothelium-dependent vasodilation. In vitro, the hal f-maximal values for acetylcholineinduced vasodilation is less in aortic strips incubated with insulin plus pioglitazone (ie, the strips are more responsive to acetylcholine) than in control strips or strips incubated with insulin alone or pioglitazone alone [16]. FIGURE 5-25 Effect of clofibrate on 20-hydroxy-eicosatetraenoic (20-HETE) produc

tion in Dahlsalt-sensitive rats. Insulin stimulates sodium reabsorption in the p roximal tubule. Consequently, lowering plasma insulin concentrations by increasi ng insulin sensitivity would potentially result in less sodium retention. In add ition, clofibrate induces renal P-450 fatty acid w-hydroxylase activity and, hen ce, increases metabolism of arachidonic acid to 20-HETE. (From Roman and coworke rs [12]; with permission.) FIGURE 5-26 20-Hydroxy-eicosotetraenoic acid inhibits chloride transport in the thick ascending limb of the loop of Henle. This inhibition results in a natriure tic effect in the Dahl-salt-sensitive rat. This may be the mechanism by which cl ofibrate prevents hypertension in this animal model. BENEFITS OF CONTROL OF HYPERTENSION AND DIABETES Hypertension Decreased nephropathy Decreased retinopathy Decreased stroke, myoca rdial infarction Drug specific (?) Diabetes (type I) Decreased nephropathy Decre ased retinopathy Decreased neuropathy FIGURE 5-27 Benefits of hypertension control and blood glucose controls are well established in diabetic patients. Noninsulin-dependent diabetes mellitus repres ents an extreme of insulin resistance, and hypertension is a major contributor t o the cardiovascular complications of diabetes. Despite the potential concern th at diuretics increase insulin resistance, overall cardiovascular disease morbidi ty and mortality are reduced in diabetic patients with hypertension by antihyper tensive therapy with regimens that include diuretics.

Insulin Resistance and Hypertension FIGURE 5-28 Course of diabetic nephropathy during effective antihypertensive tre atment in patients with overt diabetic nephropathy. Effective antihypertensive t herapy with regimens that include diuretics also decreases the rate of progressi on of renal failure (both the glomerular filtration rate and albumin excretion) in patients with diabetic nephropathy. (From Parving and coworkers [17]; with pe rmission.) 5.9 Mean arterial blood pressure, mm Hg Start of antihypertensive treatment 125 115 105 95 105 95 85 75 65 55 GFR: 0.94 (mL/min/mo) GFR: 0.29 (mL/min/mo) GFR: 0.10 (mL/min/mo) EFFECT OF ANTIHYPERTENSIVE AGENTS ON INSULIN SENSITIVITY AND RENAL FUNCTION IN D IABETIC PATIENTS Agent Angiotensin-converting enzyme inhibitors Diuretics -Blockers 1-Blockers Calcium ion antagonists Dihydropyridines Others Insulin sensitivity Renal protection Increase Decrease Decrease Increase 0 Increase + ? 0 0 -? +? Albuminuria, g/min Glomerular filtration rate, mL/min/1-73 m2 1250 750 250 2 1 0 1 2 Time, y 3 4 5 6 FIGURE 5-29 Different antihypertensive agents have different effects on insulin sensitivity, and in diabetic patients, on renal function. Question mark indicate s inconsistent study results; plus sign indicates a protective effect; minus sig n indicates no protection. 50 45 40 35 30 25 20 15 10 5 0 0.0 Percent doubling of baseline creatinine Placebo Captopril Percent risk reduction = 48.5% (1669) P = 0.007 0.5 Proportion with event 0.4 0.3 0.2 0.1 0.0 Captopril Placebo Risk reduction = 50.5% P = 0.006 0.5 1.0 A 1.5 2.0 2.5 Years of follow-up 3.0 3.5 4.0

0 1 B 2 3 Years from randomization 4 4.5 FIGURE 5-30 Cumulative incidence of events in patients with diabetic nephropathy in captopril and placebo groups. A, Time to doubling of serum creatinine. B, Ti me to end-stage renal disease or death. In type I diabetic patients with nephrop athy and either normal blood pressure or hypertension, treatment with angiotensi n-converting enzyme inhibitors decreases proteinuria and retards the rate of progression of renal insufficiency . The cumulative incidence of doubling of serum creatinine concentrations over t ime and development of end-stage renal disease are less in patients treated with captopril than in those treated with placebo. (From Lewis and coworkers [18]; w ith permission.)

5.10 Hypertension and the Kidney CHANGES OF MEAN BLOOD PRESSURE, PROTEINURIA, AND GLOMERULAR FILTRATION RATE IN T REATMENT WITH DIFFERENT ANTIHYPERTENSIVE AGENTS IN PATIENTS WITH INSULIN-DEPENDE NT DIABETES MELLITUS AND NONINSULIN-DEPENDENT DIABETES MELLITUS WHO HAVE MICROALB UMINURIA OR MACROALBUMINURIA Treatment type Placebo Conventional (diuretics and -blockers) Angiotensin-converting enzyme inh ibitors Calcium antagonists: All except nifedipine and nitrendipine Nifedipine N itrendipine Patients, n 244 213 489 63 63 39 MBP, % -2 -10 -16 -16 -12 -17 UProt, % +39 -20 -52 -42 +2 -48 GFR, % -8 -9 -1 +2 -48 +30 FIGURE 5-31 Despite similar control of hypertension, different classes of antihy pertensive agents have different effects on renal function in patients with diabetic nephropathy. GFRglomerular filtration rate; MBPmean blood pressure; Uprotu rine protein. (From Bretzel [19]; with permission.) References 1. Kotchen TA, Kotchen JM, O'Shaughnessy IM: Insulin and hypertensive cardiovascul ar disease. Curr Opin Cardiol 1996, 11:483489. 2. Lind L, Berne C, Lithell H: Pre valence of insulin resistance in essential hypertension. J Hypertens 1995, 17:14 571462. 3. Reaven GM: Role of insulin resistance in human disease. Diabetes 1988, 37:15951607. 4. Kotchen TA: Attenuation of hypertension by insulin-sensitizing a gents. Hypertension 1996, 28:219223. 5. Nadig V, Kotchen TA: Insulin sensitivity, blood pressure and cardiovascular disease. Cardiol Rev 1997, 5:213219. 6. Nation al High Blood Pressure Education Program and National Cholesterol Education Prog ram: Working Group Report on Management of Patients with Hypertension and High B lood Cholesterol. National Institutes of Health Publication No. 90-2361. Nationa l Institutes of Health, 1990. 7. Bonna KH, Thelle DJ: Association between blood pressure and serum lipids in a population: the Tromso study. Circulation 1991, 8 3:13051324. 8. Ferrari P, Weidmann P: Insulin, insulin sensitivity and hypertensi on. J Hypertens 1990, 8:491500. 9. Ferrannini E, Buzzigoli E, Bonadonna R, et al. : Insulin resistance in essential hypertension. N Engl J Med 1987, 317:350357. 10 . Bigazzi R, Bianchi S, Baldari G, et al.: Clustering of cardiovascular risk fac tors in salt-sensitive patients with essential hypertension: role of insulin. Am J Hypertens 1996, 9:2432. 11. Dubey RK, Zhang HY, Reddy SR, et al.: Pioglitazone attenuates hypertension and inhibits growth in renal arteriolar smooth muscle i n rats. Am J Physiol 1993, 265:R726R732. 12. Roman RJ, Ma Y-H, Frohlich B, et al. : Clofibrate prevents the development of hypertension in Dahl salt-sensitive rat s. Hypertension 1993, 21:985988. 13. Sung BH, Izzo JL, Wilson MF: Effects of chol esterol reduction on BP response to mental stress in patients with high choleste rol. Am J Hypertens 1997, 10:592599. 14. Pershadsingh H, Szollosi J, Benson S, et al.: Effects of ciglitazone on blood pressure and intracellular calcium metabol ism. Hypertension 1993, 21:10201023. 15. Bhalla RC, Toth KF, Tan EQ, et al.: Vasc ular effects of metformin: possible mechanisms for its antihypertensive action i n the spontaneously hypertensive rat. Am J Hypertens 1996, 9:570576. 16. Kotchen

TA, Zhang HY, Reddy S, et al.: Effect of pioglitazone on vascular reactivity in vivo and in vitro. Am J Physiol 1996, 260:R660R666. 17. Parving H-H, Andersen AR, Smidt UM, et al.: Effect of antihypertensive treatment on kidney function in di abetic nephropathy. Br Med J 1987, 294:14431447. 18. Lewis EJ, Hunsicker LG, Bain RP, et al.: The effect of angiotensinconverting-enzyme inhibition on diabetic n ephropathy. N Engl J Med 1993, 329:14561462. 19. Bretzel RG: Effects of antihyper tensive drugs on renal function in patients with diabetic nephropathy. Am J Hype rtens 1997, 10:208S217S.

The Role of Hypertension in Progression of Chronic Renal Disease Lance D. Dworkin Douglas G. Shemin H ypertension is a cause and consequence of chronic renal disease. Data from the U nited States Renal Data System (USRDS) identifies systemic hypertension as the s econd most common cause of end-stage renal disease, with diabetes mellitus being the first. Renal failure in patients with hypertension has many causes, includi ng functional impairment secondary to vascular disease and hypertensive nephrosc lerosis. Even in those in whom hypertension is not the primary process damaging the kidney, elevations in systemic blood pressure may accelerate the rate at whi ch kidney function is lost. This accelerated loss of kidney function occurs part icularly in patients with glomerular diseases and clinically evident proteinuria . Hypertension may damage the kidney by several mechanisms. Because autoregulati on of glomerular pressure is impaired in chronic renal disease, elevations in sy stemic blood pressure also are associated with increased glomerular capillary pr essure. Glomerular hypertension results in increased protein filtration and endo thelial damage, causing increased release of cytokines and other soluble mediato rs that promote replacement of normal kidney tissue by fibrosis. An important fa ctor contributing to progressive renal disease is activation of the renin-angiot ensin system, which not only tends to increase blood pressure but also promotes cell proliferation, inflammation, and matrix accumulation. Numerous studies in e xperimental animals suggest that antihypertensive drugs can slow the progression of chronic renal disease. Drugs that inhibit the renin-angiotensin system may b e more effective than are other agents in retarding renal disease progression. F or many reasons, the effects of angiotensin II receptor antagonists and angioten sin-converting enzyme (ACE) inhibitors may not CHAPTER 6

6.2 Hypertension and the Kidney classes of calcium channel blockers have equivalent renal protective effects is uncertain. Patients with hypertension and chronic renal disease should be treate d aggressively. A 24-hour urine collection determines the extent of proteinuria. The patient who excretes more than 1 g/24 h of protein or who has diabetes mell itus should receive an ACE inhibitor. The target in this group of patients is to reduce the blood pressure to lower than 120/80 mm Hg. Most often, reaching this goal requires the use of combinations of antihypertensive agents, diuretics, or calcium channel blockers. Patients who excrete less than 1 g/24 h of protein ma y be treated according to standard recommendations with diuretics, beta blockers , ACE inhibitors, or other agents. The target blood pressure for this group of p atients is lower than 130/85 mm Hg. be identical. Calcium channel blockers also are beneficial in some settings; how ever, this effect is critically dependent on the degree of blood pressure reduct ion. The relationship between hypertension and progression of chronic renal dise ase has been examined in a number of clinical trials. Individuals with systemic hypertension are at increased risk for developing end-stage renal disease. The r ate at which kidney function is lost increases in patients with poorly controlle d systemic hypertension. Antihypertensive therapy can slow the rate of loss of k idney function in patients with diabetic and nondiabetic renal disease. Studies suggest that ACE inhibitors are particularly useful in patients with hypertensio n and proteinuria of over 1g/24 h. Calcium channel blockers also may slow the pr ogression of renal disease; however, whether all Hypertension and Kidney Damage Partial loss of function Fibrosis apoptosis Compensatory growth Renin AII activation Afferent vasodilation Systemic hypertension Release of cytokines and growth factors Increased wall tension Glomerular hypertension Capillary injury Proteinuria FIGURE 6-1 Hypothesis identifying systemic hypertension as a central factor cont ributing to the progression of chronic renal disease. After partial loss of kidn ey function resulting from an undefined primary renal disease, a number of secon dary processes develop that promote progressive kidney failure. Activation of th e renin-angiotensin system is a common event in patients with chronic renal dise ase. In these patients, renin levels are either elevated or at least not appropriately suppressed for the degree of volume expansion, elevation in blood pressure, or both. Activation of the reninangiotensin system and the relative sa lt and water excess contribute to the development of systemic hypertension in mo st patients with chronic renal disease. Systemic hypertension and a decrease in preglomerular vascular resistance lead to an increase in hydraulic pressure with

in the glomerular capillaries. Glomerular hypertension has a number of adverse e ffects, including increased protein filtration, which promotes release of cytoki nes and growth factors by mesangial cells and downstream tubular epithelial cell s. A partial loss of kidney function also is a potent stimulus for compensatory renal growth. Glomerular hypertrophy and hypertension combine to increase capill ary wall tension, promoting endothelial cell activation and injury, again causin g release of cytokines and growth factors and recruitment of inflammatory cells. These mediators stimulate processes such as apoptosis, causing loss of normal k idney cells and increased matrix production, which leads to glomerular and inter stitial fibrosis and scarring. As additional nephrons are damaged secondarily th e cycle is repeated and amplified, causing progression to endstage renal failure . AIIantiotensin II.

The Role of Hypertension in Progression of Chronic Renal Disease 6.3 Typical autoregulatory response in normal kidneys RPF, GRF, and PGC vary with pe rfusion pressure in chronic renal failure PGC, RPF, or GFR FIGURE 6-2 Imaginary autoregulation curves in normal and diseased kidneys. Plott ed on the y-axis are renal plasma flow (RPF), glomerular filtration rate (GFR), and glomerular capillary hydraulic pressure (PGC) with undefined units. Ordinari ly, RPF, GFR, and PGC remain relatively constant over a wide range of perfusion pressures within the physiologic range, from approximately 80 to 140 mm Hg. Beca use autoregulatory ability is impaired in the kidneys of persons with chronic re nal disease, these patients who develop systemic hypertension also are likely to have glomerular hypertension. 40 60 80 100 120 140 160 180 Renal perfusion pressure, mm Hg PGC = PGC MAP RA Baseline RE -MAP RE -RA Increased perfusion pressure FIGURE 6-3 Mechanism of autoregulation of glomerular capillary pressure in a sin gle glomerulus from a normal kidney. A, Baseline. B, Increased perfusion pressur e. Glomerular pressure is determined by three factors: mean arterial pressure (M AP) or perfusion pressure, and the relative resistance of both the afferent and efferent arterioles. The initial response to an increase in MAP is an increase i n afferent arteriolar resistance (RA), preventing transmission of the elevated s ystemic pressure to the glomerular capillaries. Efferent arteriolar resistance ( RE) also may decline. This decrease decompresses the glomerulus, helping to limi t the increase in glomerular capillary hydraulic pressure (PGC), and maintains c onstant renal plasma flow. A B

PGC < PGC MAP RE RA Baseline -MAP RE RA FIGURE 6-4 Mechanism of failure of autoregulation in a glomerulus from a damaged kidney. A, Baseline. B, Increased perfusion pressure. To compensate for a parti al loss of function, surviving glomeruli undergo adaptive changes to increase th e filtration rate. These include a reduction in afferent (RA) and efferent (RE) arteriolar resistances, tending to increase renal plasma flow and the glomerular filtration rate. In this setting, an increase in mean arterial pressure (MAP) i s transmitted directly to the glomerular capillaries, resulting in glomerular ca pillary hypertension, increased protein filtration, and hemodynamically mediated capillary injury. PGC glomerular capillary hydraulic pressure. Increased perfusion pressure A B

6.4 Hypertension and the Kidney Effects of Antihypertensive Agents on Experimental Kidney Injury 60 40 20 Change in sclerosis, % 0 -20 -40 -60 -80 -100 -1 -2 -3 -4 -5 -6 -7 -8 9 -10 Change in PGC, mm Hg UnxSHR RemnantHD RemnantLD Docsalt NSN Results of the linear regression analysis Eff ects of going from low to high dose of triple therapy FIGURE 6-5 Effects of triple therapy on glomerular pressure and injury. Relation ship between the change in glomerular capillary hydraulic pressure (PGC) and the extent of glomerular injury (sclerosis) in five separate studies. In these studies, rats with experimental renal disease we re given similar antihypertensive agents. Studies were conducted in several diff erent animal models of hypertension and renal disease, including the following: uninephrectomized spontaneously hypertensive rats (Unx SHR); rats with a remnant kidney given either relatively high-dose (remnant-HD) or low-dose (remnant-LD) drug therapy; rats with desoxycorticosteronesaltinduced hypertension (Doc-salt); and rats with nephrotoxic serum nephritis (NSN), an immune-mediated form of glom erular disease (NSN) [15]. In all these studies, untreated rats were compared wit h those receiving a combination of three antihypertensive agents (triple therapy ), including hydralazine, reserpine, and a thiazide diuretic. In rats with remna nt kidneys, separate studies examined the effects of low or high doses of these agents. A close correlation was revealed between the degree of reduction in glom erular capillary pressure produced by triple therapy and subsequent development of glomerular sclerosis. The data are consistent with the hypothesis that antihy pertensive agents lessen glomerular injury by reducing glomerular capillary pres sure. In the studies in rats with remnant kidneys, only a relatively high dose o f the drugs was effective in reducing pressure and injury, suggesting that aggre ssive antihypertensive therapy is more likely to slow progression of renal disea se. This finding is particularly true for antihypertensive combinations that inc lude direct vasodilators, such as the triple-therapy regimen. By dilating the af ferent arteriole, regimens such as these tend to further impair autoregulation o f glomerular pressure in the setting of chronic renal disease. (From Weir and Dw orkin [6]; with permission.) FIGURE 6-6 Correlation between systolic blood press ure and glomerular injury in rats with remnant kidneys. In these rats, blood pre ssure was continuously monitored by implanting a blood pressure sensor in the ab dominal aorta connected telemetrically to a receiver. The timeaveraged blood pre ssure in rats with remnant kidneys that were untreated or given the angiotensinconverting enzyme inhibitor enalapril or triple therapy (combination of hydralaz ine, reserpine, and a thiazide diuretic) was correlated with morphologic evidenc e of glomerular injury. A close correlation was found between the average blood pressure and extent of glomerular injury that developed in these rats. It is pro posed that, because of impaired autoregulation in chronic renal disease, elevati ons in systemic blood pressure are associated with glomerular hypertension in th ese rats. The higher the systemic pressure, the higher the glomerular pressure i s predicted to be and the more glomerular injury is observed. These data provide additional evidence that systemic hypertension produces glomerular injury by ca using elevation in glomerular pressure, and that antihypertensive therapy reduce s injury by reducing glomerular capillary pressure. (From Griffen and coworkers [7]; with permission.) 400 350 Glomerular injury score 300 250 200 150 100 50 0 80 100 120 140 160 180 200 No treatment Enalapril Low dose triple therapy High dose triple therapy Overall averaged systolic blood pressure at final 8 week, mm Hg

The Role of Hypertension in Progression of Chronic Renal Disease 6.5 Tension=pressure x radius PGC T RGC RGC PGC T A B FIGURE 6-7 The wall tension hypothesis. A, Normal. B, Chronic renal failure. Aft er a partial loss of kidney function, compensatory adaptations within surviving nephrons include renal vasodilation. Vasodilation leads to an increase in glomer ular capillary pressure and compensatory renal growth associated with an increas e in the radius of the glomerular capillaries. According to the LaPlace equation , wall tension in a blood vessel is equal to the product of the transmural press ure and the radius of the vessel. In a surviving glomerular capillary of a damag ed kidney, therefore, wall tension increases not only because of the increase in glomerular pressure but also because of an increase in capillary radius. Elevat ions in wall tension contribute to progressive renal disease by damaging the end othelial and epithelial cells lining the glomerular capillaries. By reducing wal l tension, maneuvers that decrease either glomerular pressure or glomerular capi llary radius are predicted to be beneficial. PGCglomerular capillary hydraulic pr essure; RGCglomerular capillary radius; Ttension. (From Dworkin and Benstein [8]; with permission.) FIGURE 6-8 Scanning electron micrographs of vascular casts of glomeruli from normal or uninephrectomized rats. A, A glomerulus from a rat havi ng had a sham operation, showing a uniform capillary pattern. (Panels BD display casts from uninephrectomized rats.) B, A uniform pattern with most capillaries b eing approximately the same size. C and D, Nonuniform patterns in which individu al capillary loops (indicated by asterisks) are markedly dilated. In dilated cap illary loops, wall tension is elevated and capillary wall damage is most likely to occur. The segmental nature of the capillary dilation may explain why glomeru lar sclerosis that eventually develops in remnant kidneys is also focal in early stages of the disease process. (Panels AD 320.) (From Nagata and coworkers [9]; w ith permission.) A B C D

6.6 Hypertension and the Kidney Role of the Renin Angiotensin System Release of cytokines and growth factors Increased protein filtration A II Hyperplasia and hypertrophy Systemic and glomerular hypertension FIGURE 6-9 The central role of angiotensin II(AII) in promoting progressive kidn ey failure. Based on studies in which the renin-angiotensin system has been bloc ked and renal injury ameliorated, it has been suggested that activation of this system is a crucial factor promoting progressive kidney failure. Increased activ ity of the renin-angiotensin system also may help explain the association betwee n hypertension and progression of renal disease. AII may promote renal injury by several mechan isms. Activation of the renin-angiotensin system is one mechanism leading to an increase in systemic blood pressure, the result of peripheral vasoconstriction. Glomerular hypertension results not only from the increase in systemic blood pre ssure but also because of the ability of AII to constrict efferent arterioles, c ontributing to an increase in glomerular pressure. Glomerular hypertension damag es the glomerular capillary wall and promotes injury by multiple mechanisms (see Fig. 6-1). An increase in glomerular pressure tends to increase protein filtrat ion directly. In addition, evidence suggests that AII alters the permeability of the glomerular capillary wall to macromolecules, directly increasing protein fi ltration. By activating mesangial and epithelial cells, proteinuria itself is a factor promoting progressive kidney failure. Evidence also exists that AII direc tly stimulates production of various growth factors and cytokines by kidney cell s, including fibrogenic cytokines such as transforming growth factor-beta and pl atelet-derived growth factor. Release of these factors has been linked to the de velopment of glomerular sclerosis and interstitial fibrosis. AII also stimulates proliferation and growth of kidney cells that contribute to progression of rena l disease. FIGURE 6-10 Angiotensin-converting enzyme (ACE) inhibitors and low-do se triple therapy. The effects of ACE inhibitors are compared with those of lowdose triple therapy on systemic and glomerular pressure, proteinuria, and morpho logic evidence of glomerular injury in rats with remnant kidneys. Both ACE inhib itors and triple therapy caused similar reductions in mean arterial pressure in rats with remnant kidneys; however, glomerular pressure declined only in the gro up treated with ACE inhibitors, by approximately 10 mm Hg. ACE inhibitorinduced r eductions in systemic and glomerular pressure were associated with a reduction i n proteinuria and morphologic evidence of glomerular injury. The data suggest th at ACE inhibitors are superior to low-dose triple therapy in preventing glomerul ar injury in chronic renal disease. The data support the importance of increased glomerular pressure as a determinant of glomerular injury. ACE inhibitors may b e more effective than are other agents, specifically because of their ability to reduce glomerular pressure. It should be noted, however, that significant reduc tions in glomerular pressure and injury may be achieved even with the triple-the rapy regimen when significantly higher doses than those used in the current stud y are administered (see Figs. 6-5 and 6-6). Asterisk indicates P < 0.05 versus r emnant. (Data from Anderson and coworkers [10].) 120 Mean arterial pressure, mm Hg 100 80 60 40

80 Glomerular pressure, mm Hg Glomerular inj ry, % u * * * 60 40 20 20 0 Remnant 120 AC E I Triple Remnant AC I E Triple 30 0 Proteinuria, g/24 h 100 80 60 40 20 0 Remnant AC E I Triple Remnant 10 20 * * AC I E Triple 0

The Role of Hypertension in Progression of Chronic Renal Disease 6.7 Fractional volume flux at CA=0 at CA=0 1 Small selective pores Small 1 selective pores volume flux 0.1 0.1 0.01 Large nonselective pores 0.01 Large nonselective pores Fractional 0.001 0.001 0.0001 0.0005 30 40 50 60 Effective pore radius, A 0.0001 0.0005 30 40 50 60 Effective pore radius, A B A FIGURE 6-11 Effect of renal vein constriction on glomerular protein filtration. The role of angiotensin II (AII) in modulating macromolecular clearance across t he glomerular capillary wall has been examined by Yoshioka and coworkers [11]. T hese authors used a model of renal vein constriction to increase glomerular pres sure and markedly increase protein filtration. They calculated the volume flux t hrough the small selective pores (effective pore radius, 4050 ) within the glomeru lar capillary wall and through the large nonselective pores. A, Volume fluxes un der control conditions (hatched bars) and during renal vein constriction (open bars). Renal vein constriction causes an increase in filtrati on through large nonselective pores, which accounts for increased protein filtra tion. B, Effects of renal vein constriction were again examined, alone (open bar s) and during administration of the AII receptor antagonist saralasin (hatched b ars). Saralasin reduced volume flux through the large pores, indicating that inc

reased endogenous AII action was largely responsible for proteinuria during rena l vein constriction. (From Yoshioka and coworkers [11]; with permission.) FIGURE 6-12 (see Color Plate) Local activation of the renin-angiotensin system and pro duction of fibrogenic cytokines in experimental chronic renal disease. In situ r everse transcriptase was performed in rats with remnant kidneys to examine the l evel of gene expression for angiotensinogen and transforming growth factor-beta (TGF-beta). Rats still had not developed widespread morphologic evidence of glom erular injury 24 days after subtotal nephrectomy. A, At this point in time (arro ws), staining for angiotensinogen messenger RNA (mRNA) was observed along the wa ll of a dilated capillary loop (CL) and in an adjacent cluster of mesangial cell s. B, TGFbeta mRNA was present in an identical pattern in a contiguous section ( arrows). C and D, Staining for angiotensinogen (panel C) and TGF-beta (panel D) is examined in kidneys from rats treated with the angiotensin receptor antagonis t losartan from the time of nephrectomy. Administration of losartan markedly red uced expression of both factors in remnant kidneys. The findings are consistent with the hypothesis that endothelial injury is associated with increased angiote nsinogen production and local activation of the renin-angiotensin system, leadin g to increased expression of TGFbeta and progressive glomerular fibrosis. (From Lee and coworkers [12]; with permission.) A B C D

6.8 100 90 80 fg RANTES/ 104 cells 70 60 50 40 30 20 10 0 Hypertension and the Kidney ** ** Migrated monocytes * P< 0.05 vs cells treated with A II alone ** P< 0.01 vs unstimulated controls 15 * P<0.05 vs control medium ** P<0.05 vs A II medium without antibody * * 10 ** 5 * * m trol Con Control A II CGP CGP+ A II PD PD + A II los los + A II A B m Ab Ab IgG -6 M A II diu TE S TE S oat me 0 AN al g R AN A II +1 m ii-R ant EM ant nor DM +m m+ m+ m diu diu diu me me me rol A II A II ont C ediu m 0 FIGURE 6-13 Angiotensin II (AII) may be a proinflammatory molecule. The effect o f AII on production of the chemokine RANTES was examined in cultured glomerular endothelial cells. A, Effects of AII on secretion of RANTES by cultured glomerul ar endothelial cells. AII markedly stimulated RANTES secretion. Of note is that AII-induced RANTES secretion was prevented by incubation with the AT2 receptor a ntagonists SCP-42112A (CGP) or PD 1231777 (PD) but not by the AT1 receptor antag onist losartan (los). These finding suggest AT2 receptors mediate the increase i n secretion of RANTES. B, Results of a chemotactic assay for human monocytes. Mi gration of monocytes was assessed using a modified Boyden chamber. Migration of monocytes was stimula ted by conditioned medium from glomerular endothelial cells that were exposed to AII. This effect was blocked by incubation of the medium with an anti-RANTES an tibody but not by control serum. The anti-RANTES antibody alone was also without effect, as was AII in the absence of conditioned media. The findings are consis tent with the hypothesis that AII promotes glomerular inflammation by binding to AT2 receptors, promoting RANTES secretion and infiltration of inflammatory mono cytes and macrophages. fgfemtograms. (From Wolf and coworkers [13]; with permissi on.) FIGURE 6-14 Renin-angiotensin systems. For many reasons the effects of angi otensin-converting enzyme (ACE) inhibitors and angiotensin II (AII) type 1 AT1 r eceptor antagonists on the progression of chronic renal disease may not be ident ical. In the classic pathway, renin cleaves angiotensinogen to form AI, which is further cleaved by ACE to form biologically active AII. ACE inhibitors inhibit the renin-angiotensin system by reducing the activity of ACE and decreasing AII formation. ACE also catalyzes other important pathways, however, including the b

reakdown of vasodilator substances such as bradykinin, substance P, and enkephal in. Increased levels of these substances might account for some of the biologic effects of ACE inhibition. Levels of these substances would not increase after a dministration of an AT1 receptor antagonist. In contrast, inhibition of the reni nangiotensin system by ACE inhibitors may be incomplete because other proteases may catalyze to conversion of angiotensinogen to AII (on the right). CAGE chymost atin-sensitive angiotensin IIgenerating enzyme; t-PAtissue plasminogen activator. (Adapted from Dzau and coworkers [14].) Renin-angiotensin systems Angiotensinogen Bradykinin Substance P Enkephalin Renin Angiotensin I CAGE Cathe psin G Tonin Angiotensin II Other proteases Angiotensin III and IV tPA Cathepsin G Tonin ACE Inactive fragments

The Role of Hypertension in Progression of Chronic Renal Disease 6.9 Vasoconstriction AT 1 Aldosterone Growth Angiotensin II Clearance Apoptosis Proteases AT 2 Angiotensin III and IV Vasodilation AT 4 FIGURE 6-15 Subclasses of angiotensin receptors. Another theoretic reason the ac tions of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (AII) receptor antagonists may differ. All of the AII receptor antagonists currently available for clinical use selectively block the AT1 receptor. This receptor app ears to transduce most of the wellknown effects of AII, including vasoconstricti on, stimulation of cell growth, and secretion of aldosterone. Increasingly, howe ver, potentially important actions of other angiotensin receptors are being disc overed. For example, AT2 receptors may be involved in regulation of apoptosis an d modulation of inflammation by way of secretion of RANTES (see Fig. 6-13) [13,1 5]. AT4 receptors bind other angiotensins preferentially and may promote endothe lially mediated vasodilatation [16]. Activity of all pathways is reduced after a dministration of ACE inhibitors, whereas only AT1 receptormediated events are blo cked by drugs currently available. Whether these differences will have important consequences for progression of renal disease is currently unknown. FIGURE 6-16 Shown are results of studies comparing the effects of angiotensin II (AII) rece ptor antagonists and angiotensin-converting enzyme (ACE) inhibitors on experimen tal renal injury. AII receptor antagonists were as effective as were ACE inhibit ors in the remnant kidney model; streptozotocin-induced diabetic rats; the purom ycin aminonucleoside model of progressive glomerular sclerosis, preventing inter stitial fibrosis associated with obstructive uropathy; and an inherited model of glomerular sclerosis, the Munich-Wistar Furth/Ztm rat [1721]. In contrast, AII r eceptor antagonists were somewhat less effective than were ACE inhibitors in sev eral other animal models of chronic renal disease, including uninephrectomized s pontaneously hypertensive rats, obese Zucker rats, and the passive Heymann nephr itis model of membranous glomerulonephritis [2224]. Clinical trials are necessary to determine whether these classes of drugs will be equally effective in preven ting progressive renal disease in humans. ANGIOTENSIN-CONVERTING ENZYME INHIBITORS VERSUS ANGIOTENSIN II ANTAGONISTS IN EX PERIMENTAL RENAL DISEASE Angiotensin II antagonists equivalent to angiotensin-converting enzyme inhibitor s Remnant kidney Passive Heymann nephritis Chronic rejection Two-kidney, one-clip hypertension Streptozocin-induced diabetes Puromycin aminonucleoside Obstructive uropathy Munich-Wistar Furth/Ztm rat Angiotensin II antagonists inferior to angiotensin-converting enzyme inhibitors Uninephrectomized spontaneously hypertensive rats Obese Zucker rats Passive Heym ann nephritis MAP 0 Reduction, % -20 -40 -60 -80 PGC PROT

SCLER Nifedipine Felodipine Amlodipine FIGURE 6-17 Three calcium channel blockers and their effects in experimental ani mals. The results of several studies examining the effects of three different di hydropyridine calcium channel blockers on hemodynamics and injury in the unineph rectomized spontaneously hypertensive rat model of progressive glomerular sclero sis are summarized. The three drugs produced graded declines in mean arterial pr essure (MAP), with nifedipine causing the greatest and amlodipine the least redu ction in systemic pressure. Micropuncture determinations of glomerular capillary hydraulic pressure (PGC) revealed that only nifedipine and felodipine caused gl omerular pressure to decline significantly. These drugs reduced both the protein excretion rate (PROT) and morphologic evidence of glomerular injury (SCLER). Th e data are consistent with the hypothesis that antihypertensive agents ameliorat e renal damage by reducing glomerular pressure and that, for calcium channel blo ckers, significant reductions in PGC occur only when drug administration causes a marked decline in systemic pressure. (From Dworkin [25,26]; with permission.)

6.10 Hypertension and the Kidney The Effect of Hypertension on Renal Disease ROLE OF HYPERTENSION IN CHRONIC RENAL DISEASE Cause Renal artery stenosis or occlusion Atheroembolic disease Hypertensive nephroscle rosis 100 90 Contributors to disease progression Hypertensive persons, % Diabetes mellitus Glomerulonephritis Tubulointerstitial disease (?) Adult-onset polycystic kidney disease (?) 80 70 60 50 40 30 20 10 0 0 10 20 30 40 50 60 2 FIGURE 6-18 The impact of hypertension on the incidence of end-stage renal disea se (ESRD) is vastly underestimated if one considers only those patients in whom systemic hypertension is the primary process resulting in loss of kidney functio n. The group of patients in whom ESRD is attributed to hypertension undoubtedly includes persons with renal disease of several causes. Some of these causes are occlusive disease of the main renal arteries as a result of atherosclerotic dise ase, atheroembolic disease of the kidneys, and hypertensive nephrosclerosis. The exact incidence of these processes within the hypertensive population with chro nic renal disease is unknown. Even more commonly, poorly controlled systemic hyp ertension accelerates the rate of loss of kidney function in many patients in wh om the primary cause of renal injury is another process altogether. This fact is particularly true in patients with glomerular diseases such as diabetic nephrop athy and chronic glomerulonephritis [27,28]. Whether systemic hypertension also contributes to loss of kidney function in patients with tubulointerstitial or cy stic disease of the kidney is less certain [29]. 70 80 90 Mean GFR, mL/min/1.73m FIGURE 6-19 Hypertension prevalence corresponds with decreased glomerular filtra tion rate (GFR). Hypertension is common in glomerular, tubular, vascular, and in terstitial renal disease and becomes increasingly prevalent as renal function de clines. In almost 200 patients screened for the Modification of Diet in Renal Di sease study, the prevalence of hypertension increased as the GFR decreased and h ypertension was almost universal as the GFR approached 10 mL/min [29]. Volume/ total body sodium excess FIGURE 6-20 Multifactorial mechanisms for hypertension in clinical renal disease . An increased intravascular volume, owing to decreased renal excretion of sodiu m and water as the glomerular filtration rate declines, is probably the primary cause. Activation of sympathetic tone and involvement of the renin-angiotensin s ystem, which is inappropriately stimulated in the setting of volume expansion, h ave been demonstrated in renal failure. Decreased activity of nitric oxide and o ther vasorelaxants and increased activity of endothelin and other endogenous vas oconstrictors also are probably contributory. Stimulation of renin-angiotensin system

Augmented sympathetic tone

The Role of Hypertension in Progression of Chronic Renal Disease 6.11 100 80 60 40 20 0 0 (53) (30) (18) (17) 1.0 Free of renal failure, % 0.8 Probability of survival (7) (2) Normotensive (n=79) Hypertensive (n=69) 0.6 HBP before age 35 NBP after age 35 0.4 5 10 Time since biopsy, y 15 0.2 FIGURE 6-21 Consistent relationship between hypertension and progressive renal d isease. Analysis of the Modification of Diet in Renal Disease study, which invol ved patients with a heterogeneous miscellany of renal diagnoses, showed that the degree of elevation of the mean arterial blood pressure correlated with the dec line in the glomerular filtration rate [30]. This finding has been confirmed in cohorts of patients with the same renal disease. In immunoglobulin A (IgA) nephr opathy, eg, the presence of high blood pressure at diagnosis is a strong predict or for development of end-stage renal disease. In this study by Radford and cowo rkers [31] of 148 patients with IgA nephropathy, 69 patients with hypertension h ad a much higher risk of proceeding to renal failure than did the 79 patients wh o were normotensive. 0 0 10 20 30 40 50 Age, y 60 70 80 90 FIGURE 6-22 Relationship between hypertension and renal failure. Johnson and Gab ow [32] studied over one thousand patients with autosomal dominant polycystic ki dney disease. These authors demonstrated that the time of renal survival was muc h shorter for patients with hypertension compared with patients whose blood pres sure was normal (see Fig. 6-21). Renal survival was defined as the time period b efore the need for dialysis. HBPhigh blood pressure; NBPnormal blood pressure. Systolic blood pressure 100 80 Free of renal endpoints, % P<0.001 FIGURE 6-23 Hypertension accelerates progression of renal failure in children an d adults. For 2 years, Wingen and coworkers [33] followed almost 200 children an d adolescents with renal disease, aged 2 to 18 years. Here, renal survival is de fined as stability of the creatinine clearance rate. Compared with patients with systolic blood pressures lower than 120 mm Hg, those with systolic blood pressu

res higher than 120 mm Hg had more rapid development of renal death. Renal death was defined as a decrease in the creatinine clearance rate by 10 mL/min/1.73 m2 . 60 40 <120 mm Hg >120 mm Hg 0 0 1 Time, y 2

6.12 4.0 3.5 ESRD due to any cause, % 3.0 2.5 2.0 1.5 1.0 0.5 0 0 Hypertension and the Kidney hypertension to later development of renal failure. In over 300,000 men screened for the Multiple Risk Factor Intervention Trial, Klag and coworkers [34] showed that a single blood pressure measurement was strongly correlated with the risk of endstage renal disease (ESRD) later in life. Even men with high-normal blood pressures (defined as a systolic pressure of 130 to 139 mm Hg or a diastolic blo od pressure of 85 to 89 mm Hg) were at a statistically significant greater risk for ESRD than were men with blood pressures under 120/80 mm Hg. This risk increa ses sequentially with the higher stage of hypertension. This study used definiti ons of hypertension discussed in the Fifth Report of the Joint National Committe e on Detection, Evaluation and Treatment of High Blood Pressure (JNC-5). Stage I hypertension is defined as a systolic pressure of 140 to 159 mm Hg and a diasto lic pressure of 90 to 99 mm Hg. Stage II hypertension is defined as a systolic p ressure of 160 to 179 mm Hg and a diastolic pressure of 100 to 109 mm Hg. Stage III hypertension is a systolic pressure of 180 to 209 mm Hg and a diastolic pres sure of 110 to 119 mm Hg. Stage IV hypertension is a systolic pressure of 210 mm Hg or higher and a diastolic blood pressure of 120 mm Hg or greater. The highes t relative risk for renal failure was among persons with stage III or IV hyperte nsion. FIGURE 6-25 Hypertension and impact on progression of renal disease cause d by hypertension. In a study of 94 patients with essential hypertension and an initially normal serum creatinine concentration, Rostand and coworkers [35] show ed that hypertension control apparently had little impact on progression of rena l disease. When patients were divided into those with diastolic blood pressures higher and lower than 90 mm Hg, the percentage whose renal function deteriorated was equivalent in both groups. Blacks were at especially high risk; 23% of blac k patients with diastolic blood pressures below 90 mm Hg had worsened renal func tion over time, compared with 11% of white patients with diastolic blood pressur es lower than 90 mm Hg. Optimal Normal but not optimal High normal Stage 1 hypertension Stage 2 hyperten sion Stage 3 hypertension Stege 4 hypertension 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Years since screening FIGURE 6-24 There long has been controversy over whether hypertension alone, wit hout renal disease, can cause renal failure, especially in whites. Recent convin cing epidemiologic evidence, however, links Deteriorating renal function Stable renal function 16% Stable renal function 12% Deteriorating renal function Controlled diastolic blood pressure <90 min Hg Uncontrolled diastolic blood pressure <90 min Hg 0 Decline in GFR mL/min 3 6 9 12 15 B3 F4 F12 Blood pressure Low BP group Usual BP group F20 Time, mo F28 F36

FIGURE 6-26 Lower-than-usual blood pressure (BP) target. The Modification of Die t in Renal Disease study [36] also prospectively examined the effect of a lowerthan-usual BP target in a larger cohort of patients with renal insufficiency. Pa tients were randomized to two target BPs: a usual mean arterial pressure (MAP) t arget of 107 mm Hg, corresponding to a BP of 140/90 mm Hg; or a low MAP target o f 92 mm Hg, corresponding to a BP of 125/75 mm Hg. The changes in the glomerular filtration rate (GFR) in the two groups over a 3year follow-up period are depic ted. (The y-axis depicts the changes in GFR, and the x-axis represents months. F or example, F36 means 36 months after initiation of the study.) Patients in the two groups had statistically equivalent declines in GFR. Over the last 6 months of the study, however, a trend toward greater stabilization in renal function oc curred in the group randomized to the lower target.

The Role of Hypertension in Progression of Chronic Renal Disease 6.13 Patients randomized to low BP target Patients randomized to the usual BP target Study 1 0 Mean rate of GFR decline, mL/min/y Study 2 0 4 4 8 8 12 n=420 n=101 n=54 n=136 n=63 n=32 <1 1<3 3 <1 1<3 3 12 Baseline urinary protein, g/d FIGURE 6-27 Two patient groups in the study of diet in renal disease. The Modifi cation of Diet in Renal Disease (MDRD) study involved two patient groups. The gr oup in which patients had moderate renal dysfunction (glomerular filtration rate [GFR] between 25 and 55 mL/min) was called Study 1. The other group, which incl uded patients who had more severe renal dysfunction (with a GFR between 13 and 2 4 mL/min) was called Study 2. The effects of the lower blood pressure (BP) targe t on patients with proteinuria in Studies 1 and 2 are shown. The y-axis divides patients in Studies 1 and 2 into three groups, depending on urinary protein excr etion. The x-axis represents the rate of GFR decline. In the subset of patients in the MDRD trial in both Studies 1 and 2 who had massive proteinuria (protein o ver 3 g/24 h), the lower blood pressure had an especially salutary effect: the d ecline in GFR was much slower [37].

Renal survival 1.00 0.95 0.90 0.85 0.80 0.75 0.70 0.65 0.60 0 6 12 18 Time, mo 24 30 Proteinuria: <1g/24h mean BP: <107 mm Hg Proteinuria: <1g/24h mean BP: >107 mm H g Proteinuria: <13g/24h mean BP: <107 mm Hg Proteinuria: <13g/24h mean BP: >107 mm Hg 100 90 80 Creatinine clearance, mL/min 70 60 50 40 30 20 10 -12 Group A -6 0 6 G roup B Evolution of creatinine clearance 12 18 24 30 36 FIGURE 6-28 Proteinuria as a marker for progressive renal disease. Nephrotic pro teinuria may be a more important and independent marker for progression of renal disease than is hypertension. That is, patients in whom massive proteinuria and hypertension coexist have the worst renal prognosis. In a study of over 400 pat ients with renal insufficiency followed over 2 years, Locatelli and coworkers [3 8] found that patients who had both a mean blood pressure (BP) higher than 107 m m Hg and protein excretion of 1 to 3 g/24 h had the lowest rates of renal surviv al. FIGURE 6-29 The effect of reduction of proteinuria on the stabilization of renal function. The observations that the potentially correctable factors of hyperten sion and proteinuria predict the decline of renal function lead to the hypothesi s that antihypertensive agents in the angiotensin-converting enzyme (ACE) inhibi tor class may be especially important in treatment of hypertension in renal dise ase. Praga and coworkers [39] investigated 46 patients with nondiabetic renal di sease and massive proteinuria treated with the ACE inhibitor captopril. These au thors found that proteinuria was decreased by about half. In patients with the g reatest reduction in proteinuria (group A), a greater stabilization of renal fun ction occurred over time when compared with those (group B) whose reduction in p roteinuria was less.

6.14 50 45 Percentage with doubling of baseline creatinine 40 35 30 25 20 15 10 5 0 0 Hypertension and the Kidney 1.6 Ramipril Placebo 1.4 Mean rate of GFR, mL/min/mo 1.2 1.0 0.8 0.6 0.4 Placebo P=0.007 Captopril 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Years of follow-up FIGURE 6-30 Large study of patients with diabetes mellitus and renal disease ran domly assigned to captopril or placebo. Lewis and coworkers [40] have studied th e use of the angiotensin-converting enzyme inhibitor captopril in patients with type I diabetes mellitus who have diabetic nephropathy and proteinuria. Captopri l provides strong protection against progression of renal disease. Those patient s treated with captopril had a significant decrease in proteinuria and a slower rate of disease progression, as defined by the time to doubling of the serum cre atinine, as compared with patients randomized to placebo. 0.2 0 n=61 n=36 n=20 Baseline urinary protein excretion, 1g/24h FIGURE 6-31 Study of patients with renal disease not associated with diabetes ra ndomly assigned to ramipril or placebo. A study structured similarly to that in Figure 6-30 examined the use of the angiotensinconverting enzyme inhibitor ramip ril in over 150 patients with nondiabetic renal disease [41]. The primary conclu sion of the study is summarized. Blood pressure and proteinuria decreased more s ignificantly in the patients treated with ramipril. This group had significantly lower rates of decline in glomerular filtration rate (GFR) over time. This effe

ct was increasingly striking as the baseline level of proteinuria increased and was most pronounced in patients with a urinary protein excretion of over 7 g per 24 hours. FIGURE 6-32 Meta-analysis of over 1500 patients with renal insufficie ncy. A recent meta-analysis examined randomized studies comparing an angiotensin -converting enzyme inhibitor (ACE) to other antihypertensive agents [42]. None o f the individual studies showed that the relative risk for development of end-st age renal disease (ESRD) was statistically lower in patients treated with ACE in hibitors. The pooled relative risk, incorporating data from all the studies, how ever, was lower in the cohort groups treated with ACE inhibitors. Favors ACE inhibitors Favors other drugs Reference Country Year 1992 1992 1993 1 993 1994 1994 1994 1995 1996 Patients, n 121 70 112 124 103 100 51 260 70 IT Zucchelli et al. [43] DEN Kamper et al. [44] Brenner (Unpublished data) USA T oto (Unpublished data) USA HOL van Essen et al. [45] Hannedouche et al. [46] FR AUS Bannister et al. [47] Himmelmann et al. [48] SW AUS Becker et al. and Ihle e t al. [49,50] EUR Maschio et al. [51] Overall 1996 583 0.01 0.02 0.05 0.1 0.2 0.5 1 2 5 10 20 50 100 Relative risk for ESRD

The Role of Hypertension in Progression of Chronic Renal Disease Podocytes Renal survival, % Glomerular basement membrane 6.15 100 80 60 40 20 0 0 6 12 18 24 30 36 42 Time, mo Captopril Nifedipine No change in proteinuria Decreased proteinuria Dihydropyridine calcium channel blockers Nifedipine Amlodipine Felodipine Isradi pine Nisolodipine Non-dihydropyridine calcium channel blockers Diltiazem Verapamil FIGURE 6-33 Calcium channel blockers. Calcium channel blockers are prescribed wi dely to patients with normal renal function and affect renal protein excretion v ariably. The general consensus is that the nondihydropyridine calcium channel bl ockers diltiazem and verapamil decrease proteinuria, whereas the dihydropyridine agents have minimal or minor effects on proteinuria. FIGURE 6-34 The effect of calcium channel blockers on preservation of renal func tion. Most studies of angiotensin-converting enzyme (ACE) inhibitors versus othe r agents did not examine calcium channel blockers. In a paper by Zucchelli and c oworkers [43], patients with nondiabetic renal diseases and hypertension initial ly were treated with adrenergic antagonists, diuretics, and vasodilators. These patients were then randomized to treatment with the dihydropyridine calcium entr y antagonist nifedipine or to the ACE inhibitor enalapril. The rate of decline i n renal function was most rapid in the pre-randomization phase in patients treat ed with conventional antihypertensive agents, mostly adrenergic antagonists. The rate of decline then slowed after randomization. No significant difference in r ates of decline was seen in patients treated with nifedipine compared with those treated with captopril. (From Zucchelli and coworkers [43]; with permission.) F IGURE 6-35 The effect of angiotensin-converting enzyme inhibitors and other anti hypertensive agents on stabilization of renal function in noninsulin-dependent di abetes. Bakris and coworkers [52] studied patients with noninsulin-dependent diab etes mellitus, hypertension, proteinuria, and presumed diabetic nephropathy. The se patients were randomized to treatment with the angiotensin-converting enzyme inhibitor lisinopril; the beta-blocker atenolol; or a nondihydropyridine calcium channel blocker (NDCCB), either verapamil or diltiazem. The primary conclusion of the study is summarized. The change in glomerular filtration rate as a functi on of time is depicted in groups of patients receiving lisinopril, calcium chann el blockers, or atenolol. The creatinine clearance rate declined in all three gr oups. However, the slope of the decline was significantly greater in the group t reated with atenolol and not significantly different between the groups treated with lisinopril and the calcium entry antagonist. 60 Creatinine clearance, mL/min/1.73 m2 Lisinopril NDCCBs 40 20 Atenolol Lisinopril NDCCBs Atenolol 1998 18 18 16

1989 18 18 16 1990 18 18 16 1991 18 17 15 1992 16 16 13 1993 16 15 11 1994 15 15 11

6.16 120 115 110 Mean BP, mm Hg 105 100 95 90 0 Hypertension and the Kidney FIGURE 6-36 Race and ethnicity in choice of antihypertensive agents. Racial and ethnic differences also may be important in determining the choice of antihypert ensive agent to delay progression of chronic renal disease. Blacks are at much h igher risk than are whites for progression of renal disease. In addition, a more aggressive antihypertensive program may be beneficial to blacks. In the Modific ation of Diet in Renal Disease study, a trend toward a more gradual decline in r enal function in blacks randomized to the low mean blood pressure target was see n [36]. Blacks tend to have a better blood pressure response to administration o f diuretics than do whites. In a large study of patients with normal renal funct ion, blacks also responded well to calcium channel blockers [53]. The AfricanAme rican Study of Kidney Disease and Hypertension (AASK), currently in progress, is examining the hypothesis that a lower-thanusual blood pressure goal will have a renal protective effect in renal disease with hypertension. A preliminary findi ng from the study is depicted. The study randomized blacks with hypertension to the beta-blocker atenolol, the dihydropyridine calcium channel blocker amlodipin e, or the angiotensin-converting enzyme enalapril. In the initial 6 months of th e study, the mean arterial blood pressure decreased most significantly in the sh ort term with amlodipine [54]. GFRglomerular filtration rate. Atenolol Amiodipine Enalapril Baseline GFR1 GFR2 RV FV3 FV6 Time, mo Management of Hypertension in Clinical Renal Disease Blood pressure:> 130/185 mm HG or higher with renal disease Blood pressure: 130/ 85 mm Hg or higher with renal disease Proteinuria: 1g/24h or less Proteinuria: 1 G/24h or more Diabetic or primary glomerular disease Begin ACE inhibitor Target blood pressure: 125/75 mm Hg or lower Yes No If hyperkalemia or acute renal failure develops, evaluate possible causes If no other precipitant, decrease ACE inhibitor dose Add diuretic, calcium channel blo cker Treatment with ACE inhibitor Target blood pressure: 125/75 mm Hg or lower Treatment with diuretic, ACE inhibitor, or calcium channel blocker A FIGURE 6-37 Treatment of patients with renal disease and high-normal or elevat ed blood pressure (BP). A, All patients should have a measurement of 24-hour pro tein excretion. If the protein excretion is over 1 g/24 h, an angiotensin-conver ting enzyme (ACE) inhibitor should be started. The goal of hypertension control in patients with azotemia who have massive proteinuria should be a blood pressur e of 125/75 mm Hg or lower. It is unlikely that an ACE inhibitor alone will be a ble to decrease the blood pressure to this level before hyperkalemia or hemodyna mically mediated acute renal failure intervenes. A diuretic and medications from other classes, such as a calcium channel blocker, should then be added. B B, When protein excretion is less than 1 g/24 h, the blood pressure should be lo wered to at least 130/85 mm Hg. No conclusive evidence exists to support the use of one antihypertensive agent or class of agents over another. However, in pati ents at risk for progressive proteinuria (eg, diabetic patients with microalbumi nuria), ACE inhibitors should be used. Given the importance of sodium retention in the hypertension in renal disease, a loop or thiazide diuretic is a reasonabl e initial treatment. An ACE inhibitor or calcium channel blocker should be added

as a second-line agent.

The Role of Hypertension in Progression of Chronic Renal Disease 6.17 References 1. Dworkin LD, Grosser M, Feiner HD, et al.: Renal vascular effects of antihyper tensive therapy in uninephrectomized spontaneously hypertensive rats. Kidney Int 1989, 35:790798. 2. Anderson S, Meyer T, Rennke HG, Brenner BM: Control of glome rular hypertension limits glomerular injury in rats with reduced renal mass. J C lin Invest 1985, 76:612619. 3. Kakinuma Y, Kawamura T, Bills T, et al.: Blood pre ssure independent effect of angiotensin inhibition on the glomerular and nonglom erular vascular lesions of chronic renal failure. Kidney Int 1996, 42: 4655. 4. D workin LD, Feiner HD, Randazzo J: Glomerular hypertension and injury in desoxyco rticosterone-salt rats on antihypertensive therapy. Kidney Int 1987, 31:718724. 5 . Neugarten J, Kaminetsky B, Feiner H, et al.: Nephrotoxic serum nephritis with hypertension: amelioration by antihypertensive therapy. Kidney Int 1985, 28:13513 9. 6. Weir MR, Dworkin LD: Antihypertensive drugs, dietary salt and renal protec tion: How low should you go and with which therapy. Am J Kidney Dis 1998, 32:122. 7. Griffen KA, Picken M, Bidani AK: Radiotelemetric BP monitoring, antihyperten sives and glomeruloprotection in remnant kidney model. Kidney Int 1994, 46:101010 18. 8. Dworkin LD, Benstein JA: Antihypertensive agents, glomerular hemodynamics and glomerular injury. In Calcium Antagonists and the Kidney. Edited by Epstein M, Loutzenhiser R. Philadelphia, Hanley & Belfus; 1990:155176. 9. Nagata M, Scha rer K, Kriz W: Glomerular damage after uninephrectomy in young rats. I. Hypertro phy and distortion of the capillary architecture. Kidney Int 1992, 42:136147. 10. Anderson S, Rennke HG, Brenner BM: Therapeutic advantage of converting enzyme i nhibitors in arresting progressive renal disease associated with systemic hypert ension. J Clin Invest 1986, 77:19932000. 11. Yoshioka T, Mitarai T, Kon V, et al. : Role for angiotensin II in an overt functional proteinuria. Kidney Int 1986, 3 0:538545. 12. Lee LK, Meyer TM, Pollock AS, Lovett DH: Endothelial cell injury in itiates glomerular sclerosis in the rat remnant kidney. J Clin Invest 1995, 96:9 53964. 13. Wolf G, Ziyadeh FN, Thaiss F, et al.: Angiotensin II stimulates expres sion of the chemokine RANTES in rat glomerular endothelial cells. J Clin Invest 1997, 100:10471058. 14. Dzau VJ, Sasamura H, Hein L: Heterogeneity of angiotensin synthetic pathways and receptor subtypes: physiological and pharmacological imp lications. J Hypertension 1993, 11(suppl 3):S13S18. 15. Yamada T, Horiuchi M, Dza u VJ: Angiotensin II type 2 receptor mediates programmed cell death. Proc Natl A cad Sci U S A 1996, 93:156160. 16. Prsti I, Bara AT, Busse R, Hecker M: Release of nitric oxide by angiotensin (1-7) from porcine coronary endothelium: implicatio ns for a novel angiotensin receptor. Br J Pharmacol 1994, 111:652654. 17. Lafayet te RA, Mayer G, Park SK, Meyer TM: Angiotensin II receptor blockade limits glome rular injury in rats with reduced renal mass. J Clin Invest 1992, 90:766771. 18. Remuzzi A, Perico N, Amuchastegui CS, et al.: Short- and long-term effect of ang iotensin II receptor blockade in rats with experimental diabetes. J Am Soc Nephr ol 1993, 4:4049. 19. Tanaka R, Kon V, Yoshioka T, et al.: Angiotensin converting enzyme inhibitor modulates glomerular function and structure by distinct mechani sms. Kidney Int 1994, 45:537543. 20. Ishidoya S, Morrissey J, McCracken R, et al. : Angiotensin receptor antagonist ameliorates renal tubulointerstitial fibrosis caused by unilateral ureteral obstruction. Kidney Int 1995, 47:12851294. 21. Remu zzi A, Malanchini B, Battaglia C, et al.: Comparison of the effects of angiotens in-converting enzyme inhibition and angiotensin II receptor blockade on the evol ution of spontaneous glomerular injury in male MWF/Ztm rats. Experimental Nephro l 1996, 4:1925. 22. Anderson AE, Tolbert EM, Esparza AR, Dworkin LD: Effects of a n ACE inhibitor vs. an AII antagonist on hemodynamics, growth and injury in spon taneously hypertensive rats. J Am Soc Nephrol 1996, 7:A3014. 23. Crary GS, Swan SK, O'Donnell MP, et al.: The angiotensin II receptor antagonist losartan reduces blood pressure but not renal injury in obese Zucker rats. J Am Soc Nephrol 1995, 6:12951299. 24. Hutchinson FN, Webster SK: Effect of ANGII receptor antagonist o n albuminuria and renal function in passive Heymann nephritis. Am J Physiol 1992 , 263:F311F318. 25. Dworkin LD, Feiner HD, Parker M, Tolbert E: Effects of nifedi

pine and enalapril on glomerular structure and function in uninephrectomized spo ntaneously hypertensive rats. Kidney Int 1991, 39:11121117. 26. Dworkin LD, Tolbe rt E, Recht PA, et al.: Effects of amlodipine on glomerular filtration, growth, and injury in experimental hypertension. Hypertension 1996, 27:245250. 27. Breyer JA, Bain RP, Evans JK, et al.: Predictors of the progression of renal insuffici ency in patients with insulin-dependent diabetes and overt diabetic nephropathy. Kidney Int 1996, 50:16511658. 28. Gisen Group: Randomized placebo-controlled tri al of effect of ramipril on decline in glomerular filtration rate and risk of te rminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 1997, 349: 18571863. 29. Klahr S, Levey AS, Beck GJ, et al.: The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disea se. Modification of Diet in Renal Disease Study Group. N Engl J Med 1994, 330:87 7884. 30. Modification of Diet in Renal Disease Study Group: Predictors of the pr ogression of renal disease in the modification of diet in renal disease study. K idney Int 1997, 51:19081919. 31. Radford MG, Donadio JV, Bergstralh EJ, Grande JP : Predicting renal outcome in IgA nephropathy. J Am Soc Nephrol 1997, 8199207. 32 . Johnson AM, Gabow PA: Identification of patients with autosomal dominant polyc ystic kidney disease at highest risk for end-stage kidney disease. J Am Soc Neph rol 1997, 8:15601567. 33. Wingen A-M, Fabian-Bach C, Shaefer F, Mehls O for the E uropean Study Group for Nutritional Treatment of Chronic Renal Failure in Childh ood. Lancet 1997, 349:11171123. 34. Klag MJ, Whelton PK, Randall BL, et al.: Bloo d pressure and endstage renal disease in men. N Engl J Med 1996, 334:1318. 35. Ro stand SG, Brown G, Kirk KA, et al.: Renal insufficiency in treated essential hyp ertension. N Engl J Med 1989, 320:684688. 36. Klahr S, Levey A, Beck GJ, et al. f or the Modification of Diet in Renal Disease Study Group. N Engl J Med 1994, 330 :877884. 37. Peterson JC, Adler S, Burkart JM, et al. for the Modification of Die t in Renal Disease Study Group. Ann Intern Med 1995, 123:754762. 38. Locatelli F, Marcelli D, Comelli M, et al. for the Northern Italian Cooperative Study Group: proteinuria and blood pressure as causal components of progression to end-stage renal failure. Nephrol Dial Transplant 1996, 11:461467. 39. Praga M, Hernandez E , Montoyo C, et al.: Long-term beneficial effects of angiotensin-converting enzy me inhibition in patients with nephrotic proteinuria. Am J Kidney Dis 1992, 20:2 40248. 40. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD for the Collaborative Study Group: The effect of angiotensin-converting enzyme inhibition on diabetic nephro pathy. N Engl J Med 1993, 329:14561462.

6.18 Hypertension and the Kidney 48. Himmelmann A, Hansson L, Hannson BG, et al.: ACE inhibition preserves renal function better than beta-blockers in the treatment of essential hypertension. B lood Pressure 1995, 4:8590. 49. Becker GJ, Whitworth JA, Ihle BU, et al.: Prevent ion of progression in non-diabetic chronic renal failure. Kidney Int Suppl 1994, 45:S167S170. 50. Ihle BU, Whitworth JA, Shahinfar S, et al.: Angiotensin-convert ing enzyme inhibition in nondiabetic progressive renal insufficiency: a controll ed double-blind trial. Am J Kidney Dis 1996, 27:489495. 51. Maschio G, Aliberti D , Janin G, et al.: Effect of the angiotensinconverting enzyme inhibitor benazepr il on the progression of renal insufficiency. N Engl J Med 1996, 334:939945. 52. Bakris GL, Copley JB, Vicknair N, et al.: Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy. Kidne y Int 1996, 50:16411650. 53. Materson BJ, Reda DJ, Cushman WC, et al.: Single-dru g therapy for hypertensive men: a comparison of six antihypertensive agents with placebo. N Engl J Med 1993, 328:914921. 54. Hall WD, Kusek JW, Kirk KA, et al. f or the African-American Study of Kidney Disease and Hypertension Pilot Study Inv estigators. Am J Kidney Dis 1997, 29:720728. 41. Gruppo Italiano di Studi Epidemiologici in Nefrologia: Randomised placebo-co ntrolled trial of effect of ramipril on decline in glomerular filtration rate an d risk of renal failure in proteinuric, non-diabetic nephropathy. Lancet 1997, 3 49:18571863. 42. Giatras I, Lau J, Levey AS for the Angiotensin-Converting Enzyme Inhibition and Progressive Renal Disease Study Group: Effect of angiotensin-con verting enzyme inhibitors on the progression of nondiabetic renal disease: a met a-analysis of randomized trials. Ann Intern Med 1997, 127:337345. 43. Zucchelli P , Zuccala A, Borghi M, et al.: Long-term comparison between captopril and nifedi pine in the progression of renal insufficiency. Kidney Int 1992, 42:452458. 44. K amper AI, Strandgaard S, Leyssac PP: Effect of enalapril on the progression of c hronic renal failure: a randomized controlled trial. Am J Hypertens 1992, 5:42343 0. 45. van Essen GG, Apperloo AJ, Sluiter WJ, et al.: Is ACE inhibition superior to conventional antihypertensive therapy in retarding progression in non-diabet ic renal disease? J Am Soc Nephrol 1996, 7:1400. 46. Hannedouche T, Landais P, G oldfarb B, et al.: Randomized controlled trial of enalapril and beta-blockers in non-diabetic chronic renal failure. BMJ 1994, 309:833837. 47. Bannister KM, Weav er A, Clarkson AR, Woodroffe AJ: Effect of angiotensin-converting enzyme and cal cium channel inhibition on progression of IgA nephropathy. Contrib Nephrol 1995, 111:184193.

Pharmacologic Treatment of Hypertension Garry P. Reams John H. Bauer T his chapter reviews the currently available classes of drugs used in the treatme nt of hypertension. To best appreciate the complexity of selecting an antihypert ensive agent, an understanding of the pathophysiology of hypertension and the ph armacology of the various drug classes used to treat it is required. A thorough understanding of these mechanisms is necessary to appreciate more fully the work ings of specific antihypertensive agents. Among the factors that modulate high b lood pressure, there is considerable overlap. The drug treatment of hypertension takes advantage of these integrated mechanisms to alter favorably the hemodynam ic pattern associated with high blood pressure. CHAPTER 7

7.2 Hypertension and the Kidney Pathogenesis of Hypertension Pathogenesis of hypertension Autoregulation B LO O D PR E SSUR E = C AR D I AC O U T P U T PE R IPHER AL VA SCUL AR RE SISTAN CE H y p er tens i o n = I n c re a s e d CO and/or I n c re a s e d P V R - Preload - Contractility Functional constriction Structural hypertrophy - Fluid volume Volume redistribution Renal sodium retention Decreased filtration surface Sympathetic nervous overactivity Reninangiotensin excess Cell membrane alteration Hyperinsulinemia Excess sodium intake Genetic alteration Stress Genetic alteration Obesity Endotheliumderived factors FIGURE 7-1 Pathogenesis of hypertension. Mean arterial pressure (MAP) is the pro duct of cardiac output (CO) and peripheral vascular resistance (PVR). There are a large number of control mechanisms involved in every type of hypertension. (From Kaplan [1]; with permission.) 20 Increase, % FIGURE 7-2 Blood pressure changes and diet. Many hypertensive patients appear to be sodium sensitive, as first suggested by studies in 19 hypertensive subjects who were observed after normal (109 mmol/d), low (9 mmol/d), and high (249 mmol/d) sod ium intake [2]. This figure shows the percent increase in mean blood pressure in salt-sensitive (SS) and nonsalt-sensitive (NSS) patients with hypertension when their diet was changed from low sodium to high sodium. Vertical lines indicate m ean standard deviation. (From Kawasaki et al. [2]; with permission.)

10 0 SS NSS Mean arterial pressure

Pharmacologic Treatment of Hypertension 7.3 20 19 18 17 16 15 6.0 5.5 5.0 16 14 12 10 13 12 11 10 70 65 60 55 50 40 35 30 25 20 15 150 140 130 120 110 100 33 % 4% 20 % 5% Pressure gradient Mean circulatory for venous filling pressure, return, mm Hg mm Hg 60 % 20 % FIGURE 7-3 Cardiac output. An increase in cardiac output has been suggested as a mechanism for hypertension, particularly in its early borderline phase [3,4]. S odium and water retention have been theorized to be the initiating events. Seque ntial changes following salt loading are depicted [3]. The resultant high cardia c output perfuses the peripheral tissues in excess of their metabolic requiremen ts, resulting in a normal autoregulatory (vasoconstrictor) pressure. The early p hase of high cardiac output and normal peripheral vascular resistance gradually changes to the characteristic feature of the sustained hypertensive state: norma l cardiac output and high peripheral vascular resistance. Shown here are segment al changes in the important cardiovascular hemodynamic variables in the first fe w weeks following the onset of short-term salt-loading hypertension. Note especi ally that the arterial pressure increases ahead of the increase in total periphe ral resistance. (From Guyton and coworkers [3]; with permission.) Blood volume, L Extracellular fluid volume, L 35 % 44 % Cardiac output, L/min 40 % 5% Total peripheral resistance, mm Hg/L/min 38 % 11 % Set-point elevated 45 % 22.5 % Arterial pressure, mm Hg 0 4 Days 8

12 16

7.4 Hypertension and the Kidney 4000 SAP HR beats min1 150 TPRI dyn s cm5 m2 500 1000 200 3000 180 100 2000 160 BP, mm Hg 60 140 MAP 1000 70 CI L min1 m2 120 DAP 10 SI mL stroke1 m2 50 5 100 30 500 1000 500 1000 VO2 mL min1 m2 VO2 mL min1 m2 VO2 mL min1 m2 FIGURE 7-4 Peripheral vascular resistance. Most established cases of hypertensio n are associated with an increase in peripheral vascular resistance [5]. These a lterations may be related to a functional constriction, the type observed under

the influence of circulating or tissue-generated vasoconstrictors, or may be a r esult of structural alterations in the blood vessel. Solid line indicates values at start of the study [9]; dashed line indicates results after 10 years; dotted line indicates results afte r 20 years. BPblood pressure; CIcardiac index; DAPdiastolic arterial blood pressure ; HRheart rate; MAPmean arterial pressure; SAPsystolic arterial blood pressure; SIst roke index; TPRItotal peripheral resistance index; VO2oxygen consumption. (From Lu ndJohansen [5]; with permission.)

Pharmacologic Treatment of Hypertension 7.5 Classes of Antihypertensive Drugs and Their Side Effects CLASSES OF ANTIHYPERTENSIVE DRUGS Diuretics: benzothiadiazides, loop, and potassium-sparing -adrenergic and 1/ -ad renergic antagonists Central 2-adrenergic agonists Central/peripheral adrenergic neuronal-blocking agent Peripheral 1-adrenergic antagonists Moderately selectiv e peripheral 1-adrenergic antagonist Peripheral adrenergic neuronal blocking age nts Direct-acting vasodilators Calcium antagonists Angiotensin-converting enzyme inhibitors Tyrosine hydroxylase inhibitor Angiotensin II receptor antagonists FIGURE 7-5 Classes of antihypertensive drugs. There are 12 currently available c lasses of antihypertensive agents. BP PV ISF CO TPR Rx PRA Time No Rx CO TPR FIGURE 7-6 Hemodynamic response to diuretics. Diuretics reduce mean arterial pre ssure by their initial natriuretic effect [6]. Acutely, this is achieved by a re duction in cardiac output mediated by a reduction in plasma and extracellular fl uid volumes [7]. Initially, peripheral vascular resistance is increased, mediate d in part by stimulation of the reninangiotensin system. During sustained diuret ic therapy, cardiac output returns to pretreatment levels, probably reflecting r estoration of plasma volume. Chronic blood pressure control now correlates with a reduction in peripheral vascular resistance. BPblood pressure; COcardiac output; ISFinterstitial fluid; PRAplasma renin activity; PVplasma volume; Rxtreatment; TPRto tal peripheral resistance. (Adapted from Tarazi [7].)

7.6 Hypertension and the Kidney A. DIURETICS: BENZOTHIADIAZIDES (PARTIAL LIST) AND RELATED DIURETICS Generic (trade) name Hydrochlorothiazide (G) (Hydrodiuril, Microzide) Chlorthalidone (G) (Hygroton) I ndapamide (Lozol) Metolazone (Mykrox)*; (Zaroxolyn) *Marketed only for treatment of hypertension. (G)generic available. First dose, mg 12.5 12.5 1.25 Usual dose 12.550 mg QD 12.550 mg QD 2.55.0 mg Maximum dose 100 100 5 Duration of action, h 612 4872 1518 0.5 2.5 0.51.0 2.510 mg QD 1 20 1224 1224 B. DIURETICS: LOOP Generic (trade) name Bumetanide (G) (Bumex) Ethacrynic Acid (Edecrin) Furosemide (G) (Lasix) Torsemid e (Demadex) (G)generic available. First dose, mg 0.5 25 20 5 Usual dose 0.52 mg bid 2550 mg bid 20120 mg bid 550 mg bid Maximum dose 10 200 600 100 Duration of action, h 46 68 68 68 C. DIURETICS: POTASSIUM-SPARING DIURETICS Generic (trade) name Spironolactone (G) (Aldactone) Amiloride (G) (Midamor) Triamterene (G) (Dyrenium ) (G)generic available. First dose, mg 25 5 50 Usual dose 501 00 mg QD 510 mg QD 50-100 mg bid Maximum dose 400 20 300

Duration of action, h 4872 24 79 FIGURE 7-7 AC. Diuretics: benzothiadiazides and related agents, loop diuretics, a nd potassium-sparing agents. A partial list of benzothiadiazides and their relat ed agents is given [6]. With the exception of indapamide and metolazone, their d ose-response curves are shallow; they should not be used when the glomerular fil tration rate is less than 30 mL/min/1.73 m2. The second group listed is loop diuretics. Because of their steep dose-response curves and natriuretic potency, they are especially useful when the glomerular filtration rate is less than 30 m L/min/1.73 m2. The third group is the potassium-sparing diuretics. The major the rapeutic use of these drugs is to attenuate the loss of potassium induced by the other diuretics.

Pharmacologic Treatment of Hypertension Lumen Blood Lumen Na DCT diuretics Na Cl 3Na ~ 2K Na channel blockers 3Na K ~ 2K Blood 7.7 DCT PT DT PC Lumen HCO3 Na H H2CO3 CA H2O + CO2 HCO3 H2CO3 CA H2O + CO2 PT 3Na ~ Blood Lumen Blood 2K CAI CAI Loop diuretics Na K 2Cl 3Na ~ 2K CD TAL LH FIGURE 7-8 Mechanisms of action of diuretics. This figure depicts the major site s and mechanisms of action of diuretic drugs [8]. The diuretic/natriuretic actio n of benzothiadiazide-type diuretics is predicated on their gaining access to th e luminal side of the distal convoluted tubule and inhibiting Na+ - Cl- cotransp ort by competing for the chloride site. The diuretic/natriuretic action of loop diuretics is predicated on their gaining access to the luminal side of the thick ascending limb of the loop of Henle and inhibiting Na+ - K+ -2Cl- electroneutra l cotransport by competing for the chloride site. The diuretic/natriuretic action of potassium-sparing diuretics is predicated on their gaining access to the luminal side of the principal cells located in the l ate distal tubule and cortical collecting duct and blocking luminal sodium chann els. Because Na+ uptake is blocked, the lumen negative voltage is reduced, inhib iting K+ secretion. The potassium-sparing diuretic spironolactone does this indi rectly by competing with aldosterone for its cytosolic receptor. CAcarbonic anhyd rase; CAIcarbonic anhydrase inhibitor; CDcollecting duct; DCTdistal convoluted tubu le; DTdistal tubule; LHloop of Henle; PCprincipal cell; PTproximal tubule; TALthick a scending limb. (From Ellison [8]; with permission.)

7.8 Hypertension and the Kidney FIGURE 7-9 The side effect profile of diuretic therapy. The complications of diu retic therapy are typically related to dose and duration of therapy, and they de crease with lower dosages. This table lists the most common side effects of diur etics and their proposed mechanism of action [6]. THE SIDE EFFECT PROFILE OF DIURETIC THERAPY Side effects Thiazide-type diuretic Azotemia Hypochloremia, hypokalemia, metabolic alkalosis Mechanisms Enhanced proximal fluid and urea reabsorption secondary to volume depletion Incr eased delivery of sodium to distal tubule facilitating Na+K+ and Na+-H+ exchange ; increased net acid excretion; increased urinary flow rate; secondary aldostero nism Increase fractional Mg2+ excretion by inhibiting reabsorption in ascending limb of loop of Henle Impaired free water clearance (distal cortical diluting se gment) May reflect an increased protein-bound fraction secondary to volume deple tion Impair enhanced proximal fluid and urate reabsorption secondary to volume d epletion Hypokalemia impairing insulin secretion; decreased insulin sensitivity May be due to extracellular fluid depletion Hypomagnesemia Hyponatremia Hypercalcemia Hyperuricemia Carbohydrate intolerance Hyperlipidemia Increased total triglyceride Increased total cholesterol Loop-ty pe diuretics Ototoxicity Hypocalcemia Potassium-sparing diuretics Hyperkalemia D ecreased sexual function, gynecomastia, menstrual irregularity, hirsutism Renal stone High plasma concentration of furosemide or ethacrynic acid Increase fractional e xcretion of calcium by interfering with reabsorption in loop of Henle Blocks pot assium excretion Spironolactone only; lower circulatory testosterone levels by i ncreasing metabolic clearance and/or preventing compensatory rise in testicular androgen production Triamterene only

Pharmacologic Treatment of Hypertension 7.9 Adrenal gland Heart CO b1 b

lockers E NE Effector cell Kidney BP b2 + Blood vessels - TPR NE FIGURE 7-10 -adrenergic antagonists. -adrenergic antagonists attenuate sympathet ic activity through competitive antagonism of catecholamines at both 1- and 2-ad renergic receptors [6,9]. In the absence of partial agonist activity (PAA), the acute systemic hemodynamic effects are a decrease in heart rate and cardiac outp ut and an increase in peripheral vascular resistance proportional to the degree of cardiodepression; blood pressure is unchanged. Chronically, there is a gradua l decrease in blood pressure proportional to the fall in peripheral vascular res istance, which is dependent on the degree of cardiac sympathetic drive. -adrener gic antagonists with sufficient partial agonist activity to maintain heart rate and cardiac output may not evoke acute reflex vasoconstriction: Blood pressure f alls proportional to the decrease in peripheral resistance (see Fig. 7-11) [10]. BPblood pressure; COcardiac output; Eepinephrine; NE norepinephrine; TPRtotal periph eral resistance. Sympathetic neuron MAP, % 100 90 80 Cardiac output, % 100 90 80 130 FIGURE 7-11 Hemodynamic changes associated with -adrenergic blockade. Time cours e of hemodynamic changes after treatment with a -adrenergic blocker devoid of pa rtial agonist activity (PAA) (solid line) as compared with hemodynamic changes a fter administration of a -adrenergic blocker with sufficient PAA to replace basa l sympathetic tone (eg, pindolol) (broken line). MAPmean arterial pressure. (From Man in't Veld and Schalekamp [10]; with permission.) Vascular resistance, % 120 110 100 90 80 Time (hours to days)

7.10 Hypertension and the Kidney A. DOSING SCHEDULES FOR -ADRENERGIC ANTAGONISTS: NON-SELECTIVE ( ADRENERGIC ANTA GONISTS THAT LACK PARTIAL AGONIST ACTIVITY Generic (trade) name Nadolol (G) (Corgard) Propranolol (G) (Inderal) (Inderal LA) Timolol (G) (Blocka dren) Ggeneric available. 1 AND 2) First dose, mg 40 Usual daily dose, mg 40240 QD Maximum daily dose, mg 320 Duration of action, h >24 40 80 10 40120 bid 80240 QD 1030 bid 480 480 60 >12 >12 >12 B. DOSING SCHEDULES FOR -ADRENERGIC ANTAGONISTS: NON-SELECTIVE ( 1 AND 2) ADRENE RGIC ANTAGONISTS WITH PARTIAL AGONIST ACTIVITY Generic (trade) name Pindolol (G) (Visken) Carteolol (Cartrol) Penbutolol (Levatol) Ggeneric available . First dose, mg 5 2.5 10 Usual daily dose, mg 1030 bid 2.510 QD 1020 QD Maximum daily dose, mg 60 10 40 Duration of action, h 12 24 24 C: DOSING SCHEDULES FOR -ADRENERGIC ANTAGONISTS: 1-SELECTIVE ADRENERGIC ANTAGONI STS THAT LACK PARTIAL AGONIST ACTIVITY Generic (trade) name Atenolol (G) (Tenormin) Metoprolol Tartrate (G) (Lopressor) Metoprolol Succinate (Toprol-XL) Betaxolol (Kerlone) Bisoprolol (Zebeta) Ggeneric available.

First dose, mg 50 50 50 5 5 Usual daily dose, mg 50100 QD 50150 bid 100300 QD 1020 QD 520 QD Maximum daily dose, mg 200 400 400 40 40 Duration of action, h 24 12 12 >24 12 FIGURE 7-12 Dosing schedules for -adrenergic antagonists. A, Nonselective adrene rgic antagonists that lack partial agonist activity. B, Nonselective -adrenergic antagonists with partial agonist activity. C, adrenergic antagonists that lack partial agonist activity. 1-selective (Continued on next page)

Pharmacologic Treatment of Hypertension 7.11 D. DOSING SCHEDULES FOR -ADRENERGIC ANTAGONISTS: 1-SELECTIVE ADRENERGIC ANTAGONI STS WITH WEAK PARTIAL AGONIST ACTIVITY Generic (trade) name Acebutolol (Sectrol) First dose, mg 200 Usual daily dose, mg 400800 QD Maximum daily dose, mg 1200 Duration of action, h 24 E. DOSING SCHEDULES FOR -ADRENERGIC ANTAGONISTS: 1-NONSELECTIVE -ADRENERGIC ANTA GONISTS LABETALOL (G) Generic (trade) name Labetalol (G) (Normodyne) (Trandate) Carvedilol (Coreg) Ggeneric available. First dose, mg 100 Usual daily dose, mg 100-600 bid Maximum daily dose, mg 2400 Duration of action, h 12 6.25 6.25-25 bid 50 6 FIGURE 7-12 (Continued) D, 1-selective adrenergic antagonists with weak partial agonist activity. E, 1-nonselective -adrenergic antagonists.

7.12 Hypertension and the Kidney PHARMACOKINETICS OF -ADRENERGIC ANTAGONISTS First-pass hepatic metabolism <10% 60% 80% 50% <10% <10% <10% <10% 50% 50% <10% 20% 30% 60% 7080% Solubility Nadolol Propranolol Propranolol LA Timolol Pindolol Carteolol Penbutolol Atenolo l Metoprolol tartrate Metoprolol succinate Betaxolol Bisoprolol Acebutolol Labet alol Carvedilol Hydrophilic Lipophilic Lipophilic Lipophilic Lipophilic Hydrophi lic Lipophilic Hydrophilic Lipophilic Lipophilic Lipophilic Equal Lipophilic Lip ophilic Lipophilic Absorption 30%40% >90% >90% >90% >90% >90% >90% 5060% >90% >90% >90% >90% 70% >90% >90 Peak concentration, h 24 13 6 12 12 13 23 24 12 7 1.56 24 24 12 12 Active metabolite None Yes Yes None None Yes Yes None None None None None Yes None Yes Plasma half-life, h 2024 34 10 34 34 56 5 67 37 37 1422 912 34 34 710 Dose reduction in renal failure Yes No No No Yes Yes Yes Yes No No Yes Yes Yes No No FIGURE 7-13 Pharmacokinetics of -adrenergic antagonists. FIGURE 7-14 The side ef fect profile of -adrenergic antagonists. The side effect profile of betablockers is related to the specific blockade of 1 or 2 receptors. This table lists the m ore common side effects and their proposed mechanism(s) of action [6,9]. THE SIDE EFFECT PROFILE OF -ADRENERGIC ANTAGONISTS Side effects Bronchospasm Bradycardia Congestive heart failure; decrease in exercise toleranc e Claudication Constipation, dyspepsia Central nervous system manifestations (sl eep disturbances, depression) Sexual dysfunction (impotence, decrease libido) Im paired glucose tolerance Prolonged insulin-induced hypoglycemia Hepatocellular n ecrosis Withdrawal syndrome Unstable angina Myocardial infarction Dyslipidemia I ncreased total triglycerides Decreased high-density lipoproteins cholesterol Mechanisms Blockade of 2-adrenergic receptors; increased airway resistance Blockade of atri al 1/ 2-adrenergic receptors; decrease in heart rate Blockade of ventricular 1-a drenergic receptors Blockade of peripheral vascular 2-adrenergic receptors Block ade of gastrointestinal 1/ 2-adrenergic receptors; decreased motility and relaxa tion of sphincter tone Blockade of CNS 1/ 2-adrenergic receptors Unknown Impaire d 2-adrenergicmediated islet cell insulin secretion; increase hepatic glucose, an d/or decrease insulin-stimulated glucose disposal Block epinephrine-mediated cou nterregulatory mechanisms Labetalol only, idiosyncratic reaction Acute overshoot in heart rate with increased myocardial oxygen demand due to increase in number and/or sensitivity of -adrenergic receptors during chronic blockade Increased adrenergic tone; reduced lipoprotein lipase activity

Pharmacologic Treatment of Hypertension Phsysiologic effect of central a2-drenergic agonists a-Methldop guanfacine guanab enz Stimulates Central a2 adrenoceptor 7.13 Clonidine Stimulates I1-Imidazoline receptor FIGURE 7-15 Central 2-adrenergic agonists. Central 2-adrenergic agonists cross t he blood-brain barrier and stimulate 2-adrenergic receptors in the vasomotor cen ter of the brain stem [6,9]. Stimulation of these receptors decreases sympatheti c tone, brain turnover of norepinephrine, and central sympathetic outflow and ac tivity of the preganglionic sympathetic nerves. The net effect is a reduction in norepinephrine release. The central 2-adrenergic agonist clonidine also binds t o imidazole receptors in the brain; activation of these receptors inhibits centr al sympathetic outflow. Central 2-adrenergic agonists may also stimulate the per ipheral 2adrenergic receptors that mediate vasoconstriction; this effect predomi nates at high plasma drug concentrations and may precipitate an increase in bloo d pressure. The usual physiologic effect is a decrease in peripheral resistance and slowing of the heart rate; however, output is either unchanged or mildly dec reased. Preservation of cardiovascular reflexes prevents postural hypotension. NTS Nucleus tractus solitarii RVLM Rostral ventrolateral medulla Inhibition of central sympathetic activity Blood pressure reduction CENTRAL 2-ADRENERGIC ANTAGONISTS Generic (trade) name -Methyldopa (G) (Aldomet) Clonidine (G) (Catapres) Clonidine TTS (Catapres-TTS) Guanabenz (Wytensin) Guanfacine (Tenex) Ggeneric available; TTStransdermal patch. First dose, mg 250 0.1 2.5 mg (TTS-1) 4 1 Usual daily dose 2501000 mg bid 0.10.6 mg bid/tid 2.57.5 mg (TTS1 to TTS3) qwk 416 mg bid 13 mg QD Maximum daily dose 3000 2.4 15 mg (TTS-3x2) 9 wk 64 3 Duration of action 2448 h 68 h 7d 12 h 36 h FIGURE 7-16 Central 2-adrenergic agonists. -Methyldopa is a methyl-substituted a mino acid that is active only after decarboxylation and conversion to -methyl-no repinephrine. The antihypertensive effect results from accumulation of 2-adrener gic receptors, displacing and competing with endogenous catecholamines. Methyldo pa is absorbed poorly (<50%); peak plasma concentrations occur in 2 to 4 hours. It is metabolized in the liver and excreted in the urine mainly as the inactive O-sulfate conjugate. The plasma half-life of methyldopa (1 to 2 hours) and its m etabolites is prolonged in patients with renal insufficiency; dose reduction is required. Clonidine, an imidazoline derivative, acts by stimulating either centr al 2-adrenergic receptors or imidazole receptors. Clonidine may be administered orally or by a transdermal delivery system (TTS). When given orally, it is absor bed well (>75%); peak plasma concentrations occur in 3 to 5 hours. Clonidine is metabolized mainly in the liver; fecal excretion ranges from 15% to 30%, and 40% to 60% is excreted unchanged in the urine. In patients with renal

insufficiency, the plasma half-life (12 to 16 hours) may be extended to more tha n 40 hours; dose reduction is required. When clonidine is administered transderm ally, therapeutic plasma levels are achieved within 2 to 3 days. Guanabenz, a gu anidine derivative, is highly selective for central 2-adrenergic receptors. It i s absorbed well (>75%); peak plasma levels are reached in 2 to 5 hours. Guanaben z undergoes extensive hepatic metabolism; less than 2% is excreted unchanged in the urine. The plasma half-life (approximately 6 hours) is not prolonged in pati ents with renal insufficiency. Guanfacine is a phenylacetyl-guanidine derivative with a longer plasma half-life than guanabenz. It is absorbed well (>90%); peak plasma concentrations are reached in 1 to 4 hours. The drug is primarily metabo lized in the liver. Guanfacine and its metabolites are excreted primarily by the kidneys; 24% to 37% is excreted as unchanged drug in the urine. The plasma half -life (15 to 17 hours) is not prolonged in patients with renal insufficiency [6, 9].

7.14 Hypertension and the Kidney FIGURE 7-17 The side effect profile of central 2-adrenergic agonists. The side e ffect profile of these agents is diverse [6,9]. THE SIDE EFFECT PROFILE OF CENTRAL 2-ADRENERGIC AGONISTS Side effects Sedation/drowsiness Xerostoniia (dry mouth) Gynecomastia in men, galactorrhea in women Drug fever, hepatotoxicity, positive Coombs test with or without hemolyti c anemia Sexual dysfunction, depression, decreased mental acuity Overshoot hypert ension Restlessness Insomnia Headache Tremor Anxiety Nausea and vomiting A feelin g of impending doom Mechanisms Stimulation of 2-adrenergic receptors in the brain Centrally mediated inhibition of cholinergic transmission Reduced central dopaminergic inhibition of prolacti n release (methyldopa only) Long-term tissue toxicity (methyldopa only) Stimulat ion of 2-adrenergic receptor in the brain Acute excessive sympathetic discharge in the face of chronic downregulation of central 2-adrenergic receptors in an in hibitory circuit during chronic treatment when treatment is stopped Indicates blockade Brain stem Preganglionic neuron Ganglion NE Postganglionic adrenergic nerve ending FIGURE 7-18 Central and peripheral adrenergic neuronal blocking agents. Rauwolfi a alkaloids act both within the central nervous system and in the peripheral sym pathetic nervous system [6,9]. They effectively deplete stores of norepinephrine (NE) by competitively inhibiting the uptake of dopamine by storage granules and by preventing the incorporation of norepinephrine into the protective chromaffi n granules; the free catecholamines are destroyed by monoamine oxidase. The pred ominant pharmacologic effect is a marked decrease in peripheral resistance; hear t rate and cardiac output are either unchanged or mildly decreased. NE NE NE a1 b1 a2 Vascular smooth muscle cells

Pharmacologic Treatment of Hypertension 7.15 CENTRAL PERIPHERAL ADRENERGIC-NEURONAL BLOCKING AGENT Generic (trade) name Reserpine (G) (Serpasil) First dose, mg 0.1 Usual daily dose, mg 0.1.25 QD Maximum daily dose, mg 0.5 Duration of action 23 wk FIGURE 7-19 Central and peripheral adrenergic neuronal blocking agents. Reserpin e is the most popular rauwolfia product used. It is absorbed poorly (approximate ly 30%); peak plasma concentrations occur in 1 to 2 hours. Catecholamine depleti on begins within 1 hour of drug administration and is maximal in 24 hours. Catec holamines are restored slowly. Chronic doses of reserpine are cumulative. Blood pressure is maximally lowered 2 to 3 weeks after beginning therapy. Reserpine is metabolized by the liver; 60% of an oral dose is recovered in the feces. Less t han 1% is excreted in the urine as unchanged drug. The plasma half-life (12 to 1 6 days) is not prolonged in patients with renal insufficiency. THE SIDE EFFECT PROFILE OF RESERPINE Side effects Altered CNS function Inability to concentrate Decrease mental acuity Sedation Sl eep disturbance Depression Nasal congestion/rhinitis Increased GI motility, incr eased gastric acid secretion Increased appetite/weight gain Sexual dysfunction I mpotence Decreased libido Peripheral adrenergic nerve ending Indicates blockade Mechanisms Depletion of serotonin and/or catecholamine NE NE NE Cholinergic effects Cholinergic effects Unknown Unknown b1 NE NE NE NE a2 a1 Vascular smooth muscle cells FIGURE 7-20 The side effect profile of the central and peripheral adrenergic neu ronal blocking agents [10,13]. Reserpine is contraindicated in patients with a h istory of depression or peptic ulcer disease. CNScentral nervous system; GIgastroi ntestinal.

FIGURE 7-21 Peripheral 1-adrenergic antagonists. 1-Adrenergic antagonists induce dilation of both resistance (arterial) and capacitance (venous) vessels by sele ctively inhibiting postjunctional 1-adrenergic receptors [6,9]. The net physiolo gic effect is a decrease in peripheral resistance; reflex tachycardia and the at tendant increase in cardiac output do not predictably occur. This is due to thei r low affinity for prejunctional 2-adrenergic receptors, which modulate the loca l control of norepinephrine release from sympathetic nerve terminals by a negati ve feedback mechanism (see Fig. 7-22) [11]. NEnorepinephrine.

7.16 Hypertension and the Kidney FIGURE 7-22 Adrenergic synapse. Nerve activity releases the endogenous neurotran smitter noradrenaline (NA) and also adrenaline from the varicosities. Noradrenal ine and adrenaline reach the postsynaptic -adrenoceptors (or -adrenoceptors) on the cell membrane of the target organ by diffusion. On receptor stimulation, a p hysiologic or pharmacologic effect is initiated. Presynaptic 2-adrenoceptors on the membrane (enlarged area), when activated by endogenous noradrenaline as well as by exogenous agonists, inhibit the amount of transmitter noradrenaline relea sed per nerve impulse. Conversely, the stimulation of presynaptic 2-receptors en hances noradrenaline release from the varicosities. Once noradrenaline has been released, it travels through the synaptic cleft and reaches both - and -adrenoce ptors at postsynaptic sites, causing physiologic effects such as vasoconstrictio n or tachycardia. (Adapted from Van Zwieten [11].) Varicosity Postganglionic sympathetic neuron Nerve impulse induces exocytotic NA release + Presynaptic b b
receptor NA Varicosities Synaptic cleft Postsynaptic a-rece ptor a Vesicle containing NA a Smpthetic C-fiber Presynaptic a-receptor Synaptic cleft Effector cell Response NA Postsynaptic a- receptors Target organ PERIPHERAL 1-ADRENERGIC ANTAGONISTS Usual daily dose, mg 2-6 bid/tid 2-5 QD/bid 2-4 QD Generic (trade) name Prazosin (G) (Minipress) Terazosin (Hytrin) Doxazosin (Cardura) Ggeneric availabl e. First dose, mg 1 1 1 Maximum daily dose, mg 20 20 16 Duration of action 6-12 w 12-24 h 24 h FIGURE 7-23 Peripheral 1-adrenergic antagonists. Prazosin is a lipophilic highly selective 1-adrenergic antagonist. It is absorbed well (approximately 90%) but undergoes variable first-pass hepatic metabolism. Peak plasma concentrations occ ur in 2 to 3 hours. It is extensively metabolized by the liver and predominantly excreted in the feces. The plasma half-life of prazosin (2 to 4 hours) is not p rolonged in patients with renal insufficiency. Terazosin is a water-soluble quin

azoline analogue of prazosin with about one third of its potency. It is complete ly absorbed and undergoes minimal first-pass hepatic metabolism. Peak plasma con centrations occur in 1 to 2 hours. It is extensively metabolized by the liver and predominantly excreted in the feces. The plasma hal f-life of terazosin (approximately 12 hours) is not prolonged in patients with r enal insufficiency. Doxazosin is also a water-soluble quinazoline analogue of pr azosin, with about half its potency. It is absorbed well but undergoes significa nt first-pass hepatic metabolism; bioavailability is approximately 65%. Peak con centrations occur in 2 to 3 hours. It is extensively metabolized by the liver an d primarily eliminated in the feces. The plasma half-life of doxazosin (approxim ately 22 hours) is not prolonged in patients with renal insufficiency [6,9].

Pharmacologic Treatment of Hypertension 7.17 150 140 Mean BP, mm Hg 130 120 110 100 Placebo Lying Standing Day 0 FIGURE 7-24 The side effect profile of the peripheral 1-adrenergic antagonists. 1-Adrenergic antagonists are associated with relatively few side effects [6,9]; the most striking is the first-dose effect [12]. It occurs 30 to 90 minutes after the first dose and is dose dependent. It is minimized by initiating therapy in t he evening and by careful dose titration. The first-dose effect is exaggerated by fasting, upright posture, volume contraction, concurrent -adrenergic antagonism, or excessive catecholamine activity (eg, pheochromocytoma). (From Graham and co workers [12]; with permission.) 140 130 120 Mean BP, mm Hg 110 100 90 80 70 60 50 Prazosin, 2 mg Day 1 140 130 Mean BP, mm Hg 120 110 100 90 80 Prazosin, 2 mg Day 4 0700 0900 1100 1300 Time, h 1500 1700

7.18 Hypertension and the Kidney Peripheral adrenergic nerve ending Indicates blockade NE NE a2 NE NE NE NE FIGURE 7-25 Moderately selective peripheral 1-adrenergic antagonists. Phenoxyben zamine is a moderately selective peripheral 1-adrenergic antagonist [6,9]. It is 100 times more potent at 1-adrenergic receptors than at 2-adrenergic receptors. Phenoxybenzamine binds covalently to -adrenergic receptors, interfering with th e capacity of sympathomimetic amines to initiate action at these sites. Phenoxyb enzamine also increases the rate of turnover of norepinephrine (NE) owing to inc reased tyrosine hydroxylase activity, and it increases the amount of norepinephr ine released by each nerve impulse owing to blockade of presynaptic 2-adrenergic receptors [11]. The net physiologic effect is a decrease in peripheral resistan ce and increases in heart rate and cardiac output. Postural hypotension may be p rominent, related to blockade of compensatory responses to upright posture and h ypovolemia. The degree of vasodilation is dependent on the degree of adrenergic vascular tone. NE a2 b1 a1 Vascular smooth muscle cells MODERATELY SELECTIVE PERIPHERAL Generic (trade) name Phenoxybenzamine (Dibenzyline) 1-ADRENERGIC ANTAGONIST Maximum of action, mg 120 First dose, mg 10 Usual daily dose, mg 20-40 bid Duration of action 34 d FIGURE 7-26 Moderately selective peripheral 1-adrenergic antagonists. Phenoxyben zamine is the only drug in its class. Absorption is variable and incomplete (20% to 30%). Peak blockade occurs in 3 to 4 hours. Its plasma half-life is 24 hours . The duration of action is approximately 3 to 4 days. Phenoxybenzamine is primarily used in the management of preoperative or inoperative pheochromocytoma. Efficacy is dependent on the de gree of underlying excessive -adrenergic vascular tone [6,9].

Pharmacologic Treatment of Hypertension 7.19 THE SIDE EFFECT PROFILE OF PHENOXYBENZAMINE Side effects Nasal congestion Miosis Sedation Weakness, lassitude Sexual dysfunction Inhibiti on of ejaculation Tachycardia FIGURE 7-27 The side effect profile of phenoxybenzamine. The common side effects are listed [6,9]. Mechanisms -adrenergic receptor blockade -adrenergic receptor blockade Unknown Impairment o f compensatory vasoconstriction producing orthostatic hypotension -adrenergic re ceptor blockade Uninhibited effects of epinephrine, norepinephrine and direct or reflex sympathetic nerve stimulation on the heart Peripheral adrenergic nerve ending Indicates blockade NE NE NE NE FIGURE 7-28 Peripheral adrenergic neuronal blocking agents. Peripheral adrenergi c neuronal blocking agents are selectively concentrated in the adrenergic nerve terminal by an active transport mechanism, or norepinephrine pump [6,9]. They act by interfering with the release of norepinephrine (NE) from neuronal storage sit es in response to nerve stimulation and by depleting norepinephrine from nerve e ndings. Acutely, cardiac output is reduced, caused by diminished venous return a nd by blockade of sympathetic -adrenergic effects on the heart; peripheral resis tance is unchanged. Following chronic therapy, peripheral resistance is decrease d, along with modest decreases in heart rate and cardiac output. a1 b1 a2 Vascular smooth muscle cells

7.20 Hypertension and the Kidney PERIPHERAL ADRENERGIC-NEURONAL BLOCKING AGENTS Generic (trade) name Guanethidine (Ismelin) Guanadrel (Hylorel) First dose, mg 10 5 Usual daily dose, mg 2575 QD 1050 bid Maximum daily dose, mg 150 150 Duration of action 721 d 414 h FIGURE 7-29 Peripheral adrenergic neuronal blocking agents. Guanethidine is the prototype peripheral adrenergic neuronal blocking agent. Absorption is incomplet e and variable; only 3% to 30% is absorbed over 12 hours. Peak plasma levels are reached in 6 hours. The drug rapidly leaves the plasma for extravascular storag e sites, including sympathetic neurons. Guanethidine is eliminated with a plasma half-life of 4 to 8 days, a time course that corresponds with its antihypertens ive effect. Approximately 24% of the drug is excreted unchanged in the urine; th e remainder is metabolized by the liver into more polar, less active, metabolite s that are excreted in the urine and feces. When therapy is initiated or the dos age is changed, three half-lives (approximately 15 days) are required to accumul ate 87.5% of a steady-state level. By administering loading doses of guanethidine at 6-hour intervals (the nearly maximal effect from a single oral dose), blood pre ssure can be lowered in 1 to 3 days. In patients with severe renal insufficiency , drug excretion is decreased; dose reduction is required. Guanadrel is a guanet hidine derivative with a short therapeutic half-life. Absorption is greater than 85%; peak plasma concentrations are reached in 1 to 2 hours. Guanadrel is metab olized by the liver. Elimination occurs through the kidney; approximately 40% of the drug is excreted unchanged in the urine. In patients with renal insufficien cy, the plasma half-life (10 to 12 hours) is prolonged; dose reduction is requir ed [6,9]. FIGURE 7-30 The side effect profile of peripheral adrenergic neuronal blocking agents. The specific side effects of this class are related to either e xcessive sympathetic blockade or a relative increase in parasympathetic activity . GFR glomerular filtration rate. THE SIDE EFFECT PROFILE OF PERIPHERAL ADRENERGIC-NEURONAL BLOCKING AGENTS Side effects Decrease renal function (GFR) Fluid retention/weight gain Dizziness/weakness Syn cope Intestinal cramping/diarrhea Sexual dysfunction Retrograde ejaculation Impo tence Decreased libido Sinus bradycardia Atrioventricular block Bronchospasm Con gestive heart failure Mechanisms Decreased renal perfusion; effect is magnified in the upright position Decreased filtered load and fractional excretion of sodium; diuretic should be used in co mbination Postural hypotension accentuated by hot weather, alcohol ingestion, an d/or physical exercise Unopposed parasympathetic activity, increasing gastrointe stinal motility Inhibition of bladder neck closure, unknown

Interferes with cardiac sympathetic compensating reflexes Catecholamine depletio n aggravates airway resistance Decreased cardiac output

Pharmacologic Treatment of Hypertension 7.21 Plasma membrane VGC Leak ROC VGC Ca2+ Altered calcium metabolism (?) Ca2+ Ca2+ Ca2+ SR Ca2+ SR FIGURE 7-31 Direct-acting vasodilators. Direct-acting vasodilators may have an e ffect on both arterial resistance and venous capacitance vessels; however, the c urrently available oral drugs are highly selective for resistance vessels [6,9]. Their specific mechanism of vascular relaxation and reason for selectivity are unknown. By altering cellular calcium metabolism, they interfere with the calciu m movements responsible for initiating or maintaining a contractile state. The n et physiologic effect is a decrease in peripheral vascular resistance associated with increases in heart rate and cardiac output. These increases in heart rate and cardiac output are related directly to sympathetic stimulation and indirectl y to the baroreceptor reflex response. ROCreceptor-operated channel; SRsarcoplasmi c reticulum; VGCvoltage-gaited channels. Activation of Myofilaments Contraction of vascular smooth muscle Hypertension DIRECT-ACTING VASODILATORS Generic (trade) name Hydralazine (G) (Apresoline) Minoxidil (G) (Loniten) Ggeneric available. First dose, mg 10 5 Usual daily dose, mg 50100 bid/tid 1020 QD/bid Maximum daily dose, mg 300 80 Duration of action, h 1012 75

FIGURE 7-32 Direct-acting vasodilators. Hydralazine is the prototype of directac ting vasodilators. Absorption is more than 90%. Peak plasma levels occur within 1 hour but may vary widely among individuals. This is because hydralazine is sub ject to polymorphic acetylation; slow acetylators have higher plasma levels and require lower drug doses to maintain blood pressure control compared with rapid acetylators. Bioavailability for slow acetylators ranges from 30% to 35%; bioava ilability for rapid acetylators ranges from 10% to 16%. Hydralazine undergoes ex tensive hepatic metabolism; it is mainly excreted in the urine in the form of me tabolites or as unchanged drug. The plasma half-life is 3 to 7 hours. Dose reduc tion may be required in the slow acetylator with renal insufficiency. Minoxidil is a substantially more potent direct-acting vasodilator than hydralaz ine. Absorption is greater than 95%. Peak plasma levels occur within 1 hour. Fol lowing a single oral dose, blood pressure declines within 15 minutes, reaches a nadir between 2 and 4 hours, and recovers at an arithmetically linear rate of 30 % per day. Approximately 90% is metabolized by conjugation with glucuronic acid and by conversion to more polar products. Known metabolites, which are less phar macologically active than minoxidil, are excreted in the urine. The plasma halflife of minoxidil is approximately 4 hours; dose adjustments are unnecessary in patients with renal insufficiency. Minoxidil and its metabolites are removed by hemodialysis and peritoneal dialysis; replacement therapy is required [6,9].

7.22 Hypertension and the Kidney Side effects of direct-acting vasodilators - Heart rate - Myocardial contractility V enous capacitance - Peripheral vascular resistance - Cardiac output VASODILATORS - Sympathetic function Peripheral vascular resistance PROPRANOLOL Arterial pressure - Plasma renin activity - Circulating angiotensin - Aldosterone secretion DIURETICS Sodium excretion - Plasma and extracellular fluid volume FIGURE 7-33 The side effect profile of direct-acting vasodilators. The most comm on and most serious effects of hydralazine and minoxidil are related to their di rect or reflex-mediated hemodynamic actions, including flushing, headache, palpi tations, anginal attacks, and electrocardiographic changes of myocardial ischemi a [6,9]. These effects may be prevented by concurrent administration of a -adren ergic antagonist. Sodium retention with expansion of extracellular fluid volume is a significant problem. Large doses of potent diuretics may be required to pre vent fluid retention and the development of pseudotolerance [13]. (From Koch-Wes er [13]; with permission.) Repeated administration of hydralazine can lead to a reversible syndrome that resembles disseminated lupus erythematosus. The inciden ce is dose dependent; it rarely occurs in patients receiving less than 200 mg/da y. Hypertrichosis is a common troublesome but reversible side effect of minoxidi l; it develops during the first 3 to 6 weeks of therapy in approximately 80% of patients. Plasma membrane VGC ROC VGC Ca2+ Ca2+ Ca2+ Ca2+ SR Ca2+ SR Myofilaments

FIGURE 7-34 Calcium antagonists. The calcium antagonists share a common antihype rtensive mechanism of action: inhibition of calcium ion movement into smooth mus cle cells of resistance arterioles through L-type (long-lasting) voltage-operate d channels [6,9]. The ability of these drugs to bind to voltage-operated channel s, causing closure of the gate and subsequent inhibition of calcium flux from th e extracellular to the intracellular space, inhibits the essential role of calci um as an intracellular messenger, uncoupling excitation to contraction. Calcium ions may also enter cells through receptor-operated channels. The opening of the se channels is induced by binding neurohumoral mediators to specific receptors o n the cell membrane. Calcium antagonists inhibit the calcium influx triggered by the stimulation of either -adrenergic or angiotensin II receptors in a dose-dep endent manner, inhibiting the influence of -adrenergic agonist and angiotensin I I on vascular smooth muscle tone. The net physiologic effect is a decrease in va scular resistance. Although all the calcium antagonists share a basic mechanism of action, they are a highly heterogeneous group of compounds that differ marked ly in their chemical structure, pharmacologic effects on tissue specificity, pha rmacologic behavior side-effect profile, and clinical indications [6,9,14]. Beca use of this, calcium antagonists have been subdivided into several distinct clas ses: phenylalkamines, dihydropyridines, and benzothiazepines. ROCreceptor-operate d channel; SRsarcoplasmic reticulum; VGCvoltage-gaited channels.

Pharmacologic Treatment of Hypertension 7.23 A. DOSING SCHEDULES FOR CALCIUM ANTAGONISTS: PHENYLALKAMINE DERIVATIVE Generic (trade) name Verapamil (G) (Isoptin, Calan) Verapamil SR (Isoptin SR, Calan SR) Verapamil SRpe llet (Veralan) Verapamil COER-24 (Covera HS) Ggeneric available. First dose, mg 80 90 120 180 Usual dose, mg 80120 tid 90240 bid 240480 QD 180480 qhs Maximum daily dose, mg 480 480 480 480 Duration of action, h 8 1224 24 24 B. DOSING SCHEDULES FOR CALCIUM ANTAGONISTS: DIHYDROPYRIDINE DERIVATIVES Generic (trade) name Amlodipine (Norvasc) Felodipine (Plendil) Isradipine (DynaCirc) Isradipine CR (D ynaCirc CR) Nicardipine SR (Cardine SR) Nifedipine Caps (G) (Procardia) Nifedipi ne ER (Adalat CC) Nifedipine GITS (Procardia XL) Nisoldipine (Sular) Ggeneric ava ilable. First dose, mg 5 5 2.5 5 30 10 30 30 20 Usual dose, mg 510 QD 51 0 QD 2.5-5 bid 520 QD 3060 bid 1030 tid/qid 3090 QD 3090 QD 2040 QD Maximum daily dose, mg 10 20 20 20 120 120 120 120 60 Duration of action, h 24 24 12 24 12 46 24 24 24 C. DOSING SCHEDULES FOR CALCIUM ANTAGONISTS: BENZODIAZEPINE DERIVATIVE Generic (trade) name Diltiazem (G) (Cardizem) Diltiazem SR (Cardizem SR) Diltiazem CD (Cardizem CD) D iltiazem XR (Dilacor XR) Diltiazem ER (Tiazac) Ggeneric available. First dose, mg 60 180 180 180 180 Usual dose, mg 60120 tid/qid 120240 bid 240480 QD 180480 QD 180480 QD Maximum daily dose, mg 480 480 480 480 480 Duration of action, h 8 12 24 24 24 FIGURE 7-35 AC. Dosing schedules for calcium antagonists: phenylalkamine derivati ves, dihydropyridine derivatives, and benzothiazepine derivatives.

7.24 Hypertension and the Kidney PHARMACOKINETICS OF CALCIUM ANTAGONISTS Absorption, % Verapamil >90 First-pass hepatic 70%80% Peak concentration 12 h (tablet) 5 h (SR caplet) 79 h (SR pellet) 11 h (COER) 612 h 2.55 h 12 h (tablet) 718 h (CR) 14 h (SR) <30 min (cap) 2.55 h (ER) 6 h GITS) 612 h 23 h (tablet) 611 h (S R) 1014 h (CD) 46 h (XR) 7 h (ER) Route of elimination Active metabolite Plasma half-life, h Dose reduction Liver Yes 412 (tablet) 12 (SR pellet) No Amlodipine Felodipine Isradipine Nicardipine Nifedipine >90 >90 >90 >90 >90 Minimal Extensive Extensive Extensive 20%30% Liver Liver Liver Liver Liver No No No No No 3050 1116 8 89 2 24 24 712 46 57 58 510 410 No No No No No Nisoldipine Diltiazem >85 >80 Extensive 50% Liver Liver Yes Yes No Yes FIGURE 7-36 Pharmacokinetics of the calcium antagonists: phenylalkamine derivati ves, dihydropyridine derivatives, and benzothiazepine derivatives. FIGURE 7-37 T he side effect profile of calcium antagonists [10,13,18]. AVatrioventricular. THE SIDE EFFECTS PROFILE OF CALCIUM ANTAGONISTS Side effects Dihydropyridine Headache, flushing, palpitation, edema Phenylalkylamine Constipa tion Bradycardia, AV block congestive heart failure Benzodiazepine Bradyarrhythm ia, AV block congestive heart failure Mechanism Potent peripheral vasodilator Negative inotropic, dromotropic, chronotropic effe cts Negative inotropic, dromotropic, chronotropic effects

Pharmacologic Treatment of Hypertension ACE inhibition and angiotensin II type I receptor antagonists: mechanisms for de crease in peripheral vascular resistance + + Functions:: Renal tubular sodium re absorption Aldosterone release Vasoconstriction, vascular smooth muscle Remodeli ng, vascular smooth muscle Sympathetic activity (central and peripheral) Barorec eptor sensitivity + 7.25 Angiotensinogen (renin substrate) 1 Renin Angiotensin I (decapeptide) Non-renin enzymes AT1 receptor 3 Angiotensin II (octapeptide) + Blood pressure Non-ACE enzymes + + 4 2 ACE Inactive fragments + Bradykinin Nitric oxide Prostaglandin E2 Prostaglandin I2 AT2 receptor ? Function FIGURE 7-38 Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II ty pe I receptor antagonists. Angiotensin-converting enzyme inhibitors and angioten sin II type I receptor antagonists lower blood pressure by decreasing peripheral vascular resistance; there is usually little change in heart rate or cardiac ou tput [6,9,15]. Mechanisms proposed for the observed decrease in peripheral resistance are shown [15]. Sites of pharmacologic blockade in the renin angiotensin system: 1) renin inhibitors, 2) ACE inhibitors, 3) angiotensin II type I receptor antagonists, 4 ) angiotensin II type II receptor antagonists.

7.26 Hypertension and the Kidney A. DOSING SCHEDULES FOR SULFHYDRYL-CONTAINING ACE INHIBITOR Generic (trade) name Captopril (G) (Capoten) First dose, mg 12.5 Usual dose, mg 12.550 bid/tid Maximum dose, mg 150 Duration of action, h 612 B. DOSING SCHEDULES FOR CARBOXYL-CONTAINING ACE INHIBITORS Generic (trade) name Benazepril (Lotensin) Enalapril (Vasotec) Lisinopril (Prinivil,Zestril) Moexipri l (Univasc) Quinapril (Accupril) Ramipril (Altace) Trandolapril (Mavik) First dose, mg 10 5 10 7.5 510 2.5 1 Usual dose, mg 1020 QD 510 QD/bid 2040 QD 7.515 QD/bid 2040 QD 2.520 QD/bid 24 QD Maximum dose, mg 40 40 40 30 40 40 8 Duration of action, h 24 1224 24 24 24 24 24 C. DOSING SCHEDULES FOR PHOSPHINIC ACIDCONTAINING ACE INHIBITOR Generic (trade) name Fosinopril (Monopril) Ggeneric available. First dose, mg 10 Usual dose, mg 2040 QD/bid Maximum dose, mg 40 Duration of action, h 24 FIGURE 7-39 AC. Classification of and dosing schedule for angiotensin-converting enzyme (ACE) inhibitors. Angiotensin-converting enzyme inhibitors differ in prod rug status, ACE affinity, potency, molecular weight and conformation, and lipophilicity [6,9]. They are generally classified into one of three main chemical classes according to the ligand of the zinc ion of ACE: sul fhydryl, carboxyl, or phosphinic acid.

Pharmacologic Treatment of Hypertension 7.27 PHARMACOKINETICS OF ACE INHIBITORS Peak concentration (active component), h 1 12 34 68 12 2 24 410 3 Absorption, % Captopril Benazepril Enalapril Lisinopril Moexipril Quinapril Ramipril Trandolap ril Fosinopril 6075 37 5575 25 > 20 60 5060 70 36 Prodrug No Yes Yes Yes Yes Yes Yes Yes Yes Route of elimination Kidney Kidney/liver Kidney Kidney Kidney Kidney Kidney/liver Kidney/liver Kidney /liver Plasma half-life, h 2 1011 11 12 29 25 1317 1624 12 Dose reduction (renal disease) Yes Yes Yes Yes Yes Yes Yes Yes No FIGURE 7-40 Pharmacokinetics of angiotensin-converting enzyme (ACE) inhibitors: sulfhydrylcontaining, carboxyl-containing, and phosphinic acidcontaining. FIGURE 7-41 The side effect profile of angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors are well tolerated; there are few side effects [6,9]. THE SIDE EFFECTS PROFILE OF ACE INHIBITORS Side effects Cough, angioedema Laryngeal edema Lightheadedness, syncope Hyperkalemia Acute re nal failure Mechanisms Potentiation of tissue kinins Excessive hypotension in patients with high basal peripheral vascular resistance high renin states, like volume contraction, impair ed cardiac output Decreased aldosterone; potassium-containing salt substitutes a nd supplements should be avoided Extreme hypotension with impaired efferent arte riolar autoregulation

7.28 Hypertension and the Kidney FIGURE 7-42 Angiotensin-converting enzyme (ACE) inhibition in acute renal failur e. ACE inhibitors may produce functional renal insufficiency in patients with es sential hypertension and hypertensive nephrosclerosis, in patients with severe b ilateral renal artery stenosis, or in patients with stenosis of the renal artery of a solitary kidney. The postulated mechanism for this effect is diminished re nal blood flow (decrease in systemic pressure, compromising flow through a fixed stenosis) in combination with diminished postglomerular capillary resistance (i e, decrease in angiotensin IImediated efferent arteriolar tone). In unilateral re nal artery stenosis, a drop in the critical perfusion and filtration pressures m ay result in a marked drop in single-kidney glomerular filtration rate (GFR); ho wever, the contralateral kidney may show an increase in both effective renal pla sma flow (ERPF) and GFR due to attenuation of the intrarenal effects of angioten sin II on vascular resistance and mesangial tone. Thus, total net GFR may be norma l, giving the false appearance of stability [16]. Although ACE inhibition may in variably decrease the GFR of the stenotic kidney, it is unlikely to cause renal ischemia owing to preservation of ERPF; GFR usually returns to pretreatment valu es following cessation of therapy. Shown is the effect of captopril (50 mg) on t otal clearances of 131I-sodium iodohippurate (ERPF) and 126I-thalamate (GFR) in 14 patients with unilateral renal artery stenosis and in 17 patients with essent ial hypertension. The effects after 60 minutes of captopril on systolic and dias tolic intra-arterial pressure (P < 0.001) and of renin were significant. (From W enting and coworkers [16]; with permission.) Arterial pressure, mm Hg 230 190 150 110 70 Renal artery stenosis Essential hypertension Total effective renal plasma flow, mL/min Total glomerular filtration rate, mL/m in Plasma renin, mU/L 440 360 280 110 100 90 80 1000 100 10 15 0 Captopril 50 mg Captopril 50 mg 30 60 15 0 Time, min 30 60 Peripheral adrenergic nerve ending Indicates blockade Tyrosine Tyrosine hydroxylase Dihydroxyphenylalanine NE

FIGURE 7-43 Tyrosine hydroxylase inhibitor. Metyrosine ( -methyl-para-tyrosine) is an inhibitor of tyrosine hydroxylase, the enzyme that catalyzes the conversio n of tyrosine to dihydroxyphenylalanine [6,9]. Because this first step is rate l imiting, blockade of tyrosine hydroxylase activity results in decreased endogeno us levels of circulating catecholamines. In patients with excessive production o f catecholamines, metyrosine reduces biosynthesis 36% to 79%; the net physiologi c effect is a decrease in peripheral vascular resistance and increases in heart rate and cardiac output resulting from the vasodilation. The degree of vasodilat ion is dependent on the degree of blockade of adrenergic vascular tone. NEnorepin ephrine. a1 b1 a2 Vascular smooth muscle cells

Pharmacologic Treatment of Hypertension 7.29 TYROSINE HYDROXYLASE INHIBITOR Generic (trade) name Metyrosine (Demser) First dose, mg 250 Usual daily dose, mg 25 qid Maximum dose, mg 1000 qid Duration of action, h 34 FIGURE 7-44 Tyrosine hydroxylase inhibitor. Metyrosine is the only drug in its c lass. The initial recommended dose is 1 g/d, given in divided doses. This may be increased by 250 to 500 mg daily to a maximum of 4 g/d. The usual effective dos age is 2 to 3 g/d. The maximum biochemical effect occurs within 2 to 3 days. In hypertensive patients in whom there is a response, blood pressure decreases prog ressively during the first days of therapy. In patients who are usually normoten sive, the dose should be titrated to the amount that will reduce circulating or urinary catecholamines by 50% or more. Following discontinuation of therapy, the clinical and biochemical effects may p ersist 2 to 4 days. Metyrosine is variably absorbed from the gastrointestinal tr act; bioavailability ranges from 45% to 90%. Peak plasma concentrations are reac hed in 1 to 3 hours. The plasma half-life is 3 to 4 hours. Metyrosine is not met abolized; the unchanged drug is recovered in the urine. Drug dosage should be re duced in patients with renal insufficiency. Metyrosine is exclusively used in th e management of preoperative or inoperative pheochromocytoma [6,9]. FIGURE 7-45 The side effect profile of metyrosine. The adverse reactions observed with metyr osine are primarily related to the central nervous system and are typically dose dependent [6,9]. Metyrosine crystalluria (needles or rods), which is due to the poor solubility of the drug in the urine, has been observed in patients receivi ng doses greater than 4 g/d. To minimize this risk, patients should be well hydr ated. CNScentral nervous system. THE SIDE EFFECTS PROFILE OF METYROSINE Side effects CNS symptoms Sedation Extrapyramidal signs Drooling Speech difficulty Tremor Tri smus Parkinsonian syndrome Psychic dysfunction Anxiety Depression Disorientation Confusion Crystalluria, uroliathiasis Diarrhea Insomnia (temporary) Mechanisms Depletion of CNS dopamine Poor urine solubility Direct irritant to bowel mucosa Following drug withdrawal

7.30 Hypertension and the Kidney ANGIOTENSIN II RECEPTOR ANTAGONISTS Generic (trade) name Losartan (Cozaar) Valsartan (Diovan) Irbesaftan (Avapro) First dose, mg 50 80 150 Usual dose, mg 50100 QD/bid 80160 QD 150300 QD Maximum dose, mg 100 320 300 Duration of action, h 1224 24 24 FIGURE 7-46 Angiotensin II receptor antagonists. These drugs antagonize angioten sin IIinduced biologic actions, including proximal sodium reabsorption, aldostero ne release, smooth muscle vasoconstriction, vascular remodeling, and barorecepto r sensitivity. Antihypertensive efficacy appears dependent on an activated renin -angiotensin system; bilateral nephrectomy and volume expansion abolish their ac tivity. Losartan is a nonpeptide, specific angiotensin II receptor antagonist ac ting on the antagonist AT1 subtype receptor. Peak response occurs within 6 hours of dosing. It is readily absorbed; peak plasma concentrations are achieved with in 1 hour. It has a relatively short terminal half-life of 1.5 to 2.5 hours. Ora l bioavailability is approximately 33%. Losartan undergoes extensive first-pass hepatic metabolism to the predominant circulatory form of the drug Exp-3174. Thi s metabolite is 15 to 30 times more potent than losartan with a longer half-life (between 4 and 9 hours). The metabolite is cleared equally by t he liver and the kidney; there may be enhanced hepatic clearance in renal insuff iciency [15]. Dose reduction is not required in patients with renal insufficienc y. Valsartan is a nonpeptide, specific angiotensin II antagonist acting on the A T1 subtype receptor. Peak response occurs within 6 hours of dosing. Peak plasma concentrations are reached 2 to 4 hours after dosing. The average elimination ha lf-life is about 6 hours. Oral bioavailability is approximately 25%. Dose reduct ion is not required in patients with renal insufficiency [15]. Irebsartan is a n onpeptide, specific angiotensin II antagonist acting on the AT1 subtype receptor . Peak response occurs in 4 to 8 hours. There is no active metabolite. Dose redu ction is not required in patients with renal insufficiency [15]. FIGURE 7-47 The side effect profile of angiotensin II receptor antagonists. Angiotensin II rece ptor antagonists are well tolerated. In contrast to the angiotensin-converting e nzyme (ACE) inhibitors, cough and angioedema are rarely (if at all) associated w ith this class of antihypertensive drug. Similar to ACE inhibitors, however, hyp erkalemia and acute renal failure may occur in patients at risk [15]. THE SIDE EFFECTS PROFILE OF ANGIOTENSIN II RECEPTOR ANTAGONISTS Side effects Hyperkalemia Acute renal dysfunction Mechanisms Blockade of angiotensin II Reduced aldosterone secretion Hypotension with impair ed efferent anteriolar autoregulation

Pharmacologic Treatment of Hypertension 7.31 Prevention and Treatment of High Blood Pressure JNC VI CLASSIFICATION OF HYPERTENSION Category* Optimal Normal High normal Hypertension Stage 1 Stage 2 Stage 3 Systolic (mm Hg) <120 <130 130139 140/159 160/179 -180 and and or or or or Diastolic (mm Hg) <80 <85 8589 90/99 100/109 110 *Not taking anithypertensive drugs and not acutely ill. When systolic and diasto lic blood pressures fall into different categories, the higher category should b e selected to classify the individual's blood pressure status. For example, 160/92 mm Hg should be classified as stage 2 hypertension, and 174/120 mm Hg should be classified as stage 3 hypertension. Isolated systolic hypertension is defined a s systolic blood pressure of 140 mm Hg or greater and diastolic blood pressure o f less than below 90 mm Hg and staged appropriately (eg, 170/82 mm Hg is defined as stage 2 isolated hypertension). In addition to classifying stages of hyperte nsion on the basis of average blood pressure levels, clinicians should specify p resence of target organ disease and additional risk factors. This specifically i s important for risk classification. Optimal blood pressure with respect to cardi ovascular risk is below 120/80 mm Hg. Unusually low readings should be evaluated for clinical significance. Based on the average of two or more readings taken at each of two or more visits after an initial screening. JNCJoint National Committ ee. FIGURE 7-48 Prevention and treatment of high blood pressure. The aim of antihype rtensive therapy is risk reduction. Since the relationship between blood pressur e and cardiovascular risk is continuous, the goal of treatment might be the maxi mum tolerated reduction in blood pressure. There is controversy concerning what constitutes hypertension and how far systolic or diastolic blood pressure should be lowered, however. The Sixth Report of the Joint National Committee on Detect ion, Evaluation, and Treatment of High Blood Pressure (JNC VI) [17] provides a n ew classification of hypertension and recommends that risk stratification be use d to determine if lifestyle modification or drug therapy with adjunctive lifesty le modification be initiated according to the patient's blood pressure classificat ion (see Fig. 7-50). Major risk factors include smoking, dyslipidemia, diabetes mellitus, an age of 60 or older, male sex or postmenopausal state for women, and a family history of cardiovascular disease in women younger than 65 and in men younger than 55. Target organ damage includes heart disease (left ventricular hy pertrophy, angina pectoris, prior myocardial infarction, heart failure), stroke or transient ischemic attack, and nephropathy. Prevention and management of hype rtension-related morbidity and mortality may best be accomplished by achieving a systolic blood pressure below 140 mm Hg and a diastolic blood pressure below 90 mm Hg; lower if tolerable. Recently, more aggressive blood pressure control has been advocated in patients with renal disease and hypertension, particularly in those patients with a urinary protein excretion of greater than 1 g/d. Blood pr essure control in the range of 125/80 mm Hg (mean arterial pressure of 108 mm Hg ) has been shown to slow the progression of renal disease [18,19]. This targeted blood pressure control may therefore be advisable in the majority of patients w ith hypertension. Regardless, each patient should be treated according to their cerebrovascular, cardiovascular, or renal risks; their specific pathophysiology or target organ damage; and their concurrent disease states. A uniform blood pre ssure goal (target) probably does not exist for all hypertensive patients, and l ower may not always be better.

7.32 Hypertension and the Kidney FIGURE 7-49 Decision analysis for treatment based on the Sixth Report of the Joi nt National Committee on Detection, Evaluation, and Treatment of High Blood Pres sure (JNC VI) [17]. JNC VI DECISION ANALYSIS FOR TREATMENT Risk group B (at least 1 risk factor, not including diabetes; no TOD/ CCD) Lifestyle modification Lifestyle modification (up to 6 months) Drug therapy Blood pressure stages (mm Hg) High normal (130139/8589) Stage 1 (140159/9099) Stages 2 and 3 (>160/100) Risk group A (no risk factors, no TOD/CCD)* Lifestyle modification Lifestyle modification (up to 12 months) Drug therapy Risk Group C (TOD/CCD and/or diabetes, with or without other risk factors) Drug therapy Drug therapy Drug therapy Lifestyle modification should be adjunctive therapy for all patients recommended for pharmacologic therapy. *TOD/CCD indicates target organ disease/clinical car diovascular disease. For patients with multiple risk factors, clinicians should c onsider drugs as initial therapy plus lifestyle modifications. For those with hea rt failure, renal insufficiency, or diabetes. CRITERIA FOR INITIAL DRUG THERAPY Reduce peripheral vascular resistance No sodium retention No compromise in regio nal blood flow No stimulation of the renin-angiotensin-aldosterone system Favora ble profile with concomitant diseases Once a day dosing Favorable adverse effect profile Cost effective (low direct and indirect cost) FIGURE 7-50 Selection of initial drug therapy. The Sixth Report of the Joint Nat ional Committee on Prevention, Detection, Evaluation, and Treatment of High Bloo d Pressure (JNC VI) recommends that either a diuretic or a -blocker be chosen as initial drug therapy, based on numerous randomized controlled trials that show reduction in morbidity and mortality with these agents [17]. Not all authorities agree with this recommendation. In selecting an initial drug therapy to treat a hypertensive patient, several criteria should be met [6,9]. The drug should dec rease peripheral resistance, the pathophysiologic hallmark of all hypertensive d iseases. It should not produce sodium retention with attendant pseudotolerance. The drug should neither stimulate nor suppress the heart, nor should it compromi se regional blood flow to target organs such as the heart, brain, or the kidney. It should not stimulate the renin-angiotensin-aldosterone axis. Drug selection should consider concomitant diseases such as arteriosclerotic cardiovascular and peripheral vascular disease, chronic obstructive pulmonary disease, diabetes me llitus, hypertensive cardiovascular disease, congestive heart failure, and hyper lipidemia. Drug dosing should be infrequent. The drug's side effect profile, inclu ding its effect on physical state, emotional well-being, sexual and social funct ion, and cognitive activity, should be favorable. Drug costs, both direct and in direct, should be reasonable. It is readily apparent that no current class of an tihypertensive drug fulfills all these criteria.

Pharmacologic Treatment of Hypertension 7.33 CANDIDATES FOR INITIAL DRUG THERAPY OF MILD TO MODERATE HYPERTENSIVE DISEASE Angiotensin II type I receptor antagonists Decrease Increase/no change No change No No change Preserve No change Increase I ncrease Decrease/no change No effect No effect No effect May benefit No effect B enefit ACE inhibitors Peripheral vascular resistance Sodium homeostasis Urinary sodium excretion Extra cellular fluid volume Pseudotolerance Target organ function Heart rate, cardiac output Cerebral function Renal function (GFR) Renin-angiotensin-aldosterone Plas ma renin activity Plasma angiotensin II Plasma aldosterone Concurrent disease ef ficacy Coronary disease Peripheral vascular disease Obstructive airway disease D iabetes mellitus Dyslipidemia Systolic dysfunction Decrease Increase/no change N o change No No change Preserve No change/increase Increase Decrease Decrease/no change No effect No effect No effect May benefit No effect Benefit 1-adrenergic antagonists 1-adrenergic antagonists Thiazide-type Calcium antagonists diuretics Decrease Increase/no change No change No Class specific Preserve No change/incre ase No change No change No change Benefit May benefit No effect No effect No eff ect No effect Decrease Increase Decrease No No change Preserve No change Increas e Increase Increase No effect No effect No effect May aggravate Aggravate Benefi t Decrease May decrease May increase No May increase Preserve No change No change No change No change No effect No effect No effect No effect Benefit No effect Decrease No change No change No Decrease Preserve No change/decrease Decrease De crease Decrease/no change Benefit May aggravate May aggravate May aggravate May aggravate May aggravate FIGURE 7-51 Options for monotherapy. Given the drugs that we have and their phar macologic profiles, what are the best classes for initial drug therapy? Alphabet ically, they include 1) angiotensin-converting enzyme (ACE) inhibitors, 2) 1-adr energic antagonists, 3) angiotensin II type I receptor antagonists, 4) 1-adrener gic antagonists, 5) calcium antagonists, and 6) thiazide-type diuretics [6,9,15]. All these drugs, given as monotherapy, are effective in lowering blood pressure in 50% to 60% of patients with mild to mode rate hypertension. 1-adrenergic antagonists, ACE inhibitors, and angiotensin II receptor antagonists are less efficacious in blacks than in whites.

7.34 Hypertension and the Kidney Options for subsequent antihypertensive therapy Not at goal blood pressure (<140/<90 mm Hg); lower goal in patients with diabete s mellitus or renal disease No response or troublesome side effects Inadequate response but well tolerated Sustitute another drug from a different class Add a second agent from a different class (diuretic if not already used) Not a goal blood pressure FIGURE 7-52 Options for subsequent antihypertensive therapy. The majority of pat ients with mild to moderate hypertension can be controlled with one drug. If, af ter a 1- to 3-month interval, the response to the initial choice of therapy is i nadequate, however, three options for subsequent antihypertensive drug therapy m ay be considered: 1) increase the dose of the initial drug, 2) discontinue the i nitial drug and substitute a drug from another class, or 3) add a drug from anot her class (combination therapy). Recommendations from the Sixth Report of the Jo int National Committee on Detection, Evaluation, and Treatment of High Blood Pre ssure (JNC VI) are provided [17]. Continue adding agents from other classes Consider referral to a hypertension sp ecialist COMBINATION THERAPIES Mild to moderate (stage 1 or 2) hypertension Addition of low-dose thiazide-type diuretic to: ACE inhibitor 1-adrenergic antag onist 1-adrenergic antagonist Angiotensin III receptor antagonist Severe (Stage 3) hypertension Classic triple drug therapy Diuretic 1-adrenergic antagonist Dir ect-acting vasodilator ACE inhibitor plus calcium antagonist 1-adrenergic antago nist plus 1-adrenergic antagonist 1-adrenergic antagonist plus dihydropyridine c alcium antagonist FIGURE 7-53 Combination therapies. If a second drug is required, the addition of a low-dose thiazidetype diuretic to a nondiuretic drug will usually enhance the effectiveness of the first drug [6,9,17]. Newly developed formulations, using c ombinations of low doses of two agents from different classes, are available and effective and may minimize the likelihood of a dose-dependent adverse effect. T he fixed doses used in these formulations were chosen to control mild to moderat e (JNC VI stage 1 or 2) hypertension. More severe (JNC VI stage 3) cases of hype rtension that are unresponsive to this therapeutic strategy may respond either t o a variety of combination therapies given together as separate formulations or to classic triple-drug therapy (ie, diuretic, -adrenergic antagonist, and direct -acting vasodilator) [6,9]. ACEangiotensin-converting enzyme; JNCJoint National Co mmittee.

Pharmacologic Treatment of Hypertension 7.35 JNC VI LIFE STYLE MODIFICATIONS Lose weight if overweight Limit alcohol intake to no more than 1 oz (30 mL) etha nol (eg, 24 oz [720 mL] beer, 10 oz [300 mL] wine, or 2 oz [60 mL] 100-proof whi skey) per day or 0.5 oz (15 mL) ethanol per day for women and lighter weight peo ple Increase aerobic physical activity (30 to 45 minutes most days of the week) Reduce sodium intake to no more than 100 mmol/d (2.4 g sodium or 6 g sodium chlo ride) Maintain adequate intake of dietary potassium (approximately 90 mmol/d) Ma intain adequate intake of dietary calcium and magnesium for general health Stop smoking and reduce intake of dietary saturated fat and cholesterol for overall c ardiovascular health FIGURE 7-54 Follow-up in antihypertensive therapy. During follow-up visits, phar macologic therapy should be reconfirmed or readjusted. As a rule, antihypertensi ve therapy should be maintained indefinitely. Cessation of therapy in patients w ho were correctly diagnosed as hypertensive is usually (but not always) followed by a return of blood pressure to pretreatment levels. After blood pressure has been controlled for 1 year and at least four visits, however, attempts should be made to reduce antihypertensive drug therapy in a deliberate, slow, and progress ive manner; such step-down therapy may be successful in patients following lifestyl e modification [17]. Patients for whom drug therapy has been reduced or disconti nued should have regular follow-up, since blood pressure may increase again to h ypertensive levels. JNCJoint National Committee. CAUSES OF RESISTANT HYPERTENSION Patient's failure to adhere to drug therapy Physician's failure to diagnose a second ary cause of hypertension Renal parenchymal hypertension Renovascular hypertensi on Mineralocorticoid excess state (eg, primary aldosteronism) Pheochromocytoma D rug-induced hypertension (eg, sympathomimetic, cyclosporine) Illicit substances (eg, cocaine, anabolic steroids) Glucocortoid excess state (eg, Cushing's syndrome ) Coarctation of the aorta Hormonal disturbances (eg, thyroid, parathyroid, grow th hormone, serotonin) Neurologic syndromes (eg, Guillain-Barr syndrome, porphyri a, sleep apnea) Physician's failure to recognize an adverse drugdrug interaction Se e Physician's Desk Reference Physician's failure to recognize the development of sec ondary drug resistance Sodium retention with pseudotolerance, secondary to diure tic resistance or excess sodium intake Increased heart rate, cardiac output seco ndary to drug-induced reflex tachycardia Increased peripheral vascular resistanc e secondary to drug-induced stimulation of the renin-angiotensin system FIGURE 7-55 Resistant hypertension. Causes of failure to achieve or sustain cont rol of blood pressure with drug therapy are listed [6,9].

7.36 Hypertension and the Kidney FIGURE 7-56 Diuretic resistance. Diuretic resistance may result from patient non compliance, impaired bioavailability in an edematous syndrome, impaired diuretic secretion by the proximal tubule, protein binding in the tubule lumen (eg, neph rotic syndrome), reduced glomerular filtration rate, or enhanced sodium chloride reabsorption [7,8]. Resultant fluid retention will attenuate the effectiveness of most antihypertensive drugs. Renal mechanisms, problems, and solutions are pr ovided in this table [6,8,9]. DIURETIC RESISTANCE Problem Mechanism Solution Limits active transport of diuretics Reduced renal blood flow Use of large doses of a diuretic and into proximal tubular fluid, reducing appropriate dosing inte rval to achieve inhibitory effect at a more distal a therapeutic tubular drug co ncentration intraluminal membrane site Reduced glomerular filtration rate Use lo op diuretics with steep dose Limits absolute amount of sodium filtered response curve and/or block multiple sites of sodium reabsorption: loop diuretic with thi azide-like diuretic Secondary hyperaldosteronism Sodium recaptured at late dista l Addition of a potassium-sparing diuretic tubule and collecting duct to above, to maintain urine sodium/potassium ratio > 1 References 1. Kaplan NM: Clinical Hypertension, edn 6. Baltimore: Williams & Wilkins; 1994: 50. 2. Kawasaki T, Delea CS, Bartter FC, Smith H: The effect of high-sodium and low-sodium intakes on blood pressure and other related variables in human subjec ts with idiopathic hypertension. Am J Med 1978, 64:193198. 3. Guyton AC, Coleman TG, Yang DB, et al.: Salt balance and long-term blood pressure control. Annu Rev Med 1980, 31:1527. 4. Julius S, Krause L, Schork NJ: Hyperkinetic borderline hyp ertension in Tecumseh, Michigan. J Hypertens 1991, 9:7784. 5. Lund-Johansen P: Ce tra haemodynamics in essential hypertension at rest and during exercise: a 20-ye ar follow-up study. J Hypertens 1989, 7(suppl 6): 552555. 6. Bauer JH, Reams GP: Mechanisms of action, pharmacology, and use of antihypertensive drugs. In The Pr inciples and Practice of Nephrology. Edited by Jacobson HR, Striker GE, Klahr S. St. Louis: Mosby; 1995:399415. 7. Tarazi RC: Diuretic drugs: mechanisms of antih ypertensive action. In Hypertension: Mechanisms and Management. The 26th Hahnema nn Symposium. Edited by Oneti G, Kim KE, Moer JH. New York: Grune and Stratton; 1973:255. 8. Ellison DH: The physiologic basis of diuretic synergism: its role i n treating diuretic resistance. Ann Intern Med 1991, 114:886894. 9. Bauer JH, Rea ms GP: Antihypertensive drugs. In The Kidney, edn 5. Edited by Brenner BM. Phila delphia: W.B. Saunders Co.; 1995: 23312381. 10. Man in't Veld AJ, Schalekamp MADH: How intrinsic sympathomimetic activity modulates the haemodynamic responses to adrenoceptor antagonists: a clue to the nature of their antihypertensive mechani sm. Br J Clin Pharmac 1982, 13:24552575. 11. Van Zwieten PA: Antihypertensive dru g interacting with -and -adrenoceptors: a review of basic pharmacology. Drugs 19 88, 35(suppl 6):619. 12. Graham RM, Thornell IR, Gain JM, et al.: Prazosin: the f irst dose phenomenon. Br Med J 1976, 2:12931294. 13. Koch-Weser J: Vasodilation d rugs in the treatment of hypertension. Arch Intern Med 1974, 133:10171025. 14. En tel SI, Entel EA, Clozel J-P: T-type Ca2+ channels and pharmacological blockade: potential pathophysiological relevance. Cardiovasc Drugs Ther 1997, 11:723739. 1 5. Bauer JH, Ream GP: The angiotensin II type 1 receptor antagonists. Arch Inter n Med 1995, 155:13611368. 16. Wenting GJ, Tan-Tjiong HL, Derkx FMH, et al.: Split renal function after captopril in unilateral renal artery stenosis. Br Med J 19 74, 288:886890. 17. JNC VI: The Sixth Report of the Joint National Committee on D etection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1993 , 153:154183. 18. Peterson JC, Adler S, Burkart JM, et al.: Blood pressure contro l, proteinuria, and the progression of renal disease. Ann Intern Med 1995, 123:7 54762. 19. Hebert LA, Kusek JW, Greene T, et al.: Effects of blood pressure contr

ol on progressive renal disease in blacks and whites. Hypertension 1997, 30 (par t 1):428435.

Hypertensive Crises Charles R. Nolan M ost patients with hypertension remain asymptomatic for many years, until complic ations from atherosclerosis, cerebrovascular disease, or congestive heart failur e supervene. In some patients, this so-called benign course is punctuated by a h ypertensive crisis. Hypertensive crisis is defined as the turning point in the c ourse of an illness at which acute management of the elevated blood pressure pla ys a decisive role in the eventual outcome [1]. The haste with which blood press ure must be controlled varies with the type of hypertensive crisis. If the patie nt's outcome is to be optimal, however, the crucial role of hypertension in the di sease process must be identified and a plan for management of the blood pressure successfully implemented. The absolute level of the blood pressure clearly is n ot the most important factor in determining the existence of a hypertensive cris is. For example, in children, pregnant women, and other previously normotensive persons in whom mild to moderate hypertension develops suddenly, a hypertensive crisis can occur at a level of blood pressure that normally is well-tolerated by adults with chronic hypertension. Furthermore, a crisis can occur in adults wit h mild to moderate hypertension with the onset of acute end-organ dysfunction in volving the heart or brain. CHAPTER 8

8.2 Hypertension and the Kidney FIGURE 8-1 Malignant hypertension is a clinical syndrome characterized by marked elevation of blood pressure, with widespread acute arteriolar injury (hypertens ive vasculopathy). Funduscopy reveals hypertensive neuroretinopathy with flame-s haped hemorrhages, cottonwool spots (soft exudates), and sometimes papilledema. Regardless of the severity of blood pressure elevation, malignant hypertension c annot be diagnosed in the absence of hypertensive neuroretinopathy. Thus, hypert ensive neuroretinopathy is an extremely important clinical finding, indicating t he presence of a hypertension-induced arteriolitis that may involve the kidneys, heart, and central nervous system. In malignant hypertension, rapid and relentl ess progression to end-stage renal disease occurs if effective blood pressure co ntrol is not implemented. Mortality can result from acute hypertensive heart fai lure, intracerebral hemorrhage, hypertensive encephalopathy, or complications of uremia. Malignant hypertension represents a hypertensive crisis given that adeq uate control of blood pressure clearly prevents these morbid complications. Even in patients with so-called benign (nonmalignant) hypertension, in which hyperte nsive neuroretinopathy is absent, a hypertensive crisis may occur based on the d evelopment of concomitant acute end-organ dysfunction. Hypertensive crises cause d by benign hypertension with acute complications include hypertension in the se tting of hypertensive encephalopathy, acute hypertensive heart failure, acute ao rtic dissection, intracerebral hemorrhage, subarachnoid hemorrhage, severe head trauma, acute myocardial infarction or unstable angina, and active bleeding. Poo rly controlled hypertension in patients requiring surgery increases the risk of intraoperative cerebral or myocardial ischemia and postoperative acute renal fai lure. Severe postoperative hypertension, including postcoronary artery bypass hyp ertension and postcarotid endarterectomy hypertension, increases the risk of post operative bleeding, hypertensive encephalopathy, pulmonary edema, and myocardial ischemia. The various catecholamine excess states can cause a hypertensive cris is with hypertensive encephalopathy or acute hypertensive heart failure. Preecla mpsia and eclampsia represent hypertensive crises unique to pregnancy. Scleroder ma renal crisis is a hypertensive crisis because failure to adequately control b lood pressure with a regimen that includes a converting enzyme inhibitor results in rapid irreversible loss of renal function. Hypertensive crises as a result o f autonomic hyperreflexia induced by bowel or bladder distention also can occur in patients with quadriplegia. The sudden onset of hypertension in this setting can lead to hypertensive encephalopathy or acute pulmonary edema. Each hypertens ive crisis is discussed in more detail in the figures that follow. HYPERTENSIVE CRISES Malignant hypertension (Hypertensive neuroretinopathy present) Benign (nonmalign ant) hypertension with acute complications (Acute organ system dysfunction witho ut hypertensive neuroretinopathy) Hypertensive encephalopathy (also common in ma lignant hypertension) Acute hypertensive heart failure (also common in malignant hypertension) Acute aortic dissection Central nervous system catastrophe Intrac erebral hemorrhage Subarachnoid hemorrhage Severe head trauma Acute myocardial i nfarction or unstable angina Active bleeding, including postoperative bleeding U ncontrolled hypertension in patients requiring surgery Severe postoperative hype rtension Postcoronary artery bypass hypertension Postcarotid endarterectomy hypert ension Catecholamine excess states Pheochromocytoma Monoamine oxidase inhibitorty ramine interactions Miscellaneous hypertensive crises Preeclampsia and eclampsia Scleroderma renal crisis Autonomic hyperreflexia in quadriplegic patients

Hypertensive Crises 8.3 HYPERTENSIVE SYNDROMES SOMETIMES MISDIAGNOSED AS HYPERTENSIVE CRISES Severe uncomplicated hypertension (Severe hypertension without hypertensive neur oretinopathy or acute end-organ dysfunction, formerly known as urgent hypertensi on) Benign hypertension with chronic end-organ complications Chronic renal insuf ficiency from primary renal parenchymal disease Chronic congestive heart failure from systolic or diastolic dysfunction Atherosclerotic coronary vascular diseas e (previous myocardial infarction, stable angina) Cerebrovascular disease (histo ry of transient ischemic attack or cerebrovascular accident) FIGURE 8-2 Hypertensive syndromes sometimes misdiagnosed as hypertensive crises. It should be noted that the finding of severe hypertension does not always impl y the presence of a hypertensive crisis. In patients with severe uncomplicated h ypertension (formally known as urgent hypertension) in which severe hypertension is not accompanied by evidence of malignant hypertension or acute end-organ dys function, eventual complications due to stroke, myocardial infarction, or conges tive heart failure tend to occur over months to years, rather than hours to days . Long-term control of blood pressure can prevent these eventual complications. However, a hypertensive crisis cannot be diagnosed because no evidence exists th at acute reduction of blood pressure results in improvement in short- or long-te rm prognosis. Moreover, the presence of chronic hypertensive end-organ complicat ions in a patient with nonmalignant hypertension does not imply the existence of a hypertensive crisis requiring rapid control of blood pressure. The category o f benign hypertension with chronic complications includes hypertensive patients with chronic renal insufficiency due to underlying primary renal parenchymal dis ease, chronic congestive heart failure as a result of either systolic or diastol ic dysfunction, atherosclerotic coronary vascular disease (stable angina or prev ious myocardial infarction), or chronic cerebrovascular disease (previous transi ent ischemic attacks or cerebrovascular accident). Long-term inadequate blood pr essure control increases the risk of further deterioration of endorgan function in each of these conditions. However, no evidence exists that rapid control of b lood pressure is necessary to prevent further complications. Therefore, a true h ypertensive crisis does not exist.

8.4 Hypertension and the Kidney in thickening and remodeling of arteriolar walls that may be an adaptive mechani sm to prevent vascular damage from the mechanical stress of hypertension. Howeve r, when the blood pressure increases suddenly or increases to a critical level, these adaptive mechanisms may be overwhelmed, resulting in vascular damage. As a result of the mechanical stress of increased transmural pressure, focal segment s of the arteriolar vasculature become dilated, producing a sausage-string patte rn. Endothelial permeability increases in the dilated segments, leading to extra vasation of fibrinogen, fibrin deposition in the media, and necrosis of smooth m uscle cells (fibrinoid necrosis). Platelet adherence to damaged endothelium with release of platelet-derived growth factor induces migration of smooth muscle ce lls to the intima where they proliferate (neointimal proliferation) and produce mucopolysaccharide. These cells also produce collagen, resulting in proliferativ e endarteritis, musculomucoid hyperplasia, and eventually, fibrotic obliteration of the vessel lumen. Occlusion of arterioles leads to accelerated glomerular ob solescence and end-stage renal disease. Other factors may synergize with hyperte nsion to damage the arterial vasculature. Renal ischemia leads to activation of the renin-angiotensin system that can cause further elevation of blood pressure and progressive vascular damage. Spontaneous natriuresis early in the course of malignant hypertension leads to volume depletion with activation of the renin-an giotensin system or catecholamines that further elevates blood pressure. It also is possible that angiotensin II may be directly vasculotoxic. Activation of the clotting cascade within the lumen of damaged vessels may lead to fibrin deposit ion with localized intravascular coagulation. Thus, microangiopathic hemolytic a nemia is a common finding in malignant hypertension. Cigarette smoking and oral contraceptive use may contribute to development of malignant hypertension by dec reasing prostacyclin production in the vessel wall and thereby inhibiting repair of hypertensioninduced vascular injury. Low dietary intake of potassium may hel p promote vascular smooth muscle proliferation and therefore predisposes to the development of malignant hypertension in Blacks with severe essential hypertensi on. PDGFplateletderived growth factor. Pathophysiology of malignant hypertension Renal parenchymal disease Renal artery stenosis Endocrine hypertension Essential hypertension Severe hypertension Spontaneous natriuresis Critical level or Rate of increase Volume depletion - Catecholamines - Vasopressin - Renin/Angiotensin II Forced vasodilation (sausage-string) Decreased prostacyclin Oral contraceptives Cigarette smoking Vascular damage Denudation of epithelium - Endothelial permeability Localized intravascular coagulation Platelet adherence PDGF release Low potassium diet Smooth muscle proliferation D eposition of mucopolysaccharide Renal ischemia Musculomucoid intimal hyperplasia Extravasation Fibrinogen Fibrin deposition Arteriolar wall Necrosis of smooth mu

scle Fibrinoid necrosis Lumen Narrowing of vascular lumen Renal ischemia Accelerated glomerular obsolescence Tubular atrophy Interstitial fibrosis Chronic renal failure FIGURE 8-3 Pathophysiology of malignant hypertension. The vicious cycle of malig nant hypertension is best demonstrated in the kidneys. This cycle also applies e qually well to the vascular beds of the retina, pancreas, gastrointestinal tract , and brain [1]. In this scheme, severe hypertension is central. Hypertension ma y be either essential or secondary to any one of a variety of causes. Because no t all patients develop malignant hypertension despite equally severe hypertensio n, the interaction between the level of blood pressure and the adaptive capacity of the vasculature may be important. In this regard, chronic hypertension resul ts

Hypertensive Crises 8.5 Vascular lesions in malignant hypertension Malignant hypertension Fibrinoid necrosis Proliferative endarteritis Occlusion of vessels Ischemia Retinal Hemorrhages Cotton-wool spots Papilledema CNS Intracerebral hemorrhage Hypertensive encephalopathy Cardiac Left ventricular dysfunction Renal Glomerulosclerosis Tubular atrophy Interstitial fibrosis GI Hemorrhage Bowel necrosis Pancreatic Necrosis Hemorrhage FIGURE 8-4 Distribution of vascular lesions in malignant hypertension. Malignant hypertension is essentially a systemic vasculopathy induced by severe hypertens ion. Fibrinoid necrosis and proliferative endarteritis occur throughout the body in numerous vascular beds, leading to ischemic changes. In the retina, striate hemorrhages and cotton-wool spots develop. The finding of hypertensive neuroreti nopathy is the clinical sine qua non of malignant hypertension. Vascular lesions in the gastrointestinal tract (GI) can lead to hemorrhage or bowel necrosis. He morrhagic pancreatitis also can occur. Cerebrovascular lesions can lead to cereb ral infarction or intracerebral hemorrhage. Hypertensive encephalopathy also can develop as a result of failure of autoregulation with cerebral overperfusion an d edema (Fig. 8-22). Vascular lesions also can develop in the myocardium; howeve r, acute hypertensive heart failure is largely the result of acute diastolic dys function induced by the marked increase in afterload that accompanies malignant hypertension (Figs. 824 and 8-25). CNScentral nervous system. COMMON CAUSES OF MALIGNANT HYPERTENSION Primary (essential) malignant hypertension* Secondary malignant hypertension Pri mary renal disease Chronic glomerulonephritis* Chronic pyelonephritis* Analgesic nephropathy* Immunoglobulin A nephropathy* Acute glomerulonephritis Radiation n ephritis Renovascular hypertension* Oral contraceptives Atheroembolic renal dise ase (cholesterol embolism) Scleroderma renal crisis Antiphospholipid antibody sy ndromes Chronic lead poisoning Endocrine hypertension Aldosterone-producing aden oma (Conn's syndrome) Cushing's syndrome Congenital adrenal hyperplasia Pheochromocy toma *Most common causes of malignant hypertension. FIGURE 8-5 Malignant hypertension is not a single disease entity but, rather, a syndrome in which the hypertension can be either primary (essential) or secondar y to any one of a number of different causes [2]. Among Black patients the under lying cause is almost always essential hypertension that has entered a malignant phase. The most common secondary causes of malignant hypertension are primary r enal parenchymal disorders. Chronic glomerulonephritis is thought to be the caus e of malignant hypertension in up to 20% of cases. Unless a history of an acute

nephritic episode or long-standing hematuria or proteinuria is available, the un derlying glomerulonephritis may only become apparent when a renal biopsy is performed. Recently, immunoglobulin A (Ig A) nephropathy has been reported as an increasingly frequent cause of malignant hypertension. In one series of 66 patients with IgA nephropathy, 10% developed m alignant hypertension [3]. Chronic atrophic pyelonephritis in children, often a result of underlying vesicoureteral reflux, is the most common cause of malignan t hypertension [4]. In Australia, malignant hypertension complicates up to 7% of cases of analgesic nephropathy [5]. Transient malignant hypertension responsive to volume expansion has been reported in analgesic nephropathy. It has been sug gested that interstitial disease with salt-wasting is important in the pathogene sis by causing profound volume depletion with activation of the renin-angiotensi n axis. Malignant hypertension is both an early and late complication of radiati on nephritis that can occur up to 11 years after radiotherapy. Renovascular hype rtension from either fibromuscular dysplasia or atherosclerosis is a well-recogn ized cause of malignant hypertension. In a series of 123 patients with malignant hypertension, renovascular hypertension was found in 43% of Whites and 7% of Bl acks [6]. Among women of childbearing age, oral contraceptives can cause maligna nt hypertension [7]. In the absence of underlying renal disease, with discontinu ation of the drug, long-term prognosis is excellent. Severe hypertension that ma y become malignant is a common complication of atheroembolic renal disease. In p atients presenting with malignant hypertension in the weeks to months after an a rteriographic procedure, a careful history and physical should be performed to l ook for evidence of atheroembolism. Scleroderma renal crisis is the most life-th reatening complication of progressive systemic sclerosis. Scleroderma renal cris is is characterized by hypertension that may enter the malignant phase. Even in the absence of hypertensive neuroretinopathy suggesting malignant hypertension, the renal lesion in scleroderma renal crisis is virtually indistinguishable from primary malignant nephrosclerosis [8]. Patients with antiphospholipid antibody syndrome, either primary or secondary to systemic lupus erythematosus, can devel op malignant hypertension with renal insufficiency as a result of thrombotic mic roangiopathy [9]. The endocrine causes of hypertension only rarely lead to malig nant hypertension. Pheochromocytoma can cause hypertensive crises owing to hyper tensive encephalopathy or acute hypertensive heart failure in the absence of hyp ertensive neuroretinopathy (malignant hypertension).

8.6 Hypertension and the Kidney FIGURE 8-6 Tertiary hyperaldosteronism after treatment of malignant hypertension . The diagnosis of primary hyperaldosteronism must be made with caution in patie nts with a history of malignant hypertension. After successful treatment of mali gnant hypertension, plasma renin activity rapidly normalizes, whereas aldosteron e secretion may remain elevated for up to a year. This phenomenon has been attri buted to persistent adrenal hyperplasia induced by long-standing hyperreninemia during the malignant phase [10]. During this phase of tertiary hyperaldosteronis m, despite suppressed renin activity, hypokalemia, metabolic alkalosis, and aldo sterone levels that are not suppressible, mimic primary hyperaldosteronism. Adre nal imaging studies reveal bilateral nodular adrenal hyperplasia. With continued long-term control of blood pressure this hyperaldosteronism remits spontaneousl y. Tertiary hyperaldosteronism after treatment of malignant hypertension Malignant hypertension Vascular lesions heal Antihypertensive treatment with resolution of malignant hypertension Renal ischemia Activation of reninangiotensin axis Bilateral adrenal hyperplasia Renin levels decrease rapidly Resolves slowly over 1 year after control of blood pressure Nonsuppressible aldosteronism Renal potassium-wasting with hypokalemia Metabolic alkalosis RENAL CHANGES IN HYPERTENSION Retinal arteriosclerosis and arteriosclerotic retinopathy (benign hypertension) Focal or diffuse arteriolar narrowing Arteriovenous crossing changes Broadening of the light reflex Copper or silver wiring Perivasculitis (parallel white lines around the arteries) Solitary round hemorrhages Hard exudates Central or branch venous occlusion Hypertensive neuroretinopathy (malignant hypertension) General ized arteriolar narrowing Striate (flame-shaped) hemorrhage* Cotton-wool spots* Papilledema* Star figure at the macula *Features that distinguish hypertensive neuroretinopathy from retinal arterioscl erosis. FIGURE 8-7 Funduscopic findings are pivotal in the diagnosis of malignant hypert ension. Keith and Wagener [11] graded retinal findings in hypertensive patients as follows: grade I, arteriolar narrowing; grade II, arteriovenous crossing chan ges; grade III, hemorrhages and exudates; grade IV, the changes in grade III plu s papilledema. Although this classification of hypertensive retinopathy is of gr eat historical importance, its clinical utility has several limitations, eg, it is extremely difficult to quantify arteriolar narrowing. In this regard, a tende ncy exists for significant observer bias such that patients with mild hypertensi on and questionable narrowing are invariably assigned to grade I. More important ly, this classification does not distinguish the retinal changes of benign and m alignant hypertension. For example, the clinical significance of a cottonwool sp ot appearing in the fundus of a young man with severe hypertension (diagnostic of malignant hypertension) is quite different from the clinical significance of a hard exudate in the fundus of a 60-year-old man with

moderate hypertension. The prognostic and therapeutic implications of these two types of exudates clearly are different, although both would be classified as gr ade III. For this reason, the Keith and Wagener classification has been supplant ed by the more clinically useful classification of hypertensive retinopathy show n here. This classification system draws a distinction between retinal arteriosc lerosis with arteriosclerotic retinopathy, which is characteristic of benign hyp ertension, and hypertensive neuroretinopathy, which defines the existence of mal ignant hypertension [12,13]. Retinal arteriosclerosis, which is characterized hi stologically by the accumulation of hyaline material in arterioles, occurs in el derly normotensive persons or in the setting of long-standing benign hypertensio n. Funduscopic findings reflecting retinal arteriosclerosis include arteriolar n arrowing, arteriovenous crossing changes, perivasculitis, and changes in the lig ht reflex with copper or silver wiring. Arteriosclerotic retinopathy manifests a s solitary round hemorrhages in the periphery of the fundus and hard exudates. T he finding of retinal arteriosclerosis is of no prognostic significance with reg ard to the risk of coronary atherosclerosis or cerebrovascular disease. The arte ries visualized with the ophthalmoscope are technically arterioles with a diamet er of 0.1 mm. Hyaline arteriolosclerosis of the retinal vessels is a process ent irely distinct from the atherosclerotic process that affects larger muscular art eries. Thus, the finding of retinal arteriosclerosis cannot predict the presence of atherosclerosis of the coronary or cerebral vessels. This lack of clinical s ignificance of retinal arteriosclerosis in hypertensive patients contrasts drama tically with the importance and prognostic significance of the finding of hypert ensive neuroretinopathy. This finding is the clinical sine qua non of malignant hypertension. The appearance of striate hemorrhages or cottonwool spots with or without papilledema closely parallels the development of fibrinoid necrosis and proliferative endarteritis in the kidney and other organs. Thus, the presence of hypertensive neuroretinopathy predicts the development of end-stage renal disea se, or other life-threatening hypertensive complications, within a year if adequ ate control of the blood pressure is not achieved.

Hypertensive Crises 8.7 FIGURE 8-8 (see Color Plate) Fundus photography of retinal arteriosclerosis in b enign hypertension. Funduscopy in a 60-year-old man reveals the characteristic c hanges of retinal arteriosclerosis, including arteriolar narrowing, mild arterio venous crossing changes, copper wiring, and perivasculitis (parallel white lines around blood columns). The striate hemorrhages, cotton-wool spots, and papilled ema characteristic of malignant hypertension are absent. FIGURE 8-9 (see Color Plate) Fundus photography of arteriosclerotic retinopathy in benign hypertension. Funduscopy in a 52-year-old woman with benign hypertensi on demonstrates a solitary round hemorrhage characteristic of arteriosclerotic r etinopathy. FIGURE 8-10 (see Color Plate) Fundus photography of striate hemorrhages in hyper tensive neuroretinopathy. Funduscopic findings in a 53-year-old woman with secon dary malignant hypertension as a result of underlying immunoglobulin A nephropat hy, demonstrating striate or flame-shaped hemorrhages (arrows). The appearance o f small striate hemorrhages often is the first sign that malignant hypertension has developed. These hemorrhages are most commonly observed in a radial arrangem ent around the optic disc. The retinal circulation is under autoregulatory contr ol such that under normal circumstances as blood pressure increases, arterioles constrict to maintain constant retinal blood flow. The appearance of striate hem orrhages implies that autoregulation has failed. Striate hemorrhages are a resul t of bleeding from superficial capillaries in the nerve fiber bundles near the o ptic disc. These capillaries originate directly from arterioles so that when aut oregulation fails, the high systemic pressure is transmitted directly to the cap illaries. This process leads to breaks in the continuity of the capillary endoth elium. The resultant hemorrhages extend along nerve fiber bundles parallel to th e retinal surface. The hemorrhages often have a frayed distal border owing to ex travasation of blood between nerve fiber bundles.

8.8 Hypertension and the Kidney FIGURE 8-11 (see Color Plate) Fundus photography of cotton-wool spots in hyperte nsive neuroretinopathy. Cotton-wool spots (arrows) are the most characteristic f eature of malignant hypertension. They usually surround the optic disc and most commonly occur within three disc-diameters of the optic disc. Cotton-wool spots result from ischemic infarction of retinal nerve fiber bundles owing to arteriol ar occlusion caused by proliferative arteriopathy in retinal vessels. Fluorescei n angiography demonstrates that cotton-wool spots are areas of retinal nonperfus ion. Embolization of pig retina with glass beads produces immediate neuronal cel l edema followed by accumulation of mitochondria and other subcellular organelle s in ischemic nerve fibers. It has been postulated that the normal axoplasmic fl ow of subcellular organelles is disrupted by retinal ischemia such that accumula tion of organelles in ischemic nerve fiber bundles results in a visible white pa tch. Cotton-wool spots tend to distribute around the optic disc because nerve fi ber bundles are most dense in this region. The detection of cotton-wool spots is a crucial clinical finding because they are the retinal manifestation of the ma lignant hypertension-induced systemic vasculopathy that also causes proliferativ e endarteritis and ischemia in the kidney and other organs. (This is the same pa tient as in Fig. 8-10.) FIGURE 8-12 (see Color Plate) Fundus photography of papi lledema in hypertensive neuroretinopathy. Funduscopic findings in a 23-year-old Black man noted incidentally to be severely hypertensive during a routine dental clinic visit. Papilledema of the optic disc is apparent, with surrounding cotto n-wool spots and striated hemorrhages. The pathogenesis of papilledema in hypert ensive neuroretinopathy is unclear. Intracranial pressure is not always increase d in patients with malignant hypertension and papilledema. Papilledema has been produced experimentally in Rhesus monkeys by occlusion of the long posterior cil iary artery that supplies the optic nerve. As in cotton-wool spots, indeed papil ledema may result from hypertensive vasculopathyinduced ischemia of nerve fiber b undles in the optic disc. Thus, in hypertensive neuroretinopathy, papilledema es sentially may represent a giant cotton-wool spot resulting from ischemia of the optic nerve. When papilledema occurs in malignant hypertension, it almost always is accompanied by striated hemorrhages and cotton-wool spots. When papilledema occurs alone, the possibility of a primary intracranial process such as tumor or cerebrovascular accident should be considered. FIGURE 8-13 (see Color Plate) Fu ndus photography of far-advanced hypertensive neuroretinopathy. Funduscopy in th is 30-year-old man with malignant hypertension demonstrates all the characterist ic features of hypertensive neuroretinopathy. These features include striate hem orrhages, cotton-wool spots, papilledema, and a star figure at the macula.

Hypertensive Crises 8.9 10 No papilledema Papilledema 08 Estimated survival 06 04 96 43 74 28 45 16 26 10 14 6 No. with papilledema No. without papilledema FIGURE 8-14 Prognosis in accelerated hypertension versus malignant hypertension. In the original Keith and Wagener [11] classification of hypertensive retinopat hy, malignant hypertension (grade IV) was defined by the presence of papilledema , whereas the term accelerated hypertension (grade III) was used when hemorrhage s and exudates occurred in the absence of papilledema. However, more recent stud ies indicate that the prognosis is the same in hypertensive patients with striat e hemorrhages and cotton-wool spots whether or not papilledema is present. In th is regard, the World Health Organization has recommended that accelerated hypert ension and malignant hypertension be regarded as synonymous terms for the same d isease. Demonstrated are the effects of the presence or absence of papilledema o n survival among 139 hypertensive patients with hypertensive neuroretinopathy (s triated hemorrhages and cotton-wool spots) [14]. By multivariate analysis, after controlling for age, gender, smoking habit, initial serum creatinine concentrat ion, and initial and achieved blood pressure, the presence of papilledema did no t influence prognosis. (From McGregor [14] et al.; with permission.) 0 0 2 4 6 Years 8 10 FIGURE 8-15 (see Color Plate) Micrograph of fibrinoid necrosis in malignant hype rtension. Fibrinoid necrosis of the afferent arterioles and interlobular arterie s has traditionally been regarded as the hallmark of malignant hypertension. The characteristic finding is the deposition in the arteriolar wall of a granular m aterial that is a bright-pink color on hematoxylin and eosin staining. On Masson trichrome staining, as illustrated, the granular fibrinoid material is bright r ed (arrow). The fibrinoid material usually is found in the media of the vessel; however, deposition in the intima also may occur. Whole or fragmented erythrocyt es may be extravasated into the arteriolar wall. These hemorrhages account for t he petechial hemorrhages that give rise to the peculiar flea-bitten appearance o f the capsular surface of the kidney in malignant hypertension. Fibrinoid necros is is thought to result from the mechanical stress placed on the vessel wall by severe hypertension. Forced vasodilation occurs when there is failure of autoreg ulation of renal blood flow, which leads to endothelial injury with seepage of p lasma proteins into the vessel wall. Contact of plasma constituents with smooth muscle cells activates the coagulation cascade, and fibrin is deposited in the w all. Fibrin deposits then cause necrosis of smooth muscle cells (fibrinoid necro sis). (Masson trichrome stain, original magnification 100.)

8.10 Hypertension and the Kidney SPECTRUM OF CLINICAL RENAL INVOLVEMENT IN MALIGNANT HYPERTENSION Progressive subacute deterioration of renal function to end-stage renal disease Transient deterioration of renal function with initial blood pressure control Ol iguric acute renal failure Established renal failure FIGURE 8-16 (see Color Plate) Micrograph of proliferative endarteritis in malign ant hypertension (musculomucoid intimal hyperplasia). In malignant nephroscleros is, the interlobular (cortical radial) arteries reveal characteristic lesions. T hese lesions are variously referred to as proliferative endarteritis, endarterit is fibrosa, musculomucoid intimal hyperplasia, or the onionskin lesion. The typi cal finding is marked thickening of the intima that obstructs the vessel lumen. In severely affected vessels the luminal diameter may be reduced to the caliber of a single erythrocyte. Occasionally, complete obliteration of the lumen by a s uperimposed fibrin thrombus occurs. Traditionally, three patterns of intimal thi ckening have been described [15]. (1) The onionskin pattern consists of pale lay ers of elongated concentrically arranged myointimal cells along with delicate co nnective tissue fibrils that give rise to a lamellar appearance. The media often appears as an attenuated layer stretched around the expanded intima. (2) In the mucinous pattern, intimal cells are sparse. Seen is an abundance of lucent, fai ntly basophilic-staining amorphous material. (3) In fibrous intimal thickening, seen are few cells with an abundance of hyaline deposits, reduplicated bands of elastica, and coarse layers of collagen. The renal histology in Blacks with mali gnant hypertension demonstrates a characteristic finding in the larger arteriole s and interlobular arteries known as musculomucoid intimal hyperplasia, with an abundance of cells and a small amount of myxoid material (that is light blue in color on hematoxylin and eosin staining) between the cells [16, 17]. These vario us intimal findings may represent progression over time from an initially cellul ar lesion to fibrosis of the intima. Electron microscopy demonstrates that in ea ch type of intimal thickening the most abundant cellular element is a modified s mooth muscle cell. This cell is called a myointimal cell. Proliferative endarter itis is thought to occur as a result of phenotypic modulation of medial smooth m uscle cells that dedifferentiate from the normal contractile phenotype to acquir e a more embryologic proliferative-secretory phenotype. It has been proposed tha t the endothelial injury in malignant hypertension results in attachment of plat elets with release of plateletderived growth factor (PDGF) that may induce the p henotypic change in smooth muscle cells. PDGF stimulates chemotaxis of medial sm ooth muscles to the intima, where they proliferate and secrete mucopolysaccharid e and later collagen and other extracellular matrix proteins, resulting in proli ferative endarteritis, musculomucoid hyperplasia, and ultimately fibrous intimal thickening. (Hematoxylin and eosin stain, original magnification 100.) FIGURE 8-17 Malignant hypertension is a progressive systemic vasculopathy in whi ch renal involvement is a relatively late finding. In this regard, patients with malignant hypertension can present with a spectrum of renal involvement ranging from normal renal function with minimal albuminuria to end-stage renal disease (ESRD) indistinguishable from that seen in primary renal parenchymal disease. In patients initially exhibiting preserved renal function, in the absence of adequ ate blood pressure control, it is common to observe subacute deterioration of re nal function to ESRD over a period of weeks to months. Transient deterioration o f renal function with initial control of blood pressure is a well-documented ent ity in patients initially exhibiting mild to moderate renal impairment. Occasion ally, patients with malignant hypertension initially exhibit oliguric acute rena l failure, necessitating initiation of dialysis within a few days of hospitaliza tion. Because erythrocyte casts sometimes appear in the urine sediment, malignan t nephrosclerosis initially may be misdiagnosed as a rapidly progressive glomeru lonephritis or systemic vasculitis [18]. Careful examination of the fundus for e

vidence of hypertensive neuroretinopathy confirms the diagnosis of malignant hyp ertension. Patients with malignant hypertension can also present with establishe d renal failure. Often, it is impossible to determine clinically whether a patie nt initially exhibiting hypertensive neuroretinopathy and renal failure has prim ary malignant hypertension or secondary malignant hypertension with underlying p rimary renal parenchymal disease. The presence of normal-sized kidneys on ultras onography supports a diagnosis of primary malignant nephrosclerosis that potenti ally is reversible with long-term blood pressure control. However, a renal biops y may be required for definitive diagnosis. All patients with malignant hyperten sion should receive aggressive antihypertensive therapy to prevent further renal damage, regardless of the degree of renal impairment. Control of blood pressure in patients with malignant hypertension and renal insufficiency often causes fu rther deterioration of renal function, especially when the initial glomerular fi ltration rate (GFR) is less than 20 mL/min. However, a fall in GFR is not a cont raindication to intensive blood pressure control aimed at normalization of blood pressure. Control of hypertension protects other vital organs, such as the hear t and brain, whose function cannot be replaced. Moreover, with rigid blood press ure control, renal function may eventually recover over the ensuing months, even in patients with apparent ESRD owing to primary malignant nephrosclerosis [19,2 0].

Hypertensive Crises 8.11 FIGURE 8-18 (see Color Plate) Micrograph of hyaline arteriolar nephrosclerosis i n benign hypertension. It is important to draw a clear distinction between malig nant hypertension and benign hypertension with regard to renal histology and cli nical renal involvement. In benign arteriolar nephrosclerosis caused by benign h ypertension, the characteristic histologic lesion is hyaline arteriosclerosis. I n hyaline arteriosclerosis there is expansion of the intima of afferent arteriol es with hyaline material that stains a pale-pink color on periodic acidSchiff sta ining (large arrow). Patchy (focal) ischemic atrophy of the glomeruli usually is seen. Many glomeruli appear normal, whereas some are completely hyalinized. Atr ophic tubules (small arrows), sometimes filled with amorphous material, may be s een in the vicinity of ischemic glomeruli. The severity of the glomerular and tu bular changes generally reflect the extent of vascular involvement with hyaline arteriosclerosis. On gross examination, the kidneys are small with a granular-ap pearing capsular surface (contracted granular kidney). The loss of renal mass pr imarily is due to a thinning of the cortex. In untreated malignant hypertension, relentless progression to end-stage renal disease (ESRD) occurs within a year. In contrast, in benign hypertension, without underlying renal disease or superim posed malignant hypertension, despite well-established folklore to the contrary, ESRD seldom develops [21,22]. In benign hypertension, there is a usually a long asymptomatic phase, with eventual complications resulting from cerebrovascular disease, atherosclerotic disease, or congestive heart failure, in the absence of significant renal impairment despite histologic evidence of benign nephrosclero sis. In this regard, patients classified as having ESRD owing to hypertensive nep hrosclerosis typically exhibit advanced disease initially, making the original pr ocess that initiated the renal disease difficult to detect. Moreover, significan t racial bias may occur in the clinical diagnosis of the cause of ESRD [23]. Nep hrologists presented with identical case histories of hypothetical patients with ESRD and hypertension in which the race is arbitrarily stated to be Black or Wh ite, tend to diagnose hypertensive nephrosclerosis in Blacks and chronic glomeru lonephritis in Whites. It has been proposed that many of the patients presumed c linically to have ESRD owing to benign hypertension, actually have occult intrin sic renal disease with chronic glomerulonephritis, unrecognized bilateral athero sclerotic renal artery stenosis with ischemic nephropathy, atheroembolic renal d isease, or episodes of malignant hypertension that had gone undetected [21,22]. (Periodic acidSchiff stain, original magnification 100.)

8.12 Hypertension and the Kidney FIGURE 8-19 Malignant hypertension must be treated expeditiously to prevent comp lications such as hypertensive encephalopathy, acute hypertensive heart failure, and renal failure. The traditional approach to patients with malignant hyperten sion has been the initiation of potent parenteral agents. Listed are the setting s in which parenteral antihypertensive therapy is mandatory in the initial manag ement of malignant hypertension. Parenteral therapy generally should be used in patients with evidence of acute end-organ dysfunction or those unable to tolerat e oral medications. Nitroprusside is the treatment of choice for patients requir ing parenteral therapy. Diazoxide, employed in minibolus fashion to avoid sustai ned overshoot hypotension, may be advantageous in patients for whom monitoring i n an intensive care unit is not feasible. It generally is safe to reduce the mea n arterial pressure by 20% or to a level of 160 to 170 mm Hg systolic over 100 t o 110 mm Hg diastolic. The use of a short-acting agent such as nitroprusside has obvious advantages because blood pressure can be stabilized quickly at a higher level if complications develop during rapid blood pressure reduction. When no e vidence of vital organ hypoperfusion is seen during this initial reduction, the diastolic blood pressure can be lowered gradually to 90 mm Hg over a period of 1 2 to 36 hours. Oral antihypertensive agents should be initiated as soon as possi ble to minimize the duration of parenteral therapy. The nitroprusside infusion c an be weaned as the oral agents become effective. The cornerstone of initial ora l therapy should be arteriolar vasodilators such as calcium channel blockers, hy dralazine, or minoxidil. Usually, -blockers are required to control reflex tachy cardia, and a diuretic must be initiated within a few days to prevent salt and w ater retention, in response to vasodilator therapy, when the patient's dietary sal t intake increases. Diuretics may not be necessary as a part of initial parenter al therapy because patients with malignant hypertension often present with volum e depletion (Fig. 8-20). Many patients with malignant hypertension definitely re quire initial parenteral therapy. However, some patients may not yet have eviden ce of cerebral or cardiac dysfunction or rapidly deteriorating renal function an d therefore do not require instantaneous control of blood pressure. These patien ts often can be managed with an intensive oral regimen, often with a -blocker an d minoxidil, designed to bring the blood pressure under control within 12 to 24 hours. After the immediate crisis has resolved and the patient's blood pressure ha s been controlled with initial parenteral therapy, oral therapy, or both, lifelo ng surveillance of blood pressure is mandatory. If blood pressure control lapses , malignant hypertension can recur even after years of successful antihypertensi ve therapy. Triple therapy with a diuretic, -blocker, and a vasodilator often is required to maintain satisfactory long-term blood pressure control. INDICATIONS FOR PARENTERAL THERAPY IN MALIGNANT HYPERTENSION Hypertensive encephalopathy Rapidly failing vision Pulmonary edema Intracerebral hemorrhage Rapid deterioration of renal function Acute pancreatitis Gastrointes tinal hemorrhage or acute abdomen from mesenteric vasculitis Patients unable to tolerate oral therapy because of intractable vomiting

Hypertensive Crises 8.13 Role of diuretics to treat malignant hypertension Malignant hypertension Abrupt increase in blood pressure Pressure-induced natriuresis and diuresis Vici ous circle Intravascular volume depletion Activation of the renin-angiotensin axis Angiotensin IImediated vasoconstriction FIGURE 8-20 Role of diuretics in the treatment of malignant hypertension. Tradit ionally, it had been taught that patients with malignant hypertension require po tent parenteral diuretics in conjunction with potent vasodilator therapy during the initial phase of management of malignant hypertension. However, evidence now exists to suggest that parenteral diuretic therapy during the acute management phase actually may be deleterious. In experimental animals, spontaneous natriure sis appears to be the initiating event in the transition from benign to malignan t hypertension, and treatment with volume expansion leads to resolution of the m alignant phase [24]. Rapid weight loss often occurs in patients with malignant h ypertension, which is consistent with a pressure-induced natriuresis. In analges ic nephropathy, profound volume depletion often accompanies malignant hypertensi on, perhaps owing to tubular dysfunction with salt-wasting [5]. In this setting, restoration of normal volume status actually lowers blood pressure and leads to resolution of the malignant phase. Thus, some patients with malignant hypertens ion may benefit from a cautious trial of volume expansion. Volume depletion shou ld be suspected when there is exquisite sensitivity to vasodilator therapy with a precipitous decrease in blood pressure at relatively low infusion rates. Even patients with malignant hypertension complicated by pulmonary edema may not be t otal-body salt and water overloaded. Pulmonary congestion in this setting may re sult from acute hypertensive heart failure caused by an acute decrease in left v entricular (LV) compliance precipitated by severe hypertension. In this setting, pulmonary edema occurs owing to a high LV end-diastolic pressure with normal LV end-diastolic volume (Fig. 8-24). Thus, the need for diuretic therapy during th e initial phases of management of malignant hypertension depends on a careful as sessment of volume status. Unless obvious fluid overload is present, diuretics s hould not be given initially. Overdiuresis may result in deterioration of renal function owing to superimposed volume depletion. Moreover, volume depletion may further activate the renin-angiotensin system and other pressor hormone systems. Although vasodilator therapy will eventually result in salt and water retention by the kidneys, an increase in total body sodium content cannot occur unless th e patient is given sodium. Eventually, during long-term treatment with oral vaso dilators, the use of diuretics becomes imperative to prevent fluid retention and adequately control blood pressure.

8.14 Hypertension and the Kidney FIGURE 8-21 Pathogenesis and treatment of hypertensive encephalopathy. Hypertens ive encephalopathy is a hypertensive crisis in which acute cerebral dysfunction is attributed to sudden or severe elevation of blood pressure [2527]. Hypertensiv e encephalopathy is one of the most serious complications of malignant hypertens ion. However, malignant hypertension (hypertensive neuroretinopathy) need not be present for hypertensive encephalopathy to develop. Hypertensive encephalopathy also can occur in the setting of severe or sudden hypertension of any cause, es pecially if an acute elevation of blood pressure occurs in a previously normoten sive person, eg, from postinfectious glomerulonephritis, catecholamine excess st ates, or eclampsia. Under normal circumstances, autoregulation of the cerebral m icrocirculation occurs, and therefore, cerebral blood flow remains constant over a wide range of perfusion pressures. However, in the setting of sudden severe h ypertension, autoregulatory vasoconstriction fails and there is forced vasodilat ion of cerebral arterioles with endothelial damage, extravasation of plasma prot eins, and cerebral hyperperfusion with the development of cerebral edema. This b reakthrough of cerebral autoregulation underlies the development of hypertensive encephalopathy. In patients with chronic hypertension, structural changes occur in the cerebral arterioles that lead to a shift in the autoregulation curve suc h that much higher blood pressures can be tolerated without breakthrough. This p henomenon may explain the clinical observation that hypertensive encephalopathy occurs at much lower blood pressure in previously normotensive persons than it d oes in those with chronic hypertension. Clinical features of hypertensive enceph alopathy include severe headache, blurred vision or occipital blindness, nausea, vomiting, and altered mental status. Focal neurologic findings can sometimes oc cur. If aggressive blood pressure reduction is not initiated, stupor, convulsion s, and death can occur within hours. The sine qua non of hypertensive encephalop athy is the prompt and dramatic clinical improvement in response to antihyperten sive drug therapy. When a diagnosis of hypertensive encephalopathy seems likely, antihypertensive therapy should be initiated promptly without waiting for the r esults of time-consuming radiographic examinations. The goal of therapy, especia lly in previously normotensive patients, should be reduction of blood pressure t o normal or near-normal levels as quickly as possible. Theoretically, cerebral b lood flow could be jeopardized by rapid reduction of blood pressure in patients with chronic hypertension in whom the lower limit of cerebral blood flow autoreg ulation is shifted to a higher blood pressure. However, clinical experience has shown that prompt blood pressure reduction with the avoidance of frank hypotensi on is beneficial in patients with hypertensive encephalopathy [25]. Of the condi tions in the differential diagnosis of hypertension with acute cerebral dysfunct ion, only cerebral infarction might be adversely affected by the abrupt reductio n of blood pressure. Pharmacologic agents that have rapid onset and short durati on of action such as sodium nitroprusside should be used so that the blood press ure can be titrated carefully, with close monitoring of the patient's neurologic s tatus. A prompt improvement in mental status with blood pressure reduction confi rms the diagnosis of hypertensive encephalopathy. Conversely, when blood pressur e reduction is associated with new or progressive focal neurologic deficits, the presence of a primary central nervous system event, such as cerebral infarction , should be considered. Pathogenesis and treatment of hypertensive encephalopathy Malignant hypertension (hypertensive neuroretinopathy present) Sudden or severe nonmalignant hypertens ion (hypertensive neuroretinopathy absent) Sudden onset or severe hypertension Failure of autoregulation of cerebral blood flow (breakthrough of autoregulation )

Forced vasodilation of cerebral arterioles Endothelial damage (increased permeability to plasma proteins) Cerebral hyperperfusion (increased capillary hydrostatic pressure) Cerebral edema Hypertensive encephalopathy (headache, vomiting, altered mental status, seizures ) Prompt blood pressure reduction with nitroprusside New or progressive focal findings (suspect primary central nervous system proces s) Dramatic clincal improvement (diagnostic of hypertensive encephalopathy)

Hypertensive Crises 8.15 CAUSES OF HYPERTENSIVE ENCEPHALOPATHY Malignant hypertension of any cause Acute glomerulonephritis, especially postinf ectious Eclampsia Catecholamine-induced hypertensive crises Pheochromocytoma Mon oamine oxidase inhibitortyramine interactions Abrupt withdrawal of centrally acti ng 2-agonists Phenylpropanolamine overdose Cocaine-hydrochloride or alkaloid (cr ack cocaine) intoxication Phencyclidine (PCP) poisoning Acute lead poisoning in children High-dose cyclosporine for bone marrow transplantation in children Femo ral lengthening procedures Scorpion envenomation in children Acute renal artery occlusion from thrombosis or embolism Atheroembolic renal disease (cholesterol e mbolization) Recombinant erythropoietin therapy Transplantation renal artery ste nosis Acute renal allograft rejection Paroxysmal hypertension in acute or chroni c spinal cord injuries Postcoronary artery bypass or postcarotid endarterectomy hy pertension FIGURE 8-22 Hypertensive encephalopathy can complicate malignant hypertension of any cause. However, not all patients with hypertensive encephalopathy have hype rtensive neuroretinopathy, indicating the presence of malignant hypertension. In fact, hypertensive encephalopathy most commonly occurs in previously normotensi ve persons who experience a sudden onset or worsening of hypertension. In acute postinfectious glomerulonephritis, the abrupt onset of even moderate hypertensio n may cause breakthrough of autoregulation of cerebral blood flow, resulting in hypertensive encephalopathy. Eclampsia can be viewed as a variant of hypertensiv e encephalopathy that complicates preeclampsia. Moreover, hypertensive encephalo pathy is a common complication of catecholamine-induced hypertensive crises such as pheochromocytoma, monoamine oxidase inhibitortyramine interactions, clonidine withdrawal, phencyclidine (PCP) poisoning, and phenylpropanolamine overdose. Co caine use also can induce a sudden increase in blood pressure accompanied by hyp ertensive encephalopathy. In children, acute lead poisoning, high-dose cyclospor ine for bone marrow transplantation, femoral lengthening procedures, and scorpio n envenomation may be accompanied by the sudden onset of hypertension with hyper tensive encephalopathy. Acute renal artery occlusion resulting from thrombosis o r renal embolism can induce hypertensive encephalopathy. Likewise, atheroembolic renal disease (cholesterol embolization) can cause a sudden increase in blood p ressure complicated by encephalopathy. Recombinant erythropoietin therapy occasi onally results in encephalopathy and seizures. This complication is unrelated to the extent or rate of increase in hematocrit; however, it is associated with a rapid increase in blood pressure, especially if the patient was normotensive pre viously. Transplantation renal artery stenosis or acute renal allograft rejectio n may cause sudden severe hypertension with encephalopathy. Hypertensive encepha lopathy may complicate acute or chronic spinal cord injury. Sudden elevation of blood pressure occurs owing to autonomic stimulation by bowel or bladder distent ion or noxious stimulation in a dermatome below the level of the injury. Hyperte nsive encephalopathy also may complicate the rebound hypertension that follows c oronary artery bypass procedures or carotid endarterectomy.

8.16 Hypertension and the Kidney MAP, mm Hg 200 Heart rate, beats/min 120 90 Cardiac index, L/min/m2 5.0 Mean arterial pressure, mm Hg 200 150 100 50 0 0 Car diac output, L/min P<0.005 NS LVEDV, mL/m2 200 B NP B AHHF NF NP 100 AHHF 0 NS Stroke work index, g m/m2 150 NF 60 30 0 NS LVEDP, mm Hg 60 45 2.5 P<0.005 40 LVEDP, mm Hg 9 NP B 30 20 10 0 NP B NP 6 3 0 75 30 15 100 B B NP 0 0 NS P<0.005 NS A Baseline hemodynamics in acute hypertensive heart failure (A HHF) vs no failure (NF) 0 P<0.005 NS P<0.005 P<0.025 B Hemodynamic parameters at baseline (B) and during nitroprusside (NP) infusion

60 50 AHHF: baseline AHHF: with nitroprusside No failure: baseline No failure: with ni troprusside LVFP, mm Hg 40 30 20 10 0 40 80 120 160 LVEDV, mL/m2 200 240 C Left ventricular compliance at baseline and with nitroprusside FIGURE 8-23 Pathogenesis of acute hypertensive heart failure. Both malignant hyp ertension and severe benign hypertension can be complicated by acute pulmonary e dema caused by isolated diastolic dysfunction. In acute hypertensive heart failu re the compromise of left ventricular (LV) diastolic function occurs as a result of a decrease in LV compliance caused by an increased workload imposed on the h eart by the marked elevation in systemic vascular resistance. Illustrated are th e hemodynamic derangements in acute hypertensive heart failure in a study that c ompared five patients with severe essential hypertension complicated by acute pu lmonary edema with a control group of five patients with equally severe hyperten sion but no pulmonary edema [28]. Patients in both groups had electrocardiographic evidence of LV hypertrophy caused by lon g-standing hypertension. A, Baseline hemodynamic measurements before treatment r evealed that the following measurements were the same in both groups: mean arter ial pressure (MAP), heart rate, cardiac index, systemic vascular resistance, and stroke work index. Likewise, the LV end-diastolic volume (LVEDV) was similar in both groups. In fact, the only hemodynamic difference between the groups was a significant elevation of LV filling pressure (LVFP) (pulmonary capillary wedge p ressure) in the group with pulmonary edema. In acute hypertensive heart failure the finding of elevated LV end-diastolic pressures (LVEDPs), despite normal ejec tion fraction and cardiac index, implies the presence of isolated diastolic dysf unction. The increased LV end-diastolic pressure (LVEDP), despite similar LVEDV, can only be explained by a decrease in LV compliance in patients with acute hyp ertensive heart failure. B, The importance of an acute decrease in LV compliance in the pathogenesis of acute hypertensive heart failure (AHHF) was confirmed in these patients by the hemodynamic response to vasodilator therapy. Sodium nitro prusside infusion resulted in prompt resolution of pulmonary edema in the group having AHHF, with the LVEDP decreasing from a mean of 43 to 18 mm Hg. C, The dec rease in filling pressure during nitroprusside therapy in patients with AHHF was not caused by venodilation with decreased venous return because the LVEDV actua lly increased during nitroprusside infusion. Thus, the response to sodium nitrop russide therapy was mediated through a decrease in systemic vascular resistance that led to an immediate improvement in LV compliance and reduction in wedge pre ssure despite an increase in LVEDV. These findings suggest that the proximate ca use of AHHF is an elevation of the systemic vascular resistance that precipitate s acute diastolic dysfunction (decreased LV compliance) with elevated pulmonary capillary wedge pressure, resulting in pulmonary edema. NS not significant. (Adap ted from Cohn and coworkers [28]; with permission.)

Hypertensive Crises 8.17 60 Left ventricular end-diastolic pressure, mm Hg 50 40 Nitroprusside 30 HF 20 10 0 40 80 No rm al 120 160 200 240 Left ventricular end-diastolic volume, mL/m2 FIGURE 8-24 Treatment of acute hypertensive heart failure. The left ventricular (LV) end-diastolic pressure-volume relationships (compliance curves) in acute hy pertensive heart failure (AHHF) before and after treatment with sodium nitroprus side are represented schematically. In AHHF, the pressure-volume curve is shifte d up and to the left, reflecting an acute decrease in LV compliance caused by se vere systemic hypertension. In this setting, a higher than normal LV end-diastol ic pressure (LVEDP) is required to achieve any given level of LV end-diastolic v olume (LVEDV). Normal LV systolic function (ejection fraction and cardiac output ) is maintained but at the expense of a very high wedge pressure that results in acute pulmonary edema. Treatment with sodium nitroprusside causes a reduction i n the elevated systemic vascular resistance, with a concomitant decrease in impe dance to LV ejection. As a result, LV compliance improves. Pulmonary edema resol ves owing to a reduction in LVEDP, despite the fact that LVEDV actually increase s during treatment. Sodium nitroprusside is the preferred drug for treatment of AHHF. There is no absolute blood pressure goal. The infusion should be titrated until signs and symptoms of pulmonary edema resolve or the blood pressure decrea ses to hypotensive levels. Rarely is it necessary to lower the blood pressure to this extent, however, because reduction to levels still within the hypertensive range is usually associated with dramatic clinical improvement. Although hemody namic monitoring is not always required, it is essential in patients in whom con comitant myocardial ischemia or compromised cardiac output is suspected. After t he hypertensive crisis has been controlled and pulmonary edema has resolved, ora l antihypertensive therapy can be substituted as the patient is weaned from the nitroprusside infusion. As in the treatment of hypertensive patients with chroni c congestive heart failure symptoms owing to isolated diastolic dysfunction, age nts such as blockers, angiotension-converting enzyme inhibitors, or calcium chan nel blockers may represent logical first-line therapy. These agents directly imp rove diastolic function in addition to reducing systemic blood pressure. In pati ents with malignant hypertension or resistant hypertension, however, adequate co ntrol of blood pressure may require therapy with more than one drug. Potent dire ctacting vasodilators such as hydralazine or minoxidil may be used in conjunctio n with a -blocker to control reflex tachycardia and a diuretic to prevent reflex

salt and water retention. AH

8.18 Hypertension and the Kidney FIGURE 8-25 Aortic dissection. Classification of aortic dissection is based on t he presence or absence of involvement of the ascending aorta [29]. The dissectio n is defined as proximal if there is involvement of the ascending aorta. The pri mary intimal tear in proximal dissection may arise in the ascending aorta, trans verse aortic arch, or descending aorta. In distal dissections, the process is co nfined to the descending aorta without involvement of the ascending aorta, and t he primary intimal tear occurs most commonly just distal to the origin of the le ft subclavian artery. Proximal dissections account for approximately 57% and dis tal dissections 43% of all acute aortic dissections. Acute aortic dissection is a hypertensive crisis requiring immediate antihypertensive treatment aimed at ha lting the progression of the dissecting hematoma. The three most frequent compli cations of aortic dissection are acute aortic insufficiency, occlusion of major arterial branches, and rupture of the aorta with fatal hemorrhage (location of r upture-hemorrhage: ascending aortahemopericardium with tamponade, aortic archmedia stinum, descending thoracic aortaleft pleural space, abdominal aorta retroperitone um). Patients with acute dissection should be stabilized with intensive antihype rtensive therapy to prevent life-threatening complications before diagnostic eva luation with angiography. The initial therapeutic goal is the elimination of pai n that correlates with halting of the dissection, and reduction of the systolic pressure to the 100 to 120 mm Hg range or to the lowest level of blood pressure compatible with the maintenance of adequate renal, cardiac, and cerebral perfusi on [30]. Even in the absence of systemic hypertension the blood pressure should be reduced. Antihypertensive therapy should be designed not only to lower the bl ood pressure but also to decrease the steepness of the pulse wave. The most comm only used treatment regimens consist of initial treatment with intravenous -bloc kers such as propranolol, metoprolol, or esmolol followed by treatment with sodi um nitroprusside. After control of the blood pressure, angiography or transesoph ageal echocardiography, or both, should be performed. The need for surgical inte rvention is determined based on involvement of the ascending aorta. In proximal dissections, surgical therapy is clearly superior to medical therapy alone (70% vs 26% survival, respectively). In contrast, in patients with distal dissection, intensive drug therapy alone leads to an 80% survival rate compared with only 5 0% in patients treated surgically. The explanation for the advantage of surgical therapy in proximal dissection is probably that the risks of complications such as cerebral ischemia, acute aortic insufficiency, and cardiac tamponade are hig her and managed more effectively with surgery. Because these complications do no t occur in distal dissection, in the absence of occlusion of a major arterial br anch or development of a saccular aneurysm during long-term follow-up, medical t herapy is preferred. Patients with distal dissection tend to be elderly with mor e advanced aortic atherosclerosis and therefore are at higher risk of complicati ons from operative intervention. (Adapted from Wheat [29]; with permission.) Aortic dissection Transverse aortic arch Ascending aorta Descending aorta Proximal (Type A) Distal (Type B)

Hypertensive Crises 8.19 Poorly controlled hypertension in surgical patients Postpone elective surgery un til blood pressure adequately controlled for 23 weeks Inadequate preoperative blo od pressure control (diastolic blood pressure >110 mm Hg or mild to moderate hyp ertension in patients with history of cerebrovascular accident, myocardial ische mia, heart failure, or renal insufficiency General anesthesia Decreased cardiac output (30%) Decreased systemic vascular resistance (27%) Hypotension (45% Decre ase in mean arterial pressure) Increased risks of Cerebral ischemia Myocardial i schemia Acute renal failure Increased perioperative morbidity and mortality Administer blood pressure and antianginal medications the morning of surgery Manage intraoperative hypertension with sodium nitroprusside Manage postoperative hypertension with nitroprusside in patients with complicati ons or labetalol in patients without complications Carefully institute oral antihypertensives at low-dose and titrate based on orth ostatic blood pressure measurements FIGURE 8-26 Poorly controlled hypertension in the patient requiring surgery. Hyp ertension in the preoperative patient is a common problem. Poor control of preop erative hypertension, with a diastolic blood pressure higher than 110 mm Hg, is a relative contraindication to elective surgery. In such patients, perioperative morbidity and mortality are increased because of a higher incidence of intraope rative hypotension accompanied by myocardial ischemia and a heightened risk of a cute renal failure [31]. Malignant hypertension clearly represents an excessive surgical risk and all but lifesaving emergency surgery should be deferred until the blood pressure can be controlled and organ function stabilized. Mild to mode rate uncomplicated hypertension with diastolic blood pressure less than 110 mm H g does not appear to increase the risk of surgery significantly and therefore is not an absolute indication to postpone elective surgery. However, patients with mild to moderate hypertension and preexisting complications such as ischemic he art disease, cerebrovascular disease, congestive heart failure, or chronic renal insufficiency, represent a subgroup with significantly increased perioperative risk. In these patients, adequate preoperative control of blood pressure is imperative [32]. Even though the blood pressure in patients with severe or co mplicated hypertension usually can be controlled within hours using aggressive p arenteral therapy, such precipitous control of blood pressure carries the risk o f significant complications such as hypovolemia, electrolyte abnormalities, and marked intraoperative blood pressure lability. General anesthesia is accompanied by a 30% decrease in cardiac output. In normotensive persons and patients with adequately treated hypertension, anesthesia is not associated with a decrease in systemic vascular resistance. Therefore, the decrease in mean arterial pressure (MAP) is modest (2530%). However, in patients with inadequate preoperative blood pressure control, anesthesia is associated with a concomitant decrease in syste mic vascular resistance (SVR) of approximately 27%. The combined decrease in car diac output and SVR leads to a profound decrease in MAP (45%) during anesthesia [33]. This intraoperative hypotension predisposes to myocardial ischemia, cerebr ovascular accidents, and acute renal failure. Therefore, in patients with diasto lic blood pressure over 110 mm Hg or these other high-risk groups, elective surg ery should be postponed and blood pressure brought under control for a few weeks before surgery, if possible. Ideally, sustained adequate preoperative blood pre ssure control should be the goal in all hypertensive patients [34]. In patients with adequately treated hypertension, oral antihypertensive, and antianginal med ications should be continued up to and including the morning of surgery, adminis

tered with small sips of water. Because hypovolemia increases the risk of intrao perative hypotension and postoperative acute renal failure, diuretics should be withheld for 1 to 2 days preoperatively except in patients with overt heart fail ure or fluid overload. Adequate potassium repletion should be given to correct h ypokalemia well in advance of surgery. Continuation of -blockers to within a few hours of surgery does not impair cardiac function and has been shown to decreas e the risks of dysrhythmia and myocardial ischemia during surgery. In patients w ith complications and a history of cardiovascular disease or heart failure, or a fter coronary artery bypass surgery, postoperative hypertension should be manage d with short-acting agents such as nitroglycerin or nitroprusside. In patients w ithout complications, intermittent intravenous infusions of labetalol may be use ful for management of mild to moderate postoperative hypertension until the preo perative oral antihypertensive agents can be resumed. Many patients with long-st anding hypertension, even if severe, require much smaller doses of antihypertens ive medications in the early postoperative course. Thus, the preoperative regime n should not be restarted automatically. Measurement of orthostatic blood pressu res should be used as a guide to dosage adjustment during the postoperative reco very period. In most instances, the need for antihypertensive medications will g radually increase over a few days to weeks to eventually equal the preoperative requirement.

8.20 Hypertension and the Kidney may develop precipitous hypotension with even low-dose infusions of nitroglyceri n or nitroprusside. Hypertension in this setting should be treated using careful volume expansion with crystalloid solutions or blood if required. Postcoronary a rtery bypass hypertension represents a hypertensive crisis because the heightene d SVR increases the impedance to left ventricular (LV) ejection (afterload) that can result in an acute decrease in ventricular compliance with elevation of LV end-diastolic pressure (LVEDP) and acute hypertensive heart failure with pulmona ry edema (Figs. 8-23 and 8-24). The increase in LVEDP also impairs subendocardia l perfusion and can cause myocardial ischemia. Moreover, the elevated blood pres sure increases the risk of mediastinal bleeding in these recently heparinized pa tients. The initial management of postbypass hypertension should focus on attemp ts to ameliorate reversible causes of sympathetic activation, including patient agitation on emergence from anesthesia, tracheal or nasopharyngeal irritation fr om the endotracheal tube, pain, hypothermia with shivering, ventilator asynchron y, hypoxia, hypercarbia, and volume depletion. If these general measures fail to control the blood pressure, further therapy should be guided by measurement of systemic hemodynamics. Intravenous nitroglycerin or nitroprusside is the drug of choice to provide a controlled decrease in SVR and blood pressure. Nitroglyceri n may be the preferred drug because it dilates intracoronary collateral arteries [35,36]. Therapy with -blockers is not indicated in this setting and may be det rimental because these drugs impair cardiac output and cause a further increase in SVR. Labetalol also has been shown to cause a significant reduction in cardia c output in postbypass hypertension. Postbypass hypertension is usually transien t and resolves by 6 to 12 hours postoperatively, so that the vasodilatory therap y can be weaned. The hypertension usually does not recur after the initial episo de in the immediate postoperative period. Hypertensive crises after bypass surgery Coronary artery bypass graft surgery Paradoxical hypertensive response to intrav ascular volume depletion Increased sympathetic tone owing to activation or press or reflexes from heart, coronary arteries, or great vessels Increased systemic vascular resistance Treat with nitroprusside or intravenous n itroglycerin Systemic hypertension Increased risk of postoperative mediastinal bleeding Increased impedance to left ventricular ejection Hypertensive encephalopathy (Fig. 8-21) Acute diastolic dysfunction (decreased left ventricular compliance) Increased left ventricular end-diastolic pressure Impaired subendocardial perfusion causing myocardial ischemia Acute hypertensive heart failure with pulmonary edema (Figs. 8-23 and 8-24) FIGURE 8-27 Hypertensive crisis after coronary artery bypass surgery. Paroxysmal hypertension in the immediate postoperative period is a frequent and serious co mplication of cardiac surgery [35,36]. Paroxysmal hypertension is the most frequ ent complication of coronary artery bypass surgery, occurring in 30% to 50% of p atients. It occurs just as often in normotensive patients as it does in those wi

th a history of chronic hypertension. The increase in blood pressure usually occ urs during the first 4 hours after surgery. The hypertension results from a dram atic increase in systemic vascular resistance (SVR) without a change in the card iac output and is most commonly mediated by an increase in sympathetic tone owin g to activation of pressor reflexes from the heart, great vessels, or coronary a rteries. Hypervolemia, although often cited as a potential mechanism of postoper ative hypertension, is a rare cause of postbypass hypertension except in patient s with renal failure. In fact, increased SVR owing to marked sympathetic overrea ction to volume depletion is a common, often unrecognized, cause of severe posto perative hypertension [37]. Patients with this paradoxical hypertensive response to hypovolemia are exquisitely sensitive to vasodilator therapy and

Hypertensive Crises 8.21 Hypertensive crises after carotid endarterectomy Carotid endarterectomy Postoperative hypertension (mechanism unknown) Repair of high-grade stenosis Sudden increase in perfusion pressure in arteriocapillary bed that was previousl y protected from hypertension Failure of autoregulation of cerebral blood flow (breakthrough of autoregulation ) Overperfusion of cerebral circulation Vessel rupture (hemorrhage and infarction) FIGURE 8-28 Hypertensive crisis after carotid endarterectomy. Hypertension in th e immediate postoperative period occurs in up to 60% of patients after carotid e ndarterectomy [38]. A history of chronic hypertension, especially if the blood p ressure is poorly controlled preoperatively, dramatically increases the risk of postoperative hypertension. The mechanism of post-endarterectomy hypertension is unknown. The incidence of hypertension is the same whether or not the carotid s inus nerve is preserved. Hypertension after endarterectomy is a hypertensive cri sis because it is associated with increased risk of intracerebral hemorrhage and increases the postoperative mortality rate [39]. A mechanism for the developmen t of postcarotid endarterectomy cerebral hemorrhage owing to postoperative hypert ension has been proposed. In patients with high-grade carotid artery stenosis, t he distal cerebral circulation has been relatively protected from systemic hyper tension. In this regard, the autoregulatory curve may be shifted to a lower thre shold to compensate for reduced perfusion pressure. After repair of the obstruct ing lesion, a relative increase in perfusion pressure occurs in the cerebral art eriocapillary bed. In the setting of systemic hypertension the increased blood f low and perfusion pressure may overwhelm the autoregulatory mechanisms. Overperf usion and rupture may then occur, resulting in hemorrhagic infarction. Because p oor preoperative blood pressure control increases the risk of postoperative hype rtension, strict blood pressure control is essential before elective carotid end arterectomy. Furthermore, intra-arterial pressure should be monitored in the ope rating room and in the immediate postoperative period. Ideally, the patient shou ld be awake and extubated before reaching the recovery room so that serial neuro logic examinations can be performed to assess for the development of focal defic its. When the systolic blood pressure exceeds 200 mm Hg, an intravenous infusion of sodium nitroprusside should be initiated to maintain the systolic blood pres sure between 160 and 200 mm Hg. The use of a short-acting parenteral agent is im perative to avoid overshoot hypotension and cerebral hypoperfusion.

8.22 Hypertension and the Kidney infarction, hypertension tends to be very labile and exquisitely sensitive to hy potensive therapy. Thus, even modest doses of oral antihypertensive agents can l ead to profound and devastating overshoot hypotension with extension of the infa rct [42]. An additional rationale for not treating hypertension in the acute set ting is based on evidence that local autoregulation of cerebral blood flow is im paired in the so-called ischemic penumbra, which surrounds the area of acute inf arction [43]. Without intact autoregulation, the regional blood flow in this mar ginal zone of ischemia becomes critically dependent on the perfusion pressure. T hus, the presence of mild to moderate systemic hypertension may actually be prot ective, and acute reduction of blood pressure may cause a regional reduction in blood flow with extension of the infarct. Thus, in most cases of cerebral infarc tion it is prudent to allow the blood pressure to seek its own level during the first few days to weeks after the event. In most cases the hypertension tends to resolve spontaneously, without any specific therapy, over the first week as bra in function recovers. When hypertension persists for more than 3 weeks after a c ompleted infarction, reduction of the blood pressure into the normal range with oral antihypertensives is appropriate. Although benign neglect of mild to modera te hypertension is prudent in acute cerebral infarction, there may be certain in dications for active treatment of blood pressure. When the diastolic blood press ure is sustained at over 130 mm Hg, cautious reduction of blood pressure into th e ranges of 160 to 170 mm Hg systolic and 100 to 110 mm Hg diastolic may be appr opriate. In stroke patients requiring anticoagulation therapy, moderate control of severe hypertension also should be considered. Cautious blood pressure reduct ion is indicated when stroke is accompanied by other hypertensive crises such as acute myocardial ischemia or acute hypertensive heart failure. Stroke caused by carotid occlusion by a proximal aortic dissection mandates aggressive blood pre ssure reduction into the normal range to halt the dissection process. In the set ting of sudden severe hypertension, it may be difficult to distinguish hypertens ive encephalopathy with focal neurologic findings from cerebral infarction. Beca use rapid reduction of blood pressure is lifesaving in patients with hypertensiv e encephalopathy, a cautious diagnostic trial of blood pressure reduction may be warranted (Fig. 821). If blood pressure reduction is deemed necessary in patien ts with acute cerebral infarction, treatment should be initiated using small dos es of a short-acting parenteral agent such as sodium nitroprusside. Use of oral or sublingual nifedipine is associated with excessive risk of prolonged overshoo t hypotension. Oral clonidine loading also is contraindicated because of the ris k of hypotension and because sedative side effects interfere with the assessment of mental status. Risks of antihypertensive therapy in acute cerebral infarction Acute cerebral in farction Reflex increase in systemic blood pressure Even with cautious blood pressure red uction using parenteral agents Altered blood flow autoregulation in the ischemic penumbra surrounding the infar ct Exaggerated response to oral antihypertensives Spontaneous resolution within fir st week Failure of autoregulation with worsening ischemia Extension of infarct FIGURE 8-29 Risks of antihypertensive therapy in acute cerebral infarction. Cere bral infarction results from partial or complete occlusion of an artery by an at herosclerotic plaque or embolization of atherothrombotic debris from a more prox imal plaque. These atherothrombotic infarcts typically involve the cerebral cort

ex, cerebellar cortex, or pons; these infarcts are to be contrasted with hyperte nsion-induced lipohyalinosis of the small penetrating cerebral end-arteries that is the principal cause of the small lacunar infarcts occurring in the basal gan glia, pons, thalamus, cerebellum, and deep hemispheric white matter. Hypertensio n occurs in up to 85% of patients with acute cerebral infarction, even in previo usly normotensive persons [40]. This early elevation of blood pressure probably represents a physiologic response to brain ischemia. Because of the known benefi ts of antihypertensive therapy with regard to stroke prevention, it previously h ad been assumed that acute reduction of blood pressure would also be of benefit in acute cerebral infarction. However, no evidence exists to suggest that acute reduction of blood pressure is beneficial in this setting. In fact, reports exis t of worsening neurologic status, apparently precipitated by emergency treatment of hypertension in patients with cerebral infarction [41]. In the setting of ac ute cerebral

Hypertensive Crises 8.23 Hypertensive crises from intracerebral hemorrhage Intracerebral hemorrhage Reflex increase in blood pressure (Cushing's reflex) Hypertension may help maint ain blood flow in ischemic areas Cerebral hyperperfusion with cerebral edema Imp airment of autoregulation of blood flow in ischemic area surrounding hematoma (s hift of lower limit of autoregulation) Increased risk of rebleeeding (expansion of hematoma) Sodium nitroprusside Cautious blood pressure reduction by no more than 20% of pr esenting mean arterial pressure (intra-arterial and intracranial pressure monito ring to ensure adequate cerebral perfusion pressure) FIGURE 8-30 Hypertensive crises due to intracerebral hemorrhage. Chronic hyperte nsion is the major risk factor for intracerebral hemorrhage. The most common sit es of hemorrhage are the small-diameter penetrating cerebral end-arteries in the basal ganglia, pons, thalamus, cerebellum, and deep hemispheric white matter. L acunar infarcts arise from the same vessels and are similarly distributed. Intra cerebral hemorrhage characteristically begins abruptly with headache and vomitin g followed by steadily increasing focal neurologic deficits and alteration of co nsciousness [44]. More than 90% of hemorrhages rupture through brain parenchyma into the ventricles, producing bloody cerebrospinal fluid. Patients presenting w ith intracerebral hemorrhage are invariably hypertensive. In contrast to cerebra l infarction, the hypertension does not tend to decrease spontaneously during th e first week. The patient's condition worsens steadily over a period of minutes to days until either the neurologic deficit stabilizes or the patient dies. When d eath occurs, most often it is due to herniation caused by the expanding hematoma and surrounding edema. Treatment of hypertension in the setting of intracerebra l hemorrhage is controversial. An increase in intracranial pressure accompanied by a reflex increase in systemic blood pressure almost always occurs. Because ce rebral perfusion pressure is a function of the difference between arterial press ure and intracranial pressure, reduction of blood pressure could compromise cere bral perfusion. Moreover, as in cerebral infarction, autoregulation is impaired in the area of marginal ischemia surrounding the hemorrhage. In contrast, cerebr al vasogenic edema may be exacerbated by hypertension. Moreover, hypertension ma y increase the risk of rebleeding with expansion of the hematoma. Thus, in decid ing to treat hypertension in the setting of intracerebral hemorrhage, a precario us balance must be struck between beneficial reduction in cerebral edema on the one hand, and deleterious reduction of cerebral blood flow on the other. Studies have shown that the lower limit of autoregulation after intracerebral hemorrhag e is approximately 80% of the initial blood pressure; therefore, a 20% decrease in mean arterial pressure should be considered the maximal goal of blood pressur e reduction during the acute stage [45]. Antihypertensive therapy should be unde rtaken only in conjunction with intracranial and intra-arterial pressure monitor ing to allow for assessment of cerebral perfusion pressure. The short duration o f action of nitroprusside makes its use preferable over other agents with a long er duration of action and the risk of sustained overshoot hypotension, despite t he theoretic concern that nitroprusside treatment could lead to an increase in i ntracranial pressure by way of dilation of cerebral veins and arteries.

8.24 Hypertension and the Kidney Hypertensive crisis with pheochromocytoma Pheochromocytoma Episodic release of c atecholamines Paroxysmal hypertension Acute hypertensive heart failure with pulm onary edema (Figs. 8-23 and 8-24) Acute treatment with nitroprusside or phentola mine followed by b
lockers Pressure
induced natriuresis and diuresis Intravascular volume depletion Increas ed risk of intraoperative and postoperative hypotension Intracerebral hemorrhage Hypertensive encephalopathy (Fig. 8-21) FIGURE 8-31 Hypertensive crisis with pheochromocytoma. In most patients, pheochr omocytoma causes sustained hypertension that sometimes becomes malignant as evid enced by the presence of hypertensive neuroretinopathy. Paroxysmal hypertension is present in approximately 30% of patients. Spontaneous paroxysms consist of se vere hypertension, headache, profuse diaphoresis, pallor, coldness of hands and feet, palpitations, and abdominal discomfort. Paroxysmal hypertension in pheochr omocytoma represents a hypertensive crisis because it can lead to intracerebral hemorrhage, hypertensive encephalopathy, or acute hypertensive heart failure wit h pulmonary edema. Prompt control of the blood pressure is mandatory to prevent these life-threatening complications. Although the nonselective -blocker phentol amine often is cited as the treatment of choice for pheochromocytoma-related hyp ertensive crises, sodium nitroprusside is equally effective and easier to admini ster [46]. Only after blood pressure has been controlled with nitroprusside or p hentolamine can intravenous -blockers, such as esmolol, labetalol, or propranolo l, be used to control tachycardia or arrhythmias. After resolution of the hypert ensive crisis, oral antihypertensive agents should be instituted as the parenter al agents are weaned. The nonselective -blocker phentolamine usually is administ ered orally for 1 to 2 weeks before elective surgery. After adequate -blockade i s achieved, based on the presence of moderate orthostatic hypotension, oral -blo cker therapy can be initiated as needed to control tachycardia. Oral or intraven ous -blockers should never be administered before adequate -blockade. Doing so c an precipitate a hypertensive crisis as the result of intense -adrenergic vasoco nstriction that is no longer opposed by -adrenergic vasodilatory stimuli. Carefu l attention to volume status also is mandatory in the preoperative period. Catec holamine-induced hypertension induces a pressure natriuresis with volume depleti on. Moreover, alleviation of the chronic state of vasoconstriction by -blockade results in increases in both arterial and venous capacitances. Preoperative volu me expansion, guided by measurement of central venous pressure or wedge pressure often is advocated to reduce the risk of intraoperative hypotension [47]. Durin g surgery, rapid and wide fluctuations in blood pressure should be anticipated. Careful intraoperative monitoring of intra-arterial pressure, cardiac output, we dge pressure, and systemic vascular resistance is mandatory to manage the rapid swings in blood pressure. Despite adequate preoperative -blockade with phenoxybe nzamine, severe hypertension can occur during intubation or intraoperatively as a result of catecholamine release during tumor manipulation. Sodium nitroprussid e is the treatment of choice for controlling acute hypertension owing to pheochr omocytoma during surgery. At the opposite end of the spectrum, profound intraope rative hypotension can occur. Hypotension or even frank shock can supervene afte r isolation of tumor venous drainage from the circulation, with resultant abrupt decrease in circulating catecholamine levels. Volume expansion is the treatment of choice for intraoperative and postoperative hypotension [46]. Pressors only should be employed when hypotension is unresponsive to volume repletion.

Hypertensive Crises 8.25 Hypertension crises secondary to monoamine oxidase inhibitortyramine interactions Monoamine oxidase inhibitor therapy Impaired degradation of intracellular amines (epinephrine, norepinephrine, dopam ine) Accumulation of catecholamines in nerve terminal storage granules Increased circulating tyramine level Ingestion of tyramine-containing food Hepatic monamine oxidase inhibition with decreased oxidative metabolism of tyram ine Massive release of catecholamines Tachyarrhythmias Vasoconstriction (increased systemic vascular resistance) Severe paroxysm of hypertension Hypertensive encephalopathy (Fig. 8-21) Acute hypertensive heart failure with pulmonary edema (Figs. 8-24 and 8-25) Intracerebral hemorrhage FIGURE 8-32 Hypertensive crises secondary to monoamine oxidase inhibitortyramine interactions. Severe paroxysmal hypertension complicated by intracerebral or sub arachnoid hemorrhage, hypertensive encephalopathy, or acute hypertensive heart f ailure can occur in patients treated with monoamine oxidase (MOA) inhibitors aft er ingestion of certain drugs or tyraminecontaining foods [48,49]. Because MAO i s required for degradation of intracellular amines, including epinephrine, norep inephrine, and dopamine, MAO inhibitors lead to accumulation of catecholamines w ithin storage granules in nerve terminals. The amino acid tyramine is a potent i nducer of neurotransmitter release from nerve terminals. As a result of inhibiti on of hepatic MAO, ingested tyramine escapes oxidative degradation in the liver. In addition, the high circulating levels of tyramine provoke massive catecholam ine release from nerve terminals, resulting in vasoconstriction and a paroxysm o f severe hypertension. A hyperadrenergic syndrome resembling pheochromocytoma th en ensues. Symptoms include severe pounding headache, flushing or pallor, profus e diaphoresis, nausea, vomiting, and extreme prostration. The mean increase in b lood pressure is 55 mm Hg systolic and 30 mm Hg diastolic [49]. The duration of the attacks varies from 10 minutes to 6 hours. Attacks can be provoked by the in gestion of foods known to be rich in tyramine: natural or aged cheeses, Chianti wines, certain imported beers, pickled herring, chicken liver, yeast, soy sauce, fermented sausage, coffee, avocado, banana, chocolate, and canned figs. Sympath omimetic amines in nonprescription cold remedies also can provoke neurotransmitt er release in patients treated with an MAO inhibitor. Either sodium nitroprussid e or phentolamine can be used to manage this type of hypertensive crisis. Becaus e most patients are normotensive before onset of the crisis the goal of blood pr essure treatment should be normalization of the blood pressure. After blood pres sure control, intravenous -blockers may also be required to control heart rate a nd tachyarrhythmias. Because the MAO inhibitortyramine hypertensive crisis is sel f-limited, parenteral antihypertensive agents can be weaned without institution of oral antihypertensive agents.

8.26 Hypertension and the Kidney FIGURE 8-33 Mechanism of action and metabolism of nitroprusside. Sodium nitropru sside is the drug of choice for management of virtually all hypertensive crises, including malignant hypertension, hypertensive encephalopathy, acute hypertensi ve heart failure, intracerebral hemorrhage, perioperative hypertension, catechol amine-related hypertensive crises, and acute aortic dissection (in combination w ith a -blocker) [1,50]. Sodium nitroprusside is a potent intravenous hypotensive agent with immediate onset and brief duration of action. The site of action is the vascular smooth muscle. Nitroprusside has no direct action on the myocardium , although it may affect cardiac performance indirectly through alterations in s ystemic hemodynamics. Nitroprusside is an iron (Fe) coordination complex with fi ve cyanide moieties and a nitroso (NO) group. The nitroso group combines with cy steine to form nitrosocysteine and other short-acting S-nitrosothiols. Nitrosocy steine is a potent activator of guanylate cyclase, thereby causing cyclic guanos ine monophosphate (cGMP) accumulation and relaxation of vascular smooth muscle [ 51,52]. Nitroprusside causes vasodilation of both arteriolar resistance vessels and venous capacitance vessels. Its hypotensive action is a result of a decrease in systemic vascular resistance. The combined decrease in preload and afterload reduces myocardial wall tension and myocardial oxygen demand. The net effect of nitroprusside on cardiac output and heart rate depends on the intrinsic state o f the myocardium. In patients with left ventricular (LV) systolic dysfunction an d elevated LV end-diastolic pressure, nitroprusside causes an increase in stroke volume and cardiac output as a result of afterload reduction and heart rate may actually decrease in response to improved cardiac performance. In contrast, in the absence of LV dysfunction, venodilation and preload reduction can result in a reflex increase in sympathetic tone and heart rate. For this reason, nitroprus side must be used in conjunction with a -blocker in acute aortic dissection. The hypotensive action of nitroprusside appears within seconds and is immediately r eversible when the infusion is stopped. The cGMP in vascular smooth muscle is ra pidly degraded by cGMP-specific phosphodiesterases. Nitroprusside is rapidly met abolized with a half-life (t1/2) of 3 to 4 minutes. Cyanide is formed as a short -lived intermediate product by direct combination with sulfhydryl (SH) groups in erythrocytes and tissues. The cyanide groups are rapidly converted to thiocyana te by the liver in a reaction in which thiosulfate acts as a sulfur donor. Thioc yanate is excreted by the kidneys, with a half-life of 1 week in patients with n ormal renal function. Thiocyanate accumulation and toxicity can occur when a hig h-dose or prolonged infusion is required, especially in patients with renal insu fficiency. When these risk factors are present, thiocyanate levels should be mon itored and the infusion stopped if the level is over 10 mg/dL. Thiocyanate toxic ity is rare in patients with normal renal function requiring less than 3 g/kg/min for less than 72 hours [50]. Cyanide poisoning is a very rare complication, unl ess hepatic clearance of cyanide is impaired by severe liver disease or massive doses of nitroprusside (over 10 g/kg/min) are used to induce deliberate hypotensi on during surgery [50]. Mechanism of action and metabolism of nitroprusside + NO CNt1/2=34 min CNFe++ CNCNNitroprusside Combination of nitroso group with cysteine CNMetabolized by direct combination with -SH groups in erythrocytes and tissues Free cyanide (CN-)

Thiocyanate t1/2=1 wk Renal excretion Nitrosocysteine Activation of guanylate cyclase t1/2=23min cGMP accumulation in vascular smooth muscle Metabolized by cGMP-specific phosphodiesterases Venodilation (increased venous capacitance) Dilation of arteriolar resistance vessels (decreased systemic vascular resistanc e) Decreased blood pressure Afterload reduction

VARIOUS ANTIHYPERTENSIVE DRUGS FOR PARENTERAL USE IN THE MANAGEMENT OF MALIGNANT HYPERTENSION AND OTHER HYPERTENSIVE CRISES Drug Advantages Disadvantages Instantaneous Immediate Mechanism of action Onset of action Peak effect Method of Duration of action adm inistration Side effects Comments Sodium Direct arteriolar nitroprusside vasodilation and venodilation Diazoxide Direct arteriolar vasodilation 12 min 1015 min Trimethaphan camsylate Minutes Ganglionic blockage with venodilation and arteriolar vasodilation Minutes Discontinue if 23 min after infusion Continuous infusion: Precise titration of Mo nitoring in ICU Nausea, vomiting, required apprehension. stopped Initial, 0.5 g/k g/min BP. Consistently thiocyanate level Thiocyanate toxic- >10 mg/dL Average, 3 g/kg/min effective when ity with prolonged Maximum, 10 g/kg/min other drugs fail. infusion, renal Parenteral agent insufficiency of choice for hypertensive crise s Sustained Nausea, vomiting, Contraindicated in 424 h IV minibolus: 50100 mg Long duration of hypotension with hyperglycemia, IV given rapidly over action. Const ant aortic dissection, CNS and myocarmyocardial 510 min. Total dose, monitoring n ot cerebrovascular ischemia, uterine 150600 mg required after ini- dial ischemic can disease, myocardial occur. Reflex sym- atony tial titration ischemia patheti c cardiac stimulation Dry mouth, blurred Tilt-bed enhances 510 min after infuCont inuous infusion: Blocks barorecep- Parasympathetic blockade vision, urinary sion stopped Initial, 0.5 mg/min tor-mediated effect; tachyphylaxis retention, paral yt- after 2448 h; Maximum, 5.0 mg/min sympathetic ic ileus, respiratocardiac stim ulation contraindicated ry arrest in respiratory FIGURE 8-34 Sodium nitroprusside remains the treatment of choice in virtually al l hypertensive crises requiring rapid blood pressure control with Minutes 15 min after infusion Continuous infusion: stopped Initially, 5 g/min Incr ease by 5 g/min over 35 min 1618 h Minutes insufficiency and glaucoma; potentiates succinylcholine Dilates intracoronary co llaterals Nitroglycerin Labetalol Direct venodilation at low doses; combined venodilation and arteriolar dilation at higher doses Selective 1- and noncardioselective -blocker; arteriolar and ven ous dilation Minutes 550 min Fails to control BP Headache, nausea, Theoretic advanin some patients vomiting, tages over nitropalpitations, prusside in setting abdominal pain of myocardial i schemia -blockage can Nausea, vomiting, IV minibolus: Initial, 20 Continuous wor sen congestive paresthesias, mg over 2 min Then monitoring not heart failure, he

adache, 4080 mg over 10 min. required bronchospasm, bradycardia Maximum, 300 mg h eart block Useful in catecholaminerelated crises Short duration of action Phentolamine 1530 min Nonselective -blocker 23 min 5 min IV bolus: 15 mg over 5 min Contraindicated in pheochromocytoma, heart failure, asthma, heart block >1 degre e, after coronary artery bypass graft surgery Nitroprusside equally efficacious in catecholaminerelated crises Hydralazine 39 h Direct arteriolar vasodilation 1030 min 3060 min Tachycardia, arrhythmias, nausea, vomiting, diarrhea, exacerbation of peptic ulc er disease Headache, angina Contraindicated in aortic dissection, atherosclerotic coronary vascular disease Contraindicated in hypertensive encephalopathy, CNS catastrophe Hypertensive Crises Methyldopa 46 h 46 h Delayed onset IV bolus: 510 mg over Proven efficacy of action, 2030 min or continu and safety in ous infusion 400 g/mL hypertensive crises unpredictable hypotensive effect solution Loading dose: of pregnancy 200300 g/min for 3060 min Maintenance i nfusion: 50150 g/min Delayed onset Sedation IV of 250500 mg Nonenot over 68 h recomme nded for of action, unpredictable use in hypertenhypotensive effect sive crises 28 h Intramuscular: Initial, 0.51.0 mg 24 mg over 3 h 24 mg over 312 h parenteral therapy. However, other parenteral antihypertensive agents may be use ful in certain circumstances. 24 h Reserpine 24 h Decrease sympathetic nervous system activity via CNS 2 stimulation, decrease systemic vascular resistance 24 h Sympathetic dysfunction owing to central and p eripheral catecholamine dysfunction; decreased SVR, decreased CO Delayed onset Nasal congestion, Nonenot CNS sedation, recommended for of action, unpredictable bradycardia, use in hypertenhypotensive effect exacerbates pepsive crises tic ulcer disease, depression

Contraindicated in hypertensive encephalopathy, CNS catastrophe, cumulative hypo tensive response 8.27 BPblood pressure; CNScentral nervous system; COcardiac output; ICUintensive care uni t; IVintravenous; SVRsystemic vascular resistance.

8.28 Hypertension and the Kidney blood pressure required to reach the autoregulatory limit. Thus, a reduction in MAP of approximately 20% to 25% was required in each group to reach the threshol d. This result indicates that a considerable safety margin exists for blood pres sure reduction before cerebral autoregulation of blood flow fails, even in patie nts with severe untreated hypertension. Moreover, symptoms of cerebral ischemia did not develop until the blood pressure was reduced substantially below the aut oregulatory threshold because even in the face of reduced blood flow, cerebral m etabolism can be maintained and ischemia prevented by an increase in oxygen extr action by the tissues. The lowest tolerated MAP, defined as the level at which m ild symptoms of brain hypoperfusion developed (ie, yawning, nausea, and hyperven tilation), was 65 10 mm Hg in patients with uncontrolled hypertension, 53 18 mm Hg in persons with treated hypertension, and 43 8 mm Hg in normotensive persons. Th e numbers on the bars illustrate that these MAP values were approximately 45% of the baseline blood pressure level in each group. Thus, symptoms of cerebral hyp operfusion did not occur until the MAP was reduced by an average of 55% from the presenting level. In the reported cases of neurologic sequelae sustained during rapid reduction of blood pressure in patients with hypertensive crises, the MAP was reduced by more than 55% of the presenting blood pressure. This frank hypot ension was sustained for a period of hours to days, mostly as a result of treatm ent with bolus diazoxide, which has long duration of action [54]. The general gu ideline for acute blood pressure reduction in the treatment of hypertensive cris es is reduction of systolic blood pressure to 160 to 170 mm Hg and diastolic pre ssure to 100 to 110 mm Hg, which equates to MAPs of 120 to 130 mm Hg. Alternativ ely, the initial goal of antihypertensive therapy can be a 20% reduction of the MAP from the patient's initial level at presentation. This level should be above t he predicted autoregulatory threshold. Once this goal is obtained the patient sh ould be evaluated carefully for evidence of cerebral hypoperfusion. Further redu ction of blood pressure can then be undertaken in a controlled fashion based on the overall clinical status of the patient. Of course, in previously normotensiv e persons in whom hypertensive crises develop, such as patients with acute glome rulonephritis complicated by hypertensive encephalopathy, the autoregulatory cur ve should not yet be shifted. Therefore, the initial goal of therapy should be n ormalization of blood pressure. In terms of avoiding sustained overshoot hypoten sion in the treatment of hypertensive crises, the use of potent parenteral agent s with short duration of action, such as sodium nitroprusside or intravenous nit roglycerin, has obvious advantages. If neurologic sequelae develop during blood pressure reduction with these agents, these sequelae can be reversed quickly by tapering the infusion and allowing the blood pressure to stabilize at a higher l evel. Agents with a long duration of action have an inherent disadvantage in tha t excessive reduction of blood pressure cannot be reversed easily. Thus, bolus d iazoxide, labetalol, minoxidil, hydralazine, converting enzyme inhibitors, calci um channel blockers, and central 2-agonists should be used with extreme caution in patients requiring rapid but controlled blood pressure reduction in the setti ng of hypertensive crises. (Adapted from Strandgaard [53]; with permission.) 200 Mean arterial pressure, mm Hg Uncontrolled hypertensives (n=13) Controlled hypertensives (n=9) Normotensives ( n=10) 150 100 79 72 74 10% 29% 12% 50

45 6% 0 Baseline mean arterial pressure Lower limit of autoregulation 46 45 16% 12% Lowest tolerated mean arterial pressure FIGURE 8-35 Risks of rapid blood pressure reduction in hypertensive crises. It h as been argued over the years that rapid reduction of blood pressure in the sett ing of hypertensive crises may have a detrimental effect on cerebral perfusion b ecause the autoregulatory curve of cerebral blood flow is shifted upward in pati ents with chronic hypertension. Conversely, this upward shift protects the brain from hypertensive encephalopathy in the face of severe hypertension. However, t his autoregulatory shift could be deleterious when the blood pressure is reduced acutely because the lower limit of autoregulation is shifted to a higher level of blood pressure. Theoretically, aggressive reduction of the blood pressure in chronically hypertensive patients could induce cerebral ischemia. Nonetheless, i n clinical practice, moderately controlled reduction of blood pressure in patien ts with hypertensive crises rarely causes cerebral ischemia. This clinical obser vation may be explained by the fact that even though the cerebral autoregulatory curve is shifted in patients with chronic hypertension, a considerable differen ce still exists between the initial blood pressure at presentation and the lower limit of autoregulation. Illustrated are the differences in the lower autoregul atory threshold during blood pressure reduction with trimethaphan in patients wi th uncontrolled hypertension and treated hypertension, and those in the control group [53]. At least eight of the 13 patients with uncontrolled hypertension had hypertensive neuroretinopathy consistent with malignant hypertension. The contr ol groups included nine patients with a history of severe hypertension in the pa st whose blood pressure was effectively controlled at the time of study and a gr oup of 10 normotensive persons. Baseline mean arterial pressures (MAPs) in the t hree groups were 145 17 mm Hg, 116 18 mm Hg, and 96 17 mm Hg, respectively. The low er limit of blood pressure at which autoregulation failed was 113 17 mm Hg in per sons with uncontrolled hypertension, 96 17mm Hg in persons with treated hypertens ion, and 73 9 mm Hg in normotensive persons. Although the absolute level at which autoregulation failed was substantially higher in patients with uncontrolled hy pertension, the percentage reduction in blood pressure from the baseline level r equired to reach the autoregulatory threshold was similar in each group. The num bers on the bars indicate the percentage reduction from the baseline

Hypertensive Crises 8.29 Severe uncomplicated hypertension Severe hypertension (diastolic blood pressure > 115 mm Hg) Hypertensive neuroretinopathy present (striate hemorrhages, cotton-wool spots wi th or without papilledema) Treat malignant hypertension (Fig. 8-20) Hypertensive neuroretinopathy absent No acute end-organ dysfunction Acute end-organ dysfunction Treat as hypertensive crisis (see preceding figures) Severe uncomplicated hypertension Step 1 Patient education regarding the chronic nature of hypertension and importance of long-term compliance and blood pressur e control to prevent complications Step 2 Evaluate reason for inadequate blood p ressure control and adjust maintenance antihypertensive drug regimen Step 3 Arrange outpatient follow-up to document adequate blood pressure control over the ensuing days to weeks and change drug treatment regimen as required Noncompliant Compliant with current blood pressure regimen "Ran out" of medications Drug side effects Switch to drug of another class Cannot afford drugs Switch to generic thiazide diuretic Add low-dose thiazide diuretic to existing monotherapy with CCB, CEI, b
locker, a2gonist Restrt FIGURE 8-36 Severe uncomplicated hypertension. The benefits of acute reduction i n blood pressure in the setting of true hypertensive crises are obvious. Fortuna tely, true hypertensive crises are relatively rare events that almost never affe ct hypertensive patients. Another type of presentation that is much more common than are true hypertensive crises is that of the patient who initially exhibits severe hypertension (diastolic blood pressure >115 mm Hg) in the absence of hype rtensive neuroretinopathy or acute end-organ damage that would signify a true cr isis. This entity, known as severe uncomplicated hypertension, is very commonly seen in the emergency department or other acute-care settings. Of patients with severe uncomplicated hypertension, 60% are entirely asymptomatic and present for prescription refills or routine blood pressure checks, or are found to have ele vated pressure during routine physical examinations. The other 40% of patients i nitially exhibit nonspecific findings such as headache, dizziness, or weakness i n the absence of evidence of acute end-organ dysfunction. In the past, this enti ty was referred to as urgent hypertension, reflecting the erroneous notion that acute reduction of blood pressure, over a few hours before discharge from the ac ute-care facility, was essential to minimize the risk of short-term complication s from severe hypertension. Commonly employed treatment regimens included oral c lonidine loading or sublingual nifedipine. However, in recent years the practice of acute blood pressure reduction in severe uncomplicated hypertension has been questioned [55,56]. In the Veterans Administration Cooperative Study of patient

s with severe hypertension, there were 70 placebo-treated patients who had an av erage diastolic blood pressure of 121 mm Hg at entry. Among these untreated pati ents, 27 experienced morbid events at a mean of 11 8 months of follow-up. Howeve r, the earliest morbid event occurred only after 2 months [57]. These data sugge st that in patients with severe uncomplicated hypertension in which severe hyper tension is not accompanied by evidence of malignant hypertension or acute end-or gan dysfunction, eventual complications from stroke, myocardial infarction, or c ongestive heart failure tend to occur over months to years, rather than hours to days. Alt hough long-term control of blood pressure clearly can prevent these eventual com plications, a hypertensive crisis cannot be diagnosed because no evidence exists that acute reduction of blood pressure results in an improvement in short- or l ong-term prognosis. Acute reduction of blood pressure in patients with severe un complicated hypertension with sublingual nifedipine or oral clonidine loading wa s once the de facto standard of care. This practice, however, often was an emoti onal response on the part of the treating physician to the dramatic elevation of blood pressure or motivated by the fear of medico-legal repercussions in the un likely event of a hypertensive complication occurring within hours to days [55]. Although observing and documenting the dramatic decrease in blood pressure is a satisfying therapeutic maneuver, there is no scientific basis for this approach . At present, no literature exists to support the notion that some goal level of blood pressure reduction must be achieved before the patient with severe uncomp licated hypertension leaves the acute-care setting [58]. In fact, acute reductio n of blood pressure often is counterproductive because it can produce untoward s ide effects that render the patient less likely to comply with long-term drug th erapy. Instead, the therapeutic intervention should focus on tailoring an effect ive welltolerated maintenance antihypertensive regimen with patient education re garding the chronic nature of the disease process and the importance of long-ter m compliance and medical follow-up. If the patient has simply run out of medicin es, reinstitution of the previously effective drug regimen should suffice. If th e patient is thought to be compliant with an existing drug regimen, a sensible c hange in the regimen is appropriate, such as an increase in a suboptimal dosage of an existing drug or the addition of a drug of another class. In this regard, addition of a low dose of a thiazide diuretic as a second-step agent to existing monotherapy with converting enzyme inhibitor (CEI), angiotensin II receptor blo cker, calcium channel blocker (CCB), -blocker, or central 2-agonist often is rem arkably effective. Another essential goal of the acute intervention should be to arrange suitable outpatient follow-up within a few days. Gradual reduction of b lood pressure to normotensive levels over the next few days to a week should be accomplished in conjunction with frequent outpatient visits to modify the drug r egimen and reinforce the importance of lifelong compliance with therapy. Althoug h less dramatic than acute reduction of blood pressure in the acute-care setting , this type of approach to the treatment of chronic hypertension is more likely to prevent long-term hypertensive complications and recurrent episodes of severe uncomplicated hypertension.

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nt: A Problem-Oriented Approach to Management. Edited by Goldman DR, Brown FH, L evy KW et al. Philadelphia: Lippincott; 1982:7886. 35. Estafanous RG, Tarazi RC: Systemic arterial hypertension associated with cardiac surgery. Am J Cardiol 198 0, 46:685. 36. Fouad FM, et al.: Hemodynamics of postmyocardial revascularizatio n hypertension. Am J Cardiol 1978, 41:564. 37. Cohn JN: Paroxysmal hypertension and hypovolemia. N Engl J Med 1966, 275:643. 38. Skydell JL, et al.: Incidence a nd mechanism of post-carotid endarterectomy hypertension. Arch Surg 1987, 122:11 53. 39. Towne JB, Bernhard VM: The relationship of postoperative hypertension to complications after carotid endarterectomy. Surgery 1980, 88:575. 40. Wallace J D, et al.: Blood pressure after stroke. JAMA 1981, 246:2177. 41. Britton M, et a l.: Hazards of therapy for excessive hypertension in acute stroke. Acta Med Scan d 1980, 207:253. 42. Lavin P: Management of hypertension in patients with acute stroke. Arch Intern Med 1986, 146:66. 43. Meyer JS, et al.: Impaired neurogenic cerebrovascular control and dysautoregulation after stroke. Stroke 1973, 4:169. 44. Cuneo RA, et al.: The neurologic complications of hypertension. Med Clin Nor th Am 1977, 61:565. 45. Kaneko T, et al.: Lower limit of blood pressure in treat ment of acute hypertensive intracranial hemorrhage. J Cerebral Blood Flow Metab 1983, 3(suppl 1):S51. 46. Shapiro B, Rig LM: Management of pheochromocytoma. End ocrinol Metab Clin North Am 1989, 18:443. 47. Pinaud M, et al.: Preoperative acu te volume loading in patients with pheochromocytoma. Care Med 1985, 13:460. 48. Glazener RS, et al.: Pargyline, cheese, and acute hypertension. JAMA 1964, 188:7 54. 49. Blackwell B, et al.: Hypertensive interactions between monoamine oxidase inhibitors and foodstuffs. Br J Psychiatry 1967, 113:349. 50. Palmer RF, Lasset er KC: Sodium nitroprusside. N Engl J Med 1975, 292:294. 51. Gruetter CA, et al. : Relationship between cyclic guanosine 3':5' monophosphate formation and relaxation of coronary arterial smooth muscle by glyceryl trinitrate, nitroprusside, nitri te and nitric oxide. J Pharmacol Exp Ther 1981, 219:181. 52. Ignarro IJ, et al.: Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, n itroprusside, and nitric oxide. J Pharmacol Exp Ther 1981, 218:739. 53. Strandga ard S: Autoregulation of cerebral blood flow in hypertensive patients. Circulati on 1976, 53:720. 54. Franklin SS: Hypertensive emergencies: the case for more ra pid lowering of blood pressure. In Controversies in Nephrology and Hypertension. Edited by Narins RG. New York: Grune & Stratton; 1973:191197. 55. Fagan TC: Acut e reduction of blood pressure in asymptomatic patients with severe hypertension. An idea whose time has comeand gone. Arch Intern Med 1989, 149:2169. 56. Ferguso n RK, Vlasses PH: Hypertensive emergencies and urgencies. JAMA 1986, 255:1607. 5 7. Veterans Administration Cooperative Study Group on Antihypertensive Agents. E ffects of treatment on morbidity in hypertension. Result in patients with diasto lic blood pressure averaging 115 through 129 mm Hg. JAMA 1967, 202:1028. 58. Zel ler KR, et al.: Rapid reduction of severe asymptomatic hypertension. Arch Intern Med 1989, 149:2186.

Diabetic Nephropathy: Impact of Comorbidity Eli A. Friedman T hroughout the industrialized world, diabetes mellitus is the leading cause of en d-stage renal disease (ESRD), surpassing glomerulonephritis and hypertension. Bo th the incidence and the prevalence of ESRD caused by diabetes have risen each y ear over the past decade, according to reports from European, Japanese, and Nort h American registries of patients with renal failure. Illustrating the dominance of diabetes in ESRD is the 1997 report of the United States Renal Data System ( USRDS), which noted that of 257,266 patients receiving either dialytic therapy o r a kidney transplant in 1995 in the United States, 80,667 had diabetes [1], a p revalence rate of 31.4%. Also, during 1995 (the most recent year for which summa tive data are available), of 71,875 new (incident) cases of ESRD, 28,740 (40%) p atients were listed as having diabetes. In America, Europe, and Japan, the form of diabetes is predominantly type II; fewer than 8% of diabetic Americans are in sulinopenic, C-peptide-negative persons with type I disease. It follows that ESR D in diabetic persons reflects the demographics of diabetes per se [2]: 1) The i ncidence is higher in women [3], blacks [4], Hispanics [5], and native Americans [6]. 2) The peak incidence of ESRD occurs from the fifth to the seventh decade. Consistent with these attack rates is the fact that blacks older than the age o f 65 face a seven times greater risk of diabetes-related renal failure than do w hites. Within our Brooklyn and New York state hospital ambulatory hemodialysis u nits in October 1997, 97% of patients had type II diabetes. Despite widespread t hinking to the contrary, vasculopathic complications of diabetes, including hype rtension, are at least as severe in type II as in type I diabetes [7,8]. When ca refully followed over a decade or longer, cohorts of type I and type II diabetic individuals have equivalent rates of proteinuria, azotemia, and ultimately ESRD . Both types of diabetes show strong similarities in their rate of renal functio nal deterioration [9] and onset of comorbid complications. Initial nephromegaly as well as both glomerular hyperfiltration and microalbuminuria (previously thou ght to be limited to type I) is now recognized as equally in type II [10]. CHAPTER 1

1.2 Systemic Diseases and the Kidney Overview and Prevalence DIABETIC NEPHROPATHY Epidemiology IDDM vs. NIDDM Natural history Intervention measures ESRD options P romising strategies FIGURE 1-1 Diabetic neuropathy topics. People with diabetes and progressive kidn ey disease are more difficult to manage than age- and gender-matched nondiabetic persons because of extensive, often life-threatening extrarenal (comorbid) dise ase. Diabetic patients manifesting end-stage renal disease (ESRD) suffer a highe r death rate than do nondiabetic patients with ESRD owing to greater incidence r ates for cardiac decompensation, stroke, sepsis, and pulmonary disease. Concurre nt extrarenal diseaseespecially blindness, limb amputations, and cardiac diseaseli mits and may preempt their rehabilitation. For most diabetic patients with ESRD, the difference between rehabilitation and heartbreaking invalidism hinges on at taining a renal transplant as well as comprehensive attention to comorbid condit ions. Gradually, over a quarter century, understanding of the impact of diabetes on the kidney has followed elucidation of the epidemiology, clinical course, an d options in therapy available for diabetic individuals who progress to ESRD. Fo r each of the discussion points listed, improvement in patient outcome has been contingent on a simple counting (point prevalence) of the number of individuals under consideration. For example, previously the large number of diabetic patien ts with ESRD were excluded from therapy owing to the belief that no benefit woul d result. A reexamination of exactly why dialytic therapy or kidney transplantat ion failed in diabetes, however, was stimulated. IDDMinsulin dependent diabetes m ellitus; NIDDMnoninsulin-dependent diabetes mellitus. FIGURE 1-2 Maintenance hemod ialysis. In the United States, the large majority (more than 80%) of diabetic pe rsons who develop end-stage renal disease (ESRD) will be treated with maintenanc e hemodialysis. Approximately 12% of diabetic persons with ESRD will be treated with peritoneal dialysis, while the remaining 8% will receive a kidney transplan t. A typical hemodialysis regimen requires three weekly treatments lasting 4 to 5 hours each, during which extracorporeal blood flow must be maintained at 300 t o 500 mL/min. Motivated patients trained to perform self-hemodialysis at home ga in the longest survival and best rehabilitation afforded by any dialytic therapy for diabetic ESRD. When given hemodialysis at a facility, however, diabetic pat ients fare less well, receiving significantly less dialysis than nondiabetic pat ients, owing in part to hypotension and reduced blood flow [11]. Maintenance hem odialysis does not restore vigor to diabetic patients, as documented by Lowder a nd colleagues [12]. In 1986, they reported that of 232 diabetics on maintenance hemodialysis, only seven were employed, while 64.9% were unable to conduct routi ne daily activities without assistance [12]. Approximately 50% of diabetic patie nts begun on maintenance hemodialysis die within 2 years of their first dialysis session. Diabetic hemodialysis patients sustained more total, cardiac, septic, and cerebrovascular deaths than did nondiabetic patients. When initially applied to diabetic patients with ESRD in the 1970s, maintenance hemodialysis was assoc iated with a first-year mortality in excess of 75%, with inexorable loss of visi on in survivors. Until the at-first-unappreciated major contribution of type II diabetes to ESRD became evident, kidney failure was incorrectly viewed as predom inantly limited to the last stages of type I (juvenile, insulin-dependent) diabe tes. Illustrated here is a blind 30-year-old man undergoing maintenance hemodial ysis after experiencing 20 years of type I diabetes. A diabetic renal-retinal sy ndrome of blindness and renal failure was thought to be inevitable until the sal utary effect of reducing hypertensive blood pressure became evident. Without que stion, reduction of hypertensive blood pressure levels was the key step that per mitted improvement in survival and reduction in morbidity.

Diabetic Nephropathy: Impact of Cormorbidity 1.3 28,740 Diabetes 40% 43,135 All other 60% FIGURE 1-3 Statistical increase in diabetes. In the past 20 years, since the dia betic patient with endstage renal disease (ESRD) is no longer excluded from dial ytic therapy or kidney transplantation, there has been a steady increase in the proportion of all patients with ESRD who have diabetes. In the United States, ac cording to the 1997 report of the United States Renal Data System (USRDS) for th e year 1995, more than 40% of all newly treated (incident) patients with ESRD ha ve diabetes. For perspective, the USRDS does not list the actual incidence of a renal disease but rather tabulates those individuals who have been enrolled in f ederally reimbursed renal programs. The distinction may be important in that a r elaxation in policy for referral of diabetic kidney patients would be indistingu ishable from a true increase in incidence. 25 Prevalence of diabetes, % 20 15 10 5 0 4 9 Country of origin United States 23 18 15 10 7 8 15 16 19 PERCENTAGE OF PATIENTS WITH END-STAGE RENAL DISEASE WITH TYPE II DIABETES Country Japan Germany United States Pima Indians 18 14 Percentage 99 90 95 5 Black Mexican Puerto Rican Japanese Filipinos Chinese Koreans FIGURE 1-4 Prevalence of diabetes mellitus in minority populations. Attack rates (incidence) for diabetes are higher in nonwhite populations than in whites. Typ e II diabetes accounts for more than 90% of all patients with end-stage renal di sease (ESRD) with diabetes. As studied by Carter and colleagues [13], the effect of improved nutrition on expression of diabetes is remarkable. The American die t not only induces an increase in body mass but also may more than double the ex pressed rate of diabetes, especially in Asians. (From Carter and coworkers [13]; with permission.) FIGURE 1-5 Percent of diabetic ESRD. Noted first in United States inner-city dia lysis programs, type II diabetes is the predominant variety noted in those indiv iduals undergoing maintenance hemodialysis. Our recent survey of hemodialysis un its in Brooklyn, New York, found that 97% of the mainly African-American patient s had type II diabetes. Thus, there has been a reversal of the previously held i mpression that uremia was primarily a late manifestation of type I diabetes. (Fr

om Ritz and Stefanski [14] and Nelson and coworkers [15]; with permission.) Infrequent feeding Overfeeding Insulin resistance Obesity Fat in muscle NIDDM FIGURE 1-6 Thrifty gene. In addition to the artificial increase in incident pati ents with end-stage renal disease (ESRD) and diabetes that followed relaxation o f acceptance criteria, industrialized nations have experienced a real increase i n type II diabetes that correlates with an increase in body mass attributed to o verfeeding. Formerly termed noninsulin-dependent diabetes mellitus (NIDDM) or maturity-onset diabetes, the variety of diabetes observed in industrialized overfed populations is now c lassified as type II disease. According to the Thrifty Gene hypothesis, the abil ity to survive extended fasts in prehistoric populations that hunted to survive selected genes that in time of excess caloric intake are expressed as hyperglyce mia, insulin resistance, and hyperlipidemia (type II diabetes). A study by Ravus sin and colleagues of American and Mexican Pima Indian tribes illustrates the ef fect of overfeeding on a genetic predisposition to type II diabetes. Separated a bout 200 years ago, Indians with the same genetic makeup began living in differe nt areas with different lifestyles and diets. In the Arizona branch of the Pimas , who were fed surplus food and restrained to a reservation that restricted hunt ing and other activities, the prevalence of type II diabetes progressively incre ased to 37% in women and 54% in men. In contrast, Pimas living in Mexico with sh orter stature, lower body mass, and lower cholesterol had a lower prevalence of type II diabetes (11% in women and 6% in men). (From Shafrir [16] and Schalin-Ja ntti [17]; with permission.)

1.4 Systemic Diseases and the Kidney Type I and Type II Classified IGT Type II Type I Proportion on insulin, % C-PEPTIDE CRITERIA 70 60 50 40 30 20 10 0 05 510 1015 Years of NIDDM 13 33 60 Insulin requiring Type II decreased insulin secretion/sensitvity Type I b
cell des truction Type I (90% concordence between clinical criteria and C-peptide testing) Basal C -peptide <0.17 pmol/mL Increment above basal at 6 min <0.07 pmol/mL FIGURE 1-7 Type I and type II compared. Differentiating type I from type II diab etes may be difficult, especially in young nonobese adults with minimal insulin secretion. Furthermore, with increasing duration of type II diabetes, beta cells may decrease their insulin secretion, sometimes to the range diagnostic of type I diabetes. Shown here is a modification of the schema devised by Kuzuya and Ma tsuda [18] that suggests a continuum of diabetes classification based on amount of insulin secreted. Lacking in this construction is the realization of the gene tic determination of type I diabetes (all?) and the clear hereditary predisposit ion (despite inconstant genetic analyses) of many individuals with type II diabe tes. At present, classification of diabetes is pragmatic and will likely change with larger-population screening studies. IGTimpaired glucose tolerance. (From Ku zuya and Matsuda [18]; with permission.) FIGURE 1-8 Increasing insulin treatment in noninsulindependent diabetes mellitus (NIDDM). A decision to treat diabetes with insulin does not necessarily equate w ith establishing a diagnosis of type I diabetes. Terms such as insulin-requiring d o not help because the need for insulin is physician-determined and will vary fr om clinician to clinician. After 10 to 15 years of metabolic regulation of type II diabetes, treatment with insulin has been initiated in more than half of indi viduals with this disorder. Even in patients with type II diabetes treated with insulin, measured secretion of insulin may fall in the normal range. (From Claus on and coworkers [19]; with permission.) FIGURE 1-9 C-peptide criteria. Multiple strategies have been proposed to disting uish type I from type II diabetes. Each has limitations. Service and colleagues [20] employed baseline and stimulated C-peptide levels to differentiate between the two. They found satisfactory differentiation of type I from type II diabetes with minimal overlap using the screening levels shown. (From Service and cowork ers [20]; with permission.) TERMINOLOGY IN DIABETIC NEPHROPATHY Hyperfiltration A supernormal glomerular filtration rate associated with hypergl ycemia during the early years of diabetes Microalbuminuria Urinary albumin excre tion of 30 to 300 mg/day or 20 to 200 g/mina predictor of nephropathy Mesangial e xpansion An increase in mesangial matrix often but not always associated with ba sement membrane thickening FIGURE 1-10 Terminology. Clarification of the course of both types of diabetes w as made possible by recognizing two functional perturbations: microalbuminuria a nd glomerular hyperfiltration. Additionally, early glomerular mesangial expansio n was noted to be a constant finding in diabetic nephropathy.

Diabetic Nephropathy: Impact of Cormorbidity 1.5 Clinical Features of Diabetic Kidney FIGURE 1-11 Diabetic kidney characteristics. The diabetic kidney is about 140% g reater in length, width, and weight. Morphologic findings on histologic examinat ion of the kidney in diabetes include increased size of glomeruli and tubules. P hysiologic assessment of renal function is supernormal in diabetes, as shown by increases of about 150% in renal plasma flow and glomerular filtration rate in i nitial phases of diabetic nephropathy. In the induced-diabetic rat and in limite d observations of type I diabetes, establishing euglycemia will return enlarged kidneys and abnormal renal function test results to normal, suggesting that hype rglycemia is the cause of nephromegaly. A B FIGURE 1-12 Mesangial expansion. Expansion of the mesangium is depicted in light and electron microscopic views of a kidney biopsy specimen from a patient with type I diabetes with a urinary albumin concentration of 500 mg/dL. A, Electron m icroscopic view of a greatly expanded mesangium in a glomerulus is shown. B, Les s advanced changes are seen on a silver stain. C, Progression to nodular interca pillary glomerulosclerosis is shown. C

1.6 Systemic Diseases and the Kidney A B C FIGURE 1-13 Glomerular basement membrane thickening. B and D, Glomerular basemen t membrane thickening is a constant abnormality in diabetic nephropathy, as seen in these photomicrographs from a biopsy specimen in type I diabetes. Note the l oss of epithelial foot processes in D panel B. In panel D, a mesangial nodule (MN) is present. A and C, Electron photo micrographs from a normal kidney. BMbasement membrane; Ccapillary; Eepithelial cell ; MNmesangial nodule; Mmesangial cell. FIGURE 1-14 Diabetic nephropathy is a microvasculopathy. Microaneurysms are visi ble in the retina and occasionally in glomerular capillaries. A microaneurysm in a biopsy specimen from a 42-year-old woman with type I diabetes is shown. FIGURE 1-15 Key pathologic findings. Nondiabetic renal disorders (eg, amyloidosi s, cryoglobulinemia, nephrosclerosis) may simulate the nodular and diffuse inter capillary glomerulosclerosis of diabetes (both type I and type II). When associa ted with afferent and efferent arteriolosclerosis, nodular and diffuse intercapi llary glomerulosclerosis is pathognomonic for diabetic nephropathy. Aafferent art ery arteriosclerosis; Ddiffuse intercapillary glomerulosclerosis; Eefferent artery arteriosclerosis; Nnodular intercapillary glomerulosclerosis.

Diabetic Nephropathy: Impact of Cormorbidity 1.7 FIGURE 1-16 Diabetic nodules. Diabetic nodules are characterized by clear center s with cells along the periphery of the nodule, as shown here in a kidney biopsy specimen from a 44-year-old man with type II diabetes (hematoxylin and eosin st ain). FIGURE 1-17 Nodular size variability. Great variability in nodular size in diabe tic nodular glomerulosclerosis is usual, as illustrated in this totally oblitera ted glomerulus obtained by biopsy from a 65-year-old woman with type II diabetes (periodic acidSchiff stain). >4 4.0 3.5 Urinary albumin, g/d 3.0 2.5 2.0 1.5 1.0 0.5 0 0 3 6 9 12 15 18 Hyper glycemia, y 21 24 27 Clinical nephropathy A B Typically, proteinuria increases to the nephrotic range, leading to edema of the extremities and subsequent anasarca, which are often the presenting complaints in diabetic nephropathy. FIGURE 1-18 A and B, Progression of nephropathy. Microalbuminuria, the excretion of minute quantities of albumin in the urine (more than 20 mg/day), is a marker of subsequent renal deterioration in diabetic nephropathy.

1.8 Systemic Diseases and the Kidney 180 160 140 120 GFR, mL/min 100 80 60 40 20 0 0 3 6 9 12 15 18 21 24 27 Hypergly cemia, y 10 Clinical nephropathy Type 2 diabetes Type 1 diabetes (13) (12) Cumulative incidence chronic renal failure, % (69) 5 (205) (447) (1,832) (1,377) (112) (812) (75) (49) (30) 0 (136) 0 5 10 15 20 25 30 35 Years from diagnosis of diabetes FIGURE 1-19 Hyperfiltration. Almost immediately after the onset of hyperglycemia (signaling the onset of diabetes), glomerular filtration rate (GFR) increases t o the limit of renal reserve function (hyperfiltration). Over subsequent years o f hyperglycemia, a steady decline in glomerular filtration rate ensues in the 20 % to 40% of diabetic individuals destined to manifest diabetic nephropathy. Ther e is great variability in the rate of decline of GFR, from as rapid as 20 mL/min /year to 1 to 2 mL/min/year (usually seen in aging). Projection of future loss o f GFR on the basis of the slope of the curve of prior decline in function contai ns errors as high as 37%. The importance of an inconstant and thus unpredictable decline in GFR lies in interpretation of interventive studies designed to prote ct kidney function. Careful attention to both selection of sufficient untreated controls and a run-in period is vital. FIGURE 1-20 Renal failure cumulative incidence. Before careful studies of the na

tural history of type II diabetes were reported, it was not appreciated that dia betic nephropathy was a real endpoint risk. Older diabetic individuals with a tou ch of sugar are now known to be subject to the same microvascular and macrovascul ar complications that afflict individuals with type I disease. Population studie s indicate that the rate of loss of glomerular filtration is superimposable in t ype I and type II diabetes. Humphrey and colleagues [21] documented the developm ent of end-stage renal disease in diabetic subjects in Rochester, Minnesota. The y showed that chronic renal failure was as likely to develop at a superimposable rate in both diabetic subsets. Numbers in parentheses indicate number of patien ts for each line. (From Humphrey and coworkers [21]; with permission.) 130 120 110 100 90 80 70 60 50 40 30 20 10 0 1 2 Type I diabetic patients 130 120 110 100 90 80 70 60 50 40 30 20 10 0 1 2 Creatinine clearance, mL/min Creatinine clearance, mL/min Type II diabetic patients 3 4 A 5 6 Time, y 7 8 9 10 11 3 4 B 5 6 Time, y 7 8 9 10 11 FIGURE 1-21 Creatinine clearance. Further evidence of the similarity in course o

f diabetic nephropathy in type I (A) and type II (B) diabetes was presented in R itz and Stefansky's study [22] of equivalent deterioration in creatinine clearance over the course of a decade in subjects with either type of diabetes in Heidelberg, Germany. (From Ritz and Stefanski [22]; with permiss ion.)

Diabetic Nephropathy: Impact of Cormorbidity 1.9 14 >4 4.0 3.5 GFR, mL/min 3.0 2.5 2.0 1.5 1.0 0.5 0 0 3 6 9 Microalbuminuria Clinical nephropathy Clinical nephropathy Hyperfiltration >4 Serum creatinine, mg/dL 4.0 3.5 Urinary albumin, g/d 3.0 2.5 2.0 1.5 1.0 0.5 0 21 24 27 12 15 18 Hyperglycemia, y 12 10 8 6 4 2 0 0 15 30 45 60 75 90 105 120 135 150 165 Creatinine clearance, mL /min Window for conservative management FIGURE 1-22 Diabetic nephropathy in types I and II. Whereas microalbuminuria and glomerular hyperfiltration are subtle pathophysiologic manifestations of early diabetic nephropathy, transformation to overt clinical diabetic nephropathy take s place over months to many years. In this figure, the curve for loss of glomeru lar filtration rate is plotted together with the curve for transition from micro albuminuria to gross proteinuria, affording a perspective of the course of diabe tic nephropathy in both types of diabetes. While not all microalbuminuric indivi duals progress to proteinuria and azotemia, the majority are at risk for end-sta ge renal disease due to diabetic nephropathy. GFRglomerular filtration rate. FIGURE 1-23 Clinical recognition of diabetic nephropathy. The timing of renoprot ective therapy in diabetes is a subject of current inquiry. Certainly, hypertens ion, poor metabolic regulation, and hyperlipidemia should be addressed in every diabetic individual at discovery. Discovery of microalbuminuria is by consensus reason to start treatment with an angiotensin-converting enzyme inhibitor in eit her type of diabetes, regardless of blood pressure elevation. As is true for oth er kidney disorders, however, nearly the entire course of renal injury in diabet es is clinically silent. Medical intervention during this silent phase, however (c omprising blood pressure regulation, metabolic control, dietary protein restrict ion, and administration of angiotensin-converting enzyme inhibitors), is renopro tective, as judged by slowed loss of glomerular filtration. FIGURE 1-24 Renoprot ection with enzyme inhibitors. Streptozotocin-induced diabetic rats manifest slo wer progression to proteinuria and azotemia when treated with angiotensin-conver ting enzyme inhibitors than with other antihypertensive drugs. The consensus sup ports the view that angiotensin-converting enzyme inhibitors afford a greater le vel of renoprotection in diabetes than do other classes of antihypertensive drug s. Large long-term direct comparisons of antihypertensive drug regimens in type II diabetes are now in progress. In the study shown here by Lewis and colleagues [23], treatment with captopril delayed the doubling of serum creatinine concent ration in proteinuric type I diabetic patients. Trials of different angiotensinconverting enzyme inhibitors in both types of diabetes confirm their effectivene ss but not their unique renoprotective properties in humans. For patients who ca nnot tolerate angiotensin-converting enzyme inhibitors because of cough, hyperka lemia, azotemia, or other side effects, substitution of an angiotensin-convertin g enzyme receptor blocker (losartan) may be renoprotective, although clinical tr ials of its use in diabetes are uncompleted. (From Lewis and coworkers [23]; wit h permission.) 50 Doubling of base-line creatinine, % 45 40 35 30 25 20 15 10 5 0 0.0 Placebo 2 02 Captopril 207 0.5 184 199 1.0 173 190 1.5 161 180 2.0 2.5 Follow-up, y 142 16 7 99 120 3.0 75 82 3.5 45 50 4.0 22 24 Captopril Placebo P=0.007

1.10 Systemic Diseases and the Kidney FIGURE 1-25 Albumin excretion rate. In the recently completed Italian Euclid mul ticenter study, both microalbuminuric and normalbuminuric type I diabetic patien ts showed benefit from treatment with lisinopril, an angiotensin-converting enzy me inhibitor. Although microalbuminuria, with or without hypertension, is now su fficient reason to start treatment with an angiotensin-converting enzyme inhibit or, the question of whether normalbuminuric, normotensive diabetic individuals s hould be started on drug therapy is unanswered. AERalbumin excretion rate. (From Euclid study [24]; with permission.) 10 8 AER, g/min 6 4 2 0 0 n n Normoalbuminuric Microalbuminuric 70 60 AER, g/min 50 40 30 20 Lisinopril Placebo 10 0 18 25 32 24 32 37 6 12 18 24 0 6 12 Time from randomization, m 193 34 191 45 33 37 29 34 227 202 201 179 213 196 179 170 120 100 Glomerular filtration rate, mL/min/1.73 m2 80 60 40 20 0 0 10 Normal diet FIGURE 1-26 Restricting protein. Dietary protein restriction in limited trials i n small patient cohorts has slowed renal functional decline in type I diabetes. Because long-term compliance is difficult to attain, the place of restricted pro tein intake as a component of management is not defined. A, Normal diet. B, Prot ein-restricted diet. Dashed line indicates trend line slope. (From Zeller and co lleagues [25]; with permission.) 20 30 Time, mo 40 50 A 120 100 Glomerular filtration rate, mL/min/1.73 m2 80 60 40 20 0 0 10 20 Protein-restricted diet 30 Time, mo 40 50

Diabetic Nephropathy: Impact of Cormorbidity 1.11 125 80 100 Rate of change in AER, % /year Rate of change in AER, % /year 0 10 Mean Hb A 1, % 12 14 60 75 40 50 25 20 0 0 6 8 10 Mean Hb A1, % 12 14 A B FIGURE 1-27 Metabolic regulation studies. Multiple studies of the strict metabol ic regulation of type I and type II diabetes all indicate that reduction of hype rglycemic levels to near normal slows the rate of renal functional deterioration . In this study, the albumin excretion rate (AER) another way of expressing album inuriacorrelates directly with hyperglycemia, as indicated by hemoglobin A1 (Hb A1) levels in both type I (A) a nd type II (B) diabetes. As for other studies using different markers, the cours es of both types of diabetes over time were found to be equivalent. (From Gilber t and coworkers [26]; with permission.) FIGURE 1-28 Stages of nephropathy. The i nterrelationships between functional and morphologic markers of the stages of di abetic nephropathy are shown. Additional pathologic studies are needed to time w ith precision exactly when glomerular basement membrane (GBM) thickening and glo merular mesangial expansion take place. ESRDendstage renal disease. Function Hyperfiltration Pathology Mesangial expansion Microalbuminuria GBM thickening Proteinuria Glomerulosclerosis ESRD DIABETIC NEPHROPATHY: COMPLICATIONS Rate of GFR Loss Course of proteinuria Nephropathology Comorbidity Progression t o ESRD

FIGURE 1-29 Type I and II nephropathic equivalence. A summation about the equiva lence of type I and type II diabetes in terms of nephropathy is listed. Both typ es have similar complications. ESRDendstage renal disease; GFRglomerular filtratio n rate. Hyperglycemia Normotension Euglycemia Protein restriction Glomerulosclerosis FIGURE 1-30 Major therapeutic maneuvers to slow loss of glomerular filtration ra te are shown. Recent recognition of the adverse effect of hyperlipidemia is reas on to include dietary and, if necessary, drug treatment for elevated blood lipid levels.

1.12 Systemic Diseases and the Kidney PROGRESSION OF COMORBIDITY IN TYPE II DIABETES* Complication Retinopathy Cardiovascular Cerebrovascular Peripheral vascular COMORBIDITY INDEX Persistent angina or myocardial infarction Other cardiovascular problems Respira tory disease Autonomic neuropathy Musculoskeletal disorders Infections including AIDS Liver and pancreatic disease Hematologic problems Spinal abnormalities Vis ion impairment Limb amputation Mental or emotional illness Score 0 to 3: 0 = abs ent; 1 = mild; 2 = moderate; 3 = severe. Total = Index. HEART DISEASE Hyperlipidemia Hypertension Volume overload ACE inhibitor Erythropoietin Initial, % 50 45 30 15 Subsequent, % 100 90 70 50 *Creatinine clearance declined from 81 mL/min over 74 (40119) mo. Endpoint: dialy sis or death. FIGURE 1-31 Comorbidity in type II. In both type I and type II diabetes, comorbi dity, meaning extrarenal disease, makes every stage of progressive nephropathy m ore difficult to manage. In the long-term observational study in type II diabete s done by Bisenbach and Zazgornik [27], the striking impact of eye, heart, and p eripheral vascular disease was noted in a cohort over 74 months. (From Bisenbach and Zazgornik [27]; with permission.) FIGURE 1-32 Comorbidity index. We devised a Comorbidity Index to facilitate init ial and subsequent evaluations of patients over the course of interventive studi es. Each of 12 areas is rated as having no disease (0) to severe disease (3). Th e total score represents overall illness and can be both reproduced by other obs ervers and followed for years to document improvement or deterioration. FIGURE 1-33 Heart disease. Heart disease is the leading cause of morbidity and d eath in both type I and type II diabetes. Throughout the course of diabetic neph ropathy, periodic screening for cardiac integrity is appropriate. We have elicit ed symptomatic improvement in angina and work tolerance by using erythropoietin to increase anemic hemoglobin levels. ACEangiotensin-converting enzyme. A B FIGURE 1-34 Heart disease and renal transplants. A, Pretransplantation. B, Five years after kidney transplation. Experienced clinicians managing renal failure i n diabetes rapidly reach the conclusion that quality of life following successfu l kidney transplantation is far superior to that attained during any form of dia lytic therapy. In the most favorable series, as illustrated by a singlecenter re trospective review of all kidney transplants performed between 1987 and 1993, th ere is no significant difference in actuarial 5-year patient or kidney graft sur vival between diabetic and nondiabetic recipients overall or when analyzed by do nor source. It is equally encouraging that no difference in mean serum creatinin e levels at 5 years was noted between diabetic and nondiabetic recipients [28].

Remarkably superior survival following kidney transplantation compared with surv ival after peritoneal dialysis and hemodialysis is documented in the 1997 report of the United States Renal Data System (USRDS) [1]. Fewer than five in 10 0 diabetic patients with end-stage renal disease (ESRD) treated with dialysis wi ll survive 10 years, while cadaver donor and living donor kidney allograft recip ients fare far better. Rehabilitation of diabetic patients with ESRD is incompar ably better following renal transplantation compared with dialytic therapy. The enhanced quality of life permitted by a kidney transplant is the reason to prefe r this option for newly evaluated diabetic persons with ESRD who are younger tha n the age of 60. More than half of diabetic recipients of a kidney transplant in most series live at least 3 years: many survivors return to occupational, schoo l, and home responsibilities. Failure to continue monitoring of cardiac integrit y may have disastrous results, as in this relatively young type I diabetic recip ient of a cadaver renal allograft for diabetic nephropathy Although her allograf t maintained good function, coronary artery disease progressed silently until a myocardial infarction occurred We now perform annual cardiac testing in all diab etic patients who have ESRD and are receiving any form of treatment.

Diabetic Nephropathy: Impact of Cormorbidity 1.13 RETINOPATHY Hyperglycemia Hypertension Volume overload Photocoagulation Erythropoietin FIGURE 1-35 Retinopathy. Blindness due to the hemorrhagic and fibrotic changes o f diabetic retinopathy is the most dreaded extrarenal complication feared by dia betic kidney patients. The pathogenesis of proliferative retinopathy reflects re lease by retinal and choroidal cells of growth (angiogenic) factors triggered by hypoxemia, which is caused by diminished blood flow. The interrelationship amon g hyperglycemia, hypertension, hypoxemia, and angiogenic factors is now being de fined. There is reason to hope that specifically designed interdictive measures may halt progression of loss of sight. FIGURE 1-36 Retinopathic changes. Proliferative retinopathy, microcapillary aneu rysms, and dot plus blot hemorrhages are present in this funduscopic photograph taken at the time of initial renal evaluation of a nephrotic 37-year-old woman w ith type I diabetes. After prescription of a diuretic regimen, immediate consult ation with a laser-skilled ophthalmologist was arranged. A FIGURE 1-37 Panretinal photocoagulation (PRP). A, PRP is the therapeutic techniq ue performed for proliferative retinopathy using an argon laser to deliver appro ximately 1500 discrete retinal burns, avoiding the fovea and disk (IA<I). By red ucing the amount of retina to be perfused by 35%, PRP somehow lessens the stimul us to release angiogenic factors, and proliferative retinopathy regresses. B, Di sappearance of hemorrhages and nearly complete regression B of proliferative retinopathy were attained with PRP, as shown in this fundus, ph otographed 6 weeks after the one shown in panel A. Vision stabilized, and sight has been retained through the past 6 years of observation. If applied before ret inal traction and detachment supervene, PRP is effective in preserving sight in more than 90% of diabetic patients undergoing dialytic therapy or kidney transpl antation.

1.14 Systemic Diseases and the Kidney FIGURE 1-38 Amputation. After blindness, no comorbid complication limits rehabil itation in diabetic kidney patients more than lower limb amputation. A combinati on of macrovascular and microvascular disease in the limb, loss of pain percepti on due to sensory nephropathy, and impaired resistance to infection converts any minor insult to the foot into a major threat to the limb and life. Previously r egarded as unavoidable in as many as 30% of patients with end-stage renal diseas e treated with dialysis or kidney transplantation, programs that emphasize proph ylactic foot care as a component of preventive medicine have reduced the inciden ce of limb amputation to about 5% after 3 years. AMPUTATION Inspection Shoes Socks Nails Prompt treatment B FIGURE 1-39 Genesis of foot problems. The genesis of diabetic foot problems incl udes peripheral neuropathy, peripheral vascular disease, impaired vision (nail c utting), edema (heart and kidney), and slow wound healing. A, Note the demarcate d hair line indicative of peripheral vascular insufficiency. B, The foot radiogr aph shows a Charcot's joint. (From Shaw and Boulton [29]; with permission.) A FIGURE 1-40 Charcot's joint. Diabetic neuropathy may involve the proprioceptive ne rves, removing limitation of joint stretching and resulting in bone shifts and j oint destruction, as seen in the Charcot's joint shown here. An insensitive deform ed foot with a compromised blood supply is at risk of ulceration, with slow or a bsent healing after minor trauma. FIGURE 1-41 Ulcers. A collaborating podiatrist stationed within the renal clinic adds a level of protection for diabetic kidney patients. Common lesions, like t his pressure ulcer overlying the head of the first metatarsal, are managed easil y with shoe pads that shift weightbearing. The recent introduction of geneticall y engineered human skin holds promise for closing formerly unhealable diabetic f oot ulcers.

Diabetic Nephropathy: Impact of Cormorbidity 1.15 CLINICAL STRATEGY Main Collaborators Opththalmologist Podiatrist Cardiologist Nutritionist Nurse educator AUTONOMIC NEUROPATHY Cardiovascular (rate, QT, R-R) Orthostatic hypotension Gastroparesis Cystopathy Diarrhea, obstipation GASTROPARESIS IN DIABETIC NEPHROPATHY Prevalent in majority, often silent Correlates with autonomic neuropathy Symptom s not linked to delayed emptying Management includes Prokinetic agents: cisaprid e, erythromycin, metoclopramide, domperidone Serotoninergic (5-HT-3) antagonists Consultants Neurologist Vascular surgeon Endocrinologist Gastroenterologist Urologist FIGURE 1-42 Team management of neuropathy. Proper management of diabetic kidney patients requires a skilled team including collaborating specialists. Depending on the qualifications of the patient's primary physician, other professionals are recruited as needed. A nurse educator can ease the interface between otherwise i ndependent specialists. Without such a team mentality, the diabetic patient is o ften set adrift, forced to cope with conflicting instructions and unneeded repet ition of tests. Especially helpful as renal function declines toward end-stage r enal disease, patient education facilitates the choice of uremia therapy and, if appropriate, interaction with the renal transplant service. FIGURE 1-43 Autonomic neuropathy. Autonomic neuropathy accompanies advanced diab etic nephropathy. While an unvarying R-R interval may have minimal clinical impo rtance, diabetic cystopathy and reduced bowel motility, including gastroparesis, may seriously impede quality of life. Questioning to discern the presence of tr avel-limiting diarrhea, obstipation, and gastroparesis should be included in eac h initial evaluation of a diabetic kidney patient. (From Spallone and Menzinger [30]; with permission.) FIGURE 1-44 Gastroparesis. Incomplete and inconstant gastric emptying due to dia betic autonomic neuropathy (gastroparesis) may preempt good glucose regulation b ecause of an inability to match insulin dosing with food ingestion. The diagnosi s can be established by having the patient ingest a test meal with a radioisotop e tracer. Satisfactory drug treatment for gastroparesis is usually able to minim ize the problem. (From Enck and Frieling [31] and Savkan and coworkers [32]; wit h permission.) NEPHROTIC SYNDROME Precedes renal failure May arrest or revert (15%) Confused with cardiac failure I ntensifies risk to feet Management: ACEi + metolazone + furosemide FIGURE 1-45 Nephrotic syndrome. Proteinuria in diabetic nephropathy typically pr ogresses more than 3.5 g/day (nephrotic range), leading to hypoproteinemia, hype rlipidemia, and extracellular fluid accumulation (nephrotic syndrome). Managemen t of a nephrotic diabetic patient includes minimizing protein loss using an angi otensin-converting enzyme inhibitor (ACEi) and promoting diuresis with a combina tion of loop diuretics (furosemide) and thiazide diuretics (metolazone). Distinc tion between congestive heart failure and nephrotic edema requires assessment of cardiac function. (From Herbert et at. [33] and Gault and Fernandez [34]; with permission.)

ANASARCA Hypoproteinemia (renal loss, liver disease) Glycated albumin (more permeable) He art failure (coronary disease) Management includes Daily weight Metolazone + fur osemide Cardiac compensation FIGURE 1-46 Anasarca. Anasarca is a long-term management problem in diabetic nep hropathy. As renal reserve decreases, the balance between volume overload and ex cessive diuresis may be difficult to maintain. Having the patient measure and re cord weight daily as a guide for each day's dose of diuretics (metolazone plus fur osemide) is a workable strategy. Once the creatinine clearance falls below 10 mL /min, ambulatory dialysis may be the only means of continuing life outside the h ospital.

1.16 Systemic Diseases and the Kidney peritoneal dialysis (CAPD) affords the advantages of freedom from a machine, abi lity to be performed at home, rapid training, minimal cardiovascular stress, and avoidance of heparin [35]. Some enthusiasts believe CAPD to be a first choice tr eatment for diabetic patients with ESRD [36]. Consistent with the author's view, ho wever, is the report of Rubin and colleagues [37]. They found that in a largely black diabetic population, only 34% of patients continued CAPD after 2 years, an d at 3 years, only 18% remained on CAPD. In fairness, comparisons of either mort ality or comorbidity in patients receiving hemodialysis versus peritoneal dialys is suffer from the limitations of starting with unequal cohorts reflecting selec tion bias. Data subsets from the United States Renal Data System (USRDS) report for 1997 [1] show that in diabetic patients, all cohorts have a higher risk of d eath with CAPD than with hemodialysis. Furthermore, patients receiving peritonea l dialysis in the United States have a 14% greater risk of hospitalization than do patients undergoing hemodialysis [38]. Benefits of peritoneal dialysis, inclu ding freedom from a machine and electrical outlets and ease of travel, stand aga inst the disadvantages of unremitting attention to fluid exchange, constant risk of peritonitis, and disappearing exchange surface. There are no absolute criter ia for abandoning conservative management in favor of initiating maintenance hem odialysis or peritoneal dialysis. As a generalization, diabetic individuals with progressive renal disease decompensate with uremic symptoms earlier than nondia betic individuals. A decision to start dialysis is usually the culmination of un successful efforts to regain compensation after episodic dyspnea due to volume o verload or nausea and a reversed sleep pattern characteristic of renal failure. Sometimes, both physician and patient appreciate that lassitude and decreasing a ctivity in a catabolic patient signal the need to begin dialysis. FIGURE 1-48 Tr eatment for end-stage renal disease (ESRD). Ideally, treatment for ESRD should b e selected without stress or urgency on the basis of prior thought and planning. Discussions with representatives of patient self-help groups, such as the Ameri can Association of Kidney Patients, and institutional transplant coordinators ai d in communicating the information required by patients to enable them to select from available options for uremia therapy. 5 0 5 10 s tic be D ia Creatinine clearance, mL/min 60 Nondiabetic 51.5% Center hemo Transplant 36.3% 30 15 90 FIGURE 1-47 Uremia therapy, conservative management. Although enthusiastically f avored in Canada and Mexico, in the United States peritoneal dialysis sustains t he life of only about 12% of diabetic patients with end-stage renal disease (ESR D) [1]. Continuous ambulatory PLANNING FOR ESRD Expose patient to treatment options Establish vascular or peritoneal access Enco urage intrafamilial kidney donation Schedule visit with transplant surgeon Monit or creatinine, general well being Err on side of early dialysis start 75

45 Diabetic 4064 y 71.5% Center hemo Transplant 13.0% FIGURE 1-49 Management with dialysis. As tabulated in the 1997 report of the Uni ted States Renal Data System [1], diabetic patients with end-stage renal disease (ESRD) are less likely than nondiabetic patients with ESRD to receive a kidney transplant and are most often managed with maintenance hemodialysis (center hemo ). A greater proportion of diabetic patients with ESRD are managed with continuo us ambulatory peritoneal dialysis (CAPD) or machine-based continuous cyclic peri toneal dialysis (CCPD) than are nondiabetic patients with ESRD. Center hemo Home hemo CAPD CCPD Transplant

Diabetic Nephropathy: Impact of Cormorbidity 1.17 26.2 24.1 Nondiabetic transplant Nondiabetic dialysis Diabetic transplant Diabetic dialysis 100 80 Surviving, % 60 40 20 100 94.9 91.2 76.3 90.3 84.3 75.3 57.9 64.7 205.4 279.9 0 50 100 150 200 250 300 36.9 26.5 20.1 3.9 0 0 1 2 5 Time after initiatling treatment, y Deaths per 1000 Patient Years 10 FIGURE 1-50 Survival rates of diabetics and nondiabetics. As tabulated in the 19 97 report of the United States Renal Data System [1], there are sharp difference s in survival between diabetic and nondiabetic patients with end-stage renal dis ease (ESRD) as well as between treatment by dialysis versus kidney transplantati on. The highest death rate is suffered by diabetic dialysis patients (combined p eritoneal dialysis and hemodialysis), while the best survival is experienced by nondiabetic renal transplant recipients. Selection bias in choosing more fit ESR D patients for kidney transplantation while leaving a residual pool of sicker pa tients for dialysis accounts for some of the difference in mortality. Other vari ables, especially extrarenal comorbidity, are probably more important in definin g the less favorable course in diabetes. FIGURE 1-51 Survival rates of diabetic ESRD patients. After a decade of treatmen t, the remarkable superiority of renal transplantation over dialysis (combined p eritoneal dialysis and hemodialysis, lower curve) is starkly evident in these su rvival curves drawn from the 1997 report of the United States Renal Data System [1]. Fewer than 1 in 20 diabetic patients with end-stage renal disease (ESRD) tr eated with any form of dialysis will live a decade. In contrast, kidney transpla ntation from a living donor (upper curve) or a cadaver donor (middle curve) perm its substantive cohorts to survive. 42.4 40 Deaths per 1000 Patient Years 30.9 30 21.5 14.5 7.5 7.5 1.4 0 MI Nondiab MI Diab CVA Nondiab CVA Diab Cancer Nondiab Cancer Diab 2.0 1.8 8.7 6.8 3.7 0.4 1.6 0.1 +] Transplant Hemodialysis Peritoneal dialysis USRDS 1996 Ages 4564 20 15.1 10 19

6.3 2.4 4.5 3.0 1.6 0.1 [K Nondiab 4.0 [K+] Diab FIGURE 1-52 Comorbidity in ESRD. Death of diabetic patients with end-stage renal disease (ESRD) relates to comorbidity, as shown in this table abstracted from t he 1997 report of the United States Renal Data System (USRDS) [1]. Representativ e subsets of patients with ESRD with and without diabetes treated by peritoneal dialysis, hemodialysis, or renal transplantation are shown. Note that for each c omorbid cause of death, rates are higher in in those receiving hemodialysis and or undetermined reasons, deaths due in nondiabetic patients with ESRD. tassium; MImyocardial infarction. patients receiving peritoneal dialysis than are lowest in renal transplant recipients. F to cancer are less frequent in diabetic than CVAcerebrovascular accident; Diabdiabetes; K+po

1.18 Systemic Diseases and the Kidney COMPLICATIONS IN PATIENTS RECEIVING HEMODIALYSIS Inadequate vascular access Steal, thrombosis/infection Interdialytic hypotension P rogressive eye disease Progressive vascular disease Minimal rehabilitation COMPLICATIONS IN PATIENTS RECEIVING PERITONEAL DIALYSIS Peritonitis Tunnel infection Abdominal/back pain Retinopathy Progressive vascular disease Minimal rehabilitation COMPLICATIONS IN PATIENTS UNDERGOING KIDNEY TRANSPLANTATION Infections: bacterial (AFB), fungal viral (CMV); genitourinary, lung, skin, woun d Cancer: skin, lymphoma, solid organ Drug induced: gout, cataracts Allograft re jection: acute/chronic Recurrent diabetic nephropathy Progressive eye, vascular disease FIGURE 1-53 Complications prevalent in diabetic hemodialysis patients. FIGURE 1-54 Complications prevalent in diabetic peritoneal dialysis patients. FIGURE 1-55 Frequent complications reported in diabetic kidney transplant recipi ents. AFBacid fast bacteria; CMVcytomegalovirus. OPTIONS IN DIABETES WITH ESRD CAPD/CCPD First-year survival Survival >10 y Diabetic complications Rehabilitation Patient acceptance 75% <5% Progress Poor Fair Rehabilitation 100 Hemodialysis 75% <5% Progress Poor Fair Transplantation Karnofsky score >90% >25% Slow progression Fair to excellent Good to excellent Kidney transplant Hemodialysis 50 Peritoneal dialysis FIGURE 1-56 Options in diabetes with ESRD. Comparing outcomes of various options for uremia therapy in diabetic patients with end-stage renal disease (ESRD) is flawed by the differing criteria for selection for each treatment. Thus, if youn ger, healthier subjects are offered kidney transplantation, then subsequent rela tive survival analysis will be adversely affected for the residual pool treated by peritoneal dialysis or hemodialysis. Allowing for this caveat, the table depi cts usual outcomes and relative rehabilitation results for continuous ambulatory peritoneal dialysis (CAPD), continuous cyclic peritoneal dialysis (CCPD), hemod ialysis, and transplantation. Withdrawal 0 Death FIGURE 1-57 Karnofsky scores in rehabilitation. Graphic depiction of rehabilitat ion in diabetic patients with end-stage renal disease (ESRD) as judged by Karnof sky scores. Few diabetic patients receiving hemodialysis or peritoneal dialysis muster the strength to resume fulltime employment or other gainful activities. O riginally devised for use by oncologists, the Karnofsky score is a reproducible, simple means of evaluating chronic illness from any cause. A score below 60 ind

icates marginal function and failed rehabilitation.

Diabetic Nephropathy: Impact of Cormorbidity 1.19 FIGURE 1-58 Complications of the hemodialysis regimen are more frequent in diabe tic than in nondiabetic patients. A, Axillary vein occlusion proximal to an arte riovenous graft used for dialysis access is shown. B, Balloon angioplasty proffe rs only temporary respite owing to a high rate (70% in 6 months) of restenosis i n diabetic patients. The value of an intraluminal stent prosthesis is being stud ied. A B 76.2 75 USRDS 1996 PD + Hemo 74 72.6 Surviving, % 70.9 70 68.9 67.7 65.9 65 1983 1984 1985 1986 1987 1988 198 9 1990 1991 66.2 66.4 73.1 74.4 LIFE PLAN FOR DIABETIC NEPHROPATHY Explore and endorse treatment goals Enlist patient as key team member Prepare pa tient for probable course Prioritize ESRD options 1992 1993 FIGURE 1-59 Improving one year survival with dialysis. The summative effect of m ultiple incremental improvements in management of diabetic patients with end-sta ge renal disease (ESRD) is reflected in a continuing increase in survival. Shown here, abstracted from the 1977 report of the United States Renal Data System (U SRDS), is the increasing first-year survival rates for hemodialysis (hemo) plus peritoneal dialysis (PD) patients with diabetes. FIGURE 1-60 Life plan. Given the concurrent involvement of multiple consultants in the care of diabetic individuals with end-stage renal disease (ESRD), there i s a need for a defined strategy, here termed a Life Plan. Switching from hemodialy sis to peritoneal dialysis (or the reverse) and deciding on a midcourse kidney t ransplant are common occurrences that ought not to provoke anxiety or stress. Re appraisal and reconstruction of the Life Plan should be performed by patient and physician at least annually.

1.20 Systemic Diseases and the Kidney References 1. United States Renal Data System: USRDS 1997 Annual Data Report. Bethesda, MD: The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; April, 1997. 2. Zimmet PZ: Challenges in diabetes epidemio logyfrom West to the rest (Kelly West Lecture 1991). Diabetes Care 1992, 15:232252 . 3. Harris M, Hadden WC, Knowles WC, and colleagues: Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels in U.S. population aged 20 -74 yr. Diabetes 1987, 36:523534. 4. Stephens GW, Gillaspy JA, Clyne D, and colle agues: Racial differences in the incidence of end-stage renal disease in types I and II diabetes mellitus. Am J Kidney Dis 1990, 15:562567. 5. Haffner SM, Hazuda HP, Stern MP, and colleagues: Effects of socioeconomic status on hyperglycemia and retinopathy levels in Mexican Americans with NIDDM. Diabetes Care 1989, 12:1 28134. 6. National Diabetes Data Group: Diabetes in America. Bethesda, MD: NIH Pu blication No. 85-1468; August, 1985. 7. Mauer SM, Chavers BM: A comparison of ki dney disease in type I and type II diabetes. Adv Exp Med Biol 1985, 189:299303. 8 . Melton LJ, Palumbo PJ, Chu CP: Incidence of diabetes mellitus by clinical type . Diabetes Care 1983, 6:7586. 9. Biesenback G, Janko O, Zazgornik J: Similar rate of progression in the predialysis phase in type I and type II diabetes mellitus . Nephrol Dial Transplant 1994, 9:10971102. 10. Wirta O, Pasternack A, Laippala P , Turjanmaa V: Glomerular filtration rate and kidney size after six years diseas e duration in noninsulin-dependent diabetic subjects. Clin Nephrol 1996, 45:1017. 11. Cheigh J, Raghavan J, Sullivan J, and colleagues: Is insufficient dialysis a cause for high morbidity in diabetic patients [abstract]? J Am Soc Nephrol 199 1, 317. 12. Lowder GM, Perri NA, Friedman EA: Demographics, diabetes type, and d egree of rehabilitation in diabetic patients on maintenance hemodialysis in Broo klyn. J Diabet Complications 1988, 2:218226. 13. Carter JS, et al.: Non-insulin-d ependent diabetes mellitus in minorities in the United States. Ann Intern Med 19 96, 125:221232. 14. Ritz E, Stefanski A: Diabetic nephropathy in type II diabetes . Am J Kidney Dis 1996, 27:167194. 15. Nelson RG, Pettitt DJ, Carraher MJ, et al. : Effect of proteinuria on mortality in NIDDM. Diabetes 1988, 37:14991504. 16. Sh afrir E: Development and consequences of insulin resistance: lessons from animal s with hyperinsulinemia. Diabetes Metab 1996, 22:122131. 17. Schalin-Jantii C, et al.: Polymorphism of the glycogen synthase gene in hypertensive and normotensiv e subjects. Hypertension 1996, 27:6771. 18. Kuzuya T, Matsuda A: Classification o f diabetes on the basis of etiologies versus degree of insulin deficiency. Diabe tes Care 1997, 20:219220. 19. Clausson P, Linnarsson R, Gottsater A, et al.: Rela tionships between diabetes duration, metabolic control and beta-cell function in a representative population of type 2 diabetic patients in Sweden. Diabet Med 1 994, 11:794801. 20. Service FJ, Rizza RA, Zimmerman BR, et al.: The classificatio n of diabetes by clinical and C-peptide criteria: a prospective populationbased study. Diabetes Care 1997, 20:198201. 21. Humphrey LL, et al.: Chronic renal fail ure in non-insulin-dependent diabetes mellitus: a population-based study in Roch ester, Minnesota. Ann Intern Med 1989, 111:788796. 22. Ritz E, Stefanski A: Diabe tic nephropathy in type II diabetes. Am J Kidney Dis 1996, 27:167194. 23. Lewis E J, et al.: The effect of angiotensin-converting-enzyme inhibition on diabetic ne phropathy: the Collaborative Study Group. N Engl J Med 1993, 329:14561462. 24. Th e Euclid Study Group: Randomised placebo-controlled trial of lisinopril in normo tensive patients with insulin-dependent diabetes and normoalbuminuria or microal buminuria. Lancet 1997, 349:17871792. 25. Zeller K, et al.: Effect of restricting dietary protein on the progression of renal failure in patients with insulin-de pendent diabetes mellitus. N Engl J Med 1991, 324:7884. 26. Gilbert RE, Tsalamand ris C, Bach LA, et al.: Long-term glycemic control and the rate of progression o f early diabetic kidney disease. Kidney Int 1993, 44:855859. 27. Biesenbach G, Za zgornik J: High mortality and poor quality of life during predialysis period in type II diabetic patients with diabetic nephropathy. Ren Fail 1994, 16:263272. 28 . Shaffer D, Simpson MA, Madras PN, et al.: Kidney transplantation in diabetic p

atients using cyclosporine. Five-year follow-up. Arch Surg 1995, 130:287288. 29. Shaw JE, Boulton AJ: The pathogenesis of diabetic foot problems: an overview. Di abetes 1997, 46 (suppl 2): S58S61. 30 Spallone V, Menzinger G: Diagnosis of cardi ovascular autonomic neuropathy in diabetes. Diabetes 1997, 46 (suppl 2):S67S76. 3 1. Enck P, Frieling T: Pathophysiology of diabetic gastroparesis. Diabetes 1997, 46 (suppl 2):S77S81. 32. Soykan I, et al.: The effect of chronic oral domperidon e therapy on gastrointestinal symptoms, gastric emptying, and quality of life in patients with gastroparesis. Am J Gastroenterol 1997, 92:976980. 33. Hebert LA, Bain RP, Verme D, Cattran Det al.: Remission of nephrotic range proteinuria in t ype I diabetes: Collaborative Study Group. Kidney Int 1994, 46:16881693. 34. Gaul t MH, Fernandez D: Stable renal function in insulin-dependent diabetes mellitus 10 years after nephrotic range proteinuria. Nephron 1996, 72:8692. 35. Lindblad A S, Nolph KD, Novak JW, Friedman EA: A survey of the NIH CAPD Registry population with end-stage renal disease attributed to diabetic nephropathy. J Diabet Compl ications 1988, 2:227-232. 36. Legrain M, Rottembourg J, Bentchikou A, et al.: Di alysis treatment of insulin dependent diabetic patients: ten years experience. C lin Nephrol 1984, 21:72-81 37. Rubin J, Hsu H: Continuous anbulatory peritoneal dialysis: ten years at one facility. Am J Kidney Dis 1991, 17: 165-169. 38. Haba ch G, Bloembergen WE, Mauger EA, et al.: Hospitalization among United States dia lysis patients: hemodialysis versus peritoneal dialysis. J Am Soc Nephrol 1995, 11:1940-1948.

Vasculitis (Polyarteritis Nodosa, Microscopic Polyangiitis, Wegener's Granulomatos is, HenochSchnlein Purpura) J. Charles Jennette Ronald J. Falk T he kidneys are affected by a variety of systemic vasculitides [1,2]. This is not surprising given the numerous and varied types of vessels in the kidneys. The c linical manifestations and even the pathologic expressions of vasculitis often a re not specific for a particular diagnostic category of vasculitis. An accurate precise diagnosis usually requires the integration of many different types of da ta, including clinical signs and symptoms, associated diseases (eg, asthma, syst emic lupus erythematosus, rheumatoid arthritis, hepatitis virus, polymyalgia rhe umatica), vascular distribution (ie, types and locations of involved vessels), h istologic pattern of inflammation (eg, granulomatous versus necrotizing), immuno pathologic features (eg, presence and composition of vascular immunoglobulin dep osits), and serologic findings (eg, cryoglobulins, hypocomplementemia, hepatitis B antibodies, hepatitis C antibodies, antineutrophil cytoplasmic autoantibodies , antiglomerular basement membrane [GBM] antibodies, antinuclear antibodies). Spe cific diagnosis of a vasculitis is very important because the prognosis and appr opriate therapy vary substantially among different types of vasculitis. A genera l overview of the major categories of vasculitis that affect the kidneys is pres ented. The focus is primarily on polyarteritis nodosa, Henoch-Schnlein purpura, W egener's granulomatosis, and microscopic polyangiitis. CHAPTER 2

2.2 Systemic Diseases and the Kidney Overview SELECTED CATEGORIES OF VASCULITIS Large vessel vasculitis Giant cell arteritis Takayasu arteritis Medium-sized ves sel vasculitis Polyarteritis nodosa Kawasaki disease Small vessel vasculitis ANC A small vessel vasculitis Microscopic polyangiitis Wegener's granulomatosis ChurgStrauss syndrome Immune complex small vessel vasculitis Henoch-Schnlein purpura C ryoglobulinemic vasculitis Lupus vasculitis Serum sickness vasculitis Infectioninduced immune complex vasculitis AntiGBM small vessel vasculitis Goodpasture's syn drome FIGURE 2-1 Many different approaches to categorizing vasculitis exist. We use th e approach adopted by the Chapel Hill International Consensus Conference on the Nomenclature of Systemic Vasculitis [3]. The Chapel Hill System divides vasculit ides into those that have a predilection for large arteries (ie, the aorta and i ts major branches), medium-sized vessels (ie, main visceral arteries), and small vessels (predominantly capillaries, venules, and arterioles, and occasionally, small arteries). However, there is so much overlap in the size of the vessel inv olved by different vasculitides that other criteria are very important for preci se diagnosis, especially when distinguishing among the different types of small vessel vasculitis. ANCAantineutrophil cytoplasmic antibody. Distribution of renal vascular involvement Small vessel vasculitis Large vessel vasculitis Medium-sized vessel vasculitis FIGURE 2-2 Predominant distributions of renal vascular involvement. This diagram depicts the predominant distributions of renal vascular involvement by large, m edium-sized, and small vessel vasculitides [2]. Note that all three categories m ay affect arteries, although arteries are least often affected by the small vess el vasculitides and often are not involved at all by this category of vasculitis . By the Chapel Hill definitions, glomerular involvement (ie, glomerulonephritis ) is confined to the small vessel vasculitides, which provides a concrete criter ion for separating the diseases in this category from those in the other two cat egories [3].

Vasculitis (Polyarteritis Nodosa, Microscopic Polyangiitis, Wegener's Granulomatos is, Henoch-Schnlein Purpura) 2.3 RENAL INJURY CAUSED BY DIFFERENT CATEGORIES OF VASCULITIS Large vessel vasculitis Ischemia causing renovascular hypertension (uncommon) Me dium-sized vessel vasculitis Renal infarcts (frequent) Hemorrhage (uncommon) and rupture (rare) ANCA small vessel vasculitis Pauci-immune crescentic glomerulone phritis (common) Arcuate and interlobular arteritis (occasional) Medullary angii tis (uncommon) Interstitial granulomatous inflammation (rare) Immune complex sma ll vessel vasculitis Immune complex proliferative or membranoproliferative glome rulonephritis with or without crescents (common) Arteriolitis and interlobular a rteritis (rare) AntiGBM small vessel vasculitis Crescentic glomerulonephritis (co mmon) Extraglomerular vasculitis (only with concurrent ANCA disease) FIGURE 2-3 The type of renal vessel involved by a vasculitis determines the resu ltant renal dysfunction. Large vessel vasculitides cause renal dysfunction by in juring the renal arteries and the aorta adjacent to the renal artery ostia. Thes e injuries result in reduced renal blood flow and resultant renovascular hyperte nsion. Medium-sized vessel vasculitis most often affects lobar, arcuate, and int erlobular arteries, resulting in infarction and hemorrhage. Small vessel vasculi tides most often affect the glomerular capillaries (ie, cause glomerulonephritis ), but some types (especially the antineutrophil cytoplasmic antibody vasculitid es) may also affect extraglomerular parenchymal arterioles, venules, and capilla ries. Anti-GBM disease is a form of vasculitis that involves only capillaries in glomeruli or pulmonary alveoli, or both. This category of vasculitis is conside red in detail seperately in this Atlas. Large Vessel Vasculitis NAMES AND DEFINITIONS FOR LARGE VESSEL VASCULITIS Giant cell arteritis Granulomatous arteritis of the aorta and its major branches , with a predilection for the extracranial branches of the carotid artery. Often involves the temporal artery. Usually occurs in patients older than aged 50 yea rs and often is associated with polymyalgia rheumatica. Granulomatous inflammati on of the aorta and its major branches. Usually occurs in patients younger than aged 50 years. Takayasu arteritis FIGURE 2-4 The two major categories of large vessel vasculitis, giant cell (temp oral) arteritis and Takayasu arteritis, are both characterized pathologically by granulomatous inflammation of the aorta, its major branches, or both. The most reliable criterion for distinguishing between these two disease is the younger a ge of patients with Takayasu arteritis compared with giant cell arteritis [3]. T he presence of polymyalgia rheumatica supports a diagnosis of giant cell arterit is. Clinically significant renal disease is more commonly associated with Takaya su arteritis than giant cell arteritis, although pathologic involvement of the k idneys is a frequent finding with both conditions [4,5].

2.4 Systemic Diseases and the Kidney Medium-sized Vessel Vasculitis NAMES AND DEFINITIONS FOR MEDIUM VESSEL VASCULITIS Polyarteritis nodosa Necrotizing inflammation of medium-sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules. Arteritis involving large, medium-sized, and small arteries, and associated wit h mucocutaneous lymph node syndrome. Coronary arteries are often involved. Aorta and veins may be involved. Usually occurs in children. Kawasaki disease FIGURE 2-5 The medium-sized vasculitides are confined to arteries by the definit ions of the Chapel Hill Nomenclature System [3,6]. By this approach the presence of evidence for involvement of vessels smaller than arteries (ie, capillaries, venules, arterioles), such as glomerulonephritis, purpura, or pulmonary hemorrha ge, would point away from these diseases and toward one of the small vessel vasc ulitides. Both polyarteritis nodosa and Kawasaki disease cause acute necrotizing arteritis that may be complicated by thrombosis and hemorrhage. The presence of mucocutaneous lymph node syndrome distinguishes Kawasaki disease from polyarter itis nodosa. FIGURE 2-6 Photograph of kidneys showing gross features of polyarteritis nodosa. The patient died from uncontrollable hemorrhage of a ruptured aneurysm that ble d into the retroperitoneum and peritoneum. The cut surface of the left kidney an d external surface of the right kidney are shown. The upper pole of the left kid ney has three large aneurysms filled with dark thrombus. These aneurysms are act ually pseudoaneurysms because they are not true dilations of the artery wall but rather are foci of necrotizing erosion through the artery wall into the perivas cular tissue. These necrotic foci predispose to thrombosis with distal infarctio n, and if they erode to the surface of a viscera they can rupture and cause mass ive hemorrhage. The kidneys also have multiple pale areas of infarction with hem orrhagic rims, which are seen best on the surface of the right kidney. A B C aneurysms (pseudoaneurysms), and a perirenal hematoma adjacent to the right kidn ey (left sides of panels) that resulted from rupture of one of the aneurysms. (C ontinued on next page) FIGURE 2-7 Antemortem abdominal CAT scans showing polyarteritis nodosa (AE). Thes e are the same kidneys shown in Figure 2-6. Demonstrated are echogenic oval defe cts in both kidneys corresponding to the

Vasculitis (Polyarteritis Nodosa, Microscopic Polyangiitis, Wegener's Granulomatos is, Henoch-Schnlein Purpura) 2.5 FIGURE 2-7 (Continued) Antemortem abdominal CAT scans showing polyarteritis nodo sa. D E FIGURE 2-8 (see Color Plate) Micrograph of transmural fibrinoid necrosis of an a rcuate artery in acute polyarteritis nodosa. The fibrinoid necrosis results from lytic destruction of vascular and perivascular tissue with spillage of plasma c onstituents, including the coagulation proteins, into the zone of destruction. T he coagulation system, as well as other mediator systems, is activated and fibri n forms in the zone of necrosis, thus producing the deeply acidophilic (bright r ed) fibrinoid material. Marked perivascular inflammation is seen, which is the b asis for the archaic term for this disease, ie, periarteritis nodosa. Note that the glomerulus is not inflamed. (Hematoxylin and eosin stain, 200.) FIGURE 2-9 Micrograph of extensive destruction and sclerosis of an arcuate arter y in the chronic phase of polyarteritis nodosa. Severe necrotizing injury, proba bly with thrombosis as well, has been almost completely replaced by fibrosis. A few small residual irregular foci of fibrinoid material can be seen. Extensive d estruction to the muscularis can be discerned. Infarction in the distal vascular distribution of this artery was present in the specimen. (Hematoxylin and eosin stain, 150.)

2.6 Systemic Diseases and the Kidney Small Vessel Vasculitis NAMES AND DEFINITIONS FOR SMALL VESSEL VASCULITIS Henoch-Schnlein purpura Cryoglobulinemic vasculitis Wegener's granulomatosis ChurgStrauss syndrome Microscopic polyangiitis Vasculitis with IgA-dominant immune de posits affecting small vessels, ie, capillaries, venules, or arterioles. Typical ly involves skin, gut and glomeruli, and is associated with arthralgias or arthr itis. Vasculitis with cryoglobulin immune deposits affecting small vessels, ie, capillaries, venules, or arterioles, and associated with cryoglobulins in serum. Skin and glomeruli are often involved. Granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small to medium-sized v essels, eg, capillaries, venules, arterioles, and arteries. Necrotizing glomerul onephritis is common. Eosinophil-rich and granulomatous inflammation involving t he respiratory tract and necrotizing vasculitis affecting small to medium-sized vessels, and associated with asthma and blood eosinophilia Necrotizing vasculiti s with few or no immune deposits affecting small vessels, ie, capillaries, venul es, or arterioles. Necrotizing arteritis involving small and medium-sized arteri es may be present. Necrotizing glomerulonephritis is very common. Pulmonary capi llaritis often occurs. FIGURE 2-10 The small vessel vasculitides have the highest frequency of clinical ly significant renal involvement of any category of vasculitis. This is not surp rising given the numerous small vessels in the kidneys and their critical roles in renal function. The renal vessels most often involved by all small vessel vas culitides are the glomerular capillaries, resulting in glomerulonephritis. Glome rular involvement in immune complex vasculitis typically results in proliferativ e or membranoproliferative glomerulonephritis, whereas ANCA disease usually caus es necrotizing glomerulonephritis with extensive crescent formation. Involvement of renal vessels other than glomerular capillaries is rare in immune complex va sculitis but common in ANCA vasculitis. Diagnostic categorization of small vessel vasculitis with glomerulonephritis Sig ns and symptoms of small vessel vasculitis (eg, nephritis, purpura, mononeuritis multiplex, pulmonary hemorrhage, abdominal pain, arthralgias, myalgias) Cryoglobulins in blood Pauci-immune crescentic glomerulonephritis on renal biopsy IgA nephropathy on renal biopsy Type 1 MPGN on renal biopsy No granulomatous inflammation or asthma Granulomatous inflammation but no asthma Granulomatous inflammation, asthma, and eosinophilia Henoch-Schnlein purpura Cryoglobulinemic vasculitis Microscopic polyangiitis Wegener's granulomatosis

Churg-Strauss syndrome FIGURE 2-11 Algorithm for differentiating among the major categories of small ve ssel vasculitis that affect the kidneys. In a patient with signs and symptoms of small vessel vasculitis, the type of glomerulonephritis is useful for categoriz ation. Identification of IgA nephropathy is indicative of Henoch-Schnlein purpura . Type I membranoproliferative glomerulonephritis (MPGN) suggests cryoglobulinem ia and/or hepatitis C infection, and pauci-immune necrotizing and crescentic glo merulonephritis suggest some form of ANCA-associated vasculitis [1,2]. The diffe rent forms of ANCA vasculitis are distinguished by the presence or absence of ce rtain features in addition to the necrotizing vasculitis, ie, granulomatous infl ammation in Wegener's granulomatosis, asthma and blood eosinophilia in Churg-Strau ss syndrome, and neither granulomatous inflammation nor asthma in microscopic po lyangiitis. Approximately 80% of patients with active untreated Wegener's granulom atosis or microscopic polyangiitis have ANCA, but it is important to realize tha t a small proportion of patients with typical clinical and pathologic features o f these diseases do not have detectable ANCA.

Vasculitis (Polyarteritis Nodosa, Microscopic Polyangiitis, Wegener's Granulomatos is, Henoch-Schnlein Purpura) 2.7 APPROXIMATE FREQUENCY OF ORGAN SYSTEM INVOLVEMENT IN SMALL VESSEL VASCULITIS Henoch-Schnlein purpura, % 50 90 <5 60 <5 75 10 Organ system Renal Cutaneous Pulmonary Gastrointestinal Ear, nose, and throat Musculoskeletal Neurologic Cryoglobulinemic vasculitis, % 55 90 <5 30 <5 70 40 Microscopic polyangiitis, % 90 40 50 50 35 60 30 Wegener's granulomatosis, % 80 40 90 50 90 60 50 Churg-Strauss syndrome, % 45 60 70 50 50 50 70 FIGURE 2-12 All of the small vessel vasculitides share signs and symptoms of sma ll vessel injury in multiple different tissues; however, the frequency of involv ement varies among the different diseases [1]. Combined renal and pulmonary invo lvement (pulmonary-renal syndrome) is most common in ANCA vasculitis, whereas co mbined renal and dermal involvement (dermal-renal syndrome) is most common in im mune complex vasculitis. The cutaneous involvement in small vessel vasculitides usually manifests as purpura caused by venulitis, but occasionally is more nodular or necrotizing secondary to arteritis or granulomatous inflammation. Nodular cut aneous lesions, as well as neuropathies, abdominal pain, and musculoskeletal sym ptoms also can be caused by medium sized vessel vasculitis (eg, polyarteritis no dosa), and thus these clinical manifestations are not specific for a small vesse l vasculitis; whereas glomerulonephritis, purpura, or alveolar capillaritis are. Henoch-Schnlein Purpura FIGURE 2-13 Cutaneous purpura in a patient with Henoch-Schnlein purpura. This cli nical appearance could be caused by any of the small vessel vasculitides, and th us is not specific for Henoch-Schnlein purpura. Henoch-Schnlein purpura is the mos t common small vessel vasculitis in children [7]. In a young child with purpura, nephritis and abdominal pain, the likelihood of Henoch-Schnlein purpura is appro ximately 80%; however, in an older adult with the same clinical presentation, th e likelihood of Henoch-Schnlein purpura is very low and the patient has an approx imately 80% chance of having an ANCA-associated vasculitis. FIGURE 2-14 Skin biopsy from a patient with small vessel vasculitis demonstratin g the typical dermal leukocytoclastic angiitis pattern of venulitis that results in vasculitic purpura. This histologic lesion is nonspecific and can be a compo nent of any of the small vessel vasculitides. Additional immunohistologic, serol ogic, and clinical observations are required to determine what is causing the le ukocytoclastic angiitis (Figs. 2-9 and 2-10). (Hematoxylin and eosin stain.)

2.8 Systemic Diseases and the Kidney FIGURE 2-15 Direct immunofluorescence microscopy demonstrating granular IgA-domi nant immune complex deposits in dermal vessels, which is indicative of Henoch-Sc hnlein purpura. This procedure typically would show vascular IgM, IgG, and C3 cry oglobulinemic vasculitis, and little or no staining for immunoglobulins in a spe cimen from a patient with an ANCA vasculitis (a paucity of staining for immunogl obulins in vessel walls indicates pauci-immune vasculitis). FIGURE 2-16 Direct immunofluorescence microscopy demonstrating granular, predomi nantly mesangial IgA-dominant immune complex deposits in a glomerulus. This is i ndicative of some form of IgA nephropathy, including the form that occurs as a c omponent of HenochSchnlein purpura. FIGURE 2-17 Electron micrograph showing mesangial dense deposits representative of the pattern of deposition seen in patients with HenochSchnlein purpura glomeru lonephritis. The dense deposits are immediately beneath the paramesangial baseme nt membrane. FIGURE 2-18 Severe crescentic proliferative glomerulonephritis in a patient with Henoch-Schnlein purpura and rapidly progressive glomerulonephritis (Masson trich rome stain). Approximately half of patients with Henoch-Schnlein purpura have mil d nephritis with hematuria and proteinuria, but less than a quarter develop rena l insufficiency, and rapidly progressive glomerulonephritis is rare. Less than 1 0% of patients have persistent renal disease that progresses to end-stage renal disease.

Vasculitis (Polyarteritis Nodosa, Microscopic Polyangiitis, Wegener's Granulomatos is, Henoch-Schnlein Purpura) 2.9 FIGURE 2-19 Fibrinoid necrosis obliterating the wall of an arteriole in a renal biopsy specimen from a patient with Henoch-Schnlein purpura (hematoxylin and eosi n). Involvement of renal vessels other than glomeruli is rare in Henoch-Schnlein purpura. ANCA Small Vessel Vasculitis FIGURE 2-20 (see Color Plate) C-ANCA staining pattern of ethanol-fixed normal hu man neutrophils in an indirect immunofluorescence assay of serum. Approximately 90% of C-ANCA are specific for proteinase 3 (PR3-ANCA) in specific immunochemica l assays, such as enzyme immunoassay (EIA) [810]. FIGURE 2-21 (see Color Plate) P-ANCA staining pattern of ethanol-fixed normal hu man neutrophils in an indirect immunofluorescence assay of serum. Approximately 90% of P-ANCA in patients with nephritis or vasculitis are specific for myeloper oxidase (MPO-ANCA) in specific immunochemical assays, such as EIA. P-ANCA in pat ients with other types of inflammatory disease, such as inflammatory bowel disea se are typically not specific for MPO. Using ethanol-fixed neutrophils as substr ate, nuclear staining caused by anti-nuclear antibodies (ANA) cannot be distingu ished confidently from nuclear staining caused by P-ANCA. Using formalin-fixed n eutrophils as substrate, P-ANCA stain the cytoplasm but ANA do not. The differen ce in staining pattern between ethanol and formalin fixed cells is due to the ar tifactual diffusion of solubilized cationic ANCAantigens to the nucleus during s ubstrate preparation of the ethanolfixed cells, as opposed to immobilization of the antigens in the cytoplasm by covalent crosslinking during formalin fixation.

2.10 Systemic Diseases and the Kidney Pauci-immune crescentic glomerulonephritis Microscopic polyangiitis Wegener's gr anulomatosis P-ANCA/MPO-ANCA C-ANCA/PR3-ANCA FIGURE 2-22 Approximate relative frequency of P-ANCA/MPO-ANCA versus CANCA/PR3-A NCA in patients with pauci-immune necrotizing and crescent glomerulonephritis wi thout systemic vasculitis (renal-limited vasculitis), microscopic polyangiitis, an d Wegener's granulomatosis. Note that most patients with renal-limited disease hav e PANCA/MPO-ANCA, most patients with Wegener's granulomatosis have C-ANCA/PR3-ANCA , and patients with microscopic polyangiitis do not have a major preponderance o f either ANCA specificity. FIGURE 2-23(see Color Plate) Early segmental fibrinoid necrosis and infiltration by neutrophils in an ANCA-positive patient with Wegener's granulomatosis (Masson trichrome stain). There also is fibrin (red/fuchsinophilic material) in Bowman's s pace, which is a precursor event to crescent formation. FIGURE 2-24 Glomerulus from a patient with ANCA and a pauci-immune necrotizing a nd crescentic glomerulonephritis showing a large circumferential crescent and se gmental lysis of glomerular basement membranes (combined Jones silver and hemato xylin and eosin stain). Also note the adjacent tubulointerstitial inflammation, which often is pronounced in ANCA disease. This pattern of glomerular injury can be seen with any of the ANCA-small vessel vasculitides. FIGURE 2-25(see Color Plate) Direct immunofluorescence microscopy demonstrating intense staining of a crescent and adjacent segmental glomerular fibrinoid necro sis with an antiserum specific for fibrin in a renal biopsy from a patient with ANCA small vessel vasculitis. There was no staining of glomeruli in this specime n with antisera specific for IgG, IgA, or IgM.

Vasculitis (Polyarteritis Nodosa, Microscopic Polyangiitis, Wegener's Granulomatos is, Henoch-Schnlein Purpura) 2.11 FIGURE 2-26 Chronic ANCA-associate glomerulonephritis with effacement of the arc hitecture of a glomerulus by extensive sclerosis. Bowman's capsule has been destro yed and there is periglomerular fibrosis and chronic inflammation. FIGURE 2-27 Necrotizing arteritis involving an interlobular artery in a renal bi opsy specimen from a patient with ANCA-positive microscopic polyangiitis (hemato xylin and eosin). There is focal transmural fibrinoid necrosis with intense peri vascular inflammation. This pattern of arteritis is nonspecific, and could be se en, for example, in a patient with polyarteritis nodosa, microscopic polyangiiti s, or Wegener's granulomatosis. The presence of ANCA or glomerulonephritis in the patient would exclude polyarteritis nodosa. FIGURE 2-28 Direct immunofluorescence microscopy demonstrating intense staining of the fibrinoid necrosis in the wall of an interlobular artery with an antiseru m specific for fibrin in a renal biopsy from a patient with microscopic polyangi itis. FIGURE 2-29 Medullary leukocytoclastic angiitis involving vasa recta in a patien t with Wegener's granulomatosis (hematoxylin and eosin). When this process is seve re, papillary necrosis may result. The frequency of this process is unknown beca use the medulla often is not sampled in renal biopsy specimens.

2.12 Systemic Diseases and the Kidney FIGURE 2-30 Poorly defined focus of necrotizing granulomatous inflammation in th e cortex in a renal biopsy obtained from a patient with ANCA-positive Wegener's gr anulomatosis (hematoxylin and eosin). Granulomatous inflammation is only very ra rely observed in renal biopsy specimens. FIGURE 2-31 Necrotizing granulomatous inflammation in a wedge biopsy of lung fro m a patient with Wegener's granulomatosis (hematoxylin and eosin). Note the scatte red large multinucleated giant cells on the left side and the extensive necrosis and neutrophilic infiltration on the right side. The granulomatous inflammation of acute Wegener's granulomatosis has much more neutrophilic infiltration and liq uefactive necrosis than most other forms of granulomatous inflammation, which is why the lesions in the lung tend to cavitate, and why the lesions in the nose a nd sinuses tend to destroy bone. P-ANCA (MPO-ANCA) disease Systemic small vessel vasculitis (eg, MPA) Pulmonary re nal vasculitic syndrome Glomerulonephritis alone Wegener's granulomatosis FIGURE 2-32 Hemorrhagic alveolar capillaritis in a wedge biopsy from the lung of a patient with microscopic polyangiitis (hematoxylin and eosin). Note the neutr ophils within alveolar capillaries and the massive hemorrhage into the air space s. This pattern of injury can be seen in both microscopic polyangiitis and Wegen er's granulomatosis. The pulmonary hemorrhage of anti-GBM disease usually does not have conspicuous neutrophils in alveolar capillaries. Anti-GBM disease C-ANCA (PR3-ANCA) disease FIGURE 2-33 Categorization of patients with crescentic glomerulonephritis with r espect to both the immunopathologic category of disease (immune complex versus a nti-GBM versus ANCA) and the clinicopathologic expression (glomerulonephritis al one versus Wegener's granulomatosis versus Goodpasture's syndrome versus other small vessel vasculitis) [11]. Note that most patients with ANCA have some expression of systemic vasculitis rather than glomerulonephritis alone. Most patients with Wegener's granulomatosis have C-ANCA/PR3-ANCA but some have P-ANCA/MPO-ANCA. Also note that some patients with anti-GBM and some patients with immune complex dis ease also are ANCA positive. (Adapted from Jennette [11]).

Vasculitis (Polyarteritis Nodosa, Microscopic Polyangiitis, Wegener's Granulomatos is, Henoch-Schnlein Purpura) 2.13 References 1. 2. 3. Jennette JC, Falk RJ: Small vessel vasculitis. N Engl J Med 1997, 337:1 5121523. Jennette JC, Falk RJ: The pathology of vasculitis involving the kidney. Am J Kidney Dis 1994, 24:130141. Jennette JC, Falk RJ, Andrassy K, et al.: Nomenc lature of systemic vasculitides: the proposal of an international consensus conf erence. Arthritis Rheum 1994, 37:187192. Klein RG, Hunder GG, Stanson AW, et al.: Larger artery involvement in giant cell (temporal) arteritis. Ann Intern Med 19 75, 83:806812. Arend WP, Michel BA, Bloch DA, et al.: The American College of Rhe umatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum 1990, 33:11291134. Lhote F, Guillevin L: Polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome. Rheum Dis Clin North Am 1995, 21:911947 . 7. Dillon MJ, Ansell BM: Vasculitis in children and adolescents. Rheum Dis Cli n North Am 1995, 21:11151136. 8. Gross WL, Schmitt WH, Csernok E: ANCA and associ ated diseases: immunodiagnostic and pathogenetic aspects. Clin Exp Immunol 1993, 91:112. 9. Kallenberg CGM, Brouwer E, Weening JJ, Cohen Tervaert JW: Anti-neutro phil cytoplasmic antibodies: current diagnostic and pathophysiologic potential. Kidney Int 1994, 46:115. 10. Jennette JC, Falk RJ: Anti-neutrophil cytoplasmic au toantibodies: discovery, specificity, disease associations and pathogenic potent ial. Adv Pathol Lab Med 1995, 8:363377. 11. Jennette JC: Anti-neutrophil cytoplas mic autoantibody-associated disease: a pathologist's perspective. Am J Kidney Dis 1991, 18:164170. 4. 5. 6.

Amyloidosis Robert A. Kyle Morie A. Gertz T he word amyloid was first coined in 1838 by Schleiden, a German botanist, to des cribe a normal constituent of plants. Virchow [1] observed the similarity of the staining properties of the amyloid to those of starch and named it amyloid. All forms of amyloid appear homogeneous when viewed under a light microscope and ar e pale pink when stained with hematoxylin-eosin. Under polarized light, amyloid stained with Congo red dye produces the characteristic apple-green birefringence . The modification of alkaline Congo red dye by Puchtler and Sweat [2] is used m ost often. The amorphous hyalinelike appearance of amyloid is misleading because it is a fibrous protein. On electron microscopy, amyloid deposits are composed of rigid, linear, nonbranching fibrils 7.5- to 10-nm wide and of indefinite leng th. The fibrils aggregate into bundles. The deposits occur extracellularly and u ltimately lead to damage of normal tissue. In primary amyloidosis (AL) the fibri ls consist of the variable portions of monoclonal ( ) or ( ) immunoglobulin ligh t chains or, very rarely, heavy chains. In secondary amyloidosis (AA) the fibril s consist of protein A, a nonimmunoglobulin. In familial amyloidosis (AF) the fi brils are composed of mutant transthyretin (prealbumin) or, rarely, fibrinogen o r apolipoprotein. In senile systemic amyloidosis the fibrils consist of normal t ransthyretin. The amyloid fibrils associated with long-term dialysis (A 2M dialy sis arthropathy) consist of 2-microglobulin. Amyloid P component is a glycoprote in composed of 10 identical glycosylated polypeptide subunits, each with a molec ular weight of 23,500 and arranged as two pentamers. The liver produces human se rum amyloid P (SAP) component. SAP is present in healthy persons and shows 50% t o 60% homology with C-reactive protein. SAP is bound to the amyloid fibrils; it is not an integral part of the fibrillar structure. It is found in all types of amyloid, including the vessel walls in patients with Alzheimer's disease. The phys iologic function of SAP and its pathologic role in amyloidosis are unknown. Glyc osaminoglycans are present in amyloid deposits. Their role also is unknown. Cata bolism or breakdown of the fibrils is an important factor in pathogenesis; howev er, little is known of the process [3]. No obvious predisposing condition is ass ociated with primary amyloidosis. Secondary amyloidosis is associated with an in flammatory process, malignancy, and many other conditions. No monoclonal protein exits in the serum or urine. CHAPTER 3

3.2 Systemic Diseases and the Kidney Microscopic Appearance and Classification FIGURE 3-1 (see Color Plate) Blood vessel from a bone marrow biopsy specimen ind icating primary amyloidosis. The specimen was stained with Congo red dye and vie wed with a polarizing light source, producing the characteristic apple-green bir efringence. In more than half of patients, results of bone marrow testing are po sitive for amyloidosis. (From Kyle [4]; with permission.) FIGURE 3-2 Electron photomicrograph showing the fibrillar character of amyloidos is. The fibrils are 7.5- to 10-nm wide and of indefinite length. The fibrils are deposited extracellularly, are insoluble, and generally resist proteolytic dige stion. They ultimately lead to disorganization of tissue architecture and loss o f normal tissue elements. and contains 76 amino acids. It is derived from serum amyloid A, which is an acutephase protein. The level of serum amyloid A is incre ased in patients with rheumatoid arthritis and Crohn's disease. In familial amyloi dosis the Portuguese, Swedish, and Japanese variants are characterized by substi tution of methionine for valine at residue 30 (Met-30) in the transthyretin mole cule. This mutation is characterized by the development of peripheral neuropathy . Cardiomyopathy from a transthyretin mutation has been reported in Denmark (Met -111) and in the Appalachian area of the United States (Ala-60). Familial renal amyloid from a mutation of the fibrinogen -chain (Leu-554 or Glu-526) or mutatio ns of lysozyme have been reported. Amyloidosis associated with familial Mediterr anean fever consists of protein A. Senile systemic amyloidosis involving the hea rt results from the deposition of normal transthyretin. Long-term dialysis often results in systemic amyloidosis from 2microglobulin deposition. CLASSIFICATION OF AMYLOIDOSIS Amyloid type Primary amyloidosis (AL) Secondary amyloidosis (AA) Familial amyloidosis (AF) Classification Primary, including multiple myeloma Secondary Familial Neuropathic: Portugal, Sw eden, Japan, and other countries Cardiopathic: Denmark and Appalachia in the Uni ted States Nephropathic: familial Mediterranean fever Senile cardiac Dialysis ar thropathy Major protein component or light chain Protein A Transthyretin mutant (prealbumin) Transthyretin mutant (prealbumin) Protein A Transthyretin normal (prealbumin) 2-microglobulin Senile systemic amyloidosis (AS) Dialysis amyloidosis (AD) FIGURE 3-3 Classification of amyloidosis. The fibrils in primary amyloidosis con sist of monoclonal or light chains. Rarely, monoclonal heavy chains are responsi ble. The major component of the amyloid fibril in secondary amyloidosis is prote in A. It has a molecular weight of 8.5 kD

Amyloidosis 3.3 SYSTEMIC AMYLOIDOSIS Amyloid type Congo red Primary (AL) Secondary (AA) FMF Associated with long-term hemodialysis Familial (AF) Senile systemic (AS) + + + + + + Amyloid stains or + Serum amyloid A + + 2-microglobulin Transthyretin (prealbumin) + + + FIGURE 3-4 Systemic amyloidosis. Types of proteins constituting the amyloid fibr ils. In primary amyloidosis the fibrils consist of monoclonal or light chains. I n secondary amyloidosis the fibrils consist of protein A. Systemic amyloidosis a ssociated with long-term hemodialysis consists of 2-microglobulin. The amyloid fibrils consist of mutated transthyretin or, rar ely, fibrinogen or lysozyme in familial amyloidosis. Senile systemic amyloidosis is characterized by the deposition of normal transthyretin in the heart. (From Kyle and Gertz [5]; with permission.) Familial, 3.5% (5) Senile, 2% (2) Localized, 8% (11) Secondary (AA), 3.5% (5) Primary (AL), 83% (112) n=135 FIGURE 3-5 Distribution of forms of amyloidosis seen in patients at the Mayo Cli nic in 1996. Of the 135 patients with amyloidosis, 83% had the primary form. Fam ilial, secondary, and senile amyloidosis accounted for less than 10% of patients . Localized amyloid is limited to the involved organ and never becomes systemic. In localized amyloidosis, the fibrils consist of an immunoglobulin light chain; however, the patients do not have a monoclonal protein in their serum or urine. Most localized amyloidosis occurs in the respiratory tract, genitourinary tract , or skin. Primary Systemic Amyloidosis 50 40 Patients, % 30 23 22 Male: 69% (n=327) Female: 31% (n=147) Median age: 64 y (n=474) Age range: 3290 y 37 FIGURE 3-6 Pattern of primary systemic amyloidosis in patients during an 11year study at the Mayo Clinic. From 1981 to 1992, of the 474 patients seen within 30 days of diagnosis the median age was 64 years. Only 1% were younger than 40 year s, and males were affected more often than were females. (From Kyle and Gertz [5 ]; with permission.)

20 10 0 1 10 7 <40 4049 5059 6069 Age, y 7079 80

3.4 70 62 Systemic Diseases and the Kidney FIGURE 3-7 Symptoms of primary systemic amyloidosis in patients during an 11-yea r study at the Mayo Clinic. Weakness or fatigue and weight loss were the most fr equent initial symptoms seen within 30 days of diagnosis. Weight loss occurred i n more than half of patients. The median weight loss was 23 lb; five patients lo st more than 100 lb each. Purpura, particularly in the periorbital and facial ar eas, was noted in about one sixth of patients. Gross bleeding was reported initi ally in only 3%. Skeletal pain was a major symptom in only 5% and usually was re lated to lytic lesions or fractures associated with multiple myeloma. Dyspnea, p edal edema, paresthesias, light-headedness, and syncope were noted. (From Kyle a nd Gertz [5]; with permission.) 60 52 Range: 4200 lb Median: 23 lb With symptoms, % 50 40 30 20 10 0 Fatigue Weight loss Purpura Symptoms 15 5 Bone pain FIGURE 3-8 Macroglossia in a man with primary systemic amyloidosis. Macroglossia occurs initially in about 10% of patients. Note the imprint of the teeth on the dorsum of the tongue. This patient was unable to close his mouth and complained of drooling. Macroglossia may cause obstruction of the airway, sometimes necess itating a tracheostomy. (From Kyle [4]; with permission.) FIGURE 3-9 Nodules causing occlusion of mary systemic amyloidosis. The external y by nodules of amyloid. This condition be the initial symptom. (From Gertz and the auditory canal in a patient with pri auditory canal may be occluded completel frequently produces deafness, which may Kyle [6]; with permission.)

FIGURE 3-10 Shoulder pad sign in a woman with primary systemic amyloidosis. Infi ltration of the periarticular tissues with amyloid may produce this sign. The sh oulder pad sign causes pain and limitation of motion and is very difficult to tr eat. (From Kyle [4]; with permission.)

Amyloidosis 3.5 FIGURE 3-11 Hypertrophic form of primary systemic amyloidosis in a 39-year-old m an with prominent and firm muscles. Despite the muscular appearance, results of a biopsy revealed displacement of muscle fibers with amyloid. Patients often exh ibit stiffness or limitation of movement. (From Kyle and Greipp [7]; with permis sion.) 30 25 Patients, % 20 15 10 5 0 Liver palpable 5 3 9 24 FIGURE 3-12 Signs of primary systemic amyloidosis in patients during an 11-year study at the Mayo Clinic. The liver was palpable in about one fourth of patients seen within 30 days of diagnosis. Hepatomegaly is due to infiltration of amyloi d or congestion from heart failure. The spleen is palpable in only 5% of patient s and rarely extends more than 5 cm below the left costal margin. Lymphadenopath y occurs infrequently. (Adapted from Kyle and Gertz [5]; with permission.) Spleen palpable Lymphadenopathy Signs of primary amyloidosis Macroglossia HEMOGLOBIN AND PLATELET VALUES WITHIN 30 DAYS OF DIAGNOSIS OF PRIMARY SYSTEMIC A MYLOIDOSIS, MAYO CLINIC, 19811992 n=473 2.0 20% 1.31.9 25% <1.2 55% Factor Hemoglobin, g/dL (<10 g/dL in 11%) Platelets, 109/L (>500 109/L in 9%) Median 12.9 288 Range 6.618.6 4953 Median: 1.1 Range: 0.414.6 FIGURE 3-13 Hemoglobin and platelet values within 30 days of diagnosis of primar y systemic amyloidosis. Anemia was not a prominent feature. When present, it usu ally is due to multiple myeloma, renal insufficiency, or gastrointestinal bleedi ng. Thrombocytosis was relatively common; in 9% of patients the platelet count w as over 500 109/L. Functional hyposplenism from amyloid replacement of the splee n may occur [8]. Hyposplenism is manifested by the presence of HowellJolly bodie s and occurs in about one fourth of patients. (Adapted from Kyle and Gertz [5].) FIGURE 3-14 Serum creatinine (mg/dL) in patients at diagnosis of primary systemi c amyloidosis. Renal insufficiency was present in almost half of patients. Prote inuria was present in about 75% of patients.

3.6 Systemic Diseases and the Kidney Polyclonal 1% Hypogammaglobulinemia 20% b band 10% g band 38% IgM 5% k only 9% l only 15% IgD 1% 6.0 20% Negative 28% 3.05.9 16% 1.02.9 19% <1.0 45% Normal 31% n=463 IgA 10% IgG 32% n=430 Median:1.2 g/d Range: 0.124.1 g/d n=443 FIGURE 3-15 Results of serum protein electroplasmaphoresis in patients at diagno sis of primary systemic amyloidosis. The serum protein electrophoretic pattern s howed hypogammaglobulinemia in 20% of patients. Only half of patients had a loca lized band or spike in the or areas of the electrophoretic pattern. The median s ize of the M spike was 1.4 g/dL. In the remaining patients the pattern was norma l. FIGURE 3-16 Serum monoclonal (M-) protein in patients at diagnosis of primary sy stemic amyloidosis in an 11-year study at the Mayo Clinic. Immunoelectrophoresis or immunofixation of the serum showed an M-protein in 72% of patients. IgG was most common, followed by IgA. Twenty-four percent of patients had monoclonal imm unoglobulin light chains in the serum (Bence Jones proteinemia). (Adapted from K yle and Gertz [5]; with permission.) FIGURE 3-17 Urine total protein values in patients at diagnosis of primary syste mic amyloidosis in an 11-year study at the Mayo Clinic. More than one third of p atients exhibited 24-hour urine total protein values of 3.0 g/d or more. Over ha lf of patients had a urine protein value of more than 1 g/d. The electrophoretic pattern showed mainly albumin. (Adapted from Kyle and Gertz [5]; with permissio n.) k 23% l 50% Negative 27% n=429 S+, U 16% S, U 11% S, U+ 17% n=408 S+, U+ 56% FIGURE 3-18 Urine monoclonal (M-) protein in patients at diagnosis of primary sy stemic amyloidosis in an 11-year study at the Mayo Clinic. Almost three fourths of patients had monoclonal light chains in their urine on immunoelectrophoresis or immunofixation. In contrast to the type of protein found in multiple myeloma, is twice as common as is . The 24-hour total amount of monoclonal (M-) protein in the urine was less than 0.5 g/d in more than half of patients. (From Kyle and Gertz [5]; with permission.) FIGURE 3-19 Serum (S) and urine (U) proteins in patients with primary systemic a myloidosis in an 11-year study at the Mayo Clinic. Immunoelectrophoresis or immu nofixation of serum and appropriate concentrations in urine showed a monoclonal

protein in nearly 90% of patients. In the absence of monoclonal protein, one mus t search for a monoclonal population of plasma cells in the bone marrow or perfo rm immunohistochemical staining to identify the type of amyloid. (From Kyle and Gertz [5]; with permission.) FIGURE 3-20 Enlarged kidney in primary systemic amyloidosis. Involvement of the kidneys is the most common presenting feature. The kidney is frequently normal i n size, but in some instances small kidneys have been found.

Amyloidosis 3.7 100 80 Survival, % 60 40 20 0 0 1 Years after dialysis 2 3 FIGURE 3-21 (see Color Plate) Photomicrograph showing a renal biopsy specimen st ained with Congo red dye taken from a patient with primary systemic amyloidosis. Note the homogeneous deposition of amyloid in the glomerulus. Results of kidney biopsy are positive in about 95% of patients. FIGURE 3-22 Survival analysis of patients with primary systemic amyloidosis. The median survival from the onset of dialysis was 8.2 months in 37 patients. No di fference exists between patients treated with hemodialysis and those treated wit h peritoneal dialysis. Biopsy results were used to make the diagnosis in 211 pat ients. The most important predictors of which patients would ultimately require dialysis were the 24-hour urinary protein loss and serum creatinine values at th e time of diagnosis. None of the patients who had a normal serum creatinine valu e and a urine protein value of less than 2 g/d at diagnosis required dialysis du ring follow-up. Of the 37 patients who received dialysis, 31 died, and 21 of the 31 died as a result of extrarenal progression of their systemic amyloidosis. Ha lf of the deaths were caused by cardiac amyloidosis [9]. FIGURE 3-23 Gross specimen of a liver in primary systemic amyloidosis. The liver is grossly enlarged. FIGURE 3-24 Photomicrograph showing extensive amyloid deposition in the liver in primary systemic amyloidosis.

3.8 Systemic Diseases and the Kidney ALKALINE PHOSPHATASE, ASPARTATE AMINOTRANSFERASE, AND BILIRUBIN VALUES WITHIN 30 DAYS OF DIAGNOSIS OF PRIMARY SYSTEMIC AMYLOIDOSIS, MAYO CLINIC, 19811992 Factor Alkaline phosphatase Aspartate aminotransferase Total bilirubin PROTHROMBIN TIME, CAROTENE, AND B12 VALUES WITHIN 30 DAYS OF DIAGNOSIS OF PRIMAR Y SYSTEMIC AMYLOIDOSIS, MAYO CLINIC, 19811992 Factor Normal value 250 U/L 30 U/L 1.1 mg/dL Patients, % 16 6 3 Values above normal, n (%) >250 (26) 500 (11) >30 (34) 100 (3) >1.1 (11) 5 (1) Prothrombin time >13 s Carotene <48 g/dL Serum B12 <150 pg/mL FIGURE 3-25 Alkaline phosphatase, aspartate aminotransferase, and bilirubin valu es within 30 days of diagnosis of primary systemic amyloidosis. The serum alkali ne phosphatase level was increased in one fourth of 474 patients at the time of diagnosis. The aspartate aminotransferase value was increased in one third of pa tients but rarely reached 100 U/L. Hyperbilirubinemia was an infrequent finding but when present was associated with short survival [5]. (Adapted from Kyle and Gertz [5].) FIGURE 3-26 Prothrombin time, carotene, and vitamin B12 values within 30 days of diagnosis of primary systemic amyloidosis. The prothrombin time was increased i n one sixth of patients at the time of diagnosis. It has been shown that prolong ation of thrombin time occurs in 40% of patients [10]. A deficiency in factor X occurs in 15% but is not associated with bleeding. Malabsorption as manifested b y a low carotene or serum B12 level occurs infrequently. (Adapted from Kyle and Gertz [5].) PERCENTAGE OF BONE MARROW PLASMA CELLS WITHIN 30 DAYS OF DIAGNOSIS OF PRIMARY SY STEMIC AMYLOIDOSIS, MAYO CLINIC, 19811992 Plasma cells, % (median = 7%) 5 69 1019 20 Patients, % (n = 391) 44 16 22 18 FIGURE 3-27 Bone marrow aspirate specimen from a patient with primary systemic a myloidosis. This specimen contains an increase in plasma cells. FIGURE 3-28 Percentage of bone marrow plasma cells within 30 days of diagnosis o f primary systemic amyloidosis. Almost half of patients had 5% or fewer plasma c ells in the bone marrow at the time of diagnosis. About one fifth of patients ha d bone marrow plasmacytosis of 20% or more. Multiple myeloma must be considered in this setting. The plasma cells are monoclonal or . (From Kyle and Gertz [5]; with permission.)

Amyloidosis FIGURE 3-29 Radiograph showing marked cardiac enlargement in a patient with prim ary systemic amyloidosis. Overt congestive heart failure is present in about one sixth of patients at the time of diagnosis. Pleural effusion is common. 3.9 FIGURE 3-30 Electrocardiogram in a patient with primary systemic amyloidosis, sh owing low voltage in the limb leads or loss of anterior septal forces that mimic s the findings in myocardial infarction. However, ischemic heart disease is not present. Arrhythmias may include atrial fibrillation, junctional tachycardia, pr emature ventricular complexes, or heart block. 20 mm 11% 11 mm 24% 1519 mm 36% Survival, % 100 75 < 15 mm (n=64) P=0.0003 50 25 15 mm (n=57) 1214 mm 29% n=121 0 0 1 2 3 Time, y 4 5 FIGURE 3-31 Echocardiogram of a patient with primary systemic amyloidosis showin g marked thickness of the ventricular wall. Results on echocardiogram are abnorm al in two thirds of patients at the time of diagnosis. LVleft ventricle; RVright v entricle. (From Gertz and Kyle [3]; with permission.) FIGURE 3-32 Septal thickness on echocardiography in patients with primary system ic amyloidosis. Almost half of patients had septal thickness of 15 mm or more on echocardiography at the time of diagnosis. Only 24% had no increased septal thi ckness. FIGURE 3-33 Analysis of the association between septal thickness and survival in patients with primary systemic amyloidosis in an 11-year study at the Mayo Clin ic. An increase in septal thickness is associated with shorter survival. Patient s with a septal thickness of 15 mm or more had a median survival of 7 months, wh ereas in those with a septal thickness less than 15 mm the median survival was 2 6 months. (From Kyle and Gertz [5]; with permission.)

3.10 Systemic Diseases and the Kidney FIGURE 3-34 Cross section of the heart showing marked thickening of the left ven tricular wall and septum in primary systemic amyloidosis. The ventricular cavity is greatly reduced in volume. (From Gertz and Kyle [3]; with permission.) 40 30 Patients, % 20 2 5 0.5 0.5 At diagnosis During follow-up n=474 1.5 10 0 28 17 21 17 11 FIGURE 3-35 Analysis of previously unexplained syndromes in patients with primar y systemic amyloidosis at the time of diagnosis in an 11-year study at the Mayo Clinic. Nephrotic syndrome or renal failure was present in 28% of patients, cong estive heart failure (CHF) in 17%, and carpal tunnel syndrome in 21%. Peripheral neuropathy and orthostatic hypotension also were common features. The possibili ty of primary systemic amyloidosis must be considered in every patient who has m onoclonal protein in the serum or urine and who has unexplained nephrotic syndro me, CHF, sensorimotor peripheral neuropathy, carpal tunnel syndrome, hepatomegal y, or malabsorption. (Adapted from Kyle and Gertz [5]; with permission.) Nephrotic/ renal failure (142) CHF (104) Carpal tunnel (102) Peripheral Orthostatic neuropathy hypotension (58) (81) Symptoms (number of patients) 100 80 Positive, % 60 40 20 0 80 75 56 94 82 97 90 83 86 100 Abdominal Bone Rectum Kidney Carpal ligament fat marrow (20) (212) (394) (194) ( 81) Liver (32) Small intestine (23) Skin (19) Sural nerve (21) Heart (16) Presence of amyloid in tissue (number of patients)

FIGURE 3-36 Diagnosis of primary systemic amyloidosis based on the presence of a myloid in tissue in an 11-year study at the Mayo Clinic. The initial diagnostic procedure should be an abdominal fat aspirate [11]. The diagnosis will be confir med in 80% of patients. Experience in the staining technique and interpretation of the fat aspirate is important before routine use. A bone marrow aspirate and bone marrow biopsy specimen should be obtained to determine the degree of plasma cytosis, and results of amyloid stains are positive in more than half of patient s. Either the abdominal fat aspirate or bone marrow biopsy specimen is positive in 90% of patients. When amyloid is still suspected and the test results of thes e tissues are negative, one should proceed to performing a rectal biopsy, which is positive in approximately 80% of patients. The specimen must include the subm ucosa. When the test results for these sites are negative, tissue should be obta ined from an organ with suspected involvement. (From Kyle and Gertz [5]; with pe rmission.)

Amyloidosis 3.11 100 Nephrotic/renal failure (n=114) Congestive heart failure (n=80) Orthostatic hypo tension (n=41) 75 Survival, % Peripheral neuropathy (n=40) Total (n=474) 50 25 0 0 1 2 3 4 Time, y 5 6 7 8 FIGURE 3-37 (see Color Plate) Aspirate of subcutaneous abdominal fat from a pati ent with primary systemic amyloidosis. The specimen shows the characteristic app le-green birefringence when stained with Congo red dye and viewed with a polariz ing light source. FIGURE 3-38 Analysis of median survival in patients with primary systemic amyloi dosis in an 11-year study at the Mayo Clinic. The median survival of 474 patient s seen within 1 month of diagnosis was 13.2 months. The median duration of survi val was 4 months for the 80 patients who exhibited congestive heart failure on p resentation. (From Kyle and Gertz [5]; with permission.) Infection 8% Renal 6% Other 8% Unknown 13% "Primary amyloidosis" 17% n=285 Cardiac 48% FIGURE 3-39 Causes of death in patients with primary systemic amyloidosis in an 11-year study at the Mayo Clinic. Of the 285 patients who died, death was attrib uted to cardiac involvement from congestive heart failure or arrhythmias in 48%. The actual percentage of cardiacrelated deaths was probably higher because some patients whose death was attributed to primary amyloidosis almost certainly had terminal cardiac arrhythmia. (Adapted from Kyle and Gertz [5]; with permission. ) 100 80 60 40 20 0 0 1 2 3 4 5 6 Survival, y 7 8 9 10 Arm MP MPC C Months 18 17 8.5 P<0.001 FIGURE 3-40 Survival curves in patients with primary systemic amyloidosis. Becau se amyloid fibrils consist of monoclonal immunoglobulin light chains, treatment with alkylating agents that are effective against plasma cell neoplasms is warra nted. We treated 220 patients who had positive results on biopsy. The patients w ere randomized to receive colchicine (C, 72 patients), melphalan and prednisone (MP, 77), or melphalan, prednisone, and colchicine (MPC, 71). Patients were stra tified according to their chief clinical manifestations: renal disease (105 pati ents), cardiac involvement (46), peripheral neuropathy (19), or other (50). The median duration of survival after randomization was 8.5 months in the colchicine group; 18 months in the group assigned to melphalan and prednisone; and 17 mont hs in the group assigned to melphalan, prednisone, and colchicine (P < 0.001). I n patients who had a reduction in serum or urine monoclonal protein at 12 months , the overall duration of survival was 50 months; whereas among those without a

reduction in monoclonal protein at 12 months, the duration of survival was 36 mo nths (P < 0.003). Thirty-four patients (15%) survived for 5 years or longer. (Ad apted from Kyle et al. [12]; with permission.) Patients, %

3.12 Systemic Diseases and the Kidney FIGURE 3-41 Other therapy for primary amyloidosis. High-dose dexamethasone has b een reported to be beneficial in treating patients with primary systemic amyloid osis [13]. More intensive therapy consisting of high-dose chemotherapy followed by rescue with peripheral stem cells shows promise [14]. The introduction of 4 iodo-4 -deoxydoxorubicin, which has an affinity for amyloid fibrils, may be an i mportant treatment option [15]. OTHER THERAPY FOR PRIMARY AMYLOIDOSIS High-dose dexamethasone Stem cell transplantation 4'
iodo
4'
deoxydoxoruicin Secondary Amyloidosis CAUSES OF SECONDARY AMYLOIDOSIS Cause Rheumatic disease Rheumatoid arthritis Ankylosing spondylitis Other Total Infect ion Inflammatory bowel disease Bronchiectasis Osteomyelitis Other Total Malignan cy None PRESENTING CLINICAL FEATURES OF SECONDARY AMYLOIDOSIS Feature Patients, % 91 22 9 5 3 2 2 0 Patients, n 31 5 6 42 6 5 5 3 19 2 1 Proteinuria or renal insufficiency Diarrhea, obstipatio n, or malabsorption Goiter Hepatomegaly Neuropathy or carpal tunnel syndrome Lym phadenopathy Hematuria Cardiac amyloidosis FIGURE 3-42 Causes of secondary amyloidosis. Rheumatoid arthritis is the most fr equent cause of secondary amyloidosis. In our study of 64 patients, rheumatoid a rthritis was present for a median of 18 years before the diagnosis was made [16] . Inflammatory bowel disease, bronchiectasis, and osteomyelitis are not uncommon causes of secondary amyloidosis. (From Gertz and Kyle [16]; with permission.) FIGURE 3-43 Presenting features of secondary amyloidosis. Proteinuria is the mos t frequent laboratory finding in patients with secondary amyloidosis. Involvemen t of the gastrointestinal tract as manifested by diarrhea, obstipation, or malab sorption occurred in one fifth of our patients. Treatment of secondary amyloidos is depends on the underlying disease. Familial Mediterranean fever frequently is associated with secondary amyloidosis unless the patient is treated with colchi cine. (From Gertz and Kyle [16]; with permission.) 25 20 15 10 5 0 13 38 >8 0 24-h urinary protein, g/d n=55 1 1.12 2.14 >4 Serum creati nine, mg/dL n=64 14 19 17 17 14 17 14 FIGURE 3-44 Proteinuria and renal insufficiency in patients with secondary amylo idosis. The clinical target organ was the kidney in 91% of patients. (From Gertz and Kyle [16]; with permission.) Patients, n 7

Amyloidosis 3.13 100 Creatinine <2.0 mg/dL, n=32 80 Survival, % 60 40 20 0 0 24 48 Time, mo Creatinine 2.0 mg/dL, n=32 P=0.003 FIGURE 3-45 Association between serum creatinine levels and survival in patients with secondary amyloidosis. A serum creatinine value of 2 mg/dL or more was ass ociated with a shorter survival than was a value of less than 2 mg/dL. (From Ger tz and Kyle [16]; with permission.) 72 96 120 Familial Amyloidosis 2 1 2 2 1 1 1 1 7 6 2 3 2 2 3 6 1 1 3 6 2 1 1 1 2 4 3 1 5 2 1 FIGURE 3-46 Wide geographic distribution of familial amyloidosis. Familial or he reditary amyloidosis has an autosomal dominant pattern of inheritance. It accoun ts for 3.5% of our cases of amyloidosis. In our practice, the geographic distrib ution is wide and not associated with clustering. Frequently, a family history o f amyloidosis was not obtained until after amyloidosis was diagnosed [17]. More than 50 transthyretin mutations have been recognized [18]. (Adapted from Gertz e t al. [17]; with permission.) 1 2 3 4 5 6 7 Not studied for variant transthyretin Met-30 Ala-60 Tyr-77 His-58 Leu-33 Studiedn o variant transthyretin found Leu-64 3

3.14 Systemic Diseases and the Kidney of bladder and gastrointestinal function are common. Late onset may occur with t he development of symptoms in the seventh or eighth decade of life. The nephropa thic form is most often caused by familial Mediterranean fever. This form affect s persons of Mediterranean descent and is characterized by recurrent episodes of fever and abdominal pain that begin in childhood. Familial amyloidosis involvin g the kidneys has been reported by Ostertag [19] and others [2022]. Families with apolipoprotein A1 mutation, as well as mutations in the fibrinogen -chain gene, have been recognized. On presentation, patients with renal involvement exhibit hypertension and mild renal insufficiency that progresses to endstage renal fail ure. The amyloid deposits have mutations in the fibrinogen -chain gene. This for m of amyloidosis is autosomal dominant. No peripheral neuropathy develops, and t he onset of renal disease occurs in the fifth to seventh decades of life. The mu tation consists of the substitution of glutamic acid for valine at position 526 of the fibrinogen chain. A mutation in fibrinogen has been described at position 554 [23,24]. A rare form of inherited secondary amyloidosis produces nephropath y, deafness, and urticaria. This form has been referred to as the Muckle-Wells s yndrome [25]. (Adapted from Kyle and Gertz [26].) CLASSIFICATION OF FAMILIAL AMYLOIDOSIS Classification Neuropathic: Portugal, Japan, Sweden, and other countries Cardiopathic: Denmark and Appalachia in the United States Nephropathic: familial Mediterranean fever Major protein component Transthyretin (prealbumin) Transthyretin (prealbumin) Protein A FIGURE 3-47 Classification of familial amyloidosis. Clinically, familial amyloid osis can be classified most easily as neuropathic, cardiopathic, or nephropathic . The neuropathic form is characterized by a sensorimotor peripheral neuropathy beginning in the lower extremities. Disturbances Dialysis-Associated Amyloidosis RATE OF AMYLOIDOSIS ( 2-MICROGLOBULIN) WITH DIALYSIS Years of dialysis 10 15 >20 Patients with amyloidosis, % 20 3050 80100 FIGURE 3-48 Radiograph showing carpal tunnel syndrome in a patient with dialysis -associated amyloidosis. Long-term hemodialysis often results in carpal tunnel s yndrome with pain involving the shoulders, hands, wrists, hips, and knees. Cysti c radiolucencies are common in the carpal bones. Pathologic fractures have occur red from large amyloid deposits. The major component of the amyloid is 2-microgl obulin. (From Gertz and Kyle [3]; with permission.) FIGURE 3-49 Amyloidosis ( 2-microglobulin) with dialysis. The duration of dialys is is directly associated with the incidence of amyloidosis. Dialysisassociated amyloidosis will develop in more than 80% of patients after 20 years of dialysis . It occurs with both hemodialysis and peritoneal dialysis. The amyloid depositi on is systemic; however, involvement of visceral organs is usually modest [27,28 ]. Renal transplantation often leads to dramatic improvement in joint symptoms. A 2microglobulinabsorbent column may be useful in therapy [29].

Amyloidosis 3.15 References 1. Virchow R: Cited by Schwartz P: Amyloidosis: Cause and Manifestation of Senil e Deterioration. Springfield, IL: Charles C Thomas; 1970. 2. Puchtler H, Sweat F : Cited by Elghetany MT, Saleem A: Methods for staining amyloid in tissues: a re view. Stain Technol 1988, 63:201212. 3. Gertz MA, Kyle RA: Amyloidosis. In Neopla stic Diseases of the Blood, edn 3. Edited by Wiernik PH, Canellos GP, Dutcher JP , et al. New York: Churchill Livingstone; 1996:635677. 4. Kyle RA: Amyloidosis. I n Hematology: Basic Principles and Practice. Edited by Hoffman R, Benz EJ Jr, Sh attil SJ, et al. New York: Churchill Livingstone; 1991:10381047. 5. Kyle RA, Gert z MA: Primary systemic amyloidosis: clinical and laboratory features in 474 case s. Semin Hematol 1995, 32:4559. 6. Gertz MA, Kyle RA: Primary systemic amyloidosi s: a diagnostic primer. Mayo Clin Proc 1989, 64:15051519. 7. Kyle RA, Greipp PR: Amyloidosis (AL): clinical and laboratory features in 229 cases. Mayo Clin Proc 1983, 58:665683. 8. Gertz MA, Kyle RA, Greipp PR: Hyposplenism in primary systemi c amyloidosis. Ann Intern Med 1983, 98:475477. 9. Gertz MA, Kyle RA, O'Fallon WM: D ialysis support of patients with primary systemic amyloidosis: a study of 211 pa tients. Arch Intern Med 1992, 152:22452250. 10. Gastineau DA, Gertz MA, Daniels T M, et al.: Inhibitor of the thrombin time in systemic amyloidosis: a common coag ulation abnormality. Blood 1991, 77:26372640. 11. Gertz MA, Li C-Y, Shirahama T, Kyle RA: Utility of subcutaneous fat aspiration for the diagnosis of systemic am yloidosis (immunoglobulin light chain). Arch Intern Med 1988, 148:929933. 12. Kyl e RA, Gertz MA, Greipp PR, et al.: A trial of three regimens for primary amyloid osis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med 1997, 336:12021207. 13. Dhodapkar M, Jagannath S, Vesol e D, et al.: Efficacy of pulse dexamethasone (DEX) plus maintenance alpha interf eron (IFN) in primary systemic amyloidosis (AL) [abstract]. Blood 1995, 86(suppl 1):442A. 14. Comenzo RL, Vosburgh E, Sarnacki DL, et al.: High-dose melphalan w ith blood stem-cell support for AL amyloidosis [abstract]. Blood 1995, 86 (suppl 1):206A. 15. Gianni L, Bellotti V, Gianni AM, et al.: New drug therapy of amylo idoses: resorption of AL-type deposits with 4 -iodo-4 -deoxydoxorubicin. Blood 1 995, 86:855861. 16. Gertz MA, Kyle RA: Secondary systemic amyloidosis: response a nd survival in 64 patients. Medicine 1991, 70:246256. 17. Gertz MA, Kyle RA, Thib odeau SN: Familial amyloidosis: a study of 52 North American-born patients exami ned during a 30-year period. Mayo Clin Proc 1992, 67:428440. 18. Saraiva MJM: Mol ecular genetics of familial amyloidotic polyneuropathy. J Peripheral Nerv Syst 1 996, 1:179188. 19. Ostertag B: Demonstration einer eigenartigen familiaren paraamy loidose [abstract]. Zentralbl Allg Pathol 1932, 56:253254. 20. Weiss SW, Page DL: Amyloid nephropathy of Ostertag with special reference to renal glomerular giant cells. Am J Pathol 1973, 72:447460. 21. Lanham JG, Meltzer ML, De Beer FC, et al .: Familial amyloidosis of Ostertag. Q J Med 1982, 51:2532. 22. Mornaghi R, Rubin stein P, Franklin EC: Familial renal amyloidosis: case reports and genetic studi es. Am J Med 1982, 73:609614. 23. Benson MD, Liepnieks J, Uemichi T, et al.: Here ditary renal amyloidosis associated with a mutant fibrinogen alpha-chain. Nat Ge net 1993, 3:252255. 24. Uemichi T, Liepnieks JJ, Benson MD: Hereditary renal amyl oidosis with a novel variant fibrinogen. J Clin Invest 1994, 93:731736. 25. Muckl e TJ: The Muckle-Wells syndrome. Br J Dermatol 1979, 100:8792. 26. Kyle RA, Gertz M A: Amyloidosis of the liver. In Schiff's Diseases of the Liver, edn 8. Edited by S chiff ER, Sorrell MF, Maddrey WC. Philadelphia: Lippincott-Raven; in press. 27. Gejyo F, Arakawa M: 2-microglobulin-associated amyloidoses. J Intern Med 1992, 2 32:531532. 28. Kay J: 2-Microglobulin amyloidosis. Int J Exp Clin Invest 1997, 4: 187211. 29. Gejyo F, Homma N, Hasegawa S, et al.: A new therapeutic approach to d ialysis amyloidosis: intensive removal of 2-microglobulin with adsorbent column. Artif Organs 1993, 17:240243.

Sickle Cell Disease L.W. Statius van Eps H errick [1] was the first to discover sickle cell hemoglobin ( 2 S ) with sickleshaped erythrocytes. In 1910, he described 2 the case of a young black student f rom the West Indies with severe anemia characterized by peculiar elongated and si ckle-shaped red blood corpuscles. Herrick also noted a slightly increased volume of urine of low specific gravity and thus observed the most frequent feature of sickle cell nephropathy: inability of the kidney to concentrate urine normally. CHAPTER 4

4.2 Systemic Diseases and the Kidney Sickle Cell Nephropathy The term sickle cell nephropathy encompasses all the structural and functional a bnormalities of the kidneys seen in sickle cell disease. These renal defects are most pronounced in homozygous sickle cell anemia (Hb SS), double heterozygous s ickle cell hemoglobin C disease (Hb SC), sickle cell hemoglobin D disease, sickl e cell hemoglobin E disease (SE) disease, and sickle cell -thalassemia. Identifi cation of this familial autosomal codominant disorder as an abnormality of the h emoglobin molecule was made in 1949 by Pauling and coworkers [2]. Sickle Cell Anemia In 1959, Ingram [3] discovered the exact nature of the defect: substitution of v aline for glutamic acid at the sixth residue of the chain, establishing sickle c ell anemia as a disease of molecular structure, a molecular disease based on one p oint mutation. It is most fascinating that one substitution in the gene encoding , with the resulting replacement of 6 glutamic acid by valine, leads to the prot ean and devastating clinical manifestations of sickle cell disease. The structur al and functional abnormalities in the kidneys of patients with sickle cell dise ase, all resulting from that one point mutation, are described and discussed. Wh en sickle hemoglobin (Hb S) is deoxygenated the replacement of 6 glutamic acid w ith valine has as a consequence a hydrophobic interaction with another hemoglobi n molecule (reproduced schematically in Fig. 4-3). One of the two subunits forms a hydrophobic contact with an acceptor site on a subunit of a neighboring chain . An aggregation into large polymers is triggered. The twisted ropelike structur e to the right is a polymer composed of 14 strands. In a concentrated solution o f deoxygenated Hb S, large polymers and free tetramers are demonstrated readily. However, species of intermediate size cannot be detected. This means polymeriza tion of Hb S occurs easily and can be regarded as a simple crystal solution equi librium [4]. As a rule, renal hemodynamics are either normal or supernormal in p atients with Hb SS and who are less than 30 years of age. The filtration fractio n (glomerular filtration rate/effective renal plasma flow) has been found to be decreased (mean, 14% to 18%; normal, 19% to 22%). It has been suggested that sel ective damage of the juxtamedullary glomeruli might result in a lower filtration fraction because these nephrons appear to have the highest filtration fractions . Microradioangiographic studies lend support to this suggestion [5]. Speculatio n exists as to the possible mechanisms responsible for the decline in renal hemo dynamics with age, sometimes ending in renal failure with shrunken end-stage kid neys. This decline could be the result of the loss of medullary circulation, as suggested by the microradioangiographic studies. Another possible mechanism is t he relationship between supernormal hemodynamics, hyperfiltration, and glomerulo sclerosis [6]. An inability to achieve maximally concentrated urine has been the most consistent feature of sickle cell nephropathy.

Sickle Cell Disease 4.3 Molecular Pathogenic Mechanisms and Sickling EF1 EF F' F1 b2 A9 b1 E' H' A' H23 A B1 F H15 F8 FG4 H B E7 H9 G9 G C4 C3 FG3 G1 G' C' G3 C3 C6 C7 C B14 CD5 G19 E1 E B11 CD5 E1 B9 G' C5 C6 C C3 G1 FG5 FG4 FG3

G2 G G19 G9 H9 E7 C5 F' D1 B E7 A12 H' FG4 F8 E H H15 F E' a2 A' A A1 FIGURE 4-1 Three-dimensional drawing of a hemoglobin molecule. Shown are the int errelationship of the two and two chains, localization of the helices, amino aci ds in the chains, and iron molecules in the porphyria structure. Of the 1 and 2 chains the helical and nonhelical segments can be identified easily. The individ ual amino acids are marked as circles and connected to each other. The dark rect angles represent the heme group, and within their center is the iron molecule. T hese heme groups are localized between the E and F helices. The helices in a hem oglobin molecule are designated by letters from A to H, starting from the amino end. The whole molecule has a spherical form with a three-dimensional measuremen t of 64 by 55 by 50 . (Adapted from Dickerson and Geis [7]; with permission.) a1 EF EF1 Respiratory Movement of the Hemoglobin Molecule Shift of b chains F F' B' H' H GH B G H a1 F A G B G' GH F' a2 C D E a1 F C B A E F F' H ' B' A' H GH G H A G G' GH F' a2 B C D A E b1 b2 b1 b2 C E

Oxyhemoglobin Deoxyhemoglobin FIGURE 4-2 Respiratory movement of a hemoglobin molecule. From a functional poin t of view the so-called respiratory movement of the hemoglobin molecule is of gr eat importance. When the four oxygen atoms bind to oxyhemoglobin, the firmly bou nd 1- 1 and 1- 2 move away from each other slightly. After full oxygenation the heme groups of the chains are 7 closer to each other (R configuration). After de oxygenation the opposite occurs (T configuration). This respiratory movement (R in dicates the relaxed and T the tense configuration) is of great importance in our understanding of the pathogenesis of sickling: polymerization occurs when the T configuration takes place. (Adapted from Dickerson and Geis [7]; with permissio n.)

4.4 Systemic Diseases and the Kidney FIGURE 4-3 Schematic representation of the interactions of sickle red cells. Sic kle red cells (dark circles) traverse the microcirculation, releasing oxygen fro m oxyhemoglobin, and change into deoxyhemoglobin (light circles). Deoxygenation of hemoglobin S induces a change in conformation in which the subunits move away from each other. The hydrophobic patch at the site of the 6 where the valine re placement has occurred (shown as a projection) can bind to a complementary hydro phobic site of the 6 valine replacement (shown as an indentation). This mechanis m is important for the formation of a polymer (see Fig. 4-4). The diagram to the right shows the assembly of deoxyhemoglobin S into a helical 14-strand fiber: a polymer is formed (see Fig. 4-5). As the deoxyhemoglobin S polymerizes and fibe rs align, the erythrocyte is transformed into a sickle shape, observed at the bott om by scanning electron micrography. (Adapted from Bunn [4]; with permission). b b a a O2 a a b b b a a a a a a b b b b b b b b b b b a a a a a a Cell Polymer Nucleation Alignment Growth FIGURE 4-4 Polymerization of sickle cell hemoglobin. This polymerization occurs in three stages: 1) nucleation, 2) fiber growth, and 3) fiber alignment. The end stage is a complicated structure for a helical fiber: four inner fibers surroun ded by 10 outer filaments. Sickling, the process of polymerization, occurs under three different circumstances: 1) deoxygenation, 2) acidosis, and 3) extracellu lar hyperosmolality. These circumstances produce shrinking of the erythrocytes t hat causes elevation of the intracellular hemoglobin concentration. This mechani sm occurs in the inner medulla of the kidney and renal papillae as a result of c ountercurrent multiplication. Extracellular osmolality increases with the result s previously mentioned [8].

Sickle Cell Disease 4.5 Electron Microscopy and Three-Dimensional Reconstruction of a Polymerized Fiber of Hemoglobin FIGURE 4-5 Structures of polymerized fibers. A, Electron microscopy of a polymer ized fiber of hemoglobin S. BD, Structures of a three-dimensional reconstruction of such a fiber. Each small sphere represents a Hb S tetramer. B, A complete fib er, consisting of 14 grouped filaments in helical structure. C, The inner core o f four filaments. D, A combination of inner and outer filaments. (From Edelstein [9]; with permission.) A B C D Polymerization of Hemoglobin S A FIGURE 4-6 Polymerization of hemoglobin S. Polymerization of deoxygenated hemogl obin S is the primary event in the molecular pathogenesis of sickle cell disease , resulting in a distortion of the shape of the erythrocyte and a marked decreas e in its deformability. These rigid cells are responsible for the vaso-occlusive phenomena that are the hallmark of the disease [4]. Interesting shapes of varia ble forms result depending B on the localization of the polymers in the cell. A collection of electron micros copy scans of sickle cells undergoing intracellular polymerization is shown here . The slides were created in different laboratories. A, Characteristic periphera l blood smear from a patient with sickle cell anemia. Extreme sickled forms and target cells are seen. B, Electron microscopy scan of normal erythrocytes. (Cont inued on next page)

4.6 Systemic Diseases and the Kidney C D E F G H I J FIGURE 4-6 (Continued) C, Electron microscopy scan of a normal erythrocyte and a sickle cell. DL, This series of sickle cells show many possible formations of si ckled erythrocytes. The variety of shapes results from the intracellular localiz ation of the polymers. In bananaor sickle-shaped cells the polymers have formed bundles of fibers oriented along the long axis of the cell. In cells with a holl yleaf shape (panel E), the hemoglobin fibers point in different directions. K L

Sickle Cell Disease 4.7 Types of Sickle Cells and Released Membrane Structures A B C D FIGURE 4-7 Types of sickle cells and released membrane structures. Franck and co workers [10] reported that the normal membrane phospholipid organization is alte red in sickled erythrocytes. These authors presented evidence of enhanced transbilayer movement of phosphatidylcholine in deoxygenated reversibly sickled cells and put forward the hypothesis that these abnormalities in phospholipid organiz ation are confined to the characteristic protrusions of these cells. Scanning el ectron micrographs of various types of sickle cells and released membrane struct ures are shown. A, Deoxygenated despicular red sickle cells (RSC). B, Deoxygenat ed native RSC. C, Oxygenated irreversibly sickled cell. D, Spicules. E, Purified microvesicles. The free spicules released from RSC by repeated sickling and uns ickling as well as the remnant despicular cells were studied by following the fa te of 14C-labeled phosphatidylcholine. The results are shown in Figure 4-8. The free spicules have the same lipid composition as do the native cell but are defi cient in spectrin. These spicules markedly enhance the rate of thrombin and prot hrombin formation, explaining the prethrombotic state of the patient with sickle cell disease and the tendency toward the occurrence of crises. The prethromboti c state, also present in the renal circulation, stimulates sickle cell formation occurring in the inner renal medulla and papillae where hyperosmosis also contr ibutes to sickling and microthrombi formation in the vasa recta. (From Franck an d coworkers. [10]; with permission.) E

4.8 Systemic Diseases and the Kidney Penetration and Deconstruction of the Erythrocyte Membrane Spicule formation in sickled erythrocyte Spicule formation in sickled erythrocyt e A B FIGURE 4-8 Penetration and destruction of the erythrocyte membrane. A, The mem brane is penetrated and destroyed by the intracellular formation of polymers, re sulting in spicule formation. B, Interruption of the binding between the membran e and protein skeleton results in a massive exchange of lipids between the insid e and outside of the cell. This process is called flip-flop. An abnormal membran e skeleton causes an increased flip-flop. The result in the spicule is a change of the chemical structure, increasing the tendency toward coagulation of sickle cell blood (prethrombotic state). C, The relationship between the protein skelet on of the erythrocyte and lipid membrane is shown. (Adapted from Franck [11]; wi th permission.) Band 3 Actin Band 4.1 Spectrin Ankyrin C

Sickle Cell Disease 4.9 B A D C E FIGURE 4-9 Macroscopy and microradioangiographs of sickle cell kidneys. The kidn eys of patients with sickle cell disease usually are of near normal size, and mo st kidneys show no significant gross alterations. Abnormalities can be expected in the renal medulla as erythrocytes form sickles more readily in the relatively hypoxic and hyperosmotic renal medulla than in other capillary circulations. Fo rmation of microthrombi causes further impairment of the vasa recta circulation. A and B, Injection microradioangiographs of the kidney in a person without hemo globinopathy are shown: the entire kidney (panel A) and a detailed view (panel B ). C and D, Injection microradioangiographs of the kidney in a patient with sick le cell disease are shown: the entire kidney (panel C) and a detailed view (pane l D). E, Injection microradioangiograph of a kidney in a patient with sickle cel l hemoglobin C disease . In the normal kidney (panel A), vasa recta are visible radiating into the renal papilla. In sickle cell anemia (panel D), vasa recta ar e virtually absent. Those vessels that are present show abnormalities: they are dilated, form spirals, end bluntly, and many appear to be obliterated. In the pa tient with hemoglobin SC (panel E) changes are seen intermediately between patie nts with hemoglobin SC and normal persons. (From van Eps et al. [5]; with permis sion.)

4.10 Systemic Diseases and the Kidney Renal Concentrating Mechanism in a Normal Person Juxtamedullary nephron 1200 Urine osmolality, mosmol/kg 400 0 1 A 5 10 50 100 Urine arginine vasopressin, pg min1 C 1 osm 500 FIGURE 4-10 AH, Models to demonstrate the principle of countercurrent multiplier in creating high urine concentration. The first panel illustrates the relation b etween urine osmolality and arginine vasopressin excretion. The long loops of He nle and their accompanying vasa recta reaching the papillae comprise only 15% of the total nephron population but are necessary for producing concentrated urine [12]. As seen, the mechanisms of countercurrent multiplication and countercurre nt exchange create an increase in osmolality in the kidney from 280 mOsm at the cortex to about 1200 mOsm/kg H2O in the inner medulla and papillae. Reabsorption in the collecting ducts results in production of highly concentrated urine. (Co ntinued on next page) Cortex 600 Medulla Thin segment Vasa recta B

Sickle Cell Disease Urine concentration and dilution: countercurrent multiplier 4.11 FIGURE 4-10 (Continued) 285 285 285 185 285 185 285 285 385 185 385 185 385 185 485 285 385 185 385 185 385 185 685 485 385 185 385

185 385 185 885 685 385 185 385 185 385 285 1085 885 385 185 485 285 385 585 385 485 3 1285 1085 1 2 4 C Urine concentration and dilution: countercurrent multiplier Loop of Henle Descen ding limb 285 100 285 100 H 2O Urea ADH 525 525 525 325 525 525 525 Na+Cl Urea H 2O 325 525 H 2O Urea ADH 550 H 2O Urea ADH 975 975 975 1200 1200 1200 1000 1200 1200 1200 775 975 975 975 Na+Cl Urea H 2O Na+Cl Urea H 2O 775 975 H 2O Urea ADH 1000 H 2O Ur ea 1200 1200 975 750 750 525 285 ADH 300 300 300 100 300 300 300 Na+Cl Urea H 2O 100 300 300 Ascending limb

Collecting duct 750 750 750 550 750 750 750 Na+Cl Urea H 2O Urine 5 6 D

4.12 Systemic Diseases and the Kidney Urine concentration and dilution: countercurrent diffusion (exchange) FIGURE 4-10 (Continued) 285 300 300 Na+Cl Urea H 2O 100 285 100 300 Na+Cl Urea H 2O 315 Na+Cl Urea H 2O 525 Na+Cl 525 Urea H 2O 525 300 300 525 525 Na+Cl Urea H 2O 325 525 Na+Cl Urea H 2O 750 750 Na+Cl Urea H 2O 550 750 Na+Cl Urea H 2O 750 750 Na+Cl Urea H 2O 975 Na+Cl Urea H 2O 1200 750 975 975 Na+ Cl Urea H 2O 775 975 Na+Cl Urea H 2O 975 Na+Cl Urea H 2O 1200 1200 1000

975 1200 Na+Cl Urea H 2O 1200 Loop of Henle (countercurrent multiplier system) Vasa recta (countercurrent exchange system) E Urine concentration and dilution: countercurrent diffusion (exchange) 285 300 Solute H 2O 300 525 Solute H 2O 525 750 Solute H 2O 750 Solute 750 H 2O 750 Solute H 2O Solute 525 H 2O 525 Solute H 2O Solute 300 H 2O 300 Solute H 2O 285 315 Solute 300 H 2O 300 525 Solute 525 H 2O 525 750 Solute 750 H 2O 750 975 Solute H 2O 975 1200 Solute H 2O 1200 Solute 1200 H 2O 1200 Solute H 2O 1200 Solute 975 H 2O 975 Solute H 2O 975 Solute 950 H 2O 1 2 F

Sickle Cell Disease FIGURE 4-10 (Continued) Urine concentration and dilution: diluting kidney 4.13 280 Na+ClH O Urea 2 280 280 % of fil 20 28 0 280 e trat Cortex Na+Cl H 2O Urea 100 280 Na+Cl H 2O Urea 280 f 0% of 10 280 lt r a 100 te 280 3 0 % of filtrate 280 i 2 5 % of filtrate 300 100 280 280 Na+Cl H 2O 300 Na+Cl 300 Na+Cl H 2O Na+Cl Na+Cl 300 325 Na+Cl H 2O Na+Cl H 2O Na+Cl Na+Cl H 2O 350 H 2O 100 300 100 H 2O 325 H 2O 325

Na+Cl 125 Na+Cl Na+Cl 150 H 2O Na+Cl 350 375 Medulla 325 325 100 Na+Cl H 2O 350 Na+ Cl H 2O 375 350 H 2O Na+Cl Na+Cl H 2O 350 Na+Cl H 2O Na+Cl H 2O Na+Cl te 400 tra 2 0 % o f f il 375 H 2O Na+Cl 175 Na+Cl 400 100 375 375 400 H 2O 100 10% of filtrate 400 G

4.14 Systemic Diseases and the Kidney Urine concentration and dilution: concentrating kidney FIGURE 4-10 (Continued) 285 Na+ClH O Urea 2 285 285 % of fil 20 28 5 285 e trat Cortex Na+Cl H 2O Urea 100 H 2O 285 Na+Cl H 2O Urea 285 f 0% of 10 285 200 100 te lt r a H 2O ADH 285 3 0 % of filtrate 225 i 2 5 % of filtrate 375 285 Urea H 2O ADH ADH Na+Cl H 2O Urea 525 525 300 300 300 Na+Cl Urea H 2O Na+Cl Urea H 2O Na+ 525 + 100 Na Cl Urea H 2O

525 525 Cl Urea H 2O 525 Na+Cl 325 Na+Cl Urea H 2O Na+Cl 750 Medulla Na+Cl Urea H 2O 750 Na+Cl Urea H 2O 975 975 750 Na+Cl H 2O Urea 750 ADH 975 ADH 750 Na+Cl Urea H 2O 750 550 Na+Cl Urea H 2O Na+Cl Na+ Cl Urea H 2O Na+Cl H 2O Urea 975 975 ADH 1200 1% of filtrate 1200 775 1200 Na+Cl Urea H 2O + 0 120 Na Cl 0 100 25% of f iltrate 975 Na+Cl Urea H 2O Na+Cl 120 0 Na+Cl H 2O Urea H

Sickle Cell Disease 4.15 Relationship Between Maximal Urinary Osmolality and Age Hemoglobin AA Maximum osmolality, mosm/kg H2O 1400 1200 1000 800 600 400 200 0 0 20 40 60 0 20 40 60 0 20 40 60 Age, y 0 20 40 60 0 20 40 60 80 AS SS SC ACo CCo FIGURE 4-11 Relationship between maximal urinary osmolality and age in normal su bjects and in patients with hemoglobinopathies. Results of an investigation into a large group of normal persons and those with homozygotous hemoglobin disease (Hb SS; Hb SS + Hb F), heterozygotous hemoglobin disease (Hb AS), sickle cell hemoglobin C disease (SC) , hemoglobin C trait (AC), and hemoglobin C disease (Hb CC). Normal persons have a mean maximal urinary osmolality of 1058 SD 128 mOsm/kg H2O. The most marked im pairment in concentrating capacity occurs in Hb SS disease. Maximal urinary osmo lality decreases significantly in the first decade of life and stabilizes in pat ients over 10 years of age at a mean of 434 SD 21 mOsm/kg H2O. The measurement ha s been designated the fixed maximum of sickle cell nephropathy. In patients with Hb AS and Hb SC, a progressive decrease in maximal urinary osmolality can be ob served with age. C hemoglobin alone (AC or CC) does not impair the concentrating ability of the kidneys. The renal concentrating capacity of the heterozygote (H b AS) also is affected, but only later in life. (Adapted from van Eps et al. [13 ]; with permission.) Relationship Between Nephron with Long Loops and Those with Short Loops of Henle FIGURE 4-12 Relationship between nephron with long loops and those with short lo ops of Henle. In the normal human kidney, approximately 85% of the nephrons have short loops of Henle restricted to the outer medullary zone. These nephrons may be largely responsible for achieving the interstitial osmolality of about 450 m Osm/kg H2O that exists at the transition of the outer and inner medulla. The rem aining 15% of human nephrons are juxtamedullary nephrons with long loops of Henl e, extending into the inner medullary zone and renal papillae. Together with the parallel hairpin vasa recta, these units are responsible for further increasing interstitial osmolality during antidiuresis to about 1200 mOsm/kg H2O at the ti p of the papillae. In experiments with rats, selectively removing the papillae d estroys only nephrons originating in the juxtamedullary cortex. In such animal p reparations, a severe loss of concentrating capacity during fluid deprivation ha s been observed. Thus, juxtamedullary nephrons are necessary for achieving a max imal urine osmolality. These pathophysiologic mechanisms help clarify the abnorm al findings in sickle cell nephropathy. On the basis of these mechanisms, the co ncentrating defect in sickle cell disease can be explained as a consequence of t he sickling process per se and the resultant ischemic changes in the medullary m icrocirculation [5]. It has been demonstrated that Hb SS erythrocytes form sickl e erythrocytes within seconds when placed in surroundings as hyperosmotic as is the renal medulla during hydropenia [8]. Sickling of renal blood cells causes a significant increase in blood viscosity that could interfere with the normal cir culation through the vasa recta, preventing both active and passive accumulation of solute in the papillae necessary to achieve maximally concentrated urine. In creased viscosity of blood and intravascular aggregations of Hb SS erythrocytes could also produce local hypoxia and eventually infarction of the renal papillae . Cortex Subcortex Outer medulla

Inner medulla

4.16 Systemic Diseases and the Kidney Relationship Between Concentrating Capacity and Patient Age Aug. Sept. 31 10 W.J. 4 y. Red blood cellsuspension 175 mL Hemoglobin, Hb % cont ent, g% 20 5 20 30 Oct. 10 20 30 Nov. 10 20 30 Dec. Jan 10 17 20 30 Feb 10 20 Ma r. 1 100 0 A S F FIGURE 4-13 AE, Relationship between concentrating capacity and patient age. Over a prolonged period, we investigated the effect of multiple transfusions of hemo globin A erythrocytes into children and adults with sickle cell anemia (4, 7, 11 , 15, and 40 years). In the first panel, the effects of multiple transfusions of normal blood given to a 4-yearold boy with homozygotic sickle cell anemia. A si gnificant improvement in concentrating capacity can be observed. This diminishes in older patients. (Continued on next page) CInuline , CCreatinine , Urine osmolality, mL/min mL/min mosm/kg H2O CPAH , mL/m in Filtration fraction, % 900 700 500 200 50 200 50 1500 1000 500 15 5 A

Sickle Cell Disease June 10 M.V. 11 y. Red blood cellsuspension 350 mL CCreatinine , Urine osmolalit y, Hemoglobin, Hb mL/min mosm/kg H2O % content, g% 15 5 July 10 Aug. 10 20 Sept. 10 20 4.17 May June July 31 10 20 30 10 20 F.A. 7 y. Red blood cellsuspension 350 mL Hemogl obin, Hb % content, g% 15 5 30 Aug. 10 20 30 Sept. Jan. Mar. 10 6 3 20 30 20 30 30 100 0 A S F 100 0 A S F CInuline , CCreatinine , Urine osmolality, mL/min mL/min mosm/kg H2O 800 1100 900 700 200 50 200 600 400 200 50 200 50 CPAH , mL/min 50 1500 1000 500 CInuline , mL/min CPAH , mL/min Filtration fraction, % 2000 1500 1000 15 10 5 Filtration fraction, % 20 10 B FIGURE 4-13 (Continued) C

4.18 Systemic Diseases and the Kidney FIGURE 4-13 (Continued) Dec. Feb. '62 '65 Apr. May June July 29 25 22 30 10 20 30 10 20 30 10 20 M.K. 15 y. Red blood cellsuspension 350 mL Urine osmolality, Hemoglobin, Hb mosm/kg H2O % content, g% 15 5 Aug. Sept. Oct. Nov. 30 10 20 30 10 20 30 10 20 30 10 20 100 0 A S F 800 600 400 CCreatinine , mL/min CInuline , mL/min CPAH , mL/min 200 50 200 50 1500 1000 500 Filtration fraction, % 20 10 D May 1 10 A.P. 40 y. Red blood cellsuspension 300 mL CInuline , CCreatinine , Uri ne osmolality, Hemoglobin, Hb mL/min mL/min mosm/kg H2O % content, g% 15 20 30 June 10 20 30 July 10 20 30 Aug. 10 20 5 A S F 100 0 800

600 400 200 50 200 50 CPAH , mL/min 1500 1000 500 Filtration fraction, % 20 10 E

Sickle Cell Disease 4.19 Relationship Between Age and Ability to Reverse the Defect in Urinary Concentrat ion by Blood Transfusions Maximal urinary osmolality, mosm 1100 8 patients; van Eps [12] 6 patients; Keitel [13] 800 500 FIGURE 4-14 Relationship between age and ability to reverse the defect in urinar y concentration by blood transfusions in patients with sickle cell disease. A, T he maximal urinary osmolality achieved before transfusion (lower point of each v ertical line) and after multiple transfusions with normal blood (upper point of each vertical line) in 14 patients with sickle cell disease, ranging in age from 2 to 40 years. B, The percentage of increase in maximal urinary osmolality resu lting from transfusion. Maximal urinary osmolality before transfusion is depress ed at all ages; significant improvement after transfusion occurs only in childre n and adolescents. (From van Eps et al. [13]; with permission.) 200 100 80 60 40 20 0 0 10 20 30 Time, y 40 50 A Increase in maximal urinary osmolality, % B Length of the Loops of Henle in Animals Correlated with Kidney Concentrating Cap acity Normal kidney 14% juxtamedullary nephrons with long loops Cortex Outer Medulla Inner zone Sickle cell kidney Beaver kidney Long loops of Henle not functioning or absent Sickle cell trait: Progressive loss in 70 y of inner medullary concentrating fun ction Sickle cell anemia: A. Up to about 15 y: reversible concentrating defect B . Over 15 y: complete and irreversible loss of inner medullary concentrating fun ction FIGURE 4-15 Length of the loops of Henle in animals correlated with kidney conce ntrating capacity. A, Investigations of animal species [14] with different lengt hs of the loops of Henle and correlation with the concentrating capacity of thei r kidneys reveal their relationship. B, Desert animals with very long loops of H enle can produce highly concentrated urine; in contrast, beavers living in water -rich surroundings have only short loops of Henle and cannot produce urine conce ntrate over 450 mOsm. (Continued on next page) A

4.20 Systemic Diseases and the Kidney B Beaver Rabbit Psammomys FIGURE 4-15 (Continued) In sickle cell disease the long loop of Henle has been o bliterated and the concentrating capacity of the kidney is not higher than 400 mosm, much as in beavers. An overview has been reproduced. (From van Eps and De Jong [15]; with permission.) Urinary Acidification SS Anemia 75 Ammonium chloride 70 T.A., -equiv/min/1.73 m2 Ammonium chloride Blood pH 74 50 30 73 10 72 2 4 6 8 10 90 2 4 6 8 10 Ammonium chloride Ammonium chloride 7.0 NH4+, -equiv/min/1.73 m2 70 6.0 50 5.0 30 FIGURE 4-16 A, Urinary acidification. Patients with hemoglobin SS or SC demonstr ate an incomplete form of renal tubular acidosis. In response to a short-duratio n acid load, all of the patients studied by Goossens and coworkers [16] with oth erwise normal renal function were unable to decrease urine pH below 5.3, whereas normal persons achieve a urinary pH of 5.0 or lower. Titrateable acid (TA) and total hydrogen ion excretion are lower in patients with Hb SS or Hb SC; however, in most cases, ammonia excretion is appropriate for the coexisting urine pH. Th e acidification defect has been classified as distal rather than proximal, becau se no associated wasting of bicarbonate occurs, and the acidification defect is characterized by failure to achieve a normal minimal urinary pH during acid load ing. Investigators from several centers have found no evidence of metabolic acid

osis in the absence of a sickle cell crisis; however, they have found changes co nsistent with mild chronic respiratory alkalosis [15]. (Continued on next page) Urinary pH 10 4.0 2 4 6 Time, h 8 10 2 4 6 Time, h 8 10 A

Sickle Cell Disease 4.21 Normals AS 1200 SC SS FIGURE 4-16 (Continued) B, Relationship between renal concentrating and acidifyi ng capacity in Hb AS, SC, and SS and in normal persons [16]. Maximal urinary osmolality 1000 800 600 400 4.4 4.6 4.8 B 5.0 5.2 5.4 Minimal urinary pH 5.6 5.8 6.0 Tubular Reabsorption of Phosphate in Sickle Cell Nephropathy 0.50 0.40 0.30 0.20 + 0.10 0 0 1 2 3 4 5 Phosphate, mg/100 mL 6 7 8 + 0.90 1.00 0.50 0.60 0.70 0.80 TmP/GFR 2.54.2 FIGURE 4-17 Relationship between Cp/glomerular filtration rate and serum phospha te. Closed circles represent values for patients who had fasted from food and dr ink; open circles are values obtained when UpV was 0.032 mmol/min. The continuou s line shows the mean of the values in patients with sickle cell anemia, and the hatched area indicates the range for normal persons. Cpclearance of phosphate; T mP/GFRtubular maximum reabsorption of phosphate/ glomerular filtration rate. (Ada pted from De Jong and coworkers [17]; with permission.) T.R.P. UV/L

4.22 Systemic Diseases and the Kidney Blood Pressure in Sickle Cell Disease 180 ns Male ns ns ns Female <0.05 <0.01 ns P 160 140 120 100 80 60 <0.01 <0.01 ns ns <0.02 <0.05 <0.05 P FIGURE 4-18 Blood pressure and sickle cell anemia. Mean standard deviation of sy stolic and diastolic blood pressure in control subjects (dotted lines) and patie nts with sickle cell anemia (closed lines) who are matched for age and gender. ( From De Jong and van Eps [20].) mm Hg 1524 2534 3544 4554 1524 2534 3544 4554 Age, y References 1. Herrick JB: Peculiar elongated and sickle shaped red blood corpuscles in a ca se of severe anemia. Arch Intern Med 1910, 6:517. 2. Pauling L, et al.: Sickling cell anemia, molecular disease. Science 1949, 110:543. 3. Ingram VM: Gene mutat ions in human hemoglobin: the chemical difference between normal and sickle cell hemoglobin. Nature 1959, 180:326. 4. Bunn HF: Mechanisms of disease: pathogenes is and treatment of sickle cell disease. N Engl J Med 1997, 337:762769. 5. Statiu s van Eps LW, Pinedo Veels C, De Vries H, De Koning J: Nature of concentrating d efect in sickle cell nephropathy, microradioangiographic studies. Lancet 1970, 1 :450. 6. Hostetter TH, et al.: Hyperfiltration in remnant nephrons: a potentiall y adverse response to renal ablation. Am J Physiol 1981, 241:F85. 7. Dickerson R E, Geis I: The Structure and Action of Proteins. New York: Harper and Row, 1969, 1971. 8. Perillie PE, Epstein, FH: Sickling phenomenon produced by hypertonic s olutions: a possible explanation for the hyposthenuria of sicklemia. J Clin Inve st 1963, 42:570. 9. Edelstein SJ: Structure of the fibers of hemoglobin S: human hemoglobins and hemoglobinopathies: a review to 1981. Galveston: University of Texas; 1981. 10. Franck PF, Bevers EM, Lubin BH, et al.: Uncoupling of the membr ane skeleton from the lipid bilayer: the cause of accelerated phospholipid flipflop leading to an enhanced procoagulant activity of sickled cells. J Clin Inves t 1985, 75:183190. 11. Frank PFH: Studies on the phospolid organization in membra nes of abnormal erythrocytes [PhD thesis]. Utrecht: State University of Utrecht; 1984. 12. Statius van Eps LW, Schouten H, Ter Haar Romeny Wachter CCh, la Porte -Wijsman LW: The relation between age and renal concentrating capacity in sickle cell disease and hemoglobin C disease. Clin Chim Acta 1970, 27:501. 13. Statius van Eps LW, Schouten H, la Porte-Wijsman LW, Struyker Boudier AM: The influence of red blood cell transfusions on the hyposthenuria and renal hemodynamics of s ickle cell anemia. Clin Chim Acta 1967, 17:449. 14. Schmidt-Nielsen B, O'Dell R: S tructure and concentrating mechanism in the mammalian kidney. Am J Physiol 1961, 200:1119. 15. Keitel HG, et al.: Hyposthenuria in sickle cell anemia: a reversi ble renal defect. J Clin Invest 1956, 35:998. 16. Statius van Eps LW, De Jong PE : Sickle cell disease. In Diseases of the Kidney, edn 6. Edited by Schrier RW, G ottschalk CW. Boston: Little, Brown; 1997:2201. 17. Goossens JP, Statius van Eps

LW, Schouten H, Gieterson AL: Incomplete renal tubular acidosis in sickle cell disease. Clin Chim Acta 1972, 41:149. 18. De Jong PE, et al.: The tubular reabso rption of phosphate in sickle cell nephropathy. Clin Sci 1978, 55:429. 19. De Jo ng PE, Landman H, Statius van Eps LW: Blood pressure in sickle cell disease. Arc h Intern Med 1982, 142:1239. 20. De Jong PE, Statius van Eps LW: Sickle cell nep hropathy: new insights into its pathophysiology. Editorial review. Kidney Int 19 85, 27:711. Diastolic Systolic

Renal Involvement in Malignancy Richard E. Rieselbach A. Vishnu Moorthy Marc B. Garnick P atients with malignancy are particularly vulnerable to development of renal abno rmalities [1]. Additionally, patients with renal abnormalities who have undergon e kidney transplantation are at increased risk for malignancy, which may involve the kidney [2]. Malignancy may directly involve the urinary tract. More commonl y, however, the many systemic manifestations of cancer and the toxicity of its t reatment are involved in the pathogenesis of diverse clinical syndromes involvin g the kidney [3]. Malignant neoplasms directly involving the renal parenchyma, r enal pelvis, or ureter may be primary or secondary in origin. Metastatic neoplas ms are the cause of renal malignancy more frequently than primary tumors. These secondary lesions are usually asymptomatic, however, and most often are discover ed incidentally only at postmortem examination [4]. Additionally, extrarenal mal ignancy may involve the kidney by producing obstruction of urine flow via extrin sic compression of the urinary tract. This occurs most often with gynecologic an d other pelvic neoplasms in women and with prostatic cancer in men. Systemic man ifestations of cancer may involve the kidney via formation of immune complexes, which may produce glomerulonephritis [5]. Also, paraproteins generated by multip le myeloma and other lymphoid neoplasms may produce renal dysfunction [6]. In ad dition to tumor products, malignancy-induced metabolic abnormalities, such as hy percalcemia and hyperuricemia, may impair renal function. Finally, a high percen tage of cancer patients are candidates for aggressive chemotherapy or radiation therapy, or both. Nephrotoxicity due to chemotherapy may manifest as acute renal failure, chronic renal failure, or specific tubular dysfunction causing fluid a nd electrolyte imbalance [7]. The nephrotoxicity of radiation therapy may be syn ergistic with that of chemotherapy in some settings, or radiation therapy may by itself produce significant renal damage. CHAPTER 5

5.2 Systemic Diseases and the Kidney FIGURE 5-1 Clinical syndromes of renal involvement in malignancy. Renal involvem ent in malignancy may present as one or more of four clinical syndromes. Additio nally, the incidence of a broad spectrum of malignancies is increased in the ren al transplant patient, and the malignancy may directly involve the transplanted kidney. CLINICAL SYNDROMES OF RENAL INVOLVEMENT IN MALIGNANCY Acute renal failure Prerenal Intrinsic Postrenal Hematuria and/or nephrotic synd rome Chronic renal failure Specific tubular dysfunction and associated fluid and electrolyte disorders Malignancy in the renal transplant patient Prerenal Acute Renal Failure CAUSES OF PRERENAL ACUTE RENAL FAILURE Clinical syndrome ECF volume contraction (hypovolemia) Cause External fluid loss (skin, gastrointestinal, renal, hemorrhage) Internal fluid l oss (peritonitis, bowel obstruction, acute pancreatitis, hemorrhage, malignant e ffusion) Sepsis Anaphylaxis Anesthesia Drug overdose Myocardial infarct, failure Arrhythmia Pericardial tamponade Pulmonary embolus Arterial Venous Hepatorenal syndrome Drugs that inhibit prostaglandin synthesis Peripheral vasodilation Impaired cardiac function Bilateral extrarenal vascular occlusion Functional disorders of intrarenal circu lation FIGURE 5-2 Causes of prerenal failure (ARF). Prerenal ARF is encountered frequen tly in the cancer patient, particularly in association with depletion of the ext racellular fluid (ECF) volume, which is caused by excessive loss from the gastrointestinal tract due to vomiting or diar rhea induced by cancer or its therapy. Also, hypovolemia may occur owing to inte rnal fluid loss due to translocation of ECF volume with sequestration in third s paces, as seen in peritonitis, bowel obstruction, malignant effusion, or interle ukin-2 therapy [8]. A decrease in effective intravascular volume may occur owing to peripheral vasodilation, as frequently noted in sepsis. A decrease in cardia c output due to cardiac tamponade secondary to malignant pericardial disease als o may produce prerenal ARF. Hepatobiliary disease may cause alterations in intra renal hemodynamics with resultant hepatorenal syndrome, as seen in hepatic venoocclusive disease following bone marrow transplantation (see Fig. 5-3). The admi nistration of nonsteroidal anti-inflammatory agents for analgesia in the cancer patient may lead to ARF by elimination of the prostaglandin-mediated intrarenal vasodilatation. This homeostatic mechanism represents a critical hemodynamic adj ustment necessary for maintaining glomerular filtration rate in a patient with c ancer in whom renal blood flow may be decreased owing to a variety of causes.

Renal Involvement in Malignancy 60 50 40 Patients, % 30 20 10 0 10 0 Conditioning 7 14 21 Time, d 28 1y Tumor Stored lysis marrow syndrome toxicity Azotemia 5.3 ARF HUS CSA FIGURE 5-3 Time distribution and frequency of renal syndromes in the setting of bone marrow transplantation (BMT). The solid line depicts the approximate freque ncy of renal insufficiency, as defined by at least a doubling of the baseline se rum creatinine concentration (azotemia); the dotted line represents the frequenc y of dialysis required because of acute renal failure (ARF). During the period o f conditioning, tumor lysis syndrome and stored marrow-infusion toxicity are mos t common; 10 to 28 days after transplantation, the peak incidence of ARF is obse rved, most notably due to a hepatorenal-like syndrome associated with veno-occlu sive disease (VOD). After 1 month, the hemolytic-uremic syndrome (HUS) can be observed. As noted, the greatest risk for develo pment of ARF occurs 10 to 21 days after BMT, with the usual cause at this time b eing prerenal acute renal failure due to hepatic veno-occlusive disease. This ca uses a syndrome very similar to the hepatorenal syndrome (HRS). There are five c linical similarities between the two syndromes: 1) jaundice and portal hypertens ion precede the onset of ARF, 2) a very low fractional excretion of sodium alway s occurs, 3) the blood urea nitrogen (BUN)/creatinine ratio is very high, 4) mil d hyponatremia and a decrease in systemic arterial blood pressure are usually pr esent, and 5) postmortem examination of patients dying of this syndrome fails to reveal any structural or morphologic basis for ARF, suggesting a hemodynamic ca use [9]. In contrast to the very high incidence of hepatic VOD in patients under going allogeneic BMT, autologous hematopoietic support is associated with a much lower incidence. A recent study evaluating renal function in 232 women treated with high-dose chemotherapy and autologous hematopoietic support for high-risk b reast cancer revealed a frequency of hepatic VOD of 4.7 %, as compared with a re ported incidence ranging from 22% to 53% in various series of patients undergoin g allogeneic bone marrow transplantation [10]. In this series of autologous tran splants, 21% of patients developed severe renal dysfunction, which correlated mo st significantly with sepsis, liver, and pulmonary disease. The major incidence of renal failure occurred during chemotherapy, before the initiation of hematopo ietic cell support, thereby primarily incriminating the cytoreductive therapy ra ther than hematopoietic cell support [10]. CSAcell surface antigen. (From Zager [ 9]; with permission.) lonephritis. Although immune-complexmediated glomerular dis ease is not uncommon in patients with cancer [11], glomerular disease causing AR F in the cancer patient has been reported in only a few cases [12]. Hemolytic-ur emic syndrome with vascular endothelial injury in both the glomeruli and the int rarenal blood vessels may occur in patients with disseminated malignancy or afte r chemotherapy for malignancy. With respect to tubular abnormalities, ARF may ar ise either on the basis of ischemia or as a result of exposure to exogenous or e ndogenous nephrotoxins. Renal ischemia is usually the initiating factor when ATN follows sepsis or shock or when it arises as a postsurgical complication. Cance r patients are particularly vulnerable to ARF induced by exogenous nephrotoxins in view of their frequent exposure to a wide variety of nephrotoxic drugs. The i ndicated nephrotoxins of endogenous origin are encountered with increasing frequ ency in the cancer patient. The most frequent cause of interstitial abnormalitie s is acute tubulointerstitial nephritis, which may be induced in cancer patients via hypersensitivity to various drugs. These patients frequently receive the an algesics and antimicrobials associated with this form of ARF. Immunosuppressed c ancer patients may be particularly vulnerable to severe acute bacterial pyelonep hritis. ARF may occur in this setting, even in the absence of urinary tract obst

ruction or another underlying renal disease [13]. Tumor infiltration of the kidn ey may involve the interstitium but rarely causes ARF [14]. Finally, radiation n ephropathy may occur following radiation therapy for cancer and has been associa ted with ARF [15], although when it occurs, it more frequently produces chronic renal failure. The fourth major cause of intrinsic ARF is abnormalities of intra renal blood vessels. Disseminated intravascular coagulation may occur in associa tion with sepsis in the cancer patient [16]. In addition, because the cancer pat ient is more often older, atheroembolic disease or malignant hypertension must b e considered as a possible cause of intrarenal vascular occlusion in the presenc e of ARF. Finally, vasculitis is a consideration, particularly in the presence o f hepatitis B antigenemia. CAUSES OF INTRINSIC ACUTE RENAL FAILURE Glomerular abnormalities Tubular abnormalities Glomerulonephritis Hemolytic-urem ic syndrome Ischemic acute tubular necrosis (ATN) Exogenous nephrotoxins Antineo plastic agents Antimicrobials Radiocontrast media Anesthetic agents Endogenous n ephrotoxins Myoglobin Hemoglobin Immunoglobulins and light chains Calcium and ph osphorus Uric acid and xanthine Drug-induced acute tubulointerstitial nephritis Acute pyelonephritis Tumor infiltration Radiation nephropathy Disseminated intra vascular coagulation Hemolytic-uremic syndrome Malignant hypertension Vasculitis Interstitial abnormalities Abnormalities of intrarenal blood vessels FIGURE 5-4 The four major causes of malignancy-associated intrinsic acute renal failure (ARF). With glomerular abnormalities, the pathologic process most freque ntly involves diffuse proliferative or crescentic glomeru-

5.4 Systemic Diseases and the Kidney A FIGURE 5-5 (see Color Plate) Hemolytic-uremic syndrome (HUS). A 46-year-old woma n with metastatic carcinoma of the lung and congestive heart failure developed r enal insufficiency over a 12-week period. A percutaneous renal biopsy revealed t hat several glomeruli had the acute changes of swelling and detachment of endoth elial cells and luminal occlusion (panel A, periodic acidSchiff stain). The arter ioles and arteries showed intimal cellular swelling and hyperplasia and fibrin d eposition. Immunofluorescence microscopy revealed glomerular fibrin deposition ( panel B). Hemolytic-uremic syndrome is a thrombotic microangiopathy presenting a s an acute illness characterized by renal failure, thrombocytopenia, and microan giopathic hemolytic anemia. Vascular and endothelial cell injury leads to microv ascular thrombosis and ischemic organ damage. HUS can occur in diverse clinical settings, including metastatic carcinoma, particularly of the stomach, breast, o r lung [17]. The initiating factor is presumably tumor emboli. These patients ha ve an extremely poor prognosis and often die within a few weeks of diagnosis [18 ]. HUS also has been reported after chemotherapy for cancer. This form of chemot herapy-related HUS is mainly associated with mitomycin C but has also been noted after therapy with bleomycin and platinum-containing B agents. The risk of developing mitomycin Cinduced HUS is 2% to 10%, and cumulativ e doses larger than 60 mg are often associated with the disease [19]. The patien ts with cancer are often in remission at the time of diagnosis. The mortality ra te has been as high as 70%, usually in the first 2 months, and is related to ren al failure and sepsis. The diagnosis of HUS should be considered in the clinical setting of acute renal failure associated with thrombocytopenia and microangiop athic hemolytic anemia with schistocytes (seen on a peripheral blood smear). The renal biopsy results show a variety of glomerular and vascular changes, such as endothelial cell swelling, detachment of thrombi, and thrombotic occlusion of t he lumen. Fibrin is noted in the walls of blood vessels of glomeruli on immunofl uorescence microscopy. On electron microscopy, endothelial cell swelling and det achment from the basement membrane, subendothelial granular material, and lumina l thrombi may be seen in the glomeruli. Treatment is generally supportive, inclu ding dialysis. Hemolytic-uremic syndrome with vascular endothelial injury both i n the glomeruli and in the intrarenal blood vessels may occur in patients with d isseminated malignancy or after chemotherapy for malignancy. (ARF) is dose relat ed, nonoliguric, and usually reversible. The serum creatinine level may increase immediately after administration and often peaks in 3 to 10 days; dialysis is r arely required. Treatment protocols involving prehydration and vigorous diuresis with saline and mannitol have greatly decreased the incidence of ARF. A commonl y used protocol involves initiating diuresis 12 to 24 hours before cisplatin adm inistration. Cisplatin is then infused in isotonic saline over a 3-hour period, followed by an isotonic saline or mannitol infusion for 24 hours thereafter. Cis platin is usually administered in daily divided doses for 5 days until the maxim um dose is attained, usually not to exceed 120 mg/m2 of body surface area [7]. W hen this dose is exceeded, an unacceptable degree of nephrotoxicity may occur re gardless of prophylactic protocols [21]. Hypomagnesemia is frequent in patients receiving cisplatin and may be severe (0.3 to 0.5 mEq/L). It is due to induction of a tubular reabsorptive defect [22]. Magnesium wasting may be present for man y months but usually remits when cisplatin is discontinued. Associated hypocalce mia and hypokalemia may persist unless hypomagnesemia has been corrected. In rec ent years in some settings, cisplatin has been replaced with carboplatin, which is not nephrotoxic in usual doses (400 to 600 mg/m2). Transient ARF has been not ed in patients receiving very high doses (1600 to 2400 mg/m2), however. (From Ri eselbach and Garnick [1]; with permission.)

FIGURE 5-6 Renal changes in humans following cisplatin administration. The proxi mal convoluted tubules are dilated and show coagulation necrosis of the epitheli um and epithelial nuclear atypia. The tubular lumens contain eosinophilic materi al [20]. Cisplatin is the most frequently used antineoplastic agent for the trea tment of solid tumors, and the pathogenesis of its nephrotoxicity has been studi ed extensively. Cisplatin-induced acute renal failure

Renal Involvement in Malignancy 5.5 FIGURE 5-7 Methotrexate (MTX) nephrotoxicity. Renal biopsy specimen from a patie nt treated with 3 g/m2 of MTX followed by leucovorin who became dehydrated and d eveloped acute renal failure. Precipitated material in the tubules (arrow) stron gly reacted with a fluorescinated rabbit anti-MTX antibody [23]. MTX nephrotoxicity may occur with high-dose thera py (1 to 15 g/m2); at conventional doses, MTX does not produce nephrotoxicity. B efore the importance of maintaining a high urinary volume and pH was realized, r enal toxicity was noted in approximately 30% of treatment courses and was respon sible for 20% of drug-related deaths during high-dose MTX-leucovorin rescue ther apy [24]. MTX is excreted primarily by the kidneys by means of glomerular filtra tion and tubular secretion; more than 90% of an intravenous dose appears unchang ed in the urine following conventional doses [25]. During high-dose infusions, u rinary MTX levels exceed solubility and therefore drug precipitation occurs, as illustrated previously. At physiologic systemic pH, MTX is completely ionized; h owever, the un-ionized moiety predominates at the more acidic pH usually encount ered within the distal nephron, with solubility being markedly reduced. Thus, pa tients receiving high-dose MTX therapy may be more prone to development of nephr otoxicity if they are dehydrated and excreting an acidic urine. The 7-OH metabol ite of MTX also may precipitate within the nephrons. This metabolite may account for as much as 7% to 33% of the MTX appearing in the urine 24 to 48 hours after intravenous administration; its solubility is only 25% of that observed for MTX [26]. (From Rieselbach and Garnick [1]; with permission.) acute renal failure m ay be present at the time of initial diagnosis. In others, it may occur at any t ime during the disease. Renal failure can be due to diverse mechanisms. The ligh t chains produced by the monoclonal B lymphocytes may be nephrotoxic [28]. While the toxicity of the light chains leads to a variety of tubular transport disord ers, including Fanconi's syndrome, the intratubular precipitation of these protein s causes light-chain cast nephropathy and acute renal failure. The light chains (usually lambda) may be transformed into Congo-redpositive amyloid fibrils and de posited diffusely throughout the body [29]. Deposition of amyloid in renal tissu e results in the nephrotic syndrome and, often, renal failure. Biopsy of the kid ney, abdominal fat pad, or rectal mucosa is useful in the diagnosis of AL amyloi dosis. Light chains may also be deposited in a granular pattern along the baseme nt membranes of blood vessels in a variety of organs. In the kidney, these depos its are noted in the glomeruli, causing an expansion of the mesangium, and appea r as nodular glomerulosclerosis. This condition is referred to as light-chain de position disease (LCDD) [30]. Other causes of renal failure in a patient with mu ltiple myeloma include metabolic disturbances such as hypercalcemia and hyperuri cemia. Hypercalcemia may be due to direct bone erosion by the malignant cells or to the elaboration of cytokines, which activate osteoclasts. The administration of radiocontrast agents to patients with multiple myeloma may lead to interacti on with light chains and tubular precipitation, thereby causing acute renal fail ure. The prognosis for recovery from acute renal failure in a patient with multi ple myeloma is generally poor unless reversible factors such as hypercalcemia or dehydration are responsible [27]. CAUSES OF RENAL FAILURE IN MULTIPLE MYELOMA Cause Light-chain cast nephropathy AL amyloidosis Light-chain deposition disease Pathogenesis Intratubular precipitation of light chains Deposition of amyloid fibers composed of light chains (Congo red positive) Nodular glomerulosclerosis with granular d eposits (Congo red negative) of light chains along the basement membrane Often i ncidental finding at autopsy Rare cause of renal dysfunction Tubular toxicity of

light chains Bone resorption causing hypercalcemia Renal tubular precipitation of uric acid following tumor lysis Interaction between light chains and radiocon trast agents Plasma cell infiltration of the kidney Fanconi's syndrome and other tubular dysfun ction Hypercalcemic nephropathy Acute uric acid nephropathy Radiocontrast nephro pathy FIGURE 5-8 Renal failure in multiple myeloma. The patient with multiple myeloma is at increased risk for the development of acute renal failure [27]. In up to 2 5% of patients with multiple myeloma,

5.6 Systemic Diseases and the Kidney FIGURE 5-9 Light-chain cast nephropathy. The kidney at autopsy of a 68-yearold m an with multiple myeloma who died 2 years after diagnosis owing to sepsis and re nal failure. Note the dense, lamellated, and fractured casts in the renal tubule s surrounded by multinucleated giant cells. There is also interstitial fibrosis. FIGURE 5-10 Nephrocalcinosis in a patient with multiple myeloma. Irregular fract ured hematoxylinophilic deposits of calcium are seen in this fibrotic renal tiss ue. Hypercalcemia may produce serious structural changes in the kidney, resultin g in acute or chronic renal failure. Hypercalcemia is a relatively common compli cation of malignancy. Increased bone reabsorption is most often responsible owin g to bone metastases or to the release of humoral substances such as parathyroid hormonelike peptide or cytokines such as transforming growth factor- [32]. Secre tion of calcitriol, the active form of vitamin D, also may occur in some lymphom as [33]. Renal dysfunction in the setting of hypercalcemia results from both cal cium-induced constriction of the afferent arteriole and the deposition of calciu m in the tubules and interstitium, leading to intratubular obstruction and secon dary tubular atrophy and interstitial fibrosis [34]. Prompt treatment generally restores renal function, but irreversible damage can occur with long-standing hy percalcemia [35]. Recovery of the glomerular filtration rate varies inversely wi th the extent of nephrocalcinosis, interstitial scarring, associated obstructive uropathy, infection, and hypertension. All the foregoing reflect the duration a nd severity of hypercalcemia. (From Skarin [31]; with permission.) FIGURE 5-11 Acute uric acid nephropathy (AUAN). Intrarenal obstruction caused by uric acid precipitation in collecting ducts produces severe tubular dilatation (DeGalantha stain). This patient, who received chemotherapy for acute lymphocyti c leukemia before allopurinol was available, had a plasma urate concentration of 44 mg/dL at the time of death. Acute uric acid nephropathy is most frequently e ncountered in patients with a large tumor burden (often due to rapidly prolifera ting lymphoma or leukemia) in whom aggressive radiation or chemotherapy has been recently initiated. If rapid lysis of tumor cells occurs, massive quantities of uric acid precursors (and often other tumor products) are released. This induce s a marked increase in synthesis of uric acid and thus acute hyperuricemia. The subsequent renal uricosuric response may be of sufficient magnitude to exceed so lubility limits for uric acid in the distal nephron, particularly in the presenc e of dehydration or metabolic acidosis. The resultant intrarenal obstruction pro duces a characteristic pattern of acute renal failure [36]. In the setting of pa rticularly extensive disease with rapid cell lysis, profound hyperkalemia, hyper phosphatemia, and hypocalcemia (due to precipitation of calcium phosphate) may b e observed. This is termed acute tumor lysis syndrome [37]. This syndrome usuall y occurs after treatment of poorly differentiated lymphoma or leukemia; if it ar ises spontaneously, hyperphosphatemia is not prominent because phosphate is inco rporated into rapidly proliferating tumor cells. Rarely, xanthine nephropathy ca n occur during tumor lysis when allopurinol is used to prevent the production of uric acid. The resultant xanthine oxidase inhibition can produce a marked incre ase in blood and urine xanthine and hypoxanthine concentrations. Xanthine, like uric acid, is poorly soluble in an acidic urine; xanthine crystalluria occurs wh en its concentration exceeds its solubility, thereby causing obstructive nephrop athy [38].

Renal Involvement in Malignancy 5.7 PROPHYLAXIS AND TREATMENT OF ACUTE URIC ACID NEPHROPATHY AND ACUTE TUMOR LYSIS S YNDROME Prophylaxis A. Patients presenting (before chemotherapy) with evidence of large, rapidly proliferating tumor burden and hyperuricemia 1. Correct initial electro lyte and fluid imbalance, and azotemia, if possible; dialysis as indicated for e stablished renal failure or unresponsive electrolyte or metabolic abnormalities 2. Maintain adequate hydration and urine output (>3 L/d). May require 4 to 5 L/2 4 h of intravenous hypotonic saline or bicarbonate; diuretics as indicated 3. Gi ve Allopurinol* (300 mg/m2) at least 3 days before therapy if possible 4. Alkali nize urine to pH >7.0 (hypotonic NaHCO3 infusion; Diamox if necessary) 5. Postpo ne chemotherapy (if possible) until uric acid and electrolytes are reasonably no rmalized 6. Continuous-flow leukapheresis might be indicated for patients with a high circulating blast count (white cell count >100,000/mm3) B. Patients presen ting (before chemotherapy) with normouricemia, but still at risk 1. Allopurinol* 300 mg/m2; at least 2 days before therapy if possible 2. 4 to 5 L/d of intraven ous fluid as described above 3. Urinary alkalinization as described above Treatm ent C. Patients presenting (usually after chemotherapy) with renal failure 1. Sa me as for patients with tumor and hyperuricemia if sufficient renal function rem ains. If dialysis is necessary, continuous hemodialysis or hemofiltration may be preferable if severe hyperuricemia or hyperkalemia is present 2. Discontinue ur ine alkalinization when uric acid homeostasis is achieved (to avoid Ca3[PO412]pr ecipitation) 3. Treat symptomatic hypocalcemia after correction of hyperphosphat emia *Allopurinol dosage must be adjusted for level of renal function. FIGURE 5-12 Prevention and management of acute uric acid nephropathy (AUAN) and the acute tumor lysis syndrome (ATLS). The metabolic consequences of rapid malig nant cell lysis are many, ranging from moderate hyperuricemia to death from hype rkalemia. The measures employed for prevention and management vary according to the type and extent of the tumor and whether cytolytic therapy has been initiate d. In recent years, with appropriate prophylaxis and dialytic therapy, AUAN and ATLS rarely represent life-threatening problems. When acute renal failure (ARF) does occur, prognosis is excellent. The approach to AUAN and ATLS is divided int o two stages. The first is to prevent or minimize the metabolic consequences, an d the second involves treatment if prophylaxis has not been successful. The appr oach to both prophylaxis and treatment includes inhibition of xanthine oxidase, forced diuresis, and urinary alkalinization. If treatment is not successful and ARF develops, these patients respond very well to hemodialysis, with morbidity a nd mortality usually related to the underlying disease process [39]. OH N H C N C C C N CH N H Hypoxanthine OH N H C N C C C C N N Xanthine oxidase HO H N C Xanthine oxidase HO N C OH C C C N Xanthine OH C C C N C N N H N CH N H Xanthine oxidase HO N C OH C C C N Uric acid N COH N H H Allopurinol (4-Hydroxypyrazolo pyrimidine) H Oxypurinol (Alloxanthine) (4,6-Dihydroxypyrazolo pyrimidine) FIGURE 5-13 Allopurinol structure and metabolism. Allopurinol is a crucial compo nent of therapy for the prevention and management of acute uric acid nephropathy and acute tumor lysis syndrome. Its metabolism and pharmacology must be considered to avoid life-threatening toxicit y [40]. Allopurinol is a structural analogue of hypoxanthine. The product of the

enzymatic oxidation of allopurinol is the xanthine analogue oxypurinol. Both al lopurinol and oxypurinol act as xanthine oxidase inhibitors. Allopurinol is rapi dly absorbed from the gastrointestinal tract and is not protein bound. It has a half-life of just 2 to 3 hours because it has a clearance equal to the glomerula r filtration rate and is rapidly converted to oxypurinol via enzymatic oxidation . By contrast, oxypurinol has a half-life of 18 to 30 hours because it undergoes extensive tubular reabsorption and is dependent on renal excretion for eliminat ion. Thus, allopurinol dosage must be modified according to renal function. Seri ous toxicity may occur in the presence of a sustained increase in oxypurinol con centration. Oxypurinol may be removed effectively with dialysis, since it is not protein bound. (From Rieselbach and Garnick [1]; with permission.)

5.8 Systemic Diseases and the Kidney throughout the cortex of the kidney. The pelvic and parenchymal hemorrhages are secondary to severe thrombocytopenia. Microscopically, many myeloblasts are seen in the interstitial infiltrates. Interstitial infiltration by hematologic neopl asms is usually bilateral, diffuse, and more prominent in the cortex [14]. Renal failure is unusual. When it does occur, affected patients generally present wit h relatively acute renal failure and a benign urinalysis. The kidneys are grossl y enlarged, as may be demonstrated by renal ultrasound, by CT scan, or in some c ases even by physical examination. The differential diagnosis in this setting in cludes obstruction and other tubulointerstitial disorders. The presence of large kidneys without hydronephrosis on ultrasonography in a patient with lymphoma or leukemia, however, is highly suggestive of tumor infiltration. The renal progno sis is dependent on the responsiveness of the tumor to radiation or chemotherapy . A rapid reduction in renal size and return of renal function toward the baseli ne level may be seen within a few days with responsive tumors. (From Skarin [31] ; with permission.) FIGURE 5-14 Interstitial tumor infiltration due to leukemia. Leukemic infiltrate s in this case of acute myelocytic leukemia are diffusely present B A FIGURE 5-15 Renal involvement in lymphoma. A, Renal involvement in a patient wit h diffuse large cell lymphoma. There is little remaining parenchyma in this spec imen, which exhibits many large, gray-white nodules of tumor. Although primary r enal lymphoma is rare, 5% to 10% of patients with disseminated lymphoma exhibit clinically detectable renal involvement. At autopsy, the incidence of renal invo lvement by lymphoma has been estimated by several series to be more than 30% [41 ]. The incidence was higher in patients with lymphosarcoma or histiocytic lympho ma than in those having Hodgkin's disease, with its occurrence in mycosis fungoide s being intermediate in frequency. The majority of patients had involvement of b oth kidneys. Lymphoma may involve the kidney by multinodular or diffuse infiltra tion or occasionally by the presence of a large solitary tumor. Renal failure du e to parenchymal infiltration by lymphoma cells is extremely rare. In one large series, uremia resulting from lymphomatous replacement of kidney tissue was the cause of death in only 0.7% of patients [42]. As with leukemia, when lymphoma ha s caused renal failure, chemotherapy and radiation therapy have led to improveme nt in kidney function. B, Lymphoma with renal infiltration. A 65-year-old-man pr esented with left flank pain and microscopic hematuria of 6 weeks' duration. He ha d a left renal mass demonstrable on abdominal ultrasound. Left renal perihilar a nd retroperitoneal lymph node enlargement was noted on a CT scan. He was normote nsive and had a serum creatinine level of 1.2 mg/dL. A needle biopsy of the rena l mass, under CT guidance, revealed renal parenchymal infiltration with lymphoid cells with neoplastic characteristics. (Panel A from Skarin [31]; with permissi on.)

Renal Involvement in Malignancy 5.9 Postrenal Acute Renal Failure CAUSES OF POSTRENAL ACUTE RENAL FAILURE Anatomic site Urethral obstruction Bladder neck obstruction Bilateral ureteral obstruction (or unilateral obstruction with single kidney) Cause Prostatic hypertrophy Prostatic or bladder cancer Functional: neuropathy or drug s Extraureteral Cancer of prostate or uterine cervix Periureteral fibrosis Accid ental ureteral ligation during pelvic surgery for cancer Intraureteral Uric acid crystals or stones Blood clots Pyogenic debris Edema Necrotizing papillitis FIGURE 5-16 The etiology of postrenal failure involves obstruction at various an atomic sites by tumors of the urinary tract or surrounding tissues. Some of the more common causes of bladder neck obstruction in the cancer patient include pro static hypertrophy [43] and prostatic or bladder cancer [44]. Postrenal acute re nal failure may also be produced by bilateral obstruction of both ureters (or un ilateral ureteral obstruction in the presence of a single kidney). This may be c aused by invasion of the ureters by bladder neoplasms or, more commonly, by retr operitoneal spread of malignancies, particularly of colon, prostate, bronchus, o r breast origin. Nodal obstruction Uterus Bladder ulceration Stricture Uretovaginal fistula Bladder Vesicovaginal fistula Vagina FIGURE 5-17 Urinary tract obstruction. Obstruction is a prominent feature of uri nary tract involvement in gynecologic cancers [45]. The ureters may be invaded b y tumor or compressed by the tumor mass or tumor-filled lymph nodes. Ureteral st ricture may be the cause of obstruction following radiation therapy or surgery. Also, the bladder may be subject to direct extension of tumor with occlusion of ureteral orifices. In this figure, the anterior wall of the bladder is cut away to illustrate these as well as other forms of urinary tract involvement by gynec ologic cancers. In this setting, obstruction may produce either acute or chronic renal failure depending on the location of the obstruction and the rapidity of tumor growth. (Adapted from Rieselbach and Garnick [1].)

5.10 Systemic Diseases and the Kidney Diagnostic approach to acute renal failure STEP I ACUTE Normal recent function Normal renal size on ultrasound Normal HCT S TEP II History, physical exam Prerenal Edema CHF Cirrhosis ECFV contraction Drug s Intrinsic renal Hypotension Nephrotoxins Systemic symptoms Trauma/surgery STEP III Urinalysis Eosinophils RBC casts and/or dysmorphic RBCs Dipsticknegative pr oteinuria Epithelial cells Granular, pigmented casts Uric acid crystals Benign O rthotolidine positive on dipstick but RBC negative in sediment Postrenal Distend ed bladder Pelvic mass ( ) Enlarged kidney(s) Flank pain Prostatism ( ) CHRONIC Prior renal dysfunction Small kidneys on ultrasound Anemia Acute tubulointerstitial Glomerulonephritis nephritis or vasculitis UPE Bone mar row biopsy Light-chain cast nephropathy Acute tubular necrosis Acute uric acid nephropathy Prerenal or postrenal Myoglobin Hemoglobun Gallium scan Renal biopsy STEP IV Blood chemistries -BUN/creatinine ratio -Calcium -Uric acid -Phoshorus -CPK, aldolase STEP V Other blood studies SPEM spike C3/C4 (complement) Haptoglobin Eosinophilia Urinary diagnostic indicies Prerenal or glomerulonephritis UNA<20, FENA<1% UOSM> 500 Acute uric acid nephropathy Urine uric acid/ creatinine >1.0 Anuria Light ch ain nephropathy Urine positive for light chains ATN or obstruction UNA>40, FENA> 3% UOSM<350 Renal biopsy Glomerulonephritis Obstruction Bilateral cortical necrosis Bilateral renal artery or vein occlusion Magnetic re sonance angiography Duplex ultrasonography Digital subtraction angiography Renal arteriography/venography Exclude obstruction Ultrasound CT scan Retrograde pyelogram FIGURE 5-18 Diagnostic approach to acute renal failure. Acute renal failure deve loping in a patient with malignancy may be due to diverse causes. It is importan t to employ an organized diagnostic approach to define the specific cause in a c osteffective manner. The approach outlined in this figure involves five steps. S tep I addresses the distinction between acute and chronic renal failure, and ste p II lists the various causes of prerenal, intrinsic, and postrenal acute renal failure (see Figs. 5-2, 5-4, and 5-16) according to data obtained from the histo ry and physical examination. Urinalysis is very useful in the workup of a patien t with acute renal failure, particularly due to intrinsic renal disease, as outl ined in step III. The presence of red blood cell (RBC) casts or dysmorphic RBCs

in the urine sediment is suggestive of glomerulonephritis, while eosinophiluria is indicative of acute interstitial nephritis. Step IV involves obtaining blood chemistries and o ther blood studies, abnormalities that may strongly support a given diagnosis. S tep V is employed in the presence of oliguric acute renal failure. Urinary diagn ostic indices are used to distinguish between prerenal acute renal failure and g lomerulonephritis, as opposed to acute tubular necrosis or acute obstruction. Ev aluation of the urine is also helpful in detecting the presence of light chains of immunoglobulins, which may be diagnostic of multiple myelomainduced acute ren al failure. Also, an increased urinary uric acid/creatinine ratio may indicate a cute uric acid nephropathy. In the patient who is anuric (<50 mL of urine per da y), it is particularly important to rule out obstruction. Bilateral cortical nec rosis or glomerulonephritis must be considered in this setting; a renal biopsy m ay be necessary for definitive diagnosis. If bilateral renal artery or vein occl usion is a consideration, angiography may be indicated. ATNacute tubular necrosis ; BUN blood urea nitrogen; CHFcongestive heart failure; CPKcreatine phosphokinase; ECFV extracellular fluid volume; FENafractional extraction of sodium; Hcthematocrit ; SPE serum protein electrophoresis; Unaurine sodium; Uosmurine osmolality; UPEurine protein electrophoresis.

Renal Involvement in Malignancy 5.11 Hematuria and/or the Nephrotic Syndrome CAUSES OF HEMATURIA AND/OR THE NEPHROTIC SYNDROME Paraneoplastic glomerulonephritis Membranous glomerulonephritis Minimal change n ephrotic syndrome Crescentic glomerulonephritis Membranoproliferative glomerulon ephritis Primary or metastatic renal cancer Chemotherapy agents causing nephroti c syndrome Mitomycin C Gemcitabine Interferon FIGURE 5-19 Causes of hematuria and/or the nephrotic syndrome. Hematuria and/or the nephrotic syndrome may occur in association with malignancy without causing acute or chronic renal failure. Causes may include one of the many paraneoplasti c types of glomerulonephritis, with proteinuria and often the nephrotic syndrome resulting from the glomerular injury; hematuria is also noted in some cases. In contrast, isolated hematuria is the predominant feature when primary or metasta tic renal cancer erodes the intrarenal vasculature. Proteinuria, and in some cas es the nephrotic syndrome, may be the presenting nephrotoxicity of cancer chemot herapy agents. A FIGURE 5-20 Membranous glomerulonephritis and the nephrotic syndrome in a patien t with bronchogenic carcinoma. A 76-year-old veteran presented with ankle edema and weight gain of 8 weeks' duration. He was noted to have the nephrotic syndrome with 5 grams of proteinuria per day. A chest radiograph revealed a perihilar mas s. A bronchoscopic biopsy of the mass was diagnostic of malignancy. He was manag ed conservatively with diuretics and radiotherapy for the B chest mass. He died 10 months later. Membranous glomerulonephritis and bronchoge nic carcinoma were diagnosed at autopsy. A, Light microscopic study of the kidne y of this patient. Note the thickening of capillary walls and spikes (PAM stain) . B, Immunofluorescence microscopy of renal tissue showing peripheral glomerular capillary deposition of IgG in a granular pattern indicative of immune-complexmediated glomerulonephritis. (Continued on next page)

5.12 Systemic Diseases and the Kidney C FIGURE 5-20 (Continued) C, Electron microscopy of the glomerulus showing subepit helial electron-dense deposits along the capillary walls. There is effacement of the epithelial cell foot processes, which is a common finding in patients with nephrotic syndrome. D, Bronchogenic carcinoma noted at autopsy in this patient ( hematoxylin and eosin stain). Membranous glomerulonephritis is an immune-complexm ediated glomerular disease, often resulting in nephrotic syndrome as a clinical manifestation. In adults older than the age of 50, a coexisting malignancy, usua lly a carcinoma, may be present in up to 10% D of cases [5]. Although a variety of malignancies have been observed to be associ ated with membranous glomerulonephritis, the most common sites are the breast, t he lung, and the colon. In some instances, the tumor antigen or antitumor antibo dies have been detected in the glomeruli. Development of the nephrotic syndrome has been temporally related to the malignancy in several instances, and successf ul cure of the malignancy has led to a remission in the nephrotic syndrome. Rela pses have been associated with reappearance of proteinuria [46]. A FIGURE 5-21 Minimal change nephrotic syndrome in Hodgkin's disease. A, Light micro scopic study of a renal biopsy specimen from a 57-year-old man with nephrotic sy ndrome of 3 months' duration. Urine protein excretion was 7.1 g/d. The serum creat inine concentration was 1.3 mg/dL. The patient also had cervical lymphadenopathy , biopsy of which revealed Hodgkin's disease of the mixed cellularity type. He was treated with irradiation to the upper mantle region with resolution of the lymp hadenopathy. Proteinuria also declined to 2 g/d in 2 weeks and was absent in 8 w eeks. The glomerulus was normocellular with delicate capillary walls diagnostic of minimal change nephrotic syndrome (PAM stain). B, Electron microscopy of a gl omerulus from the same patient showing glomerular capillaries with extensive eff acement of the epithelial foot processes but without electron-dense deposits. In patients with Hodgkin's disease and other malignancies arising from lymph nodes a s well as different types of chronic leukemias, the B occurrence of glomerular diseases has been noted [5,46]. Several histologic type s of glomerular diseases have been documented in these instances; the most commo n type has been minimal change nephrotic syndrome [47]. The glomeruli of these p atients are normal on light microscopic study and are devoid of hypercellularity or capillary wall thickening. No immunoglobulins are noted in the glomeruli on immunofluorescence microscopy. On electron microscopy, effacement of the epithel ial cell foot processes is the only abnormality present. Proteinuria has been no ted to remit with cure of lymphoma (with use of surgery, radiotherapy, or chemot herapy) in some cases; relapses in nephrotic syndrome occur with recurrence of t he tumor. This has been documented to occur several times in some patients [47]. The pathogenesis of minimal change nephrotic syndrome in patients with malignan cy remains unknown. It is possible that a cytokine or tumor cell product may be responsible for the increase in glomerular permeability with resultant proteinur ia [48].

Renal Involvement in Malignancy 5.13 A. COMPARISON OF PARAPROTEINEMIAS Diagnosis Multiple myeloma Frequency* Yes Clinical Findings Proteinuria (light chain) Acute renal failure Hypercalcemia Proteinuria Nephroti c syndrome Proteinuria Nephrotic syndrome Chronic renal failure No renal symptom s or minimal proteinuria Proteinuria Nephrotic syndrome Renal Lesions Light-chain cast nephropathy Acute tubular necrosis Deposits of amyloid fibrils in the kidney Nodular glomerulosclerosis with granular deposition of light chain s along the glomerular and tubular basement and membrane; usually kappa light ch ains Intraglomerular coagula of IgM Proliferative glomerulonephritis in some case Diagnostic Means Immunoelectrophoresis or bone marrow Light chains in urine Renal or rectal biops y Immunoelectrophoresis Renal biopsy Bone marrow biopsy Immunoelectrophoresis Im munoelectrophoresis Bone marrow biopsy Immunoelectrophoresis Bone marrow biopsy Renal biopsy AL amyloidosis Light-chain deposition disease Yes No Waldenstrm's macroglobulinemia Monoclonal gammopathy of unknown significance (MGUS) Rarely Rarely * Frequency of renal involvement. B FIGURE 5-22 (see Color Plate) A, Paraprotein abnormalities as a cause of nephrot ic syndrome. This table compares the characteristics of various paraproteinemias . Paraproteins are abnormal immunoglobulins or abnormal immunoglobulin fragments produced by B lymphocytes. They are monoclonal, appear in the serum or urine (o r both), and cause renal damage by several different mechanisms. Paraproteinemia s comprise a group of disorders characterized by overproduction of different par aproteins. Multiple myeloma is a common type of paraproteinemia. The overproduct ion of immunoglobulins or light chains, or both, causes renal toxicity, directly affecting the tubular cells or forming casts after prec ipitation in the tubular lumen. The light chains may be transformed into amyloid fibrils and deposited in various tissues, including the kidney. Amyloidosis is diagnosed by performing a biopsy of the involved organ and staining the tissue w ith Congo red stain. On occasion, the light chains do not form fibrils but are d eposited as granules along the basement membrane of blood vessels and glomeruli. Kappa chains often behave in this manner. This entity is called light-chain dep osition disease [6] (panel B). Paraproteins composed of IgM are noted in Waldens trm's macroglobulinemia. Renal dysfunction is uncommon in this condition [49]. Hype rviscosity is present. On rare occasions, thrombi composed of IgM may be noted i n the glomeruli of these patients. In the most common form of paraproteinemia, m onoclonal protein is detected in the serum of an otherwise healthy person. This

condition is referred to as monoclonal gammopathy of unknown significance (MGUS) and may on occasion progress to multiple myeloma or amyloidosis [50]. B, Lightchain deposition disease (LCDD) in a patient with multiple myeloma. A light micr oscopic study of a renal biopsy specimen from a 65-year-old man with recently di agnosed multiple myeloma who was found to have an elevated serum creatinine conc entration (2.6 mg/dL) and proteinuria of 3 g/d. Note the nodular mesangial lesio ns, capillary wall thickening, and hypercellularity resembling diabetic nodular glomerulosclerosis. Immunofluorescence staining was positive for kappa light cha ins but negative for lambda light chains.

5.14 Systemic Diseases and the Kidney because of the myriad paraneoplastic signs and symptoms, now renal cancer is oft en termed the radiologist's tumor [51,52]. Most forms of renal cancer arise from the cells of the proximal tubular epithelium, not from adrenal rests of cells. Thus , the term hypernephroma (ie, tumor arising from above the kidney) should not be employed to describe this lesion. Risk factors for the development of renal can cer include cigarette smoking, occupational exposure to cadmium, obesity, excess ive exposure to analgesics, acquired cystic disease in dialysis patients, adult polycystic kidney disease, and other industrial exposures, such as to asbestos, leather tanning, and certain petroleum products. Genetic and familial forms of t he disease occur, most notably with von Hippel-Lindau disease, an autosomal domi nant disorder characterized by the development of multiple tumors of the central nervous system, pheochromocytomas, and bilateral renal carcinomas. Several fami lies have been reported also to have a high incidence of renal cancer. Genetic a nalyses of these patients demonstrate a balanced translocation between the short arm of chromosome 3 and either chromosome 6 or 8. Other abnormalities have been reported as well [52]. It should be noted that other primary tumors of the kidn eys in the adult include transitional cell carcinoma of the renal pelvis and oth er neoplasms, such as angiomyolipoma and oncocytoma. Metastatic lesions of the k idney include those arising from the common epithelial cancers such as breast, l ung, colon, and infiltrative lesions secondary to lymphoma and leukemias. (From Skarin [31]; with permission.) FIGURE 5-24 Presenting signs and symptoms of rena l cell carcinoma. Patients with renal cell cancer present with symptoms produced by the local neoplasm, with signs and symptoms of paraneoplastic phenomena, or with other aspects of systemic disease. Alternatively, the patient may be totall y asymptomatic and may be diagnosed from a radiologic abnormality detected on ul trasound or abdominal CT scanning. Fewer than 10% of patients present with the c lassic triad of hematuria, abdominal mass, and flank pain. The most common featu res include hematuria (70%), flank pain (50%), palpable mass (20%), fever (15%), and erythrocytosis (infrequent). Other features may include acute onset of lowe r extremity edema, or, in males, the presence of a left-sided varicocele, indica ting obstruction of the left gonadal vein at its point of entry into the left re nal vein by a tumor thrombus [53,54]. FIGURE 5-23 Renal cell carcinoma. With massive invasion by tumor, the renal vein may become occluded by adherent tumor thrombus. Renal adenocarcinoma is the mos t common tumor of the kidney [51]. In the past, many of these tumors achieved la rge sizes before being detected and hence were advanced in their stage and limit ed in their curability by surgical resection. Today, many renal cancers are ofte n detected with routine abdominal computed tomography for nonrelated indications . Once called the internist's tumor PRESENTING SIGNS AND SYMPTOMS OF RENAL CELL CARCINOMA Feature Hematuria Pain Flank or abdominal mass Weight loss Symptoms from distant metasta tic spread Fever Classic triad (pain, hematuria, mass) Polycythemia Acute varico cele Frequency, % 4065 2050 2040 30 10 1520 10 <5 <5

Renal Involvement in Malignancy 5.15 FREQUENCY OF SYSTEMIC EFFECTS IN PATIENTS WITH RENAL CELL CARCINOMA Symptom Elevated ESR Anemia Hypertension Cachexia Pyrexia Abnormal liver function Elevat ed alkaline phosphatase Hypercalcemia Polycythemia Neuromyopathy Amyloidosis Incidence, % 362/6.51 (55.6) 409/991 (41.3) 89/237 (37.6) 338/979 (34.5) 164/954 (17.2) 60/40 0 (15.0) 64/434 (14.7) 33/577 (5.7) 33/903 (3.7) 13/400 (3.3) 12/573 (2.1) FIGURE 5-25 Frequency of systemic effects. The most frequent systemic manifestat ions of renal cell cancer are noted [55]. Other paraneoplastic and systemic mani festations include liver function abnormalities, high-output congestive heart fa ilure, and manifestations of the secretion of substances such as prostaglandins, renin, glucocorticoids, and cytokines (eg, interleukin-6). At presentation, a s mall percentage of tumors are bilateral, while nearly a third of patients have d emonstrable metastatic disease, which may occur in virtually any organ. Most com mon sites of metastases include lung, bone, liver, and brain. ESRerythrocyte sedi mentation rate. (From Chisholm and Roy [55]; with permission.) Stage I Stage III Vena cava Aorta Stage II Stage IV Stage I: Confined to kidney Stage II: Including renal vein involvement Stage III : Lymph node and caval involvement Stage IV: Adjacent organ metastases FIGURE 5-26 The staging of renal adenocarcinoma. Renal cell cancer can be staged using one of two systems in common use. The TNM (tumor, node, metastasis) syste m has the advantage of being more specific but the disadvantage of being cumbers ome; a modification of the Robson staging system (as illustrated here) is more p ractical and more widely used in the United States. In this system, stage I repr esents cancer that is confined to the kidney capsule; stage II indicates invasio n through the renal capsule, but not beyond Gerota's fascia; stage III reflects in volvement of regional lymph nodes and the ipsilateral renal vein or the vena cav a; and stage IV indicates the presence of distant metastases [57]. With regard t o pathologic assessment, previously renal carcinomas were classified according t o cell type and growth pattern. The former included clear cell, spindle cell, an d oncocytic carcinoma, while the latter included acinar, papillary, and sarcomat oid varieties. Recently, this classification has undergone a transformation to r eflect more accurately the morphologic, histochemical, and molecular basis of di ffering types of adenocarcinoma [58]. Based on these studies, five distinct type s of carcinoma have been identified: clear cell, chromophilic, chromophobic, onc ocytic, and collecting duct. Each of these types has a unique growth pattern, ce ll of origin, and cytogenetic characteristics [59,60]. (From Brenner and Rector [56].)

5.16 Systemic Diseases and the Kidney 360 Dialysate Serum Osmolality, mOsm/L 340 Osmotic equilibrium 320 300 0 1 2 Dwell time, h 3 4 C ADK-vol05 chap04 fig07c24p6 x 14 p au:Khanna art:Weischedel FIGURE 5-27 Diagnostic evaluation of and therapeutic approach to primary renal c anceran algorithm for diagnosis and management of a renal mass. The discovery of evidence during the history or physical examination that suggests a renal abnorm ality should be followed by either an intravenous pyelogram or an abdominal ultr asound. With increasing frequency, however, evidence of a space-occupying lesion in the kidney is found incidentally during radiographic testing for other unrel ated conditions. Renal ultrasonography may help distinguish simple cysts from mo re complex abnormalities. A simple cyst is defined sonographically by the lack o f internal echoes, the presence of smooth borders, and the transmission of the u ltrasound wave. If these three features are present, the cyst is most likely ben ign. At one time, cyst puncture was used, but it seems to be unnecessary today i n the asymptomatic patient without hematuria. Periodic repetition of the ultraso und is suggested for follow-up. If a change in the lesion occurs, cyst puncture, needle aspiration, or CT scanning should be considered to evaluate the lesion f urther. If the sonographic criteria for a simple cyst are not met or the intravenous pye logram suggests a solid or complex mass, a CT scan should be performed. If a ren al neoplasm is demonstrated on CT scanning, renal vein or vena caval involvement should be assessed with CT scanning or magnetic resonance imaging. Although use d frequently in the past, selective renal arteriography has assumed a more limit ed use, mainly in further evaluating the renal vasculature in patients who are t o undergo partial nephrectomy (nephron-sparing surgery). CT scanning is also ver y helpful in determining the presence of lymphadenopathy. The differential diagn osis of a renal mass detected on CT scanning includes primary renal cancers, met astatic lesions of the kidney, and benign lesions. The latter include angiomyoli pomas (renal hamartomas), oncocytomas, and other rare or unusual growths. If a r enal cancer is considered based on the radiographic studies of the kidney, the p atient should undergo a preoperative staging evaluation to assess the presence o f metastases in the lung, bone, or brain. (Continued on next page)

Renal Involvement in Malignancy (Continued) The operative and diagnostic approach is dictated according to the p reoperative stage of the patient. For example, the patient who presents with sta ge IV disease by virtue of a positive bone scan may need only a needle biopsy of either the kidney lesion or the bone lesion to establish the tissue diagnosis a nd thus avoid more extensive surgery on the kidney. In contrast, a patient with an isolated pulmonary lesion may be considered for both nephrectomy and pulmonar y nodulectomy at one operative intervention. The standard therapy for localized renal cell carcinoma is radical nephrectomy, which includes removal of the kidne y, Gerota's fascia, the ipsilateral adrenal gland, and regional hilar lymph nodes. The value of an extended hilar lymphadenectomy seems to be its ability to provi de prognostic information, since there is rarely a therapeutic reason for perfor ming this portion of the operation. In the past, the removal of the ipsilateral adrenal gland was done routinely; today, most data suggest that it is involved l ess than 5% of the time, more frequently with large upper-pole lesions. Thus, to day, ipsilateral adrenalectomy is reserved for those patients with abnormal-appe aring glands or enlarged glands on CT scan or those with large upperpole lesions , in which the probability of direct extension of the tumor to the adrenal gland is more likely [61]. Partial nephrectomy (nephron-sparing surgery) has become m ore popular, especially for patients with small tumors, for those at risk for de veloping bilateral tumors, or for patients in whom the contralateral kidney is a t risk for other systemic diseases, such as diabetes or hypertension [62]. The m ain concern associated with partial nephrectomy is the likelihood of tumor recur rence in the operated kidney, since many renal cancers may be multicentric. Loca l recurrence rates of 4% to 10% have been reported; lower rates have been report ed when partial nephrectomy was performed for smaller lesions (< 3 cm) with a no rmal contralateral kidney. Lesions that are centrally located, however, still re quire radical nephrectomy. Frequent follow-up, usually with CT scanning or ultra sonography, will be necessary in those patients who undergo partial nephrectomy. Inferior vena caval involvement with renal cancer occurs more frequently with r ightsided tumors and is usually associated with metastases in nearly 50% of pati ents. Vena caval obstruction may lead to the diagnosis; it may present with abdo minal distention from ascites, hepatic dysfunction, nephrotic syndrome, abdomina l wall venous collaterals, varicocele, malabsorption, or pulmonary embolus. The anatomic location of the caval thrombus is important prognostically; supradiaphr agmatic lesions, which may involve the heart, can be resected, but the prognosis is poor. Subdiaphragmatic lesions enjoy a better 5-year survival, but the survi val rate is usually less than 50% [63]. In the surgical management of these pati ents, a team of specialists is required, especially if a cardiac tumor thrombect omy is contemplated. The role of surgery in the management of metastatic disease either at initial presentation or later remains controversial. Although most da ta that support nephrectomy plus metastatectomy are anecdotal, many patients wit h synchronous renal cell cancer and an isolated pulmonary nodule may be consider ed for surgical resection of both lesions. Likewise, patients who develop an iso lated lesion in the liver or lung some time following the removal of the kidney also may be considered for surgical removal of the metastasis. Nevertheless, eve n when such vigorous surgery is carried out, most patients do poorly. Additional controversy surrounds the practice of performing nephrectomy in patients with w idespread metastatic disease as a means of potentially improving their response to systemic therapy. Many investigative programs require such resection, but at this writing, the practice should be considered investigational. A patient who d oes experience an excellent response to systemic therapy should be 5.17 considered for nephrectomy following the response, however. Finally, since many renal tumors can become quite large, consideration should be given to palliative nephrectomy (in the setting of metastatic disease), especially if the patient e xperiences uncontrollable hematuria or pain or is catabolic secondary to the she er mass of the tumor. The medical management of patients with either locally adv

anced renal cancer or metastatic disease provides a great challenge to physician s and clinical investigators. Although chemotherapy and hormonal treatments have been studied extensively in patients with metastatic renal cancer, no single tr eatment protocol or program has been uniformly effective. Therefore, most physic ians treating the disease usually rely on novel modalities of treatment, includi ng biologic response modifiers, investigational anticancer agents, differentiati on agents (such as retinoic acid), vaccines, and gene therapy. Interferon therap y with interferon- , - , or - has led to responses in approximately 15% to 20% o f treated patients [64]. Interferons demonstrate antiproliferative activity agai nst renal cell cancers in vitro, stimulate immune cell function, and can modulat e the expression of major histocompatibility complex molecules. Although respons es have been seen in cancers involving many different anatomic areas, patients w ho have had a prior nephrectomy with isolated pulmonary metastases and who are o therwise well may enjoy a higher response rate [65]. Duration of response is usu ally less than 2 years; longer lasting remissions have been noted in a few selec ted patients. Interferons have been combined with other immune modifiers as well as with chemotherapy agents with no real improvement in patient outcome in larg er-scale trials. Several smaller trials have combined interferon with interleuki n-2 or chemotherapy agents (eg, 5-fluorouracil) with some encouraging preliminar y results. Interleukin 2 (Il-2) has received a great deal of attention as a pote ntial advance in the treatment of renal cell cancer. This agent enhances both pr oliferation and functioning of lymphocytes involved in antigen recognition and t umor elimination. Initial studies used very high doses of Il-2 in association wi th ex vivo populations of lymphoid cells grown and matured under the influence o f Il-2 [66]. These programs resulted in substantial toxicity, including patient deaths, but nevertheless had early and encouraging therapeutic results. Unfortun ately, the initial encouraging results were not consistently observed in largerscale trials. Efforts are now directed at selectively manipulating the immune-en hancing features of the treatment, with modification of the toxic effects. In se veral recent studies, the use of lower doses of Il-2 without the cellular compon ents has resulted in comparable results with less toxicity. The toxicity of Il-2 is related to alterations in vascular permeability, leading to a capillary leak type of syndrome. Although the drug is approved by the Food and Drug Administra tion for the management of patients with metastatic renal cell cancer, its use s hould be restricted to those patients who can tolerate the side effect profile a nd those patients with acceptable cardiac, renal, pulmonary, and hepatic functio n. Investigational therapies continue to be studied for renal cell cancer. These include novel cytokines such as interleukin-12, combinations of biologics with or without chemotherapeutic agents, circadian timing of chemotherapy administrat ion, vaccine therapy, various forms of cellular therapy, and gene therapy [67]. Although all these approaches have a solid scientific preclinical rationale, non e, unfortunately, can be considered standard treatment. The sobering fact still remains that nearly 50% of all patients diagnosed with renal cell cancer die of their disease within 5 years of diagnosis, and a substantial proportion have adv anced stages of cancer spread at initial presentation.

5.18 Systemic Diseases and the Kidney FIGURE 5-28 Metastatic malignant melanoma involving the kidney. The urinary trac t is a common site of melanoma metastases. If not amelanotic, the metastatic nod ules are brownish black. Metastatic infiltration of the kidneys is often an inci dental finding at autopsy but is a rare cause of functional impairment [68]. Mos t renal metastases are multiple and bilateral. Glomeruli tend to be spared, poss ibly because of their lack of lymphatic channels. Pulmonary carcinoma is the mos t commonly reported form of metastatic solid tumor involving the kidneys, follow ed by metastatic stomach and breast carcinoma [69]. Metastatic melanoma is an ex ample of a tumor that may be transplanted at the time of cadaver kidney transpla ntation, with subsequent rapid proliferation in the immunosuppressed recipient; tumor rejection may occur with cessation of immunosuppressive therapy [70] (see Fig. 5-37). The presence of renal metastases is often overlooked during life due to the absence of any specific physical or laboratory findings. The laboratory finding most likely to occur is hematuria due to tumor erosion of intrarenal ves sels. (From Skarin [31]; with permission.) Chronic Renal Failure CAUSES OF CHRONIC RENAL FAILURE Glomerular abnormalities Glomerulonephritis Amyloidosis Primary renal cancer Ant ineoplastic agents Immunoglobulins or light chains Radiation nephropathy Leukemi c infiltration Lymphomatous infiltration Metastatic infiltration Chronic pyelone phritis Antineoplastic agents Hypertension due to malignancy Peripheral vascular involvement by renal or nonrenal cancer Renal vein thrombosis Hemolytic-uremic syndrome Cancer Prostate Cervix Bladder Retroperitoneal lymphoma Primary renal U ric acid or calcium stones Periureteral fibrosis Tubulointerstitial abnormalities Renovascular disease Obstruction FIGURE 5-29 Causes of chronic renal failure. The glomerular abnormalities listed may be associated with cancer but most often do not cause a significant degree of chronic renal failure; their clinical expression most often involves hematuri a or the nephrotic syndrome. Disordered immunoglobulin production associated wit h multiple myeloma is a frequent cause of interstitial abnormalities, producing chronic renal failure in association with cancer. Renal failure has been reporte d to develop in up to half of patients with myeloma at some time during their il lness and is associated with a significantly worse prognosis [71]. The multiple causes of renal failure in myeloma have been previously reviewed (see Fig. 5-8). Radiation nephropathy may produce chronic renal failure owing to interstitial a bnormalities and may be associated with severe hypertension. Interstitial involv ement by metastatic infiltration of the kidneys or by hematologic neoplasms may rarely cause chronic renal failure. The immunosuppressed status of many cancer p atients serves to increase their susceptibility to bacterial and fungal invasion of the renal interstitium. Thus, chronic pyelonephritis may be a cause of chron ic renal failure in the cancer patient, particularly in association with chronic obstruction. With regard to renal vascular disease, hypertension due to maligna ncy may produce nephrosclerosis. Hypertension may be associated with the hyperca lcemia of malignancy and is observed frequently in patients with renal carcinoma . Perirenal vascular involvement may be observed with primary renal cancer or no nrenal cancer; renal vein thrombosis or occlusion may occur because of external compression by tumor or direct extension of tumor. When obstruction is present a t any level of the urinary tract, the continued production of urine results in a n increase in volume and pressure proximal to the obstruction. If the obstructio n persists, the kidney may be damaged progressively with resultant chronic renal

failure. The causes in obstruction causing chronic renal failure in association with cancer are similar to those noted in Figure 5-16 in the production of post renal acute renal failure.

Renal Involvement in Malignancy 5.19 A FIGURE 5-30 (see Color Plate) Amyloidosis. A, Light microscopic study of a renal biopsy specimen from a patient with multiple myeloma and AL amyloidosis showing eosinophilic, fluffy amyloid deposits in the glomerulus. (Periodic acidSchiff st ain.) B, When stained with Congo red and viewed under polarized light, the amylo id deposits show applegreen birefringence. C, The amyloid fibrils viewed by mean s of electron microscopy. Amyloidosis is a generic term for a group of disorders in which there is extracellular deposition of insoluble fibrillar proteins in a characteristic B-pleated sheet configuration [29]. Although the proteins may be different, they all bond to Congo red stain. When the stained tissue is viewed under polarized light, it displays apple-green birefringence. In 10% to 15% of p atients with multiple myeloma, AL amyloidosis (composed of light chains) may occ ur in association with the nephrotic syndrome and renal insufficiency. There is no specific therapy for renal amyloidosis. Some patients have experienced remiss ion of the nephrotic syndrome with chemotherapy for myeloma, however. Dialysis ( hemodialysis or peritoneal dialysis) and transplantation have been of value in a small number of patients with AL amyloidosis and end-stage renal disease [72]. B C

5.20 Systemic Diseases and the Kidney POTENTIALLY NEPHROTOXIC CHEMOTHERAPEUTIC AGENTS Risk Drug Alkylating agents Cisplatin Carboplatin Cyclophosphamide Ifosfamide Streptozotoc in Semistine (methyl-CCAU) Carmustine (BCNU) Antimetabolites Methotrexate Cytosin e arabinoside (Ara-A) 5-Fluorouracil (5-FU) 5-Azacitidine 6-Thiognanine Antitumor antibiotics Mitomycin Mithramycin Doxorubicin Biologic agents Interferons Interle ukin-2 Type of renal failure Low Acute X X X X X X X X X X X X X X X X Time Course Immediate X X X X High X Intermediate Chronic X X Specific tubular damage X X X X X Delayed X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X *Fanconi's syndrome as the most severe manifestation. Only seen with intermediate t o high dose regimens. Only seen when given in combination with mitomycin C. Hemoly tic-uremic syndrome as the most severe manifestation. Frequent with antineoplasti c doses, rare in doses used for hypercalcemia. FIGURE 5-31 Toxic therapeutic agents. Nephrotoxicity due to antineoplastic agent s may result in chronic renal failure but also may manifest as acute renal failu re, specific tubular dysfunction, or the nephrotic syndrome. Nephrotoxicity has been observed with use of alkylating agents, antimetabolites, antitumor antibiot ics, and biologic agents, as outlined in the table. These neoplastic agents may induce nephrotoxicity soon after initiation of therapy or only after long-te rm administration. The risk of nephrotoxicity varies with each agent. This table summarizes the risk of nephrotoxicity, time of onset, and type of functional im pairment produced by each agent. (From Massry and Glassock [73]; with permission .) FIGURE 5-32 Semustine nephropathy. A, Photomicrograph of the late stages of s

emustine nephrotoxicity in a specimen obtained at autopsy. (Continued on next pa ge) A

Renal Involvement in Malignancy 5.21 B FIGURE 5-32 (Continued) B, Photomicrograph of a renal biopsy specimen from a pat ient with advanced semustine nephrotoxicity. Semustine (methyl-CCNU) is a lipids oluble nitrosourea that is structurally similar to carmustine (BCNU) and lomusti ne (CCNU). Because of the ability of these agents to cross the blood-brain barri er due to their high lipid solubility, and because of their broad spectrum of an titumor activity and ease of administration, they have been used widely. Nephrot oxicity has been a factor limiting more widespread use, however. Semustine has p roved to be the most nephrotoxic of these compounds. The degree of toxicity appe ars to be dose dependent. Evidence of renal damage often is not apparent until 1 8 to 24 months following the completion of therapy [74]. When it occurs, renal f ailure is usually progressive and irreversible. As noted in this figure, toxicit y involves glomerulosclerosis, focal tubular atrophy, and varying degrees of int erstitial fibrosis on light microscopic examination. (From Harmon and coworkers [74]; with permission.) A B FIGURE 5-33 Radiation nephritis is the basis for the atrophy of the superior por tion of the left kidney shown in this intravenous pyelogram. The right kidney sh ows straightening of its medial border due to irradiation atrophy. A, Preirradia tion pyelogram; B, film showing radiation field. Radiation nephropathy refers to damage to the kidney parenchyma and vasculature as a result of ionizing radiati on [14]. Fortunately, this disease is relatively uncommon. It was more prevalent before meticulous detail to abdominal organ shielding was widely practiced or u nderstood. Historically, patients receiving whole abdominal radiation therapy fo r lymphoma, seminoma, or other retroperitoneal tumors were the most likely to su ffer the consequences of this disorder. Doses greater than 30 to 35 gray and sin gle large fractions were likely to cause damage. Pathologically, the disease is characterized by damage to the microvasculature, proliferation of fibrous tissue , and disruption of the renal capillaries and arterioles. Clinically, the diseas e manifests predominantly with renal dysfunction and hypertension. Hematuria, ol iguria, fatigue, and gradually developing renal atrophy are common manifestation s. The chronic form of radiation nephropathy may occur 10 to 15 years after the radiation treatments. (From Rieselbach and Garnick [1]; with permission.) FIGURE 5-34 Bilateral ureteral obstruction by diffuse large-cell lymphoma. Exten sive retroperitoneal involvement is evident. Confluent adenopathy of retroperito neal lymph nodes has led to bilateral encasement and compression of the ureters by pink-tan, fleshy tumor. This may produce chronic renal failure if tumor invol vement is slowly progressive or involves predominantly one ureter. (From Skarin [31]; with permission.)

5.22 Systemic Diseases and the Kidney Specific Renal Tubular Dysfunction and Associated Fluid and Electrolyte Disorder s RENAL TUBULAR DYSFUNCTION IN MALIGNANCY Cause Tumor-induced inappropriate hormone concentrations PTH-like substances Excess AD H Deficient ADH Adrenocortical excess Adrenocortical insufficiency Tumor product s or metabolites Lysozyme (AML) Immunoglobulin light chains (MM) Hypercalcemia ( MM, osseous metastases) Reabsorptive urate transport inhibitor (Hodgkin's, solid t umors) Intrinsic Amyloid deposits in collecting ducts (MM) Partial intrarenal ob struction (MM cast nephropathy) Antineoplastic agents Cyclophosphamide Ifosfamid e Vincristine Cisplatin Streptozocin Clinical presentation Hypercalcemia Hypophosphatemia Hyponatremia (SIADH) Hypernatremia (central DI) H ypokalemia Hyperkalemia Hypokalemia Fanconi's syndrome Renal tubular acidosis Fanc oni's syndrome Urinary concentrating defect Multiple transport defects Hypouricemi a Nephrogenic DI Nephrogenic DI SIADH Fanconi's syndrome SIADH Hypomagnesemia Rena l tubular acidosis Hypophosphatemia Fanconi's syndrome FIGURE 5-35 Renal tubular dysfunction. Specific tubular dysfunction may be encou ntered in association with the four major causes listed. Normal renal tubular fu nction is controlled by a delicate balance of humoral mediators. Thus, a tumor-i nduced inappropriate concentration of a hormone that normally contributes to the modulation of this balance may result in a profound disturbance of tubular func tion, thereby causing impairment of fluid and electrolyte balance as well as oth er homeostatic defects. A tumor product appears to be the basis for renal phosph ate loss in some cases, in that the resultant hypophosphatemia regresses when th e tumor is removed [75]. Hyponatremia occurs frequently in the patient with canc er; it is frequently caused by the syndrome of inappropriate antidiuretic hormon e secretion (SIADH). Bronchogenic carcinoma is the most frequent cause of this s yndrome. A number of other tumors have also been reported to cause SIADH. Disapp earance of the syndrome on removal of the tumor or improvement following success ful chemotherapy has been observed frequently [76]. Cancer is a common cause of central diabetes insipidus; metastatic lesions have been reported to cause 5% to 20% of all cases, with breast cancer being the primary malignancy in more than half the cases reported [77]. Adrenocortical steroid excess may be associated wi th malignancies and often manifests with hypokalemia and metabolic alkalosis due to excessive mineralocorticoid effect in the distal nephron. Adrenal insufficie ncy may develop owing to metastatic lesions of the adrenal glands, producing hyp erkalemia and hyponatremia due to mineralocorticoid deficiency and affecting tubular transport at the same site . Hypercalcemia is the most common setting in which tumor products or metabolite s can cause specific tubular defects. In this case, profound tubular dysfunction is observed involving impairment of bicarbonate or sodium transport, urinary co ncentration, hydrogen ion secretion, or the renal handling of potassium, phospho rus, or magnesium [35]. Massive lysozymuria may be associated with renal damage, leading to kaliuresis and hypokalemia [78]. Elevations of lysozyme levels are s een with acute myelogenous leukemia. In this setting, proximal tubular defects i n urate, phosphate, and amino acid reabsorption have also been noted [79]. Isola ted hypouricemia has been reported in patients with advanced Hodgkin's disease; th ese patients have increased renal clearance of urate despite decreased serum ura te levels. Abnormal urate clearance was corrected by successful treatment of the underlying Hodgkin's disease, suggesting a humoral basis for this tubular defect. Hypouricemia, in association with other types of proximal tubular dysfunction, has been associated with a variety of solid tumors. In multiple myeloma, the pro

liferation of abnormal plasma cells produces large quantities of a variety of im munoglobulins. These may produce changes in tubular function, which result from tubular reabsorption of the freely filtered low-molecular-weight tumor products. These in turn interfere with normal metabolism of proximal tubular cells after their reabsorption. This toxicity produces Fanconi's syndrome, which is a complex proximal tubulopathy associated with multiple reabsorption defects, and renal tu bular acidosis, which may be of the proximal or distal variety. Intrinsic renal lesions produced by cancer may cause nephrogenic diabetes insipidus, in which th e kidney is unresponsive to the action of antidiuretic hormone (ADH), with resul tant formation of inappropriately dilute urine. This may be seen in multiple mye loma, in which causative intrinsic lesions could include intratubular obstructio n by myeloma proteins or amyloid deposition in collecting ducts. Various antineo plastic agents produce a wide array of tubular dysfunction, with defective reabs orptive transport of magnesium constituting the defect of greatest clinical sign ificance. AMLacute myelogenous leukemia; DIdiabetes insipidus; MMmultiple myeloma; PTHparathyroid hormone.

Renal Involvement in Malignancy 5.23 Malignancy in the Renal Transplant Patient MALIGNANCY IN THE RENAL TRANSPLANT PATIENT Cancer of the skin and lips Squamous cell carcinoma Basal cell carcinoma Maligna nt melanoma Malignant lymphoma Non-Hodgkin's lymphoma Reticulum cell sarcoma B-cel l lymphoproliferative syndromes (Epstein-Barr virus) Kaposi's sarcoma Cutaneous fo rm Visceral and cutaneous form Genitourinary cancer Carcinoma of the native kidn ey (acquired cystic kidney disease) Carcinoma of the transplanted kidney Renal c ell carcinoma Malignant melanoma Carcinoma of the urinary bladder (cyclophospham ide associated) Uroepithelial tumors (associated with analgesic abuse) Gynecolog ic cancer Carcinoma of the cervix Ovarian cancer FIGURE 5-36 Malignancy in the renal transplant patient. In patients with end-sta ge renal disease with an adequately functioning renal allograft, there is an inc reased incidence of malignancy at various sites [80]. The most common form of ma lignancy is skin cancer. Its incidence may be as high as 24% in countries such a s Australia where excessive exposure to the sun occurs. Other forms of cancer al so occur with increased incidence in the transplant recipient. Malignant lymphom a, especially at extranodal sites (such as the central nervous system), occurs w ith increased frequency. Women with renal transplants have been observed to have an increased incidence of cervical cancer. Kaposi's sarcoma can account for 5% to 10% of posttransplant neoplasms. This tumor may be confined to the skin or may involve the viscera. Several factors contribute to the increased risk of cancer in the immunosuppressed renal transplant recipient. These include loss of immune surveillance, chronic antigenic stimulation, oncogenic potential of the immunos uppressant agents, and viral infections leading to neoplasia. Epstein-Barr virus has been implicated in the polyclonal B-cell lymphoproliferative disease in the se patients. Lymphoproliferative disorders have been noted to occur after a medi an period of 56 months when azathioprine and prednisone are used as immunosuppre ssive therapy. After the introduction of cyclosporine, lymphoproliferative disor ders develop sooner, with a median interval of only 6 months [81]. The prognosis for patients with skin cancer remains good. Preventive measures such as avoidin g sun exposure, utilization of sun-blocking creams, and careful periodic skin ex aminations are important. Patients with Kaposi's sarcoma confined to the skin may have remission rates of up to 50% with cessation of immunosuppression or with ch emotherapy. Patients with Kaposi's sarcoma involving the viscera or with other lym phoproliferative disorders do poorly, with a more rapid course than seen in nont ransplant patients with malignancy. Even those patients responding to chemothera py tend to have only short remissions and a poor outcome. FIGURE 5-37 Malignant lymphoma in the transplanted kidney. A 55-year-old man with end-stage renal dise ase due to diabetic nephropathy received a cadaveric renal transplant. He was ma naged with prednisone, azathioprine, and antilymphocyte globulin (ALG). The allo graft functioned poorly despite therapy a week later with OKT3. Results of a per cutaneous renal biopsy were suspicious for a lymphoproliferative disorder in the renal allograft. He had a transplant nephrectomy 5 weeks after the original sur gery. Pathologic study of the allograft showed extensive infiltration of the int erstitium, renal pelvis, and blood vessels with large round and ovoid lymphocyte s with many nucleoli and scant cytoplasm, diagnostic of a malignant lymphoma. Sp ecial studies revealed the lymphoid cells to be polyclonal in nature, and the pa tient's serologic testing was positive for Epstein-Barr virus. Immunosuppression w as stopped, and therapy with ganciclovir was started.

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Renal Involvement in Tropical Diseases Rashad S. Barsoum Magdi R. Francis Visith Sitprija T ropical nephrology is no longer a regional issue. With the enormous expansion of travel and immigration, the world has become a global village. Today, a health problem in a particular region has worldwide repercussions. Typical examples are the acquisition of malaria in European airports, renal disease associated with herbal medications, and increasing encounters of parasitic infections in immunoc ompromised persons [13]. Lessons learned from the study of tropical diseases have considerably enriched worldwide medical knowledge of the basic and clinical asp ects of nontropical diseases. Examples include better understanding of macrophag e function in vitro, the role of cytokines in acute renal failure, and the impor tance of immunoglobulin A deposits in the progression of glomerular disease [47]. The so-called typical tropical nephropathies are broadly classified as infectiv e or toxic. Infective nephropathies include renal diseases associated with endem ic bacterial, viral, fungal, and parasitic infections. Toxic tropical nephropath ies include exposure to poisons of animal origin, such as snake bites, scorpion stings, and intake of raw carp bile, and plant origin, such as certain mushrooms and the djenkol bean [3]. Tropical bacterial infections often are associated wi th renal complications that vary according to the causative organism, severity o f infection, and individual susceptibility. The principal acute infections repor ted to affect the kidneys are salmonellosis, shigellosis, leptospirosis, melioid osis, cholera, tetanus, scrub typhus, and diphtheria [816]. Renal involvement in mycobacterial infections such as tuberculosis and leprosy usually pursues a suba cute or chronic course [1719]. CHAPTER 6

6.2 Systemic Diseases and the Kidney Mycotic infections are described in detail elsewhere. Discussed here is a fairly common mycotic infection, mucormycosis, which occurs in underdeveloped tropical regions, particularly among immunocompromised patients. Also described is ochra toxin, a fungal toxin often incriminated in the pathogenesis of Balkan nephropat hy. Ochratoxin also contributes to progressive interstitial nephropathy in Afric a [20]. Three ways exist by which parasitic infections cause renal disease: 1) d irect physical invasion of the kidneys or urinary tract, as in schistosomiasis, echinococcosis, and filariasis; 2) renal injury as a consequence of the acute sy stemic effects of parasitic infection, eg, falciparum malaria; and 3) immunemedi ated renal injury resulting from the concomitant host-parasite interaction, eg, schistosomiasis, malaria, filariasis, leishmaniasis, trichinosis, echinococcosis , toxoplasmosis, and trypanosomiasis [2132]. The clinical spectrum of renal involvement extends all the way from asymptomatic proteinuria or urinary sediment abnormalities to fatal acute renal failure. The respective renal pathologies include glomerular, microvascular, and tubulointer stitial lesions. The pathogenesis of renal complications in tropical bacterial i nfections is multifactorial. The principal factors are direct tissue invasion by the causative organisms and remote cellular and humoral effects of bacterial an tigens and endotoxins. The relative significance of the different pathogenetic m echanisms varies with the causative organism. In tropical zones many viral nephr opathies are endemic, such as those associated with human immunodeficiency virus and hepatitis A, B, and C viruses. These are addressed in Chapter 7. Here the f ocus is on an important viral disease endemic in Southeast Asia that often cause s minor epidemics in Africa and other tropical countries, dengue hemorrhagic fev er. Infective Tropical Nephropathies Bacterial Infections CLINICAL MANIFESTATIONS OF TROPICAL BACTERIAL NEPHROPATHIES Disease Salmonellosis Shigellosis Leptospirosis Melioidosis Cholera Tetanus Scrub typhus Diphtheria Tuberculosis Leprosy Abnormal sediment +++ ++++ +++++ + + + ++ ++ Proteinuria ++++ ++++ + ++++ ++ + +/+++ +++ ARF + + ++++ ++ + +++ + + + CRF + + HUS + ++* + Hemolysis + + + DIC + + + Jaundice + + ++++

Commonly associated features Gastrointestinal Neurologic Hemorrhagic tendency Polyuria Hyponatremia Hypokalemia, acidosis Sympathetic overflow Myocarditis, polyneuritis Retroperitoneal nodes L epromas + + *Associated with Shigella serotype I endotoxin [33]. Visual disturbances, drowsin ess, seizures, and coma in 40% of cases [34]. In 90% of cases [12]. Nephrogenic di abetes insipidus [35]. ARFacute renal failure; CRFchronic renal failure; DICdissemi nated intravascular coagulation; HUShemolytic uremic syndrome; +<10%; ++10%24%; +++25 %49%; ++++50%80%; +++++>80%. Dash indicates not reported. FIGURE 6-1 Clinical manifestations of tropical bacterial nephropathies. Note the wide spectrum of clinical manifestations that may ultimately reflect on the kid neys [3335].

Renal Involvement in Tropical Diseases 6.3 SPECTRUM OF RENAL PATHOLOGY IN TROPICAL BACTERIAL INFECTIONS Other tubular changes Disease Glomerulonephritis Deposits of immunoglobulins, complement, and antigen G,M,A,C3,Ag + M,C3 Vasculitis AIN ATN MPGN Salmonellosis Shigellosis Leptospirosis Melioidosis Cholera Tetanus Scrub typhus Diphtheria Tuberculosis Leprosy ++ + + + EXGN ++* MCGN MN NG CGN Amyloid ++ + + ++ +++ + + + +/+++ + + + G,M,A,C3 + ++ + + + + +++ + ++ ++ + +/++ +/+++** Cloudy swelling Cloudy swelling Cloudy swelling Vacuolation Cloudy swelling Degen eration Functional defects *When associated with Schistosoma mansoni infection in Egypt [9]. Vi antigen deposits [8]. Hypokalemic nephropathy [36]. Exotoxin-induced inhibition of protein synthesis in tubule cells [37]. Usually complicates amyloidosis: 2.4%8. 4% [18]. **63% in lepromatous leprosy; 2% in nonlepromatous types [38]. AINacute

interstitial nephritis; ATNacute tubular necrosis; CGNcrescentic glomerulonephriti s; EXGNexudative glomerulonephritis; MCGNmesangiocapillary glomerulonephritis; MNme mbranous glomerulopathy; NGnecrotizing glomerulitis; +<10%; ++10%24%; +++25%50%. FIGURE 6-2 Spectrum of renal pathology in tropical bacterial infections [3638]. A FIGURE 6-3 Glomerular lesions associated with tropical bacterial infections. A, Simple proliferative glomerulonephritis in a B patient with shigellosis. B, Exudative glomerulonephritis in a patient with salm onellosis. (Continued on next page)

6.4 Systemic Diseases and the Kidney C D FIGURE 6-3 (Continued) C, Necrotizing vasculitis in a patient with leptospirosis . D, Membranous nephropathy associated with leprosy. (Hematoxylin-eosin stain 15 0.) FIGURE 6-4 Glomerular amyloid deposits in a patient with leprosy. (Hematoxyl in-eosin stain 200.) FIGURE 6-5 Acute tubular pathology associated with bacterial infections. A, Acut e tubular necrosis with erythrocyte aggregates in the tubular lumina in a patien t with leptospirosis. (Hematoxylin-eosin stain 250.) B, Cortical necrosis in a c hild with severe shigellosis and hemolytic uremic syndrome. (Hematoxylin-eosin s tain 200.) A B

Renal Involvement in Tropical Diseases 6.5 FIGURE 6-6 Extensive vacuolation of the proximal tubules (hypokalemic nephropath y) in a patient with cholera. (Hematoxylin-eosin stain 300.) (From Sinniah and c oworkers [39]; with permission.) A B C FIGURE 6-7 Interstitial lesions associated with bacterial infections. A, Acute i nterstitial nephritis in a patient with diphtheria. (Hematoxylin-eosin stain 100 .) B, Perivenular monocytic infiltration in a patient with scrub typhus. (Hemato xylin-eosin D stain 100.) C, Renal abscess in a patient with septicemic melioidosis. (Hematoxy lin-eosin stain 75.) D, Microabscesses in a patient with typhoid fever [40]. (He matoxylineosin stain 75.)

6.6 Systemic Diseases and the Kidney FIGURE 6-8 Low-power electron micrograph. Here leptospires (arrow) in the peritu bular cortical interstitial space are seen in a patient with leptospirosis. (Mag nification 12,000.) FIGURE 6-9 Renal tuberculosis. Seen here are multiple tuberculous granulomata wi th Langhans' giant cells. Diffuse interstitial tuberculosis without definite granu lomatous formation also has been described. (Hematoxylin-eosin stain 200.) Bacterial infection Direct invasion Monocyte activation Endothelial injury Nonspecific inflammatory effects T-cell response Monokines Humoral Hematologic B-cell response Antibodies IL-1,6 TNF-a NO ROM Adhesion molecules Complement/coagulation Platelets Erythrocytes Immune complexes Endothelin Renal ischemia DIC Hemolysis Abscess Hypovolemia Cholestasis Glomerulonephritis Interstitial nephritis

ATN Jaundice FIGURE 6-10 Common pathogenetic mechanisms of renal injury in tropical bacterial infections. Depending on the bacterial species and strain, as well as on the ho st's resistance and genetic background, bacteria may directly invade the renal par enchyma, induce an immune reaction, injure the capillary endothelium or provoke a nonspecific humoral or hematologic response. The subsequent evolution of these pathways may lead to different forms of renal injury. The asterisk indicates th at the role of hemolysis is augmented in patients with glucose-6-phosphate dehyd rogenase (G6PD) deficiency. ATNacute tubular necrosis; DICdisseminated intravascul ar coagulation; ILinterleukin; NOnitric oxide; ROMreactive oxygen molecules; TNF- tu mor necrosis factor- .

Renal Involvement in Tropical Diseases 6.7 PATHOGENETIC MECHANISMS IN ACUTE TUBULAR NECROSIS Disease Salmonellosis Shigellosis Leptospirosis Melioidosis Cholera Tetanus Scrub typhus Diphtheria Leprosy Monokines + + ++ + + ++ + + + Hypovolemia + ++ + + +++ + + + Hemolysis + + + Rhabdomyolysis + + + ++* Disseminated intravascular coagulation + + + Complement activation ++ + + + *Elevated creatine phosphokinase in 88%, myoglobinuria in 39% of cases [14]. +<10 %; ++10%24%; +++24%50%. FIGURE 6-11 Pathogenetic mechanisms in acute tubular necrosis associated with ba cterial infections. Note the multiplicity of factors depending on the bacterial species and their host targets. Viral Infections 90 80 70 Incidence, % 60 50 40 30 20 10 0 Urinary sediment abnormalities Proteinuria Hyponatremia Lactic acidosis Acute re nal failure FIGURE 6-12 Clinical manifestations of renal involvement in dengue hemorrhagic f ever. Note that proteinuria and abnormal urinary sediment are the most common ma nifestations. Also note the high incidence of hyponatremia, like with many other tropical infections [40,41]. Selected important features

6.8 Systemic Diseases and the Kidney FIGURE 6-13 Renal lesions in a patient with dengue hemorrhagic fever. A, Mesangi al proliferative glomerulonephritis, which usually is associated with deposits o f immunoglobulins G and M and complement 3. (Hematoxylineosin stain 200.) B, Acu te tubular necrosis, which is associated with interstitial edema and mononuclear cell infiltration. (Hematoxylin-eosin stain 175.) A B Mycotic Infections FIGURE 6-14 Section from a patient with mucormycosis, showing extensive tissue n ecrosis, weak inflammatory cellular infiltration, and fungal hyphae branching at right angles. (Hematoxylin-eosin stain 150.) FIGURE 6-15 Ochratoxin-Ainduced interstitial fibrosis, showing marked intertubula r scarring with patchy atrophy and collapse of tubules. This patient's serum ochra toxin-A and urinary ochratoxin-A levels were 5.18 and 3.87 ng/mL, respectively ( the means for a control group were 1.6 and 1.85 ng/mL, respectively) [20]. (Mass on trichrome stain 200.)

Renal Involvement in Tropical Diseases 6.9 Parasitic Infections Schistosoma hemalobium Schistosoma mansoni Echinococcosis Quartan malaria Plasmodium falciparum FIGURE 6-16 Global distribution of important parasitic nephropathies. Note the h igh prevalence of schistosomal, malarial, filarial, and echinococcal renal compl ications in Africa; S. mansoni and hydatid in South America; falciparum malaria and filariasis in South East Asia and filariasis in India [3]. Schistosoma mansoni Filariasis FIGURE 6-17 Urinary schistosomiasis. A, A sheet of Schistosoma haematobium ova i n tissues. (Silver stain 350.) B, S. haematobium granuloma. Shown is a delayed h ypersensitivity reaction of the host to soluble oval antigens released from the ova through micropores in their shells. The granuloma is composed of mononuclear cells, a few neutrophils, eosinophils, and fibroblasts, surrounding a distorted egg. (Hematoxylineosin stain 300.) A B

6.10 Systemic Diseases and the Kidney A B C FIGURE 6-18 Cystoscopic appearances of different bladder lesions associated with Schistosoma haematobium infection. A, Bilharzial (schistosomal) pseudotubercles . B, Bilharzial submucous mass covered by pseudotubercles. C, Bilharzial ulcer s urrounded by pseudotubercles. D, Bilharzial ulcer surrounded by sandy patches. ( Courtesy of N. Makar, MD.) D FIGURE 6-19 Postmortem specimen showing advanced bilharzial involvement of the u rinary tract. Note the dirty bladder mucosa, fibrosed muscle layer, and neoplast ic growth (histologically a squamous cell carcinoma) cut through transversely. T he ureters are dilated, with a clear stricture at the lower end of the right ure ter. Also seen in this patient are bilateral hydroureters with submucous cystic lesions (bilharzial ureteritis cystica). The kidneys show considerable scarring, with the right kidney also showing chronic back pressure changes. FIGURE 6-20 F ilariasis of the abdominal lymphatics. Lymphangiogram shows the dilated retroper itoneal lymphatics in a patient with filarial chyluria.

Renal Involvement in Tropical Diseases 6.11 Antigens Merozoites Erythrocyte Hemolysis Cell membrane changes Monocyte TH1 TH2 Platalet Endothelial activation Hemodynamic changes Acute tubular necrosis TNF-a CD8+ B CIC Immunoglobulins Acute inflammatory Immune complex disease Proliferative glomerulonephritis Tubulointerstitial nephropathy Acute glomerulonephritis FIGURE 6-21 The pathogenesis of falciparum malarial renal complications. Note th e infection triggers two initially independent pathways: red cell parasitization and monocyte activation. These subsequently interact, as the infected red cells express abnormal proteins that induce an immune reaction by their own right, in addition to providing sticky points (knobs) for clumping and adherence to plate lets and capillary endothelium. TNF- released from the activated monocytes share s in the endothelial activation. As both pathways proceed and interact, a variet y of renal complications develop, including acute tubular necrosis, acute inters titial nephritis and acute glomerulonephritis. BB-lymphocyte; CD8cytotoxic T cell; CICcirculating immune complexes; THT-helper cells (1 and 2); TNF- tumor necrosis f actor- . FIGURE 6-22 Erythrocyte knobs in a patient with falciparum malaria [43]. These e rythrocyte knobs contain novel proteins, mainly Plasmodium falciparum erythrocyt e membrane protein (PfEMP), histidine-rich protein 1, and histidine-rich protein 2, that are synthesized under the influence of the DNA of the parasite [4446]. T hese proteins constitute the sticky points (arrows) by which parasitized erythro cytes aggregate and adhere to blood platelets and endothelial cells [47,48]. ENel ectron microphotograph. (Magnification 12,000.) B FIGURE 6-23 Renal lesions in a patient with falciparum malaria. A, Proliferative and exudative glomerulonephritis, an immune-complexmediated lesion that may lead to an acute nephritic syndrome, which usually is reversible by antimalarial tre atment. (Hematoxylin-eosin stain 175.) B, Acute tubular necrosis (ATN) associate d with interstitial mononuclear cell infiltration. ATN is seen in 1% to 4% of pa tients with falciparum malaria and in up to 60% of those with malignant malaria. (Hematoxylin-eosin stain 200.) (Continued on next page) A

6.12 Systemic Diseases and the Kidney FIGURE 6-23 (Continued) C, Subendothelial and mesangial malarial antigen deposit s seen on immunofluorescence. Often, complement 3, immunoglobulins M and G, and fibrinogen also are seen. (Hematoxylin-eosin stain 200.) C FIGURE 6-24 The broad lines of the immune response to parasitic infections. Note the pivotal role of the monocyte, activated by exposure to parasitic antigens, in stimulating both T-helper 1 (TH1) and T-helper 2 (TH2) cells. The different c ytokine mediators and parasite elimination mechanisms are shown. BB-lymphocyte; IFN -interferon; CICcirculating immune complexes; GM-CSFgranulocytemacrophage colon y-stimulating factor; Igimmunoglobulin; ILinterleukin. + ADCC Eosinophil + + CDCT ACDC Parasite + + + Neutrophil Complement CIC + IgM,E,G,A Antigen IL-5,13 IL-2 IL-1,6,12 GM-CSF + TH2 TH1 g-IFN IL-2 IL-4,5,10 + B + Active monocytes TH2, CD8 cells IgG1,2,3 IL-1,6;+gIFN Inactive monocytes TH2 ,CD8 cells IgM,IgG4,IgA IL-4,5,10 FIGURE 6-25 The T-helper1T-helper 2 (TH1-TH2) cell balance that determines the cl inical expression of different parasitic nephropathies. TH1 predominance leads t o either reversible acute proliferative glomerulonephritis or acute interstitial nephritis. TH2 predominance tends to lessen the severity of the lesions and may lead to chronic glomerulonephritis in the presence of copathogenic factors such as concomitant infection (malaria, schistosomiasis), autoimmunity (malaria, fil ariasis, schistosomiasis), or immunoglobulin A (IgA) switching (Schistosoma mans oni) [7, 9, 4952]. CD4T-helper cells; CD8cytotoxic cells; -INF -interferon; ILinterle ukin. Initial events Late events

Renal Involvement in Tropical Diseases 6.13 FIGURE 6-26 Leishmaniasis. A, Amastigotes in peripheral blood monocytes. Amastig otes downregulate the host cells that show no attempt at eradicating the parasit e. (Hematoxylineosin stain 450.) B, Interstitial nephritis representing a TH1 pr edominant state, which is self-limited owing to the parasiteinduced monocyte inh ibition [53]. (Hematoxylin-eosin stain 175.) A B FIGURE 6-27 Trichinosis. A, Here Trichinella spiralis is encysted in the muscle tissue of a patient. (Hematoxylin-eosin stain 75.) B, Associated proliferative g lomerulopathy in a patient. This lesion usually is subclinical but may be manife sted as an acute nephritic syndrome that can be resolved with antiparasitic trea tment. This lesion represents a TH1 predominant state. (Hematoxylineosin stain 1 50.) A B

6.14 Systemic Diseases and the Kidney B A FIGURE 6-28 Echinococcosis. A, Mesangiocapillary type III glomerulonephritis. (H ematoxylin-eosin stain 200.) B, Electron micrograph showing subepithelial deposi ts. (Hematoxylin-eosin stain 25,000.) C, Peripheral part of a hydatid cyst showi ng the daughter cysts in a patient. (Hematoxylineosin stain 75.) C FIGURE 6-29 Onchocercosis. A, The parasite Onchocerca volvulus deposits lesions in tissues. (Hematoxylin-eosin stain 150.) B, Associated mesangial proliferative lesion. This lesion represents a TH1 predominant state. Some patients, however, develop an autoimmune reaction that leads to progressive glomerulonephritis. (H ematoxylin-eosin stain 175.) A B

Renal Involvement in Tropical Diseases 6.15 FIGURE 6-30 Quartan malarial nephropathy. A, Proliferative glomerulonephritis wi th capillary wall thickening. (Hematoxylin-eosin stain 200.) B, Subendothelial d eposits with splitting of the basement membrane. (Silver stain 500.) This lesion occurs under TH2 predominance and usually is encountered in genetically predisp osed persons. This lesion also is associated with autoimmunity or concomitant vi ral infection. A B A B FIGURE 6-32 Patient with hepatosplenic schistosomiasis, complicating intestinal mansoniasis. Note the shrunken liver and very large spleen, surface marked on th e abdominal wall by black ink. Of these patients, 15% develop clinically overt g lomerular lesions. Half of the 15% become hypertensive, most become nephrotic at some stage, and almost all progress to end-stage disease [54]. FIGURE 6-31 Intestinal schistosomiasis. A, Pair of adult Schistosoma mansoni wor ms in colonic mucosa. (Hematoxylin-eosin stain 75.) B, Colonic granuloma around a viable ovum. (Hematoxylin-eosin stain 150.)

6.16 Systemic Diseases and the Kidney FIGURE 6-33 Early glomerular lesion in a patient with schistosomiasis. A, Mesang ial proliferation. (Hematoxylin-eosin stain 200.) B, Schistosomal gut antigen de posits in the mesangium. Other immunofluorescent deposits at this stage include immunoglobulins M and G and complement C. This lesion may be encountered in infe ction by Schistosoma mansoni, S. haematobium, or S. japonicum. The lesion does n ot necessarily progress any further. (Hematoxylin-eosin stain 300.) A B A B C FIGURE 6-34 Histologic lesions in a patient with progressive Schistosoma mansoni glomerulopathy. A, Mesangial proliferative glomerulonephritis. (Hematoxylin-eos in stain 150.) B, Exudative glomerulonephritis, often encountered with concomita nt Salmonella paratyphi A infection [9]. (Hematoxylin-eosin stain 150.) C, Mesan gial proliferation with areas of mesangiocapillary changes. (Hematoxylin-eosin s tain 150.) D, Focal and D segmental glomerulosclerosis. (Masson trichrome stain 150.) The two lesions in p anels C and D are associated with advanced hepatic fibrosis, impaired macrophage function, and predominant immunoglobulin A mesangial deposits [7,55]. The lesio ns shown are categorized, respectively, as classes I to IV schistosomal glomerul opathy according to the classification system of the African Association of Neph rology [54].

Renal Involvement in Tropical Diseases Pathogenesis of S. mansoni glomerulotherapy Adult worms in the portal vein Egg granulomata in the portal tracts Egg granulom ata in the colonic mucosa 6.17 Autoimmunity Antigens Mucosal breach Switching IgG,M,E Periportal fibrosis Immune complexes IgA Impaired macrophage function Portosystemic collaterals Glomerular deposits FIGURE 6-35 Pathogenesis of Schistosoma mansoni glomerulopathy. Note the crucial role of hepatic fibrosis, which 1) induces glomerular hemodynamic changes; 2) p ermits schistosomal antigens to escape into the systemic circulation, subsequent ly depositing in the glomerular mesangium; and 3) impairs clearance of immunoglo bulin A (IgA), which apparently is responsible for progression of the glomerular lesions. IgA synthesis seems to be augmented through B-lymphocyte switching und er the influence of interleukin-10, a major factor in late schistosomal lesions [7]. B A C FIGURE 6-36 (see Color Plate) Renal amyloidosis in schistosomiasis. A, Schistoso mal granuloma (top), three glomeruli with extensive amyloid deposits (bottom), a nd dense interstitial infiltration and fibrosis in a patient with massive Schist osoma haematobium infection. (Hematoxylin-eosin stain 75.) B, Amyloid deposition in the mesangium associated with mild mesangial cellular proliferation in a pat ient with S. mansoni glomerulopathy (African Association of Nephrology class V). (Hematoxylin-eosin stain 175.) C, Early amyloid deposits seen as green (birefri ngent) deposits in a glomerulus with considerable mesangial proliferation in a p atient with hepatosplenic schistosomiasis. (Congo red stain 200, examined under polarized light.)

6.18 Systemic Diseases and the Kidney Pathogenesis of schistoma-associated amyloidosis FIGURE 6-37 Pathogenesis of sch istosoma-associated amyloidosis. The monocyte continues to release interleukin-1 and interleukin-6 under the influence of schistosomal antigens. These antigens stimulate the hepatocytes to release AA protein, which has a distinct chemoattra ctant function. The monocyte is the normal scavenger of serum AA protein, a func tion that is impaired in hepatosplenic schistosomiasis. Serum AA protein accumul ates and tends to deposit in tissue. + Antigen Uptake Interleukin-1,6 Hepatocyte AA protein Matrix adhesion Tissue deposition Chemoattraction Toxic Tropical Nephropathies Toxins of Animal Origin NEPHROPATHIES ASSOCIATED WITH EXPOSURE TO ANIMAL TOXINS Acute renal failure Snake bite Scorpion sting Insect stings Jelly fish sting Spider bite Centipede b ite Raw carp bile +++ + + + + + ++ Vasculitis Subnephrotic proteinuria + + (MPGN) Nephrotic syndrome FIGURE 6-38 Nephropathies associated with exposure to toxins of animal origin. N ote that acute renal failure is the most common and important renal complication . Vascular and glomerular lesions are occasionally encountered with specific exp osures [5662]. ++ (MCD, MPGN, MN) MCDminimal change disease; MNmembranous glomerulonephritis; MPGNmesangial prolifera tive glomerulonephritis; +<10%; ++10%24%; +++25%50%.

Renal Involvement in Tropical Diseases Pathogenetic mechanisms in snake venom nephrotoxicity Snake venom Direct toxicity Immunologic reaction 6.19 Disseminated intravascular coagulation Hemolysis Rhabdomyolysis Cytokines Mediators Mesangiolysis FIGURE 6-39 Pathogenetic mechanisms in snake venom nephrotoxicity. The immediate effect of exposure is attributed to direct hematologic toxicity involving the c oagulation system and red cell membranes. The massive release of cytokines and r habdomyolysis also contribute. Late effects may be encountered as a consequence of the immune response to the injected antigens. Hemodynamic changes Vasculitis Renal ischemia Acute glomerulonephritis Acute tubular necrosis Glomerulonephritis Toxins of Plant Origin NEPHROPATHIES ASSOCIATED WITH EXPOSURE TO PLANT TOXINS Acute renal failure Djenkol bean Mushroom poisoning Callilepis laureola Semecarpus anacardium +++ + +++ + Hypertension ++ Proteinuria +++ + Hematuria ++++ FIGURE 6-40 Nephropathies associated with exposure to toxins of plant origin. No te that with the exception of Djenkol bean nephrotoxicity, most plant toxins lea d to acute renal failure due to hemodynamic effects [6366]. +<10%; ++10%24%; +++25%49%; ++++50%80%. Acknowledgment The authors acknowledge the help of Professor Amani Amin Soliman, Chairperson of the Parasitology Department, Cairo University, for providing very valuable mate rial included in this work. References 1. 2. Giacomini T, Toledano D, Baledent F: The severity of airport malaria. Bull Soc Pathol Exot Faliales 1988, 81:345350. Vanherweghem JL: A new form of nephrop athy secondary to the absorption of Chinese herbs. Bull Mem Acad R Med Belg 1994 , 149:128135. Barsoum R, Sitprija V: Tropical nephrology. In Diseases of the Kidn ey, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown and Compan

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Renal Involvement in Tropical Diseases 54. Barsoum RS: Schistosomal glomerulopathies. Kidney Int 1993, 44:112. 55. Barso um RS, Sersawy G, Haddad S, et al.: Hepatic macrophage function in schistosomal glomerulopathy. Nephrol Dial Transplant 1988, 3:612616. 56. Chugh KS: Snake bite induced renal failure in India. Kidney Int 1989, 194. 57. Waterman J: Some notes on scorpion poisoning in Trinidad. Trans R Soc Trop Med Hyg 1993, 32:607. 58. B arss P: Renal failure and death after multiple stings in Papua New Guinea. Ecolo gy, prevention and management of attacks by vespid wasps. Med J Aust 1989, 151:6 59. 59. Spielman FJ, Bowe EA, et al.: Acute renal failure as a result of Physali a physalis sting. South Med J 1982, 75:1425. 60. Kibukamusoke JW, Chugh KS, Sakh uja V: Renal effects of envenomation. In Tropical Nephrology. Edited by Kibukamu soke JW. Canberra, Australia: Citforge Pty; 1984:170. 6.21 61. Logan JL, Ogden DA: Rhabdomyolysis and acute renal failure following the bit e of the giant desert centipede, Scolopendra heros. West J Med 1985, 142:549. 62 . Lin CT, Huang PC, Yen TS, et al.: Partial purification and some characteristic nature of a toxic fraction of the grass carp bile. Clin Biochem Soc 1977, 6:1. 63. Eiam-Ong S, Sitprija V, Saetang P, et al.: Djenkol bean nephrotoxicity in So uthern Thailand. Proceedings of the First Asia Pacific Congress on Animal, Plant and Microbial Toxins. Singapore; 1989:628. 64. McClain JL, Hause DW, Clark MA: Amanita phalloides mushroom poisoning: a cluster of four fatalities. J Forensic Sci 1989, 34:83. 65. Bye BN, Coetzer TH, Dutton MF: An enzyme immunoassay for at ractyloside, the nephrotoxin of Callilepis laureola (Impila). Toxicology 1990, 2 8:997. 66. Matthai TP, Date A: Renal cortical necrosis following exposure to sap of the marking nut tree (Semecarpus anacardium). Am J Trop Med Hyg 1979, 28:773 .

Renal Disease in Patients Infected with Hepatitis and Human Immunodeficiency Vir us Jacques J. Bourgoignie T.K. Sreepada Rao David Roth I nfection with hepatitis B virus (HBV) may be associated with a variety of renal diseases. In the past, HBV was the major cause of viral hepatitis in patients wi th end-stage renal disease (ESRD). Introduction of rigorous infection-control st rategies has led to a remarkable decline in the spread of HBV infection in dialy sis units. Physicians also are increasingly recognizing the association between chronic hepatitis C virus (HCV) infection and glomerular disease, both in native kidneys and renal allografts. Liver disease caused by HCV is a major factor in morbidity and mortality among patients with ESRD treated with dialysis and trans plantation. The first part of this chapter focuses mainly on issues related to H CV infection. The second part of this chapter examines the renal complications i n patients with human immunodeficiency virus (HIV) infection. Our knowledge abou t HIV has increased greatly, and dramatic advances have occurred in the treatmen t of patients with acquired immunodeficiency syndrome (AIDS). For the first time since the discovery of the disease, deaths are decreasing. Nevertheless, in the United States, as of June 30, 1997, there were over 600,000 cumulative cases of HIV infection, with over 400,000 deaths. Worldwide, the HIV epidemic continues to spread; an estimated 20 million persons are infected with HIV. Recent advance s in the clinical management of these patients result from better understanding of the replication kinetics of HIV, assays to measure viral load, availability o f CHAPTER 7

7.2 Systemic Diseases and the Kidney with HIV infection now is common. The incidence of renal complications in this p opulation is expected to increase further as patients live longer. new effective drugs against HIV, and demonstration that aggressive protocols com bining antiviral drugs substantially reduce HIV replication. Thus, prolonged sur vival of patients Hepatitis B and C Virus RENAL DISEASE ASSOCIATED WITH HEPATITIS B VIRUS INFECTION Lesion Membranous nephropathy Polyarteritis nodosa Clinical presentations Nephrotic syndrome Vasculitis, nephritic Pathogenesis Deposition of HBeAg with anti-HBeAb Deposition of circulating antigen-antibody c omplexes Deposition of complexes containing HBsAg and HBeAg Membranoproliferative glomerulonephritis Nephrotic, nephritic HBeAghepatitis B antigen; HBsAghepatitis B surface antigen. FIGURE 7-1 Renal disease associated with hepatitis B. Infection with hepatitis B virus (HBV) may be associated with a variety of renal diseases [1,2]. Many pati ents are asymptomatic, with plasma serology positive for hepatitis B surface ant igen (HBsAg), hepatitis B core antibody (HBcAb), and hepatitis B antigen (HBeAg) . The pathogenetic role of HBV in these processes has been documented primarily by demonstration of hepatitis B antigen-antibody complexes in the renal lesions [1,3,4]. Three major forms of renal disease have been described in HBV infection . In membranous nephropathy, it is proposed that deposition of HBeAg and anti-HB e antibody forms the classic subepithelial immune deposits [1,35]. Polyarteritis nodosa is a medium-sized vessel vasculitis in which antibody-antigen complexes m ay be deposited in vessel walls [1,2]. Finally, membranoproliferative glomerulon ephritis is characterized by deposits of circulating antigen-antibody complexes in which both HBsAg and HBeAg have been implicated [3]. recent studies have note d one or more of the following features in over 95% of patients with this disord er: circulating anti-HCV antibodies; polyclonal immunoglobulin G anti-HCV antibo dies within the cryoprecipitate; and HCV RNA in the plasma and cryoprecipitate [ 6,7]. Furthermore, evidence exists suggesting direct involvement of HCV-containi ng immune complexes in the pathogenesis of this renal disease [6]. Sansono and c olleagues [12] demonstrated HCV-related proteins in the kidneys of eight of 12 p atients with cryoglobulinemia and membranoproliferative glomerulonephritis (MPGN ) by indirect immunohistochemistry. Convincing clinical data exist suggesting th at HCV is responsible for some cases of MPGN and possibly membranous nephropathy [1315]. In one report of eight patients with MPGN, purpura and arthralgias were uncommon and cryoglobulinemia was absent in three patients [13]. Circulating ant i-HCV antibody and HCV RNA along with elevated transaminases provided strong evi dence of an association with HCV infection. Establishing the diagnosis of HCV in fection in these diseases is important because of the potential therapeutic bene fit of -interferon treatment [13]. A number of reports exist that demonstrate a beneficial response to chronic antiviral therapy with -interferon [6,13,16,17]. Even more compelling evidence for a beneficial effect of -interferon in HCV-indu ced mixed cryoglobulinemia was demonstrated in a randomized prospective trial of 53 patients given either conventional therapy alone or in combination with -int

erferon [18]. ith cessation times weekly sing regimens

Because of the likely recurrence of viremia and cryoglobulinemia w of -interferon therapy after conventional treatment (3 106 U three for 6 mo), extended courses of therapy (up to 18 mo) and higher do are being studied [1921].

RENAL DISEASE ASSOCIATED WITH HEPATITIS C VIRUS INFECTION Disease Mixed cryoglobulinemia [611] Membranoproliferative glomerulonephritis [13] Renal manifestations Serologic testing Membranous nephropathy [14,15] Hematuria, proteinuria Positive cryoglobulins; (often nephrotic), rheumatoid fac tor variable renal insufficiency often present Hematuria, proteinuria Hypocomple mentemia; (often nephrotic) rheumatoid factor and cryoglobulins may be present P roteinuria Complement levels normal; (often nephrotic) rheumatoid factor negativ e FIGURE 7-2 Renal disease associated with hepatitis C. Hepatitis C virus (HCV) in fection is associated with parenchymal renal disease. Chronic HCV infection has been associated with three different types of renal disease. Type II or essentia l mixed cryoglobulinemia has been strongly linked with HCV infection in almost a ll patients with this disorder [611]. The clinical manifestations of this renal d isease include hematuria, proteinuria that is often in the nephrotic range, and a variable degree of renal insufficiency. Essential mixed cryoglobulinemia had b een considered an idiopathic disease; however,

Renal Disease in Patients Infected with Hepatitis and Human Immunodeficiency Vir us 7.3 FIGURE 7-3 Membranoproliferative glomerulonephritis with hepatitis C. Micrograph of a biopsy showing membranoproliferative glomerulonephritis (MPGN) in a patien t with hepatitis C virus (HCV) infection. A lobulated glomerulus with mesangial proliferation and an increase in the mesangial matrix are seen. Although still a n idiopathic disease in many cases, HCV appears to be responsible for some cases of MPGN [13,16]. It has been suggested that the decline in the incidence of idi opathic type 1 MPGN may be partly a result of more careful screening by blood ba nks, leading to a decrease in the overall incidence of HCV infection and subsequ ent glomerulonephritis [16]. FIGURE 7-4 Electron microscopy of membranoproliferative glomerulonephritis from the biopsy specimen shown in Figure 7-3. Mesangial cell interposition is noted w ith increased mesangial matrix. Abundant subendothelial immunocomplex deposits a re noted. Fusion of the epithelial cell foot processes also is seen. Envelope Capsid glycoproteins 341 Nucleotides Open-reading frame Protein helicase NS2 Replicase WORLDWIDE PREVALENCE OF ANTIHEPATITIS C AMONG PATIENTS ON DIALYSIS Continent North America [2529] South America [30] Europe [3141] Asia [4249] New Zealand and A ustralia [50,51] ELISA-1enzyme-linked immunosorbent assay-1. C E1 E2 NS3 NS4a NS4b NS5a NS5b 5-1-1 RIBA2 ELISA-1 positive, % 836 39 154 1751 1.210 C200 Epitope SA2 ELI BA2 RI RIBA 2 C33c C100-3 Epitope Epitope 2 ELISA C22-3 Epitope ELISA RIBA1+2 2 3000 Amino acids

5' Genomic HCV RNA 3' FIGURE 7-5 Diagnostic tests for HCV infection. In 1989, hepatitis C virus (HCV) was cloned and identified as the major cause of parenterally transmitted non-A, non-B hepatitis [22]. The first serologic test for HCV employed an enzyme-linked immunosorbent assay (ELISA-1) that detected a nonneutralizing antibody (anti-HC V) to a single recombinant antigen. Limitations of the sensitivity and specifici ty of this test led to development of second-generation tests, ELISA-2 and a rec ombinant immunoblot assay (RIBA-2) [23]. The standard for identifying active HCV infection remains the detection of HCV RNA by reverse transcriptase polymerase chain reaction. (Adapted from Roth [24].) FIGURE 7-6 Prevalence of anti-HCV among dialysis patients. Patients receiving di alysis clearly are at greater risk for acquiring hepatitis C virus (HCV) infecti on than are healthy subjects, based on the seroprevalence of anti-HCV antibodies among patients with end-stage renal disease. These results of ELISA-1 testing l ikely underestimate true positivity because studies have demonstrated a nearly t wofold increase in seropositivity when screening dialysis patients with the ELIS A-2 assay [52]. Additional studies have demonstrated that most patients receivin g dialysis who have anti-HCV seropositive test results have circulating HCV RNA by polymerase chain reaction analysis, indicating active viral replication.

7.4 Systemic Diseases and the Kidney FIGURE 7-7 Risk of HCV in the ESRD population. Numerous studies have demonstrate d a strong association between the prevalence of hepatitis C virus (HCV) infecti on among patients receiving dialysis and both the number of transfusions receive d and duration of dialysis [53,61]. Although these two variables are related, th e prevalence of anti-HCV in these patients has been shown to be independently as sociated with both factors by regression analysis. In contrast to patients recei ving hemodialysis, patients receiving peritoneal dialysis consistently have a lo wer prevalence of anti-HCV antibody [6070]. Moreover, units with a low prevalence of anti-HCV have been shown to have a lower seroconversion rate [71]. The latte r two observations coupled with the independent association of duration of dialy sis with seropositivity argue in favor of nosocomial transmission of HCV in hemo dialysis units. This conclusion is further supported by data showing a decreased incidence of HCV seroconversion in dialysis units employing isolation and dedic ated equipment for patients who test positive for HCV infection [72]. RISK FACTORS IN THE POPULATION WITH END-STAGE RENAL DISEASE AND HEPATITIS C VIRU S INFECTION Transfusions [24,27,30,32,5457] Duration of end-stage renal disease [29,30,32,35, 37,5361] Mode of dialysis [6070] Prevalence of hepatitis C virus infection in the dialysis unit [71,72] TRANSMISSION OF HEPATITIS C VIRUS IN HEMODIALYSIS UNITS Breakdown in universal precautions [73,74] Dialysis adjacent to an infected pati ent [71,75] Dialysis equipment [46,60] Type of dialyzer membrane [7678] Reuse [71 ,72] FIGURE 7-8 Transmission of HCV during dialysis. Convincing data are available th at demonstrate an increased risk of anti-HCV seroconversion associated with both a failure to strictly follow infection control procedures and the performance o f dialysis at a station immediately adjacent to that of a patient testing positi ve for anti-HCV [7175]. Units using dedicated machines have shown a decreased inc idence of seroconversion [51]. The literature provides conflicting data on the l ikelihood of passage of HCV RNA into dialysis ultrafiltrate and the risk of cont amination by reprocessing filters [71,72,7678]. At this time the Centers for Dise ase Control does not recommend that patients who are HCV positive be isolated or dialyzed on dedicated machines and has no official policy concerning reuse of m achines in these patients [79]. Pericentral fibrosis 3% Other 6% Cirrhosis 9% Chronic active hepatitis 42% Hemosiderosis 15% Reactive hepatitis 18% Chronic persistent hepatitis 6% FIGURE 7-9 Liver disease among anti-HCVpositive dialysis patients. Serum alanine aminotransferase levels are elevated in only 24% to 67% of dialysis patients who test positive for the anti-hepatitis C virus (HCV) [80]. Caramelo and colleague s [81] evaluated liver biopsies from 33 patients on hemodialysis who tested posi tive using ELISA-2 and found a variety of histologic patterns; however, over 50% of these patients had chronic hepatitis or cirrhosis. No correlation has been f ound between mean levels of serum aminotransferase and severity of liver disease

[81]. At this time, liver biopsy is the only reliable method to determine the e xtent of hepatic injury in patients with end-stage renal disease infected with H CV. Liver function tests and HCV serology testing may help identify patients who are at risk for liver disease. However, a liver biopsy should be obtained befor e initiating therapy or as part of the evaluation before transplantation. Liver biopsy can identify patients with advanced histologic liver injury who may not b e good candidates for transplantation or can be used as a baseline before starti ng -interferon therapy. (From Caramelo and colleagues [81]; with permission.)

Renal Disease in Patients Infected with Hepatitis and Human Immunodeficiency Vir us 7.5 PREVALENCE OF LIVER DISEASE AFTER KIDNEY TRANSPLANTATION First decade, % Acute liver disease: 565 Chronic liver disease: 515 Second decade, % Chronic liver disease: 540 Death from liver failure: 1030 FIGURE 7-10 Liver disease after kidney transplant. Biochemical abnormalities ref lecting liver injury have been reported in 7% to 34% of kidney recipients in the early period after transplantation [23,8286]. Morbidity and mortality associated with liver disease, however, are rarely seen until the second decade after tran splantation [87]. Liver dysfunction can be secondary to viral infections, such a s hepatitis B and C, herpes simplex virus, Epstein-Barr virus, and cytomegalovir us, in addition to the hepatotoxicity associated with several immunosuppressive agents (azathioprine, tacrolimus, and cyclosporine) [88]. However, hepatitis C v irus infection has been demonstrated convincingly to be the primary cause of pos ttransplantation liver disease in renal allograft recipients [89,90]. FIGURE 7-1 1 Organ donor hepatitis C virus (HCV) transmission. Most recipients of a kidney from a donor positive for hepatitis C virus RNA will become infected with HCV if the organ is preserved in ice. ELISA1 testing of serum samples from 711 cadaver ic organ donors identified 13 donors positive for anti-HCV infection; 29 recipie nts of organs from these donors were followed [91,92]. The prevalence of HCV RNA in these allograft recipients increased from 27% before transplantation to 96% after transplantation. In contrast, studies from centers using pulsatile perfusi on of the kidney during preservation have confirmed transmission of HCV in only about 56% of cases [93,94]. Several factors might explain the discrepancy in tra nsmission rates. One possibility may involve differences in organ preservation. Zucker and colleagues [97] demonstrated that pulsatile perfusion removed 99% of the estimated viral burden in the kidney, and centers using pulsatile perfusion have consistently reported lower transmission rates than do centers preserving o rgans on ice. Additional factors could include geographic variation in HCV quasi -species and the magnitude of the circulating viral titer in the donor at the ti me of harvesting. FIGURE 7-12 Patterns of hepatitis C virus (HCV) infection afte r transplantation of a kidney from a positive donor into a positive recipient. I n a simple but important study, Widell and colleagues [98] demonstrated three di ffering virologic patterns of HCV infection emerging after kidney transplantatio n from a donor infected with HCV into a recipient infected with HCV. Superinfect ion with the donor strain, persistence of the recipient strain, or long-term coinfection with both the donor and recipient strain may result. The clinical sign ificance of infection with more than one HCV strain has not been determined in t he transplantation recipient with immunosuppression, although no data exist to s uggest that co-infection confers a worse outcome. For this reason, many centers will transplant a kidney from a donor who was infected with HCV into a recipient infected with HCV rather than discard the organ. (Data from Widell and colleagu es [98]; with permission.) TRANSMISSION OF HEPATITIS C VIRUS INFECTION BY CADAVERIC DONOR ORGANS Posttransplantation HCV infection status Reference Pereira et al. [91,92] Roth et al. [93] Tesi et al. [94] Vincente et al. [95] Wr eghtt et al. [96] Anti-HCV, n/n (%) 16/24(67) 10/31(32) 15/43(35) 1/7(14) 6/15(40) HCV RNA, n/n (%)

23/24(96) Not available 21/37(57) 1/7(14) 12/14(86) Recipient 3a (Donor 1a) 5 Recipient 1b (Donor 1a) Recipient strain Donor strain Both strains 4 Patient, n Recipient 2b (Donor 3a) 3 Recipient 2b (Donor 3a) 2 Recipient 2b (Donor 3a) 1 Pretransplant 0 3 6 9 12 15 18 Months after transplant 21 24 27

7.6 Systemic Diseases and the Kidney FIGURE 7-13 Pretransplant HCV infection effect on outcome. Reports have varied f rom different centers concerning the impact of pretransplantation hepatitis C vi rus (HCV) infection on outcome after transplantation. Patient survival and graft survival were significantly worse among patients with anti-HCV infection in som e studies [99,100]; in other studies a measurable impact could not be detected [ 90,101]. Some of these differences could be attributed to geographic variation i n the prevalence of various HCV genotypes, differing immunosuppressive protocols , and length of follow-up after transplantation. IMPACT ON OUTCOME OF HEPATITIS C VIRUS INFECTION CONTRACTED BEFORE TRANSPLANTATI ON After transplantation* Reference Fritche et al. [99] Pereira et al. [100] Roth et al. [90] Ynares et al. [101] Antihepatitis C virus infection ELISA-2 positive ELISA-2 negative ELISA-2 positive ELISA-2 negative RIBA-2 posit ive RIBA-2 negative ELISA-1 positive ELISA-1 negative Actuarial graft survival, % Actuarial patient survival, % 32(10) 53(10) 50 59 81(5) 80(5) 33(10) 25(10) 58(8) 82(8) 59 85 63(5) 63(5) 53(1 0) 54(10) ELISAenzyme-linked immunosorbent assay; RIBArecombinant immunoblot assay. *Numbers in parentheses indicate years after transplatation. GLOMERULAR DISEASE IN KIDNEY RECIPIENTS INFECTED WITH HEPATITIS C VIRUS Histologic diagnosis MGN MPGN DPGN 0 7 0 15 5 0 5 0 1 0 0 0 Reference Cockfield and Prieksaitis [102] Huraib et al. [103] Morales et al. [104] Roth et al. [105] Morales et al. [106] Number of antiHCVpositive patients 51 30 166 98 409 CGN 1 0 0 0 Total cases of GN 11* 7 7 5 15 CGNcrescentic glomerulonephritis; DPGNdiffuse proliferative GN; MGNmembranous GN; M PGNmembranoproliferative GN. *No specific diagnosis. FIGURE 7-14 Glomerular disease in HCV positive recipients. Chronic hepatitis C v irus (HCV) infection has been associated with several different immune-complexmed iated diseases in the renal allograft, including membranous and membranoprolifer ative glomerulonephritis (MPGN) [102106]. From a cohort of 98 renal allograft recipients with HCV, Roth and colle agues [105] detected de novo membranoproliferative glomerulonephritis in the bio psies of five of eight patients with proteinuria of over 1 g/24 h [105]. Compare d with a control group of nonproteinuric kidney recipients infected with HCV, pa tients with MPGN had viral particles present in greater amounts in the high-dens ity fractions of sucrose density gradients associated with significant amounts o f IgG and IgM. Thus, deposition of immune complexes containing HCV genomic mater

ial may be involved in the pathogenesis of this form of MPGN. The differential d iagnosis for significant proteinuria in a patient infected with HCV after transp lantation should include immune-complex glomerulonephritis. Similarly, if the re nal allograft biopsy shows immune-complex glomerulonephritis, the patient should be tested for HCV infection without regard to serum alanine aminotransferase le vels.

Renal Disease in Patients Infected with Hepatitis and Human Immunodeficiency Vir us 7.7 INTERFERON THERAPY FOR PATIENTS IN END-STAGE RENAL DISEASE WITH HEPATITIS C VIRU S INFECTION Reference Pol et al. [107] Casanovas et al. [108] Koenig et al. [109] Duarte et al. [110] Raptopoulou-Gigi et al. [111] Magnone et al. [112] Rostaing et al. [113] Harihar a et al. [114] Thervet et al. [115] Izopet et al. [116] Ozgur et al. [117] Study population Patients, n Clearing of HCV RNA, % Comments HD HD HD HD HD TX TX TX TX TX TX 19 10 37 5 19 7 16 3 13 15 5 53 10 65 NA 77 NA 33 0 0 0 NA 6/7 (86%) rejection 6/16 (37%) acute renal failure 3/3(100%) renal f ailure 2/3 (67%) acute renal failure 5/15 (33%) acute renal failure All with imp roved liver histology HDhemodialysis; NAnot available; TXtransplantation. FIGURE 7-15 Interferon in HCV-positive end-stage renal disease (ESRD) and transp lant patients. Interferon therapy in patients infected with hepatitis C virus (H CV) who have ESRD has been studied in both patients receiving dialysis and trans plantation recipients. Some studies have reported encouraging early responses [1 07111]. Relapses are common after cessation of treatment, however, and many trans plantation recipients have experienced deterioration in allograft function [11211 6]. Based on the poor outcomes reported in transplantation recipients, additiona l studies are needed. These studies would evaluate the long-term benefits of a s trategy in which infected patients who have ESRD are treated with -interferon wh ile on dialysis in an effort to clear viremia before the planned transplantation . Further study of protocols using extended treatment periods coupled with diffe ring dosing regimens are necessary to determine the optimal therapy for the pati ent infected with HCV who has ESRD. Human Immunodeficiency Virus RENAL COMPLICATIONS OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION Acid-base and electrolyte disturbances Acute renal failure Human immunodeficienc y virusassociated nephropathies Renal infections and tumors FIGURE 7-16 Renal complications of HIV. Renal complications are frequent, and th ese rates are expected to increase as patients with HIV live longer. Many renal diseases are incidental and are the consequences of opportunistic infections, ne oplasms, or the treatment of these infections and tumors. The renal diseases inc lude a variety of acidbase and electrolyte disturbances, acute renal failure hav ing various causes, specific HIV-associated nephropathies, and renal infections and tumors. PATHOGENESIS OF HYPONATREMIA IN PATIENTS WITH ACQUIRED IMMUNODEFICIENCY SYNDROME Hypovolemia Tubular dysfunction Mineralocorticoid deficiency Syndrome of inappro priate antidiuretic hormone Hemodilution FIGURE 7-17 Hyponatremia pathogenesis in AIDS. Single and mixed acid-base distur bances, as well as all types of electrolyte disorders, can be observed in patien ts with AIDS. These disturbances and disorders develop spontaneously in patients with complications of AIDS or follow pharmacologic interventions and usually ar e not associated with structural lesions in the kidneys unless renal failure als o is present. Hyponatremia is the most prevalent electrolyte abnormality, occurr ing in 36% to 56% of patients hospitalized with AIDS [118122]. In the absence of an evident source of fluid loss, volume depletion may be related to renal sodium wasting as a result of Addison's disease or hyporeninemic hypoaldosteronism [12312

5]. In euvolemic patients, hyponatremia is compatible with nonosmolar inappropri ate secretion of antidiuretic hormone [120,121,126]. Hyponatremia in patients wi th hypervolemia is dilutional in origin as a result of excessive free water inta ke in a context of renal insufficiency [122].

7.8 Systemic Diseases and the Kidney foscarnet, pentamidine, cidofovir, rifampin, and amphotericin B), other organ to xicity (didanosine, foscarnet, and rifampin), or interference with uric acid met abolism. Hypernatremia may be the result of drug-induced diabetes insipidus. Hyp erkalemia can occur in 16% to 24% of patients with AIDS, even in the absence of renal insufficiency. Hypokalemia is associated with tubular nephrotoxicity. Hypo calcemia may result from urinary losses of magnesium and hypomagnesemia (pentami dine and amphotericin B) or from drug-induced pancreatitis (pentamidine, didanos ine, and foscarnet). Hypercalcemia occurs in association with granulomatous diso rders, disseminated cytomegalovirus infection, lymphoma, human T-cell leukemia ( HTLV) related to HTLV-I infection or foscarnet administration. Hypouricemia was described in 22% of patients as a result of an intrinsic tubular defect in urate transport unrelated to drug therapy. In contrast, hyperuricemia usually is the result of drug interference with purine metabolism (didanosine) or tubular urate secretion (pyrazinamide and ethambutol). In the absence of clinical manifestati ons that readily explain acid-base or electrolyte disturbances, a careful review of the pharmacopeia used to treat patients with HIV infection is mandated. Exte nsive reviews of the complications associated with drugs are available [127,128] . ELECTROLYTE COMPLICATIONS OF DRUGS USED TO TREAT ACQUIRED IMMUNODEFICIENCY SYNDR OME Hypernatremia: foscarnet, rifampin, amphotericin B Hyperkalemia: pentamidine, ke toconazole, trimethoprim Hypokalemia: rifampin, didanosine, amphotericin B, fosc arnet Hypomagnesemia: pentamidine, amphotericin B Hypocalcemia: foscarnet, penta midine, didanosine Hypercalcemia: foscarnet Hypouricemia: rifampin Hyperuricemia : didanosine, pyranzinamide, ethambutol Tubular acidosis: amphotericin B, trimet hoprim, cidofovir, rifampin, foscarnet FIGURE 7-18 Drugs causing electrolyte complications. A number of drugs used in t he treatment of patients with AIDS can induce acid-base or electrolyte abnormali ties from direct renal toxicity (didanosine, CAUSES OF ACUTE RENAL FAILURE Prerenal azotemia, acute tubular necrosis Allergic interstitial nephritis Obstru ctive nephropathy Rhabdomyolysis, myoglobinuric acute renal failure Thrombotic t hrombocytopenic purpura, hemolytic uremic syndrome Rapidly progressive glomerulo nephritis FIGURE 7-19 Causes of acute renal failure. Acute renal failure is related to com plications of AIDS, its treatment, or the use of diagnostic agents in about 20% of patients [129,130]. Acute tubular necrosis occurs with a prevalence of 8% to 30%, most often in patients with AIDS and prerenal azotemia from hypovolemia, hy potension, severe hypoalbuminemia, superimposed sepsis, or drug nephrotoxicity ( radiocontrast dyes, foscarnet, acyclovir, pentamidine, cidofovir, amphotericin B , nonsteroidal anti-inflammatory drugs, and antibiotics) [129138]. The clinical p resentation, laboratory findings, and course of acute tubular necrosis do not di ffer in patients with AIDS and those in other clinical settings. Prevention incl udes correction of fluid and electrolyte abnormalities and dosage adjustments of potentially nephrotic drugs. Identification and withdrawal of the offending age nts usually result in recovery of renal function. Dialysis may be needed before renal function improves. Less frequent causes of acute renal failure include all ergic acute interstitial nephritis; complicating treatments with trimethoprim an d sulfamethoxazole, rifampin, or acyclovir; and acute obstructive nephropathy, r esulting from the intrarenal precipitation of crystals of sulfadiazine, acyclovi r, urate, or protease inhibitors [134,139146]. Obstructive uropathy without hydro nephrosis also may develop in patients with lymphoma as a result of lymphomatous

ureteropelvic infiltration or retroperitoneal fibrosis [147149]. Rhabdomyolysis with myoglobinuric acute renal failure usually occurs in the setting of cocaine use [150]. Instances of acute renal failure associated with intravascular coagul ation related to thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic s yndrome (HUS) have been reported (vide infra). Rare causes of acute renal failur e include disseminated microsporidian infection or histoplasmosis [151,152]. A c linical presentation of acute renal failure also can be seen in patients with ac ute immunocomplex postinfectious glomerulonephritis, crescentic glomerulonephrit is, or fulminant HIV-associated glomerulosclerosis. FIGURE 7-20 Acyclovir nephro toxicity. Drugs may induce acute renal failure by more than one mechanism. For i nstance, acute renal failure may complicate the use of acyclovir as a result of intrarenal precipitation of acyclovir crystals, acute interstitial nephritis, or acute tubular necrosis [139,144,153]. An example of nonoliguric acute tubular n ecrosis associated with administration of large doses of intravenous acyclovir i s illustrated, which was readily reversible on decreasing the dose of acyclovir from 2.4 to 0.4 g/24 h. Patients infected with HIV can exhibit a broad spectrum of conditions that may affect the kidneys. Renal biopsy is useful for diagnostic and prognostic purposes when the cause of acute renal failure is not clinically evident. In a recent study of 60 patients with acute renal failure, a percutane ous renal biopsy yielded a pathologic diagnosis in 13% that was not expected cli nically [154]. Acyclovir, g/d IV 2.4 1.4 0.4 -0.6 7 6 5 4 3 2 1 0 1 2 3 4 Day 5 6 7 8 7 6 5 4 3 2 1 0 Serum creatinine, mg/dL Urine volume, L/d

Renal Disease in Patients Infected with Hepatitis and Human Immunodeficiency Vir us 7.9 MANAGEMENT OF SEVERE ACUTE RENAL FAILURE HIV Conservative Recovered Needing dialysis Not initiated Initiated Recovered NS not significant. 20 (14%) 85% 126 42% 73 56% Non-HIV 42 (14%) 83% 264 22% 207 47% NS 0.003 NS FIGURE 7-21 Acute renal failure management. Rao and Friedman [155] compared the course of 146 patients with severe acute renal failure (serum creatinine >6 mg/d L) infected with HIV with a group of 306 contemporaneous persons not infected wi th HIV but with equally severe acute renal failure. The patients infected with H IV were younger than those in the group not infected (mean age 38.4 and 55.2 yea rs, respectively; P<0.001) and were more often septic (52% and 24%, respectively ; P<0.001). Over 80% of patients in each group recovered renal function when con servative therapy alone was sufficient. When dialysis intervention was needed, i t was not initiated more often in the group with HIV than in the control group ( 42% and 24%, respectively; P<0.003). In those patients in whom dialysis was init iated, recovery occurred in about half in each group. Overall, the mortality in patients with severe acute renal failure was not significantly different in thos e with HIV infection from those in the group not infected with HIV (immediate mo rtality, 60% and 56%, respectively; mortality at 3 months, 71% and 60%, respecti vely). NEPHROPATHIES ASSOCIATED WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION Focal segmental or global glomerulosclerosis Diffuse and global mesangial hyperp lasia Minimal change disease Others: Immune-complex glomerulopathies Hemolytic u remic syndrome, thrombotic thrombocytopenic purpura FIGURE 7-22 Nephropathies associated with HIV. The literature refers to the glom erulosclerosis associated with human immunodeficiency virus (HIV) as HIV-associa ted nephropathy. However, HIVassociated nephropathies may include a spectrum of renal diseases, including HIV-associated glomerulosclerosis, HIV-associated immu ne-complex glomerulonephritis (focal or diffuse proliferative glomerulonephritis , immunoglobulin A nephropathy) and HIV-associated hemolytic uremic syndrome/thr ombotic thrombocytopenic purpura (HUS/TTP). Diffuse mesangial hyperplasia and mi nimal change disease also may be associated with HIV, particularly in children. Therefore, the nomenclature of HIV-associated nephropathies should be amended to list the associated qualifying histologic feature [156]. All types of glomerulo pathies have been observed in patients with HIV-infection. Their prevalence and severity vary with the population studied. Focal segmental or global glomerulosc lerosis is most prevalent in black adults. In whites, proliferative and other ty pes of glomerulonephritis predominate. In children with perinatal acquired immun odeficiency syndrome, glomerulosclerosis, diffuse mesangial hyperplasia, and pro liferative glomerulonephritis are equally prevalent. 100 75 Percent Glomerulosclerosis Diff. mesangial hyperplasia Other 50 25

0 Caribbean blacks (n=22) American blacks (n=11) Whites (n=12) FIGURE 7-23 Glomerulosclerosis associated with HIV. In the United States, HIVass ociated focal segmental or global glomerulosclerosis was described originally in 1984 in large East Coast cities, particularly New York and Miami [157159]. This entity initially was considered with skepticism because it was not seen in San F rancisco, where most patients testing seropositive were white homosexuals [160,1 61]. In New York, patients with glomerulosclerosis were largely black intravenous (IV) drug abusers, a group of patients in whom heroin nephropathy was prevalent. Thus, concern existed that this entity merely represe nted the older heroin nephropathy now seen in HIV-infected IV drug abusers. Howe ver, in a Miamibased population of adult non-IV drug users with glomerular disea se and HIV infection, 55% of Caribbean and American blacks had severe glomerulos clerosis, 9% had mild focal glomerulosclerosis, and 27% had diffuse mesangial hy perplasia. In contrast, two of 12 (17%) whites had a mild form of focal glomerul osclerosis, 75% had diffuse mesangial hyperplasia, and none had severe glomerulo sclerosis. These morphologic differences were reflected in more severe clinical presentations, with blacks more likely to manifest proteinuria in the nephrotic range (>3.5 g/24 h) and renal insufficiency (serum creatinine concentration (>3 mg/dL). Whites often had proteinuria under 2 g/24 h and serum creatinine values less than 2 mg/dL [162]. In blacks, glomerulosclerosis has been described in all groups at risk for HIV infection, including IV drug users, homosexuals, patient s exposed to heterosexual transmission or to contaminated blood products, and ch ildren infected perinatally [163,164]. Subsequent reports confirmed the unique c linical and histopathologic manifestations of HIV-associated glomerulosclerosis and its striking predominance in blacks independent of IV drug abuse [165]. Raci al factors explain the absence of HIV-associated glomerulosclerosis in whites an d Asians. The cause of this strong racial predilection is unknown.

7.10 Systemic Diseases and the Kidney FIGURE 7-24 These two patients illustrate typical presenting features of HIV-ass ociated glomerulosclerosis, ie, proteinuria, usually in the nephrotic range; nor mal-sized or large echogenic kidney; and renal insufficiency rapidly progressing to endstage renal disease (ESRD). The onset of the nephropathy is often abrupt, with uremia and massive nonselective proteinuria (sometimes in excess of 20 g/2 4 h). These fulminant lesions may present as acute renal failure in patients who were well only a few weeks or months before hospitalization. In other patients, minimal proteinuria and azotemia at presentation increase insidiously over a pe riod of several months until a nephrotic syndrome becomes evident, with rapid ev olution thereafter to uremia and ESRD. Hypertension and peripheral edema may be absent even in the context of advanced renal insufficiency or severe nephrotic s yndrome. The status of the patient's HIV infection rather than the presence of ren al disease per se has the greatest impact on survival. TWO CASE HISTORIES OF PATIENTS WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION ASSOC IATED WITH GLOMERULOSCLEROSIS 41-year-old black Jamaican woman October 1985: Viral syndrome. 135 lbs; proteinuria, 1+; serum creatinine, 0.5 mg /dL; blood pressure, 130/70 mm Hg December 1986: Fever, fatigue, cough. 120 lbs; proteinuria, 1+; interstitial pneumonia; serum creatinine, 1.5 mg/dL; ex-husban d used intravenous drugs; 11-cm, echogenic kidneys February 1987: 3+ edema. 116 lbs; proteinura, 12.7 g/24 h; serum creatinine, 11.4 mg/dL; albumin, 2.5 g/dL; b lood pressure, 150/86; renal biopsy showed focal segmental glomerulosclerosis Ma y 1987: 100 lbs; patient died after 3 months of hemodialysis from sepsis and cry ptococcal meningitis 28-year-old black Haitian man A dockworker until 3 months before admission, when fevers began to occur. No ide ntifiable risk factor. He presented with a blood pressure of 110/80 mm Hg, perio rbital and trace ankle edema, interstitial pneumonia, and diffuse adenopathies. Serum creatinine increased from 5.3 to 9 mg/dL in 6 days; albumin, 1.6 g/dL; pro teinuria, 6.9 g/24 h; 15-cm, echogenic kidneys. Renal biopsy showed focal segmen tal glomerulosclerosis. Lymph node biopsy showed Mycobacterium gordonae. This pa tient returned to Haiti after six hemodialyses. PATHOLOGIC FEATURES OF GLOMERULOSCLEROSIS ASSOCIATED WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION Collapsed glomerular capillaries Visceral glomerular epitheliosis Microcystic tu bules with variegated casts Focal tubular simplification Interstitial lymphocyti c infiltration Endothelial reticular inclusions FIGURE 7-25 Ultrasonography of a hyperechogenic 15-cm kidney in a patient with H IV-associated glomerulosclerosis, nephrotic syndrome, and renal failure. FIGURE 7-26 Pathologic features of glomerulosclerosis. None of the features list ed is pathognomonic. The concomitant presence of glomerular and tubular lesions with tubuloreticular inclusions in the glomerular and peritubular capillary endo thelial cells, however, is highly suggestive of glomerulosclerosis associated wi th human immunodeficiency virus infection [134,166171].

Renal Disease in Patients Infected with Hepatitis and Human Immunodeficiency Vir us 7.11 FIGURE 7-27 Glomerulosclerosis. Micrograph of segmental glomerulosclerosis with hyperplastic visceral epithelial cells (arrows). FIGURE 7-28 More advanced glomerulosclerosis. Micrograph of a more advanced stag e of glomerulosclerosis with large hyperplastic visceral epithelial cells loaded with hyaline protein droplets, interstitial infiltrate, and tubules filled with proteinaceous material. FIGURE 7-29 Collapsing glomerulosclerosis. Micrograph of global collapsing glome rulosclerosis. No patent capillary lumina are present. In the same patient, norm al glomeruli, glomeruli with segmental sclerosis, and glomeruli with global scle rosis may be found [172]. FIGURE 7-30 Dilated microcystic tubules. Micrograph of massively dilated microcy stic tubules filled with variegated protein casts adjacent to normal-sized glome ruli. These casts contain all plasma proteins. The tubular epithelium is flatten ed. The tubulointerstitial changes likely play an important role in the pathogen esis of the renal insufficiency and offer one explanation for the rapid decrease in renal function.

7.12 Systemic Diseases and the Kidney FIGURE 7-31 Diffuse mesangial hyperplasia and nephrotic syndrome. Micrograph of diffuse mesangial hyperplasia in a child with perinatal AIDS and nephrotic syndr ome. Both diffuse and global mesangial hyperplasia are identified in 25% of chil dren with perinatal AIDS and proteinuria. The characteristic microcystic tubular dilations and the kidney enlargement of glomerulosclerosis associated with huma n immunodeficiency virus infection are absent in patients with diffuse mesangial hyperplasia. FIGURE 7-32 Tubuloreticular cytoplasmic inclusions. Micrograph of tubuloreticula r cytoplasmic inclusions in glomerular endothelial cell. The latter are virtuall y diagnostic of nephropathy associated with HIV infection, provided systemic lup us erythematosus has been excluded. On immunofluorescent examination, findings i n the glomeruli are nonspecific and similar in HIV-associated glomerulosclerosis and idiopathic focal segmental glomerulosclerosis. These findings consist large ly of immunoglobulin M and complement C3 deposited in a segmental granular patte rn in the mesangium and capillaries. The same deposits also occur in 30% of pati ents with AIDS without renal disease [134,163,167]. HIV infection HIV in glomerular, tubular epithelial cells HIV in lymphocytes, monocytes Cytopathic effects HIV gene products Cytokines, growth factors Glomerular epithelial cell proliferation Tubular epithelial cell apoptosis and p roliferation FIGURE 7-33 Possible pathogenic mechanisms of glomerulosclerosis associated with HIV infection. HIV-associated glomerulosclerosis is not the result of opportuni stic infections. Indeed, the nephropathy may be the first manifestation of HIV i nfection and often occurs in patients before opportunistic infections develop. H IV-associated glomerulosclerosis also is not an immune-complex-mediated glomerul opathy because immune deposits are generally absent. Three mechanisms have been proposed: direct injury of renal epithelial cells by infective HIV, although dir ect renal cell infection has not been demonstrated conclusively and systematical ly; injury by HIV gene products; or injury by cytokines and growth factors relea sed by infected lymphocytes and monocytes systemically or intrarenally or releas ed by renal cells after uptake of viral gene products. The variable susceptibili ty to glomerulosclerosis also suggests that unique viral-host interactions may b e necessary for expression of the nephropathy [132,156,166,173175]. Glomerulosclerosis Tubular microcysts

Renal Disease in Patients Infected with Hepatitis and Human Immunodeficiency Vir us 7.13 Transplantation of kidneys between normal mice and mice transgenic of noninfecti ous HIV TREATMENT OPTIONS OF GLOMERULOSCLEROSIS ASSOCIATED WITH HUMAN IMMUNODEFICIENCY V IRUS INFECTION Antiretroviral therapy Corticosteroids Cyclosporine Angiotensin-converting enzym e inhibitors Dialysis Transgenic kidney in normal mouse Normal kidney in transgenic mouse Kidney develops glomerulosclerosis Kidney remains disease-free FIGURE 7-34 HIV proteins in glomerulosclerosis. HIV-associated glomerulosclerosi s has been viewed as a complication that occurs either as a direct cellular effe ct of HIV infection or HIV gene products in the kidney, as an indirect effect of the dysregulated cytokine milieu existing in patients with acquired immunodefic iency syndrome, or both. Studies involving reciprocal transplantation of kidneys between normal and mice transgenic of noninfectious HIV clearly show that the p athogenesis of HIV-glomerulosclerosis is intrinsic to the kidney [176]. In these studies, HIV-glomerulosclerosis developed in kidneys of transgenic mice transpl anted into nontransgenic littermates, whereas kidneys from normal mice remained disease-free when transplanted into HIV-transgenic mice [176]. These findings su ggest that HIV gene proteins, rather than infective HIV, may induce the nephropa thy either through direct effects on target cells or indirectly through the rele ase of cytokines and growth factors. FIGURE 7-35 Treatment of glomerulosclerosis. There have been no prospective cont rolled randomized trials of any therapy in patients with nephropathy associated with HIV infection. Thus, the optimal treatment is unknown. Individual case repo rts and studies, often retrospective, on a small number of patients suggest a be neficial effect of monotherapy with azidothymidine (AZT) on progression of renal disease [177179]. No reports exist on the effects of double or triple antiretrov iral therapy on the incidence or progression of renal disease in patients with H IV who have modest proteinuria or nephrotic syndrome. The incidence of HIV-assoc iated glomerulosclerosis may be declining as a result of prophylaxis with AZT, t rimethoprim and sulfamethoxazole, or other drugs. Using logistic regression anal ysis, Kimmel and colleagues [180] demonstrated an improved outcome related speci fically to antiretroviral therapy. Steroids usually have been ineffective on pro teinuria or progression of renal disease in adults and children. Recently, 20 ad ult patients with HIV-associated glomerulosclerosis or mesangial hyperplasia wit h proteinuria over 2 g/24 h and serum creatinine over 2 mg/dL were studied. Thes e patients showed impressive decreases in proteinuria and serum creatinine when given 60 mgd of prednisone for 2 to 6 weeks [181]. Complications of steroid ther apy, however, were common. These include development of new opportunistic infect ions, steroid psychosis, and gastrointestinal bleeding. The short-term improveme nt in renal function may correlate with an improvement in tubulointerstitial mon onuclear cell infiltration [182]. In a single report of three children with peri natal AIDS, HIV-associated glomerulosclerosis, and normal creatinine clearance, cyclosporine induced a remission of the nephrotic syndrome [183]. This report ha s not been confirmed, and the use of cyclosporine in adults with HIV-associated glomerulosclerosis has not been studied.

7.14 Systemic Diseases and the Kidney FIGURE 7-36 Effect of angiotensin-converting enzyme (ACE) inhibitors on progress ion of glomerulosclerosis associated with HIV infection. Serum ACE levels are in creased in patients with HIV infection [184]. Kimmel and colleagues [180], using captopril, and Burns and colleagues [185], using fosinopril, demonstrated a ren oprotective effect of ACE inhibitors in patients with biopsy-proven HIV-associat ed glomerulosclerosis. In the former study, the median time to end-stage renal d isease was increased from 30 to 74 days in nine patients given 6.25 to 25 mg cap topril three times a day. In the latter study, 10 mg of fosinopril was given onc e a day to 11 patients with early renal insufficiency (serum creatinine <2 mg/dL ). Serum creatinine and proteinuria remained stable during 6 months of treatment with fosinopril. In contrast, patients not treated with fosinopril exhibited pr ogressive and rapid increases in serum creatinine and proteinuria. Similar outco mes prevailed in patients with proteinuria in the nephrotic range and serum crea tinine levels less than 2 mg/dL. Captopril also is beneficial to the progression of the nephropathy in HIV-transgenic mice [186]. The mechanism(s) of the renopr otective effects of ACE inhibitors are unclear and may include hemodynamic effec ts, decreased expression of growth factors, or an effect on HIV protease activit y. Renal biopsy early in the course of the disease is important to define the re nal lesion and guide therapeutic intervention. Serum creatinine, mg/dL 4.0 3.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 P=0.006 Fosinopril Control 0 9 8 Urinary protein, g/24 h 7 6 5 4 3 2 1 0 0 4 8 12 Week 16 20 24 P=0.006 Fosinopril Control 4 8 12 Week 16 20 24 SURVIVAL OF PATIENTS WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION RECEIVING CHRON IC HEMODIALYSIS Reference

Rao et al. [187] Ortiz et al. [188] Feinfeld et al. [189] Ribot et al. [190] Sch rivastava et al. [191] Kimmel et al. [192] Ifudu et al. [193] Year 1987 1988 1989 1990 1992 1993 1997 Patients 79 AIDS 17 AIDS 12 carriers 5 AIDS 10 carriers 8 AIDS 28 carriers 44 AIDS 23 AID S 34 AIDS Mean survival, mo <3 3 16 13 16 88% <12 96% >12 41% >15 14.7 57 FIGURE 7-37 Survival rates in dialysis patients. Once end-stage renal disease (E SRD) develops and supportive maintenance dialysis is needed, the complications o f HIV are the dominant factor in patient survival, as they are in patients with HIV infection without renal involvement. Asymptomatic patients on chronic hemodi alysis survive longer than do patients with AIDS on chronic hemodialysis. Patien ts with AIDS also may develop malnutrition, wasting, and failure to thrive that are unresponsive to intensive nutritional support [131]. Recent studies, however , show that the survival of patients with AIDS maintained on chronic hemodialysi s is improving. Enhanced survival has been attributed to antiviral drugs, better prophylaxis, and aggressive treatment of opportunistic infections. We have seen four patients with HIV infection survive for more than 10 years on hemodialysis . Chronic hemodialysis and chronic ambulatory peritoneal dialysis are equally ap propriate treatments for patients with HIV infection and ESRD. Universal precaut ions should be used for peritoneal dialysis and hemodialysis alike, because infe ctious HIV is present in peritoneal effluent and blood.

Renal Disease in Patients Infected with Hepatitis and Human Immunodeficiency Vir us 7.15 PREDICTORS OF SURVIVAL OF PATIENTS WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION R ECEIVING CHRONIC HEMODIALYSIS R CD4 Blood pressure, systolic Infection rate Proteinuria Edema +/ Antiretroviral therapy +/0.668 0.496 0.519 0.537 14.5 vs 6.1 mo 15.2 vs 62. mo P <0.001 <0.02 <0.01 <0.02 <0.01 <0.01 FIGURE 7-38 Predictors of survival. Perinbasekar and colleagues [194] analyzed t hose factors associated with better survival in patients infected with HIV recei ving chronic hemodialysis. A low CD4 lymphocyte count, low systolic blood pressu re, increased infection rate, nephrotic range proteinuria, lack of edema, and la ck of antiretroviral therapy are associated with decreased survival. RECOMMENDED ANTIRETROVIRAL THERAPY Combination of two reverse transcriptase inhibitors Aggressive triple therapy, i ncluding a protease inhibitor for patients who are Symptomatic of acquired immun odeficiency syndrome Asymptomatic with CD4 <500 cells/L Asymptomatic with CD4 >50 0 cells/L but viral load > 20,000 FIGURE 7-39 Antiretroviral therapy. Recommended antiretroviral therapy for patie nts with HIV infection without renal disease includes therapies with two drugs f or all patients, combining two reverse transcriptase inhibitors. Aggressive earl y intervention with triple antiviral drugs, one of which is a protease inhibitor , should be offered to patients symptomatic of AIDS, asymptomatic patients with CD4 counts under 500/L, and asymptomatic patients with CD4 counts over 500/L and p lasma HIV RNA levels over 20,000 copies/mL [195]. Reduced dosages are required f or reverse transcriptase inhibitors in renal insufficiency. Although the clearan ce information on these drugs is limited, additional dosing is not necessary in patients receiving maintenance dialysis. No dosage reduction is needed for prote ase inhibitors. OTHER NEPHROPATHIES ASSOCIATED WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION Immune-complex glomerulopathies Proliferative glomerulonephritis Membranous glom erulonephritis Lupus-like nephropathy Immunoglobulin A nephropathy Hemolytic ure mic syndrome, thrombotic thrombocytopenic purpura FIGURE 7-40 Other nephropathies associated with HIV. A variety of immune-complex -mediated glomerulopathies have been documented in patients with HIV infection. Some represent glomerular diseases associated with HIV infection, whereas others may be incidental or manifestations of associated diseases. Proliferative glomerulonephritides represent instances of postinfectious glomeru lonephritis or manifestations of hepatitis C co-infection [196199]. Alternatively , proliferative glomerulonephritides may result from renal depository of preform ed circulating immune complexes with specificity for HIV proteins and are HIV-as sociated [199]. In patients infected with HIV, membranous glomerulonephritis has been associated with hepatitis B, hepatitis C, syphilis, and systemic lupus ery thematosus [198,200203]. Lupus-like nephritis has been reported in children and a dults with HIV infection in association with membranous, mesangial, and intracap illary proliferative glomerular lesions [204]. IgA nephropathy has been reported in association with HIV infection. The occurrence of IgA nephropathy may not be coincidental and is HIV-associated. Indeed, circulating immune complexes compos ed of idiotypic IgA antibody reactive with anti-HIV IgG or IgM were identified i

n two patients, and the identical immune complex was eluted from the renal biops y tissue of one patient studied [199,205]. Unlike HIV-associated glomerulosclero sis, HIV-associated IgA nephropathy has been reported exclusively in white patie nts with early HIV infection exhibiting microscopic or macroscopic hematuria, ab sent or modest azotemia, and slowly progressive disease [206]. Instances of intr avascular coagulation related to TTP or HUS are recognized with increased freque ncy and may be the first manifestation of HIV infection, although most develop a t a late stage of the disease. The cause of hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP) in patients infected with HIV is unknown. Pl asma tissue plasminogen activator is increased in patients infected with HIV who have thrombotic microangiopathy [207]. There is no association with Escherichia coli 0154:H7 infection, and intercurrent infections have been demonstrated in o nly one third of patients. Renal involvement in TTP usually is minimal, whereas vascular and glomerular involvement are more frequent and extensive in HUS and c an lead to renal cortical necrosis. Therapy with plasmapheresis, using fresh fro zen plasma replacement, should be instituted as soon as the diagnosis of HIV-rel ated HUS/TTP is made [208].

7.16 Systemic Diseases and the Kidney FIGURE 7-41 Other renal findings in patients with AIDS include infections and tu mors. Almost all opportunistic infections seen in patients with AIDS may localiz e in the kidneys as manifestations of systemic disease. However, rarely are thes e infections expressed clinically, and often they are found at autopsy. Cytomega lovirus infection is the most common [209]. Referrals to a urologist are reporte d for renal and perirenal abscesses with uncommon organisms (Candida, Mucor myco sis, Aspergillus, and Nocardia). Nephrocalcinosis can occur in association with pulmonary granulomatosis, Mycobacterium aviumintracellulare infection, or as a ma nifestation of extrapulmonary pneumocystis infection. Renal tuberculosis is a ma nifestation of miliary disease. Non-Hodgkin's lymphoma and Kaposi's sarcoma are the most frequently found renal neoplasms in patients with AIDS, usually as a manife station of disseminated involvement. RENAL INFECTIONS AND TUMORS ASSOCIATED WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTI ON Pathogens Cytomegalovirus Candida Nocardia Cryptococcus Pneumocystis Mycobacterium Toxopla sma Histoplasma Aspergillus Herpes Neoplasms Kaposi's sarcoma Carcinoma Lymphoma Myeloma References 1. Johnson RJ, Couser WG: Hepatitis B infection and renal disease: clinical, imm unopathogenetic and therapeutic considerations. Kidney Int 1990, 37:663. 2. Lai KN, Lai FM: Clinical features and natural history of hepatitis B virusrelated glo merulopathy in adults. Kidney Int 1991, 35(suppl):S40. 3. Takekoshi Y, Tochimaru H, Nagatta Y, Itami N: Immunopathogenetic mechanisms of hepatitis B virusrelated glomerulopathy. Kidney Int 1991, 35(suppl):S34. 4. Lai KN, Li PK, Lui SF, et al .: Membranous nephropathy related to hepatitis B virus in adults. N Engl J Med 1 991, 324:1457. 5. Lin CY: Clinical features and natural course of HBV-related gl omerulopathy in children. Kidney Int 1991, 35(suppl):S46. 6. Agnello V, Chung RT , Kaplan LM: A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med 1992, 327:14901495. 7. Misiani R, Bellavita P, Fenili D, et al.: He patitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med 1992, 117:573577. 8. Disdier P, Harle JR, Weiller PJ: Cryoglobulinemi a and hepatitis C infection. Lancet 1991, 338:11511152. 9. Dammacco F, Sansono D: Antibodies to hepatitis C virus in essential mixed cryoglobulinemia. Clin Exp I mmunol 1992, 87:352356. 10. Galli M, Monti G, Monteverde A: Hepatitis C virus and mixed cryoglobulinemias. Lancet 1992, 1:989. 11. Ferri C, Greco F, Longobardo G : Antibodies to hepatitis C virus in patients with mixed cryoglobulinemia. Arthr itis Rheum 1991, 34:16061610. 12. Sansono D, Gesualdo L, Mano C, et al.: Hepatiti s C virus related proteins in kidney tissue from hepatitis C virusinfected patien ts with cryoglobulinemic membranoproliferative glomerulonephritis. Hepatology 19 97, 25:12371244. 13. Johnson RJ, Gretch DR, Yamabe H, et al.: Membranoproliferati ve glomerulonephritis associated with hepatitis C virus infection. N Engl J Med 1993, 328:465470. 14. Rollino C, Roccatello D, Giachino O, et al.: Hepatitis C vi rus infection and membranous glomerulonephritis. Nephron 1991, 59:319320. 15. Dav da R, Peterson J, Weiner R, et al.: Membranous glomerulonephritis in association with hepatitis C virus infection. Am J Kidney Dis 1993, 22:452455. 16. Johnson R J, Willson R, Yamabe H, et al.: Renal manifestations of hepatitis C virus infect ion. Kidney Int 1994, 46:1255. 17. Johnson RJ, Gretch DR, Couser WG, et al.: Hep atitis C virus associated glomerulonephritis: effect of -interferon therapy. Kid ney Int 1994, 46:1700. 18. Misiani R, Bellavita P, Fenili D, et al.: Interferon-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 1994, 330:751. 19. Poynard T, Bedossa P, Chevallier M, et al.: A comparison of three interferon- -2b regimens for the long-term treatment of chronic nonA, non-

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ted patients with acute renal failure? A retrooperative study. J Am Soc Nephrol 1997, 8:130A. 155. Rao TK, Friedman EA: Outcome of severe acute renal failure in patients with acquired immunodeficiency syndrome. Am J Kidney Dis 1995, 25:39039 8. 156. Bourgoignie J: Glomerulosclerosis associated with HIV infection. Contemp Issues Nephrol 1996, 29:5975. 157. Rao TK, Filippone EJ, Nicastri AD, et al.: As sociated focal and segmental glomerulosclerosis in the acquired immunodeficiency syndrome. N Engl J Med 1984, 310:669673. 158. Pardo V, Aldana M, Colton RM, et a l.: Glomerular lesions in the acquired immunodeficiency syndrome. Ann Intern Med 1984, 101:429434. 159. Gardenswartz MH, Lerner CW, Seligson GR, et al.: Renal di sease in patients with AIDS: a clinicopathologic study. Clin Nephrol 1984, 21:19 7204. 160. Mazbar SA, Schoenfeld PY, Humphreys MH: Renal involvement in patients infected with HIV: experience at San Francisco General Hospital. Kidney Int 1990 , 37:13251332. 161. Humphreys MH: Human immunodeficiency virusassociated nephropat hy: east is east and west is west? Arch Intern Med 1990, 150:253255. 162. Bourgoi gnie JJ, Ortiz-Interian C, Green DF, et al.: The epidemiology of human immunodef iciency virusassociated nephropathy. In Nephrology, vol 1. Edited by Hatano M. To kyo: Springer-Verlag; 1991:484492. 163. Pardo V, Meneses R, Ossa L, et al.: AIDSrelated glomerulopathy: occurrence in specific risk groups. Kidney Int 1989, 31: 11671173. 164. Strauss J, Abitbol C, Zilleruelo G, et al.: Renal disease in child ren with the acquired immunodeficiency syndrome. N Engl J Med 1989, 321:625630. 1 65. Nochy D, Gotz D, Dosquet P, et al.: Renal disease associated with HIV infect ion: a multicentric study of 60 patients from Paris hospitals. Nephrol Dial Tran splant 1993, 8:1119. 166. D'Agati V, Appel GB: HIV infection and the kidney. J Am S oc Nephrol 1997, 8:138152. 167. Cohen AH, Nast CC: HIV-associated nephropathy: a unique combined glomerular, tubular and interstitial lesion. Modern Pathol 1988, 1:8797. 168. Soni A, Agarwal A, Chander P, et al.: Evidence for an HIV-related r ephropathy: a clinicopathological study. Clin Nephrol 1989, 31:1217. 169. Bourgoi gnie JJ, Pardo V: The nephropathology in human immunodeficiency virus (HIV-1) in fection. Kidney Int 1991, 35:S19S23. 170. Cohen AH: Renal pathology of HIV-associ ated nephropathy. Contemp Issues Nephrol 1996, 27:155180. 171. Pardo V, Strauss J , Abitbol C: Renal disease in children with HIV infection. Contemp Issues Nephro logy 1996, 29:135154. 172. Langs C, Gallo GR, Schacht RG, et al.: Rapid renal fai lure in AIDSassociated focal glomerulosclerosis. Arch Intern Med 1990, 150:287292 . 173. Humphreys MH: Human immunodeficiency virusassociated glomerulosclerosis. K idney Int 1995, 48:311320. 174. Shuka RR, Kimmel PL, Jumar A: Molecular biology o f HIV-1 and kidney disease. Contemp Issues Nephrol 1996, 29:329389.

7.20 Systemic Diseases and the Kidney 192. Kimmel PL, Umana WO, Simmens SJ, et al.: Continuous ambulatory peritoneal d ialysis and survival of HIV infected patients with endstage renal disease. Kidne y Int 1993, 44:373378. 193. Ifudu O, Mayers JD, Matthew JJ, et al.: Uremia therap y in patients with end-stage renal disease and human immunodeficiency virus infe ction: Has the outcome changed in the 1990s? Am J Kidney Dis 1997, 29:549552. 194 . Perinbasekar S, Brod-Miller S, Pal S, et al.: Predictors of survival in HIV-in fected patients on hemodialysis. Am J Nephrol 1996, 16:280286. 195. Carpenter C, Fischl M, Hammer S, et al.: Antiretroviral therapy for HIV infection in 1996. JA MA 1996, 276:146154. 196. Casanova S, Mazzucco G, Barbiano di Belgiojoso G, et al .: Pattern of glomerular involvement in human immunodeficiency virus-infected pa tients: an Italian study. Am J Kidney Dis 1995, 26:446453. 197. Korbet SM, Schwar tz MM: Human immunodeficiency virus infection and nephrotic syndrome. Am J Kidne y Dis 1992, 20:97103. 198. Stokes MB, Chawla H, Brody RI, et al.: Immune complex glomerulonephritis in patients co-infected with human immunodeficiency virus and hepatitis C virus. Am J Kidney Dis 1997, 29:514525. 199. Kimmel PL, Phillips TM: Immune-complex glomerulonephritis associated with HIV infection. Contemp Issues Nephrol 1996, 29:77110. 200. Guerra IL, Abraham AA, Kimmel PL, et al.: Nephrotic syndrome associated with chronic persistent hepatitis B in an HIV antibody posi tive patient. Am J Kidney Dis: 1987, 10:385388. 201. Schectman JM, Kimmel PL: Rem ission of hepatitis Bassociated membranous glomerulonephritis in human immunodefi ciency virus infection. Am J Kidney Dis 1991, 17:716718. 202. Kusner DJ, Ellner J J: Syphilis, a reversible cause of nephrotic syndrome in HIV infection [letter]. N Engl J Med 1991, 324:341342. 203. D'Agati V, Seigle R: Coexistence of AIDS and l upus nephritis: a case report. Am J Nephrol 1990, 10:243247. 204. Contreras G, Gr een DF, Pardo V, et al.: Systemic lupus erythematosus in two adults with human i mmunodeficiency virus. Am J Kidney Dis 1996, 28:292295. 205. Kimmel PL, Phillips TM, Farkas-Szallasi T, et al.: Idiotypic IgA nephropathy in patients with HIV in fection. N Engl J Med 1992, 327:702706. 206. Bourgoignie JJ, Pardo V: Human immun odeficiency virus: associated nephropathies [editorial]. N Engl J Med 1992, 327: 729730. 207. Peraldi MN, Berrou J, Flahaut A, et al.: Elevated plasma tissue type plasminogen activator (tPA) in HIV-infected patients with thrombotic microangio pathy [abstract]. J Am Soc Nephrol 1996, 7:1377. 208. Berns JS: Hemolytic uremic syndrome and thrombotic thrombocytopenic purpura associated with HIV infection. Contemp Issues Nephrol 1996, 29:111133. 209. Nadasdy T, Miller KW, Johnson LD, e t al.: Is cytomegalovirus associated with renal disease in AIDS patients? Modern Pathol 1992, 5:277282. 175. Barisoni L, Bruggeman L, Schwartz E, et al.: Pathogenesis of HIV-associated nephropathy in transgenic mice. J Am Soc Nephrol 1997, 8:492A. 176. Bruggeman L A, Dikman S. Meng C, et al.: Nephropathy in human immunodeficiency virus-1 trans genic mice is due to renal transgene expression. J Clin Invest 1997, 100:8492. 17 7. Babut-Gay ML, Echard M, Kleinknecht D, et al.: Zidovudine and nephropathy wit h human immunodeficiency virus (HIV) infection [letter]. Ann Intern Med 1989, 11 1:856857. 178. Harrer T, Hunzelmann N, Stoll R, et al.: Therapy for HIV-1 related nephritis with zidovudine. AIDS 1990, 4:815817. 179. Ifudu O, Rao TK, Tan CC, et al.: Zidoudine is beneficial in human immunodeficiency virus associated nephrop athy. Am J Nephrol 1995, 15:217221. 180. Kimmel PL, Mishkin GJ, Umana WO: Captopr il and renal survival in patients with human immunodeficiency virus nephropathy. Am J Kidney Dis: 1996, 28:202208. 181. Smith MC, Austen JL, Carey JT, et al.: Pr ednisone improves renal function and proteinuria in human immunodeficiency virus -associated nephropathy. Am J Med 1996, 101:4148. 182. Watterson MK, Detwiler RD, Bolin P Jr: Clinical response to prolonged corticosteroids in a patient with hu man immunodeficiency virus-associated nephropathy. Am J Kidney Dis 1997, 29:62462 6. 183. Ingulli E, Tejani A, Fikrig S, et al.: Nephrotic syndrome associated wit h acquired immunodeficiency syndrome in children. J Pediatr 1991, 119:710716. 184 . Ouelette DR, Kelly JW, Anders JT: Serum angiotensin converting enzyme level is elevated in patients with HIV-infection. Arch Intern Med 1992, 152:321324. 185.

Burns G, Paul SK, Sivak SL, et al.: Effect of angiotensin-converting enzyme inhi bition in HIV-associated nephropathy. J Am Soc Nephrol 1997, 8:11401146. 186. Bir d JE, Kopp JB, Gitlitz P, et al.: Captopril intervention is of benefit in HIV-tr ansgenic mice. J Am Soc Nephrol 1997, 8:611A. 187. Rao TKS, Friedman EA, Micastr i AD: The types of renal disease in human acquired immunodeficiency syndrome. N Engl J Med 1987, 316:10621068. 188. Ortiz C, Meneses R, Jaffe D, et al.: Outcome of patients with human immunodeficiency virus on maintenance hemodialysis. Kidne y Int 1988, 34:248253. 189. Feinfeld DA, Kaplan R, Dressler R, et al.: Survival o f human immunodeficiency virus infected patients on maintenance dialysis. Clin N ephrol 1989, 32:221224. 190. Ribot S, Dean D, Goldblat M, et al.: Prognosis of HI V positive dialysis patients [abstract]. Kidney Int 1990, 37:315. 191. Schrivast ava D, Delano BG, Lundin P, et al.: Factors affecting survival of HIV+ patients undergoing maintenance hemodialysis [abstract]. J Am Soc Nephrol 1992, 3:320.

Renal Involvement in Sarcoidosis Garabed Eknoyan S arcoidosis is a clinicopathologic syndrome resulting from dispersed organ involv ement by a noncaseating granulomatous process of unknown cause. The clinical man ifestations of sarcoidosis are protean, depending on the affected organs; howeve r, the principal targets of sarcoidosis are the lungs and thoracic lymph nodes, which almost always are involved. As a rule, it is a disease of insidious onset that pursues a chronic course, with episodic remissions and exacerbations. The s everity and diversity of its clinical manifestations depend on the extent of inf iltrating granulomatous lesions of the involved organs and that of the number of affected organs. When diffuse and widespread the disease may pursue an acute fu lminant course. Diagnosis depends on demonstration of the characteristic patholo gic lesion of noncaseating granulomas within the affected organ. Sarcoidosis is a common (1 to 40 cases per 100,000 population) disease of the relatively young (mean age 40 years), with a proclivity for racial (3.5 times more in blacks), et hnic (Scandinavian), and seasonal occurrence (summer rather than winter). Report s of community outbreaks, work-related risks, familial clustering, occurrence af ter organ transplantation, and experimental induction in animals by injection of affected tissue homogenates from humans strongly suggests an infective cause th at remains to be identified. Two associated metabolic abnormalities of diagnosti c and clinical import are elevated levels of calcitriol (1,25-dihydroxy-vitamin D3) and angiotensin-converting enzyme (ACE). Neither is unique to sarcoidosis. E levated levels of calcitriol are consequent to the capacity of the infiltrating macrophages of the granulomas to synthesize calcitriol. Elevated levels of ACE a re consequent to that of the multinucleated giant and epithelioid cells that ult imately develop in the granulomas, along with that of the infiltrating macrophag es, to produce ACE. Of these, the elevated levels of calcitriol are the more imp ortant because they account for the abnormal calcium metabolism that occurs in m ost patients. Elevated levels of ACE are of no known clinical consequence CHAPTER 8

8.2 Systemic Diseases and the Kidney the active granulomatous lesions. Close monitoring of patients is essential duri ng tapering and after discontinuation of steroid therapy, because 25% of treated patients experience relapse. Other drugs that have been used in cases unrespons ive to steroids are methotrexate, chloroquine, azathioprine, and cyclophosphamid e. Of these, methotrexate seems to be more effective. The prognosis is worse in blacks, the elderly, and those patients who fail to respond to steroids or have extensive multiorgan involvement. and are of limited value in diagnosis; however, they can be useful in follow-up of the course of the disease and patient response to treatment. In symptomatic c ases, steroids are highly effective in suppressing the cellular inflammatory rea ction of sarcoidosis and in reversing most forms of organ dysfunction caused by granulomatous infiltration. Therapy with prednisone (30 to 40 mg/d) for 8 to 12 weeks, with gradual tapering of the dose (10 to 20 mg/d) over 6 to 12 months, is usually sufficient. Persistent dysfunction can result from residual fibrosis af ter reversal of Pathophysiology and Diagnosis A B C FIGURE 8-1 (see Color Plate) Pathology of granulomatous lesions in lungs affecte d by sarcoidosis. The diagnosis of sarcoidosis depends on demonstration of the c haracteristic lesion of noncaseating granulomas within the affected organs. As w ith other epithelioid granulomas, the more commonly involved organs are the lung s and liver. A, A section of a normal lung is shown. (Pentachrome stain 10.) B, Multiple noncaseating granulomas and areas of mononuclear cell infiltration of t he lung interstitium characD teristic of sarcoidosis are shown. (Hematoxylin-eosin stain 10.) C and D, Lesion s in the lung are illustrated, showing their course from a cellular inflammatory response, which may be asymptomatic (panel C), to that of the fibrotic resoluti on (panel D). The fibrotic response usually accounts for the permanent loss of n ormal parenchyma and organ function. (Hematoxylin-eosin stain 10 and pentachrome 10, respectively.) (From Newman et al. [1]; with permission.)

Renal Involvement in Sarcoidosis Pathogenesis of granulomatous lesions Mononuclear cell infiltration 8.3 Macrophage aggregation - Synthesis of 1,25-dihydroxy-vitamin D3 Epithelioid and multinucleated giant cells - Synthesis of angiotensin-converting enzyme Encapsulating rim CD4>CD8 (except in rare cases) B cells, few Fibroblasts Mast c ells FIGURE 8-2 Pathogenesis of granulomatous lesions. Mononuclear cell infiltration is the initial step in the sequence of events that leads to granuloma formation. Recruited macrophages then differentiate into epithelioid and multinucleated gi ant cells. Activated lymphocytes are interspersed in the evolving lesion and com e to form a rim around the granulomas. In time, fibroblasts, mast cells, and col lagen fibers begin to encapsulate the mature sarcoid granuloma. Cultured granulo matous homogenates exhibit 1 -hydroxylase activity and are capable of converting 25-hydroxy-vitamin D3 to its active 1,25-dihydroxylated form, calcitriol. This capacity resides in the infiltrating macrophages and is not unique to sarcoidosi s but a feature of most other granulomatous disorders. Although lacking in speci ficity to be of diagnostic merit, radioactive gallium scans can be used as nonin vasive methods of assessing the activity of sarcoid granulomas. The uptake of ra dioactive gallium by the macrophages and lymphocytes reflects the activity of th e infiltrating cells in affected organs. CYTOKINES IMPLICATED IN PERPETUATING GRANULOMAS SARCOIDOSIS FREQUENCY OF ORGAN INVOLVEMENT Patients, % InterferonInterleukin-2, 6, and 1 Chemoattractants Adhesion molecules Tumor necr osis factorFIGURE 8-3 Cytokines implicated in perpetuating granulomas. Cytokines released b y the infiltrating mononuclear cells and T-cell lymphocytes initiate the cascade of inflammatory reaction that results in subsequent formation of the noncaseati ng granulomas that characterize sarcoidosis. It is the loss of the otherwise bal anced ability of cytokines to modulate the inflammatory response that accounts f or the progression of the initial inflammatory reaction to granulomatous formati on, and ultimately to the more detrimental process of fibrosis. Macrophages are critical in inducing fibroblasts to proliferate and deposit fibronectin and coll agen in the extracellular matrix. Thoracic Stage I: hilar adenopathy Stage II: hilar adenopathy plus pulmonary inf iltration Stage III: pulmonary infiltration Dermatologic Erythema nodosum, lupus pernio, papules, macules, plaques Ophthalmic Uveitis, iritis, conjunctivitis Ne rvous system Peripheral neuropathy, Bell's palsy Central nervous system Gastrointe stinal Liver Spleen Cardiac Renal Musculoskeletal Polyarthritis, lower > upper 90100 25 25 10

FIGURE 8-4 Frequency of organ involvement. Sarcoidosis is a multisystem disease. Parenchymal involvement by granulomatous lesions is most common in the lungs, w hereas that of renal involvement is relatively rare. 4070 510 120 1015

8.4 Systemic Diseases and the Kidney FIGURE 8-5 Differential diagnosis of pulmonary sarcoidosis. The lungs are the pr incipal organs involved in sarcoidosis. Pulmonary involvement may or may not be associated with hilar lymphadenopathy. In contrast to the pulmonary diseases lis ted, pulmonary symptoms may be absent in sarcoidosis even in the presence of ext ensive pulmonary lesions seen on chest radiographs. Pulmonary symptoms develop w hen the disease is in its late fibrotic phase and are associated with airway obs truction. DIFFERENTIAL DIAGNOSIS OF PULMONARY SARCOIDOSIS Sarcoidosis Beryllium exposure Hypersensitivity pneumonitis Idiopathic pulmonary fibrosis Mycobacterial infection Fungal infections Methotrexate-induced pneumon itis Wegener's granulomatosis LABORATORY FINDINGS IN SARCOIDOSIS Hyperglobulinemia Abnormal liver function tests Anergy Leukopenia Hyperuricemia Hypercalciuria Hypercalcemia Elevated calcitriol (1,25-dihydroxy-vitamin D3) Ele vated angiotensin-converting enzyme Cryoglobulinemia FIGURE 8-6 Laboratory findings in sarcoidosis. The diagnosis of sarcoidosis depe nds on the demonstration of the characteristic pathologic lesion of noncaseating granulomas within the affected organs. Several laboratory abnormalities charact erize sarcoidosis and are useful in supporting but not establishing the diagnosi s. Hyperglobulinemia is a principal feature, being present in two thirds of case s. About half of patients have liver involvement, with some abnormality of liver function tests; anergy is present in about half of patients; leukopenia is pres ent in 25% to 30%. Hypercalciuria is common because of increased levels of calci triol. In 50% to 60% of patients levels of angiotensin-converting enzymes are el evated. Fever is present in about one third of patients. RENAL INVOLVEMENT IN SARCOIDOSIS Patients, % Calcium metabolism Hypercalciuria Hypercalcemia Nephrolithiasis Nephrocalcinosis Tubulointerstitial nephritis Granulomatous Fibrotic Glomerulopathy Membranous P roliferative Focal segmental glomerulosclerosis Arteritis Granulomatous angiitis Obstructive nephropathy Retroperitoneal lymphadenopathy Retroperitoneal fibrosi s 5060 1020 10 510 1540 1020 Rare FIGURE 8-7 Renal involvement in sarcoidosis. The principal manifestations of ren al involvement in sarcoidosis are the functional abnormalities resulting from th e altered metabolism of calcium as a result of the increased synthesis of 1,25-d ihydroxy-vitamin D3 by the macrophages of the granulomatous lesions. The consequ ent increased calcium absorption from the gastrointestinal tract results in the hypercalciuria that can be detected in more than half of patients. The frequency of hypercalciuria depends on the extent of granulomatous lesions and on the tim e of the year, being more common in spring and summer when exposure to the sun i s greatest. Hypercalcemia is less common and usually depends on coexistent deter ioration of renal function when the capacity of the kidney to excrete calcium is compromised. In most patients, hypercalciuria is asymptomatic. Its principal ma nifestations are inability to concentrate the urine and polyuria. Nephrolithiasi s occurs in about 10% of patients; another 10% develop nephrocalcinosis. Rare Rare

Renal Involvement in Sarcoidosis Abnormal calcium metabolism and pathophysiology of renal involvement in sarcoido sis Sarcoid granulomas 8.5 Parathyroid hormone secretion - Levels of calcitriol - Intestinal calcium absorption and - bone resorption Tubular calcium absorption - Cal cium load for renal excretion Renal Function Total calcium excretion Hypercalcemi a Renal calcium deposition Outflow tract parenchymal Hypercalciuria Nephrolithiasis Nephrocalcinosis FIGURE 8-8 Abnormal calcium metabolism and pathophysiology of renal involvement in sarcoidosis. Increased synthesis of calcitriol (1,25-dihydroxy-vitamin D3) by the macrophages of the granulomatous lesions of sarcoidosis are at the core of the abnormal calcium metabolism that accounts for the principal manifestations o f renal involvement of sarcoidosis (gray boxes). Patients with hypercalciuria, w hich by far is the most common, may remain asymptomatic, and the disease may go undetected. Polyuria and a reduced capacity to c oncentrate the urine are its main manifestations. Either of these two features m ay be the result of tubulointerstitial nephritis caused by sarcoidosis, and can be present in the absence of any altered calcium metabolism. Nephrocalcinosis al so may be asymptomatic. In contrast, nephrolithiasis presents as renal colic or hematuria. Hypercalcemia develops only when the load of calcium to be excreted e xceeds the ability of the kidneys to excrete the calcium load, either because of reduced renal function or, less commonly, when the amount of calcium absorbed i s excessive. The magnitude of hypercalcemia determines its symptomatology. The c irculating level of parathyroid hormone should be determined in patients with hy percalcemia. An increase in the prevalence of parathyroid adenomas seems to occu r in sarcoidosis. In hypercalcemia caused by elevated levels of calcitriol and b y reduced renal excretion of calcium, parathyroid hormone levels should be negli gible. Detection of elevated levels of parathyroid hormone should lead to the se arch for an adenoma. Patient management is directed at reducing calcitriol synth esis by treating the granulomatous lesions with steroids. Equally important meas ures in the management of such patients are restriction of calcium intake, avoid ance of dietary supplements that contain vitamin D, shunning exposure to sunligh t, and increased fluid intake. FIGURE 8-9 (see Color Plate) Micrograph of granulomatous lesions of the renal in terstitium that are observed in 15% to 40% of patients with sarcoidosis. The hig hest rate reported in the literature is 40%. This figure is based on autopsy fin dings, which often reveal occasional granulomas of the kidney without any eviden ce of functional or clinical abnormality. The lower figure of 15%, or less, more clearly reflects diffuse infiltration of the kidneys with granulomas associated with clinical evidence of abnormal renal function, as shown here. Generally, en larged kidneys are noted on renal ultrasonography.

8.6 Systemic Diseases and the Kidney FIGURE 8-10 Differential diagnosis of granulomatous lesions in renal sarcoidosis . Once considered rare, granulomatous interstitial nephritis is now observed in 10% of kidney biopsy results. Most of these are seen in cases of drug hypersensi tivity. The commonly implicated drugs are antibiotics and nonsteroidal anti-infl ammatory drugs. Sarcoidosis and Wegener's granulomatosis each account for 5% to 10 % of cases observed on kidney biopsy. Other less common and rather rare causes i nclude tuberculosis, angiitis, and lupus erythematosus. In some 15% to 20% of ca ses, the cause of the granulomatous lesions is never established. DIFFERENTIAL DIAGNOSIS OF GRANULOMATOUS LESIONS IN RENAL SARCOIDOSIS Lesion Drug-induced Sarcoid Wegener's granulomatosis Other (less common): Tuberculosis Br ucellosis Vasculitis Systemic lupus erythematosus Idiopathic Patients, % 5570 510 510 1520 Clinical Course FIGURE 8-11 Micrograph of fibrosis. As a rule, abnormal renal function in patien ts with sarcoidosis is due to tubulointerstitial nephritis rather than granuloma tous infiltration, which certainly is true in patients with progressive loss of renal function. Fibrosis may occur in the absence of granulomas but generally re flects the residual fibrosis of granulomatous lesions that have subsided or resp onded to steroid therapy. It is important to monitor renal function closely in s uch patients and initiate proper measures to retard the course of progressive re nal failure. As with all other forms of tubulointerstitial nephritis, tubular dy sfunction is a common finding in such cases. The reduction in the glomerular fil tration rate usually is modest but can progress to end-stage renal disease. Prog ression to end-stage disease tends to occur in older men who have minimal pulmon ary involvement.

Renal Involvement in Sarcoidosis 8.7 8 Serum creatinine, mg/100mL 7 6 5 4 3 2 1 Pre-R R FIGURE 8-12 Clinical course of granulomatous nephritis. Extensive granulomatous infiltration of the kidneys can result in acute renal failure as a presenting cl inical feature of sarcoidosis in the absence of any evidence of other organ invo lvement. As a rule, improvement in renal function occurs after steroid therapy ( R), as shown here, in the clinical course of one such patient. (From Bolton et a l. [2]; with permission.) 60 50 Creatinine clearance, mL/min Hematocrit, % 40 30 20 10 40 30 20 10 Prednisone qod, mg 60 30 September October Nov. Dec. Jan. Feb. Mar. April May Ju ne July Time, mo CASE REPORT OF A PATIENT WITH SARCOIDOSIS HAVING RETROPERITONEAL FIBROSIS Patient profile A man aged 40 years with established diagnosis of pulmonary sarcoidosis that had responded to steroids Presentation: hypertension (200/140 mm Hg) and proteinuri a (4 g/d) Intravenous pyelogram: asymmetric kidneys with delayed appearance of c ontrast on right Surgery: sclerotic matrix affecting aorta and proximal renal ar tery Kidney biopsy: focal and global glomerulosclerosis, interstitial fibrosis P ostoperative course: persistent hypertension FIGURE 8-13 Obstructive nephropathy due to sarcoidosis. Acute deterioration of r enal function in sarcoidosis very rarely results from obstructive nephropathy ca used by intrarenal granulomatous infiltrates or from extensive retroperitoneal l ymphadenopathy or fibrosis causing obstruction of the renal vasculature or urete ral outflow [3,4]. (From Grodin et al. [3]; with permission.)

8.8 Systemic Diseases and the Kidney CASE REPORT OF A PATIENT WITH SARCOIDOSIS HAVING GLOMERULOPATHY Patient profile A man aged 57 years with 3 months' history of progressive edema Past history: pulm onary sarcoidosis, treated with steroids for 10 years, on 5 mg 4 times a day on admission Physical examination: blood pressure, 180/95 mm Hg; peripheral edema L aboratory test results: blood urea nitrogen, 32 mg/dL; creatinine, 4.3 mg/dL; al bumin, 2.9 g/dL; cholesterol, 543 mg/dL; urinalysis, 68 erythrocyte/high-power fi eld, 3 + protein; 24-h urine protein, 1.5 g Kidney biopsy: membranous glomerulop athy; no granulomas CASE REPORT OF A PATIENT WITH RECURRENT GRANULOMATOUS SARCOID NEPHRITIS IN A TRA NSPLANTED KIDNEY Aged 13 y Sarcoidosis with pulmonary, hepatic, and ophthalmic symptoms Responded to steroids Steroids discontinued due to cataract and hypertension Renal involv ement progressive to end-stage renal disease Cadaveric transplantation after 3 m onths of dialysis Medications: azathioprine, 75 mg per day; prednisone tapered t o 15 mg 4 times a day Creatinine, 3.1 mg/dL; creatinine clearance, 20 mL/min; bl ood pressure, 150/84 mm Hg Transplanted kidney biopsy: diffuse granulomatous inf iltration Treatment: prednisone increased to 60 mg/d for 6 wk Response: creatine , 2.5 mg/dL; creatinine clearance, 35 mL/min Aged 19 y Aged 26 y FIGURE 8-14 Sarcoid-associated glomerulopathy. Whereas renal involvement in sarc oidosis primarily is due to abnormalities of calcium metabolism and tubulointers titial nephritis, rare cases of glomerulopathy have been associated with sarcoid osis. The detection of an abnormal urine sediment and proteinuria in a patient w ith sarcoidosis should always lead to consideration of glomerular disease. A var iety of glomerular lesions have been reported in patients with sarcoidosis, incl uding membranous glomerulopathy, minimal change disease, membranoproliferative g lomerulonephritis, focal glomerulosclerosis, immunoglobulin A nephropathy, and c rescentic glomerulonephritis. Of these, membranous glomerulopathy is more common . These rare cases may represent a chance coexistence of two separate diseases; however, their occurrence in a disease of altered immunity may reflect a causati ve association. Mesangial deposits of C3 have been observed in cases of sarcoid granulomatous nephritis in the absence of any clinical evidence of glomerular di sease. Circulating immune complexes are detected in about half of cases of sarco idosis in the absence of any evidence of renal involvement by granulomatous neph ritis or glomerular lesions. As such, the presence of immune-mediated glomerulop athy may well be more than coincidental in occasional cases in which the patient may be predisposed by genetic or other as yet unidentified factors. (From Taylo r et al. [5]; with permission.) FIGURE 8-15 Recurrent granulomatous sarcoid nephritis in a transplanted kidney. In patients with sarcoidosis having renal involvement whose renal failure has pr ogressed to end-stage renal disease, kidney transplantation can be successful. H owever, due consideration should be given to the fact that recurrence of sarcoid osis in renal allografts have been reported. Conversely, documented cases exist in which sarcoidosis was transmitted by cardiac or bone marrow transplantation. This observation has been taken as evidence of an infectious or transmissible ca use of sarcoidosis that highlights the problem of transplantation in patients wi th sarcoidosis. (From Shen et al. [6]; with permission.) References

1. 2. Newman LS, Rose CS, Maier LA: Sarcoidosis. N Engl J Med 1997, 336:12241234. Bolton WK, Atuk NO, Rametta C, et al.: Reversible renal failure from isolated g ranulomatous renal sarcoidosis. Clin Nephrol 1976, 5:8892. Grodin M, Filastre JP, Ducastelle T, et al.: Sarcoidosis retroperitoneal fibrosis, renal arterial invo lvement and unilateral focal glomerulosclerosis. Arch Intern Med 1980, 140:124012 42. 4. 5. Cuppage FE, Emmott DF, Duncan KA: Renal failure secondary to sarcoidos is. Am J Kidney Dis 1990, 11:519521. Taylor RG, Fisher C, Hoffbrand BI: Sarcoidos is and membranous glomerulonephritis: a significant association. Br Med J 1982, 284:12971298. Shen SY, Hall-Craggs M, Posner JN, Shalozz B: Recurrent sarcoid gra nulomatous nephritis and reactive tuberculin test in a renal transplant recipien t. Am J Med 1986, 80:699702. 3. 6 Selected Bibliography Casella FJ, Allon M: The kidney in sarcoidosis. J Am Soc Nephrol 1993, 3:15551562 . Romer FK: Renal manifestations and abnormal calcium metabolism in sarcoidosis. Quart J Med 1980, 49:233247. Fuss M, Pepersack T, Gillet C, et al.: Calcium and vitamin D metabolism in granulomatous diseases. Clin Rheumatol 1992, 11:2836. Han edouche T, Grateau G, Noel LH, et al.: Renal granulomatous sarcoidosis: Report o f 6 cases. Nephrol Dial Transplant 1990, 5: 1824.

Renal Involvement in Essential Mixed Cryoglobulinemia Giuseppe D'Amico Franco Ferrario U p to the end of the 1980s, the cause of about 30% of both type II and III mixed cryoglobulinemias (MC) in patients was not known, and this subgroup of patients were referred to as having essential mixed cryoglobulinemia. Essential mixed cry oglobulinemia was characterized clinically by systemic signs, mainly purpura, ar thralgias, and fever, together with hepatic, neurologic, and renal symptoms. Dur ing this decade, antibodies against hepatitis C virus (HCV) antigens and HCV RNA (which is a marker of active viremia) have been detected in the serum of up to 90% of these patients. Only when a monoclonal rheumatoid factor, usually an immu noglobulin Mk (IgMk), is the anti-IgG component of the mixed cryoglobulinemia (t ype II MC) does this distinctive glomerular and vascular involvement of the kidn ey occur. The most frequent histologic picture, especially in the acute stages, is a membranoproliferative glomerulonephritis (MPGN) with subendothelial deposit s, with some characterizing features both by light and electron microscopy. Howe ver, a less distinctive picture of lobular MPGN is found at biopsy in 20% of pat ients, and of a mesangioproliferative glomerulonephritis in another 20%. In all cases, the two components of MC, IgG, and IgM, together with complement, are fou nd by immunofluoroscopy. The clinical picture varies during the long-term course of the disease, being characterized by periods of temporary reactivation (nephr itic or nephrotic syndrome, sometimes with rapidly occurring renal insufficiency ) and long-lasting periods of partial remission. Only infrequently does end-stag e renal failure develop; however, mortality as a result of the other complicatio ns of the systemic disease (mainly cardiovascular) is rather frequent. CHAPTER 9

9.2 Systemic Diseases and the Kidney ized events might induce the shift to abnormal proliferation of a clone of B cel ls, producing a monoclonal IgM rheumatoid factor. Thus, a type II MC is induced that can be considered a lymphoproliferative disorder. It has been suggested tha t the IgMk produced by this permanent clone of B cells has affinity for the glom erular matrix and can deposit, in the glomerulus together with the IgG to which it binds in the blood, IgG that probably acts as an anti-HCV antigen antibody. During acute flare-ups, antiviral treatment (interferon- ) is insufficient to co ntrol the renal disease, even when it reduces viremia. Steroids, usually associa ted with immunosuppressive drugs (cyclophosphamide), are then necessary to contr ol renal disease. Hepatitis C virus can infect B lymphocytes and stimulate them to synthesize the cryoprecipitating polyclonal rheumatoid factors responsible fo r type III MC. In some patients with this polyclonal B-cell activation, addition al but as yet uncharacterCLASSIFICATION OF CRYOGLOBULINEMIAS AND ASSOCIATED DISEASES Type I: single monoclonal IgA, IgG, or IgM Multiple myeloma Waldenstrm's macroglobulinemia Chronic lymphocytic leukemia Idiopa thic monoclonal gammopathy Type II: polyclonal IgG bound to monoclonal anti-IgG rheumatoid factor* B-lymphocytic neoplasm Diffuse lymphoma Chronic lymphocytic leukemia Sjgren's syndr ome Essential Type III: polyclonal IgG bound to polyclonal anti-IgG rheumatoid factor* Autoimmune diseases: SLE, polyarteritis nodosa, rheumatoid arthritis, scleroderm a, Sjgren's syndrome, and Hench-Schonlein purpura Infections diseases: mononucleosis , cytomegalovirus, hepatitis B, subacute bacterial endocarditis, leprosy, malari a, schistosomiasis, toxoplasmosis, AIDS Miscellaneous diseases: primary prolifer ative glomerulonephritis, lymphoma, chronic hepatitis, biliary cirrhosis Essenti al *Usually IgM. From Brouet and coworkers [1]; with permission. FIGURE 9-1 Classification of cryoglobulinemias and associated diseases as propos ed by Brouet and coworkers in 1974 [1]. Up to the end of the 1980s, the cause of about 30% of both types II and III mixed cryoglobulins was not clear, and this group of mixed cryoglobulinemias was called essential [2,3]. As indicated in Figure 9-4, it now is evident that most essential mixed cryoglo bulinemias are associated with hepatitis C virus infection. FIGURE 9-2 Correct m ethodology for detecting circulating cryoglobulins. Cryoglobulins are immunoglob ulins that precipitate reversibly from cooled serum. DETECTION OF CIRCULATING CRYOGLOBULINS AND DETERMINATION OF CRYOPRECIPITATE Prewarm syringe, needle, and tubes at 37C Take 20 mL of whole blood and put it im mediately at 37C Incubate for 2 h at 37C to allow clotting Centrifuge twice at 170 0 g X 10 at 37C to discard platelets and erythrocytes Cryoglobulins precipitate r eversibly from cooled serum Keep serum at 4C in a conical graduate tube Look at t he serum after 7 d Centrifuge serum at 400 g X 10 at 4C and calculate the cryocri t as the percentage of packed cryoglobulins and serum ratio

Renal Involvement in Essential Mixed Cryoglobulinemia 9.3 A B FIGURE 9-3 (see Color Plate) Immunoglobulin composition and clonality of mixed c ryoglobulins characterized by immunofixation. The cryoglobulins (isolated, as in dicated in Fig. 9-2) are resuspended in three volumes of cold phosphate-buffered saline at 4C and then washed by centrifuging at 1700 g for 10 minutes at 4C; the supernatant is discarded. This procedure is repeated at least four times. Next, the cryoprecipitate is solubilized in three volume s of phospate-buffered saline at 37C before gel electrophoresis is performed. A, Example of type II mixed cryoglobulin; the immunoglobulin M rheumatoid factor co ntains but not light chains and therefore is monoclonal. B, Example of type III mixed cryoglobulin; the immunoglobulin M rheumatoid factor contains both and lig ht chains and therefore is polyclonal. (Beckman Paragon IFE gel.) PREVALENCE OF HEPATITIS C VIRUS AND HEPATITIS C VIRUS RNA IN ESSENTIAL AND SECON DARY MIXED CRYOGLOBULINEMIAS* Study Ferri et al. [5] Galli et al. [6] Pechre-Bertschi et al. [7] Agnello et al. [8] M isiani et al. [9] Pasquariello et al. [10] Cacoub et al. [11] Bichard et al. [12 ] D'Amico, Unpublished data Types of mixed cryoglobulinema II and III EMC II and III EMC II and III EMC II EMC II EMC II EMC with GN II and III EMC SMC II and III EMC II EMC II EMC wtih GN III EMC Serum HCV antibodies Patients tested, n 52 129 63 15 19 75 26 63 52 41 28 13 Serum HCV RNA Patients tested, n Positive patients, % Positive patients, % 54 80 70 87 42 96 100 52 27 95 93 77 7 19 28 7 16 15 41 28 13 71 84 93 100 63 93 95 93 77 *According to published data [4]. EMCessential mixed cryoglobulinemia; GNglomerulo nephritis; HCVhepatitis C virus; SMCsecondary mixed cryoglobulinemia. FIGURE 9-4 Second-generation enzyme-linked immunosorbent assay has been used by all the authors listed here (with the exception of Agnello and coworkers [9], wh o used a recombinant immunoblot assay) to measure antihepatitic C virus (HCV) antibodies. The prevalence of positivity of HCV RNA in the 15 patients studied b y Bichard and coworkers [12] increased from 60% to 93% when cryoprecipitate from serum was tested.

9.4 Systemic Diseases and the Kidney FREQUENT EXTRARENAL SIGNS IN PATIENTS WITH TYPES II AND III MIXED CRYOGLOBULINEM IA Signs and symptoms Cutaneous purpura Arthralgias Fever Hepatosplenomegaly Neuropathy Abdominal pain Prevalence during course of disease, % 95 85 60 95 40 30 FIGURE 9-5 Extrarenal signs frequently present in patients with types II and III mixed cryoglobulinemia, either essential or due to hepatitis C virus infection, with or without cryoglobulinemic nephropathy. In patients with cryoglobulinemic nephropathy, the systemic signs usually appear months or years before renal com plications develop. The onset of these signs, however, may be concomitant with o r even subsequent to the onset of renal signs. Abdominal pain is due to mesenter ic vsasculitis [13]. FIGURE 9-6 A purpuric rash of the legs in a patient with mixed cryoglobulinemia associated with hepatitis C virus infection. DISTINCTIVE FEATURES OF MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS, OR CRYOGLOBULI NEMIC GLOMERULONEPHRITIS Exudative component The major constituent of intracapillary proliferation is an infiltration of leukocytes, mainly monocytes, that sometimes is massive. Intralu minal thrombi Huge deposits of cryoglobulins called intraluminal thrombi sometim es fill the capillary lumen. Interposition of monocytes in the double contour of the capillary wall Monocytes, in close contact with the subendothelial deposits of cryoglobulins, are interposed between the glomerular basement membrane and t he newly formed membranelike material, to give the double-contoured appearance o f the capillary wall, whereas peripheral interposition of mesangial matrix and c ells is moderate. Structured crystalloid deposits on electron microscopy Intralu minal and subendothelial deposits of cryoglobulins sometimes show a specific fib rillar structure on electron microscopy. Vasculitis of small and medium-sized ar teries Necrotizing arteritis, without concomitant features of segmental necrotiz ing glomerulonephritis, is found in one third of patients. FIGURE 9-7 The distinctive features of the membranoproliferative glomerulonephri tis. This disorder, called cryoglobulinemic glomerulonephritis, occurs only in p atients with type II mixed cryoglobulinemia, especially in the acute stage of th e disease [4,14]. In about 20% of patients with type II mixed cryoglobulinemia, a less distinctive picture of lobular membranoproliferation is found, whereas an additional 20% exhibit mild mesangial proliferation. These various types of his tologic lesions can be found by repeat biopsies in the same patient during diffe rent stages of the disease.

Renal Involvement in Essential Mixed Cryoglobulinemia 9.5 FIGURE 9-8 Membranoproliferative exudative glomerulonephritis in patients with t ype II mixed cryoglobulinemia. The marked endocapillary hypercellularity also is due to massive intraglomerular infiltration of mononuclear leukocytes, mainly m onocytes (Fig. 9-9). Mesangial cell proliferation and mesangial matrix expansion are mild. Many loops show a thickened glomerular capillary wall, with frequent double-contoured basement membrane. (Trichrome stain 250.) FIGURE 9-9 Immunohistochemical staining with antimonocyte-macrophage antibody (CD 68). This reaction confirms that the intracapillary hypercellularity is due main ly to accumulation of these mononuclear leukocytes. Their average number in acut e stages of cryoglobulinemic glomerulonephritis is four times greater than in se vere proliferative lupus nephritis [15]. (Immunoperoxidase 250.) FIGURE 9-10 (see Color Plate) Monocyte in close contact with a massive endocapil lary deposit showing phagocytic activity. (Uranyl acetatelead citrate 8000.) (Cou rtesy of Department of Pathology, San Carlo Borromeo Hospital, Milan, Italy.) FIGURE 9-11 (see Color Plate) Presence of huge intracapillary deposits typical o f cryoglobulinemic glomerulonephritis. These huge intracapillary deposits are ca lled intraluminal thrombi. The only possible differential diagnosis is with glom erulonephritis secondary to Waldenstrm macroglobulinemia. The glomerulus shows mo rphologic lesions similar to those seen in Figure 9-8, characterized by marked e ndocapillary hypercellularity mainly a result of mononuclear leukocyte accumulat ion. Two large intraluminal deposits, stained in green and red, are evident in t he part of the glomerular tuft opposite the vascular pole. It is now well known that these deposits are expressions of acute and massive intracapillary precipit ation of circulating cryoglobulins. (Trichrome stain 250.)

9.6 Systemic Diseases and the Kidney FIGURE 9-12 Electron microscopy of subendothelial and endocapillary deposits sho wing an amorphous structure. In a minority of cases, as illustrated here, a spec ific annular and cylindrical structure is shown. This structure is identical to that seen in the in vitro precipitate of the same patients and consists of cylin ders 100- to 1000-m long, with a hollow axis, appearing in cross-sections as annu lar bodies [16]. (Uranyl acetatelead citrate 22,000.) (Courtesy of Department of Pathology, San Carlo Borromeo Hospital, Milan, Italy.) FIGURE 9-13 Silver stain showing the double-contoured appearance of the basement membrane. This morphologic aspect is diffuse and more clearly visible than in i diopathic membranoproliferative glomerulonephritis or lupus nephritis. (Silver s tain 250.) FIGURE 9-14 Interposition of monocytes in cryoglobulinemic glomerulnephritis. Tw o monocytes containing lysosomes are interposed, together with electron-dense su bendothelial deposits, between the glomerular basement membrane and the newly fo rmed basement-membranelike material of the double-contoured capillary wall. The i nterposition of monocytes is a distinctive feature of cryoglobulinemic glomeruln ephritis [17,18]. Mesangial matrix and mesangial cell interposition, however, us ually are less evident than in idiopathic membranoproliferative glomerulonephrit is, as is glomerular sclerosis. (Uranyl acetate-lead citrate 8000.) (Courtesy of Department of Pathology, San Carlo Borromeo Hospital, Milan, Italy.) FIGURE 9-1 5 Morphologic pattern of lobular glomerulonephritis. This pattern is present in 20% of cases, characterized by intense mesangial proliferation and peripheral me sangial matrix expansion associated with centrolobular sclerosis. This histologi c picture is indistinguishable from that of idiopathic membranoproliferative glo merulonephritis type I, except for the presence of some degree of monocyte infil tration. (Trichrome 250.)

Renal Involvement in Essential Mixed Cryoglobulinemia 9.7 FIGURE 9-16 The glomerulus showing only mild mesangial proliferation and mesangi al matrix expansion. Thickening of the glomerular basement membrane is not evide nt. This picture frequently is present in cases clinically characterized only by mild urinary abnormalities (inactive phase). Moreover, in many cases in which a biopsy is taken during the acute phase of the disease with typical membranoprol iferative patterns with or without thrombi, a second renal biopsy will show clea r regression of the morphologically acute lesions with only mild mesangioprolife rative alteration. (Trichrome 250.) A B FIGURE 9-17 (see Color Plate) The pattern of immunohistologic glomerular stainin g varies according to the different glomerular patterns seen on light microscopy . A, Diffuse granular subendothelial deposits along the capillary walls, with or without very rare intraluminal thrombi. (Immunoglobulin M 250). B, Intense mass ive staining of the deposits totally filling the capillary lumina. Faint and irr egular parietal deposits also are present. (Immunoglobulin 250.) C, Parietal dep osits with more evident peripheral lobular distribution. (Immunoglobulin 250.) T he components of mixed cryoglobulinemia immunoglobulin M and G, usually associat ed with C3, are the most frequently found immunoreactants. C

9.8 Systemic Diseases and the Kidney FIGURE 9-18 Interstitial infiltrates having different degrees of intensity and d iffusion. When present, these infiltrates are composed not only of T lymphocytes and monocyte macrophages, as in most glomerular diseases, but also of B lymphoc ytes. (Periodic acidSchiff reaction 100.) FIGURE 9-19 (see Color Plate) Arteritis of small and medium-sized arteries. In a bout one third of cases an arteritis of small and medium-size arteries also is p resent. The artery shows diffuse fibrinoid necrosis of the vessel wall (in red) and intraparietal and perivascular leukocyte infiltration. It is worth emphasizi ng that even in the presence of renal arteritis we have never found in patients with cryoglobulinemia a picture of necrotizing crescentic glomerulonephritis, no w considered a specific aspect of capillaritis in primary vasculitis (antineutro phil cytoplasm antibodyassociated). This finding suggets that the vasculitic dama ge is limited to arterial vessels of larger size. (Trichrome 100.) FIGURE 9-20 R enal syndrome at presentation in patients with cryoglobulinemic glomerulonephrit is and associated histologic lesion. During the course of this disease, both the systemic and renal signs may vary remarkably, with periods of exacerbation alte rnating with periods of quiescence. Very often, exacerbation of the extrarenal s igns is associated with exacerbation of renal disease (recurrent episodes of nep hritic or nephrotic syndrome); however, a flare-up of renal disease may occur ev en in the absence of exacerbation of the extrarenal signs. Partial or total prol onged remission occurs spontaneously or after treatment in 10% to 15% of patient s. Arterial hypertension frequently is severe and is present in most patients wi th cryoglobulinemic nephropathy. RENAL SYNDROME AT PRESENTATION IN PATIENTS WITH CRYOGLOBULINEMIC GLOMERULONEPHRI TIS AND ASSOCIATED HISTOLOGIC LESION Renal syndrome Isolated proteinuria with microscopic hematuria, sometimes associated with moder ate chronic renal insufficiency Acute nephritic syndrome, sometimes complicated by acute oliguric renal failure Patients, % 55 Frequent histologic features Membranoproliferative glomerulonephritis (MPGN), with moderate infiltration of m onocytes Lobular MPGN Mesangioproliferative glomerulonephritis MPGN with leukocy tic infiltration, or intraluminal thrombi owing to abrupt massive precipitation of cryoglobulins, usually associated with renal and systemic vasculitis, or both MPGN, frequently of lobular type, with some infiltration of monocytes 25 Nephrotic syndrome 20

Renal Involvement in Essential Mixed Cryoglobulinemia 9.9 LABORATORY ABNORMALITIES IN ESSENTIAL MIXED CRYOGLOBULINEMIA Circulating cryoglobulins Cryocrits ranging from 2% to 70%, with large variation s during the course of the disease Hypocomplementemia Very low levels of early C components (C1q and C4) and CH50; slightly low levels of C3; and high levels of late C components, C5 and C9 CLINICAL OUTCOMES OF 105 PATIENTS STUDIED IN THREE MILAN HOSPITALS FROM 1966 TO 1990 49% cumulative 10-year probability of survival, without renal failure 40% of pat ients died, mostly from cardiovascular diseases, liver failure, or infections 14 % of patients progressed to chronic renal failure and required dialysis 14% of p atients achieved complete and prolonged remission of renal symptoms FIGURE 9-21 Relevant laboratory abnormalities in essential mixed cryoglobulinemia. During the course of this disease, cryoglobulins may temporarily become undetec table. Low levels of serum C4 cannot be corrected by treatment. Low levels of C3 frequently are found during clinical flare-ups and can be corrected by treatmen t. FIGURE 9-22 The clinical outcomes in 105 patients studied in three hospitals in Milan, Italy, between 1966 and 1990. The medial total follow-up time from clinic al onset was approximately 11 years [19]. TREATMENT OF ACUTE RENAL EXACERBATIONS OF CRYOGLOBULINEMIC GLOMERULONEPHRITIS AN D VASCULITIS Steriods are used to control inflammatory renal and systemic involvement Cytotox ic drugs are used to block production of new cryoglobulins by the specific lymph ocytic clone that produces the monoclonal immunoglobulin Mk RF, and therefore, t he precipitating cryoglobulins Plasma exchange is used to remove circulating cry oglobulins from the blood before they deposit in the glomerulus and arterial wal ls FIGURE 9-23 This approach to treatment of the acute renal exacerbations of cryog lobulinemia and vasculitis used previously when the viral cause of the disease w as unknown is still valid now that the viral cause is evident. It is a common ex perience that the antiviral agent interferon- , when given alone, does not contr ol renal complications in the acute stage of the disease [20]. PROPOSED TREATMENT FOR MIXED CRYOGLOBULINEMIA ASSOCIATED WITH HEPATITIS C VIRUS INFECTION Drug InterferonSteriods Dosage 3.06.0 MU, 3 times weekly Methylprednisolone, 0.751.0 g/d, intravenously Prednison e, 0.5 mg/kg of body weight tapered over a few weeks until maintenance dose of 1 015 mg/d is achieved 2 mg/kg of body weight Exchanges of 3 L of plasma, 3 times w eekly Duration 612 mo 3d 6 mo Cyclophosphamide Plasmapheresis 34 mo 23 wk

FIGURE 9-24 The proposed treatment for mixed cryoglobulinemia associated with he patitis C virus infection in the presence of severe acute signs of renal involve ment, ie, glomerulonephritis and vascultits. Plasma exchange is used only when a cute renal insufficiency caused by massive precipitation of cryoglobulins is pre sent. Interferon- is given for more than 6 months only when negation of hepatiti s C virus RNA is achieved in the first months, suggesting a beneficial effect on the viremia. Only the antiviral treatment with interferon- eventually associate d with low doses of steriods to conrol the systemic signs of mixed cryoglobuline mias should be given if renal involvement is mild. The association of interferon - with another antiviral agent ribavirin, 0.6 to 1.0 g/d orally, now is being te sted in patients with hepatitis C virus infection, with promising results [20].

9.10 Systemic Diseases and the Kidney FIGURE 9-25 The mechanisms of renal complications induced by hepatitis C virus ( HCV) infection, with or without associated mixed cryoglobulinemia, according to our hypothesis. As illustrated, the prevalent pathogenetic mechanism is the depo sition in the glomerulus of a monoclonal IgM rheumatoid factor (RF) with particu lar affinity for the glomerular matrix, which is produced by permanent clones of B lymphocytes infected by HCV. It is unknown whether the IgM RF deposits in the glomerulus alone, with subsequent in situ binding of IgG (perhaps bound already to viral antigens, or as a complex composed of HCV antigens, IgG anti-HCV antib odies, and IgMk RF). Only recently have specific HCV-related proteins been detec ted in glomerular structures using indirect immunochemistry. As depicted on the left, it is possible that in a minority of cases immune complexes composed of HC V antigens and anti-HCV IgG antibodies can deposit directly in the glomerular st ructures, in the absence of a concomitant type II MC with a monoclonal IgM RF. T his deposition induces an immune-complex glomerulonephritis similar to that desc ribed in patients infected with the hepatitis B virus. (Adapted from D'Amico [21]. ) Infection by HCV Emergence of a permanent clone producing IgMk RF B lymphocyte IgMk RF HCV HCV-IgG IgG Ab Serum HCV-IgG-IgMk Deposition of anti-HCV Precipitation of In situ binding of immune complexes the circulating HCV-IgG Ab to predeposited IgMk Glomerulus type II cryo MPGN without cryoglobulinemia Cryoglobulinemic GN Acknowledgments We thank Dr. M.P. Rastaldi of the Division of Nephrology and Drs. E. Schiaffino and R. Boeri of the Department of Pathology of the Hospital of San Carlo Borrome o for their help. References 1. Brouet JC, Clauvel JP, Danon F, et al.: Biological and clinical significance of cryoglobulins: a report of 86 cases. Am J Med 1974, 57:775778. 2. Meltzer M, F ranklin EC, Elias K, et al.: Cryoglobulinemia: a clinical and laboratory study. II. Cryoglobulins with rheumatoid factor activity. Am J Med 1966, 40:837856. 3. G orevic PD, Kassab HJ, Levo Y, et al.: Mixed cryoglobulinemia: clinical aspects a nd long-term follow-up of 40 patients. Am J Med 1980, 69:287308. 4. D'Amico G: Cryo globulinemic glomerulonephritis: a membranoproliferative glomerulo-nephritis ind uced by hepatitis C virus. Am J Kidney Dis 1995, 25:361369. 5. Ferri C, Greco F, Longobardo G: Antibodies to hepatitis C virus in patients with mixed cryoglobuli nemia. Arthritis Rheum 1991, 34:16061610. 6. Galli M, Monti G, Munteverde A: Hepa titis C virus and mixed cryoglobulinemias. Lancet 1992, 1:989. 7. Pechre-Bertschi A, Perrin L, De Sassure P, et al.: Hepatitis C: a possible etiology for cryoglo bulinemia type II. Clin Exp Immunol 1992, 89:419422. 8. Agnello V, Chung RT, Kapl an LM: A role for hepatitis C virus infection in type II cryoglobulinemia. N Eng l J Med 1992, 327:14901495. 9. Misiani R, Bellavita P, Fenili D: Hepatitis C viru s and cryoglobulinemia [letter]. N Engl J Med 1993, 328:1121. 10. Pasquariello A , Ferri C, Moriconi L, et al.: Cryoglobulinemic membranoproliferative glomerulon ephritis associated with hepatis C virus [letter]. Am J Nephrol 1993, 13:300304. 11. Cacoub P, Lunel Fabiani F, Musset L, et al.: Mixed cryoglobulinemia and hepa titis C virus. Am J Med 1994, 96:124132. 12. Bichard P, Ounanian A, Girard M, et al.: High prevalence of hepatitis C virus RNA in the supernatant and the cryopre cipitate of patients with essential and secondary type II mixed cryoglobulinemia . J Hepatol 1994, 21:5863. 13. D'Amico G, Ferrario F, Colasanti G, Bucci A: Glomeru lonephritis in essential mixed cryoglobulinemia (EMC). In Proceedings of the XXI

Congress of the European Dialysis and Transplant Association. Edited by Davison PJ, Guillou PJ. London: Pitman; 1985:527547. 14. D'Amico G, Colasanti G, Ferrario F, Sinico RA: Renal involvement in essential mixed cryoglobulinemia. Kidney Int 1989, 35:10041014. 15. Castiglione A, Bucci A, Fellin G, et al.: The relationship of infiltrating renal leukocytes to disease activity in lupus and cryoglobuline mic glomerulonephritis. Nephron 1988, 50:1423. 16. Cordonnier D, Martin H, Grosla mbert P, et al.: Mixed IgG-IgM cryoglobulinemia with glomerulonephritis. Immunoc hemical fluorescent and ultrastructural study of kidney and in vitro cryoprecipi tate. Am J Med 1975, 59:867872. 17. Mazzucco G, Monga G, Casanova S, Cagnoli L: C ell interposition in glomerular capillary walls in cryoglobulinemic glomerulonep hritis: ultrastructural investigation of 23 cases. Ultrastruct Pathol 1986, 10:3 55361. 18. D'Amico G, Colasanti G, Ferrario F et al.: L'atteinte rnale dans la cryoglo bulinmie mixte essentielle: un type particulier de nphropathie mdiation immunologiq ue. In Actualits Nphrologiques. Edited by Flammarion Mdecine Sciences; 1987:201219. 19. Tarantino A, Campise M, Banfi G, et al.: Long-term predictors of survival in essential mixed cryoglobulinemic glomerulonephritis. Kidney Int 1995, 47:618623. 20. D'Amico G, Fornasieri A: Cryoglobulinemia. In Current Therapy in Nephrology a nd Hypertension: A Companion to Brenner and Rector's the Kidney. Edited by Brady H R, Wilcox CS. Philadelphia: WB Saunders Company; 1998 (in press). 21. D'Amico G: I s type II mixed cryoglobulinaemia an essential part of hepatitis C virus (HCV)-a ssociated glomerulonephritis? Nephrol Dial Transplant 1995, 12791282.

Kidney Disease and Hypertension in Pregnancy Phyllis August K idney disease and hypertensive disorders in pregnancy are discussed. Pregnancy i n women with kidney disease is associated with significant complications when re nal function is impaired and hypertension predates pregnancy. When renal functio n is well preserved and hypertension absent, the outlook for both mother and fet us is excellent. The basis for the close interrelationship between reproductive function and renal function is intriguing and suggests that intact renal functio n is necessary for the physiologic adjustments to pregnancy, such as vasodilatio n, lower blood pressure, increased plasma volume, and increased cardiac output. The renal physiologic adjustments to pregnancy are reviewed, including hemodynam ic and metabolic alterations. The common primary and secondary renal diseases th at may occur in pregnant women also are discussed. Some considerations for the m anagement of end-stage renal disease in pregnancy are given. Hypertensive disord ers in pregnancy are far more common than is renal disease. Almost 10% of all pr egnancies are complicated by either preeclampsia, chronic hypertension, or trans ient hypertension. Preeclampsia is of particular interest because it is associat ed with life-threatening manifestations, including seizures (eclampsia), renal f ailure, coagulopathy, and rarely, stroke. Significant progress has been made in our understanding of some of the pathophysiologic manifestations of preeclampsia ; however, the cause of this disease remains unknown. The diagnostic categories of hypertension in pregnancy, pathophysiology of preeclampsia, and important pri nciples of prevention and treatment also are reviewed. CHAPTER 10

10.2 Systemic Diseases and the Kidney Anatomic Changes in the Kidney During Pregnancy FIGURE 10-1 Anatomic changes in the kidney during pregnancy. During pregnancy, k idney size increases by about 1 cm. More striking are the changes in the urinary tract. The calyces, renal pelvis, and ureters dilate. The dilation is more mark ed on the right side than the left and is apparent as early as the first trimest er. Hormonal mechanisms and mechanical obstruction are responsible. Intravenous pyelography may demonstrate the iliac sign in which ureteral dilation terminates at the level of the pelvic brim where the ureter crosses the iliac artery. Uret eral dilation and urinary stasis contribute to the increased incidence of asympt omatic bacteriuria and pyelonephritis in pregnancy. Increased kidney size Increased renal blood flow Increased glomerular filtration rate Dilation of urin ary tract Changes in Renal Function During Pregnancy Uric acid reabsorption - Renin Renal vasodilation - Glomerular filtration rate - Renal blood flow Serum creatinine Urinary protein - Aldosterone - Sodium reabsorption - Water reabsorption - Urinary calcium - Glucosuria - Am inoaciduria FIGURE 10-2 Changes in renal function during pregnancy. Marked renal hemodynamic changes are apparent by the end of the first trimester. Both the glomerular fil tration rate (GFR) and effective renal plasma flow (ERPF) increase by 50%. ERPF probably increases to a greater extent, and thus, the filtration fraction is dec reased during early and mid pregnancy. Micropuncture studies performed in animal s suggest the basis for the increase in GFR is primarily the increase in glomeru lar plasma flow [1]. The average creatinine level and urea nitrogen concentratio n are slightly lower than in pregnant women than in those who are not pregnant ( 0.5 mg/d and 9 mg/dL, respectively). The increased filtered load also results in increased urinary protein excretion, glucosuria, and aminoaciduria. The uric ac id clearance rates increase to a greater extent than does the GFR. Hypercalciuri a is a result of increased GFR and of increases in circulating 1,25-dihydroxy-vi tamin D3 in pregnancy (absorptive hypercalciuria). The renin-angiotensin system is stimulated during gestation, and cumulative retention of approximately 950 mE q of sodium occurs. This sodium retention results from a complex interplay betwe en natriuretic and antinatriuretic stimuli present during gestation [2].

Kidney Disease and Hypertension in Pregnancy 10.3 Serum Electrolytes in Pregnancy Serum sodium and Posm with Osmotic Threshold for the argenine vasopressin releas e and thirst A Altered osmoregulation: B Serum chloride levels are unchanged compared with women who are not pregnant Na+ 136 mEq/L 3.7 mEq/L K+ Cl104 mEq/L 20 mEq/L HCO3 observed due to - glomerular filtration rate, - urine flow, and - aldosterone C Mild hypokalemia may be D Mild respiratory alkalosis is associated with small decreases in plasma bicarbonate FIGURE 10-3 Serum electrolytes in pregnancy. A, During normal gestation, serum o smolality decreases by 10 mosm/L and serum sodium (Na+) decreases by 5 mEq/L. A resetting of the osmoreceptor system occurs, with decreased osmotic thresholds f or both thirst and vasopressin release [3]. B, Serum chloride (Cl-) levels essen tially are unchanged during pregnancy. C, Despite significant increases in aldos terone levels during pregnancy, in most women serum potassium (K+) levels are ei ther normal or, on average, 0.3 mEq/L lower than are values in women who are not pregnant [4]. The ability to conserve potassium may be a result of the elevated progesterone in pregnancy [5]. D, Arterial pH is slightly increased in pregnanc y owing to mild respiratory alkalosis. The hyperventilation is believed to be an effect of progesterone. Plasma bicarbonate (HCO-3) concentrations decrease by a bout 4 mEq/L [6]. Blood Pressure and the Renin-Aldosterone System in Pregnancy 120 110 Blood pressure, mmHg 100 90 80 70 60 50 4 8 12 16 20 24 28 32 36 40 PP ( N) Sitting Standing 14 12 PRA, ng/mL/h 10 8 6 4 2 0 PRA Postpartum angiotensinogen values * ** * * * (7) (16) (18) (18) (18) (19) (18) (18)(15) ** * (19) 4 8

12 16 20 24 28 32 36 38 PP A Gestation, wk B Gestation, wk FIGURE 10-4 Blood pressure and the renin-aldosterone system in pregnancy. Normal pregnancy is associated with profound alterations in cardiovascular and renal p hysiology. These alterations are accompanied by striking adjustments of the reni n-angiotensinaldosterone system. A, Blood pressure and peripheral vascular resis tance decrease during normal gestation. The decrease in blood pressure is appare nt by the end of the first trimester of pregnancy and often approaches prepregnancy levels at term. B, Despite the decre ase in blood pressure, plasma renin activity (PRA) increases during the first fe w weeks of pregnancy; on average, close to a fourfold increase in PRA occurs by the end of the first trimester, with additional increases until at least 20 week s. The source of the increased renin is thought to be the maternal renal release of renin. (Continued on next page)

10.4 Systemic Diseases and the Kidney Urine aldosterone Plasma aldosterone 200 Urine sodium Urine potassium 120 150 Urine aldosterone, g/d 100 80 60 40 20 100 80 60 40 20 0 24-hr Na+ and K+ , mEq Plasma aldosterone, ng/100mL 100 50 0 8 12 16 20 24 28 32 36 38 PP C 0 D Gestation, wk FIGURE 10-4 (Continued) C, Changes in renin are associated with commensurate cha nges in the secretory rate of aldosterone. Although a correlation exists between the increase in renin and that of aldosterone, the latter increases to a greate r degree in late pregnancy. This observation suggests that other factors may reg ulate secretion to a greater degree than does angiotensin II in late gestation. Urinary aldosterone increases in late gestation to a greater degree than does plasma aldosterone, wh ich may reflect an increased production of the 3-oxo conjugate measured in urine . D, Despite the marked increases in aldosterone during pregnancy, 24-hour urina ry sodium and potassium excretion remain in the normal range. PP postpartum. (Fro m Wilson and coworkers [7]; with permission.) Functional Significance of the Stimulated Renin-Angiotensin System in Pregnancy Pregnant (n = 9) Nonpregnant (n = 8) 85 80 PRA, mg/mL/h MAP, mm Hg 75 70 65 60 P < 0.005 * 25 20 15 10 5 0 T=0 T = 60 * P < .05 A B T=0 T = 60 FIGURE 10-5 Functional significance of the stimulated renin-angiotensin system ( RAS) in pregnancy. We determine whether changes in the RAS in pregnancy are prim ary, and the cause of the increase in plasma volume, or whether these changes ar e secondary to the vasodilation and changes in blood pressure. To do so, we admi nistered a single dose of captopril to normotensive pregnant women in their firs

t and second trimesters and age-matched normotensive women who were not pregnant . We then measured mean arterial pressure (MAP) and plasma renin activity (PRA) before and 60 minutes after the dose. A, Despite similar baseline blood pressure s, blood pressure decreased more in pregnant women compared with those who were not pregnant in response to captopril. This observation suggests that the RAS pl ays a greater role in supporting blood pressure in pregnancy. B, Baseline PRA wa s higher in pregnant women compared with those who were not pregnant, and pregna nt women had a greater increase in renin after captopril compared with those who were not pregnant. Ttime. (From August and coworkers [8]; with permission.)

Kidney Disease and Hypertension in Pregnancy 10.5 Pregnancy and the Course of Renal Disease INTERRELATIONSHIPS BETWEEN PREGNANCY AND RENAL DISEASE Impact of pregnancy on renal disease Hemodynamic changes hyperfiltration Increased proteinuria Intercurrent pregnancy -related illness, eg, preeclampsia Possibility of permanent loss of renal functi on Impact of renal disease on pregnancy Increased risk of preeclampsia Increased incidence of prematurity, intrauterine growth retardation FIGURE 10-6 Pregnancy may influence the course of renal disease. Some women with intrinsic renal disease, particularly those with baseline azotemia and hyperten sion, suffer more rapid deterioration in renal function after gestation. In gene ral, as kidney disease progresses and function deteriorates, the ability to sust ain a healthy pregnancy decreases. The presence of hypertension greatly increase s the likelihood of renal deterioration [2]. Although hyperfiltration (increased glomerular filtration rate) is a feature of normal pregnancy, increased intragl omerular pressure is not a major concern because the filtration fraction decreas es. Possible factors related to the pregnancy-related deterioration in renal fun ction include the gestational increase in proteinuria and intercurrent pregnancy -related illnesses, such as preeclampsia, that might cause irreversible loss of renal function. Women with renal disease are at greater risk for complications r elated to pregnancy such as preeclampsia, premature delivery, and intrauterine g rowth retardation. Diabetes Mellitus and Pregnancy RENAL DISEASE CAUSED BY SYSTEMIC ILLNESS Gestation in pregnant women with diabetic nephropathy is complicated by the foll owing: Increased proteinuria, 70% Decreased creatinine clearance, 40% Increased blood p ressure, 70% Preeclampsia, 35% Fetal developmental problems, 20% Fetal demise, 6 % FIGURE 10-7 Diabetes mellitus is a common disorder in pregnant women. Patients w ith overt nephropathy are likely to develop increased proteinuria and mild but u sually reversible deteriorations in renal function during pregnancy. Hypertensio n is common, and preeclampsia occurs in 35% of women. (From Reece and coworkers [9]; with permission.)

10.6 Systemic Diseases and the Kidney Pregnancy and Systemic Lupus Erythematosus RENAL DISEASE ASSOCIATED WITH SYSTEMIC ILLNESS Pregnancy and SLE* Poor outcome is associated with the following: Active disease at conception Dise ase first appearing during pregnancy Hypertension, azotemia in the first trimest er High titers of antiphospholipid antibodies or lupus anticoagulant Antiphospholipid antibody syndrome in pregnancy Increased fetal loss Arterial and venous thromboses Renal vasculitis, thrombotic microangiopathy Preeclampsia Treatment: heparin and aspirin? *Systemic lupus erythematosus (SLE) is unpredictable during pregnancy. FIGURE 10-8 Patients with systemic lupus erythematosus (SLE) often are women in their childbearing years. Pregnancies in women with evidence of nephritis are po tentially hazardous, particularly if active disease is present at the time of co nception or if the disease first develops during pregnancy. When hypertension an d azotemia are present at the time of conception the risk of complications incre ases, as it does with other nephropathies [1014]. The presence of high titers of antiphospholipid antibodies also is associated with poor pregnancy outcome [15]. The presence of antiphospholipid antibodies or the lupus anticoagulant is assoc iated with increased fetal loss, particularly in the second trimester; increased risk of arterial and venous thrombosis; manifestations of vasculitis such as th rombotic microangiopathy; and an increased risk of preeclampsia. Treatment consi sts of anticoagulation with heparin and aspirin. Lupus Versus Preeclampsia LUPUS FLARE-UP VERSUS PREECLAMPSIA SLE Proteinuria Hypertension Erythrocyte casts Azotemia Low C3, C4 Abnormal liver fu nction test results Low platelet count Low leukocyte count + + + + + + + PE + + + +/+/FIGURE 10-9 In the second or third trimester of pregnancy a clinical flare-up of lupus may be difficult to distinguish from preeclampsia. Treatment of a lupus f lare-up might involve increased immunosuppression, whereas the appropriate treat ment of preeclampsia is delivery. Thus, it is important to accurately distinguis h these entities. Preeclampsia is rare before 24 weeks' gestation. Erythrocyte cas ts and hypocomplementemia are more likely to be a manifestation of lupus, wherea s abnormal liver function test results are seen in preeclampsia and not usually in lupus. Ccomplement; minus signabsent; plus signpresent; PEpreeclampsia; SLEsystemic lupus er ythematosus.

Kidney Disease and Hypertension in Pregnancy 10.7 Chronic Primary Renal Disease in Pregnancy CAUSES OF CHRONIC PRIMARY RENAL DISEASE IN PREGNANCY Anatomic, congenital Glomerulonephritis Interstitial nephritis Polycystic kidney disease FIGURE 10-10 Primary renal disease in pregnancy that is chronic (ie, preceded pr egnancy) may result from any of the causes of renal disease in premenopausal wom en. Overall, the outcome in pregnancy is favorable when the serum creatinine lev el is less than 1.5 mg/dL and blood pressure levels are normal in early pregnanc y. Advanced Renal Disease Caused by Polycystic Kidney Disease POLYCYSTIC KIDNEY DISEASE AND PREGNANCY Increased incidence of urinary tract infection Maternal hypertension associated with poor outcome Extrarenal complications: subarachnoid hemorrhage, liver cysts FIGURE 10-11 Although advanced renal disease caused by polycystic kidney disease (PKD) usually develops after childbearing, women with this condition may have h ypertension or mild azotemia. Certain considerations are relevant to pregnancy. Pregnancy is associated with an increased incidence of asymptomatic bacteriuria and urinary infection that may be more severe in women with PKD. The presence of maternal hypertension has been shown to be associated with adverse pregnancy ou tcomes [16]. Pregnancy has been reported to be associated with increased size an d number of liver cysts owing to estrogen stimulation. Women with intracranial a neurysms may be at increased risk of subarachnoid hemorrhage during labor. Management of Chronic Renal Disease During Pregnancy MANAGEMENT OF CHRONIC RENAL DISEASE DURING PREGNANCY Preconception counseling Multidisciplinary approach Frequent monitoring of blood pressure (every 12 wk) and renal function (every mo) Balanced diet (moderate sod ium, protein) Maintain blood pressure at 120140/8090 mm Hg Monitor for signs of pr eeclampsia FIGURE 10-12 Management of chronic renal disease during pregnancy is best accomp lished with a multidisciplinary team of specialists. Preconception counseling pe rmits the explanation of risks involved with pregnancy. Patients should understa nd the need for frequent monitoring of blood pressure and renal function. Protei n restriction is not advisable during gestation. Salt intake should not be sever ely restricted. When renal function is impaired, modest salt restriction may hel p control blood pressure. Blood pressure should be maintained at a level at whic h the risk of maternal complications owing to elevated blood pressure is low. Pa tients should be monitored closely for signs of preeclampsia, particularly in th e third trimester.

10.8 Systemic Diseases and the Kidney Renal Disease During Pregnancy MOST COMMON CAUSES OF DE NOVO RENAL DISEASE IN PREGNANCY Glomerulonephritis Lupus nephritis Acute renal failure Interstitial nephritis Ob structive uropathy FIGURE 10-13 Renal disease may develop de novo during pregnancy. The usual cause s are new-onset glomerulonephritis or interstitial nephritis, lupus nephritis, o r acute renal failure. Rarely, obstructive uropathy develops as a result of ston e disease or large myomas that have increased in size during pregnancy. Investigation of the Cause of Renal Disease During Pregnancy RENAL EVALUATION DURING PREGNANCY Serology Function Ultrasonography Biopsy: <32 wk Deteriorating function Morbid n ephrotic syndrome FIGURE 10-14 Investigation of the cause of renal disease during pregnancy can be conducted with serologic, functional, and ultrasonographic testing. Renal biops y is rarely performed during gestation. Renal biopsy usually is reserved for sit uations in which renal function suddenly deteriorates without apparent cause or when symptomatic nephrotic syndrome occurs, particularly when azotemia is presen t. Almost no role exists for renal biopsy after gestational week 32 because at t his stage the fetus will likely be delivered, independent of biopsy results [17] . New-Onset Azotemia, Proteinuria, and Hypertension Occurring in the Second Half o f Pregnancy INTRINSIC RENAL DISEASE VERSUS PREECLAMPSIA Renal disease Serum creatinine Urinary protein Uric acid Blood pressure Liver function test re sults Platelet count Urine analysis >1.0 mg/dL Variable Variable Variable Normal Normal Variable Preeclampsia 0.81.2 mg/dL >300 mg/d >5.5 mg/dL >140/90 mm Hg May be increased May be decreased Protein, with or without erythrocytes, leukocytes FIGURE 10-15 New-onset azotemia, proteinuria, and hypertension occurring in the second half of pregnancy should be distinguished from preeclampsia. Most cases o f preeclampsia are associated with only mild azotemia; significant azotemia is m ore suggestive of renal disease. Azotemia in the absence of proteinuria or hyper tension would be unusual in preeclampsia, and thus, would be more suggestive of intrinsic renal disease. Thrombocytopenia, elevated liver function test results, and significant anemia are not typical features of renal disease (except for th rombotic microangiopathic syndromes) and are features of the variant of preeclam psia known as the hemolysis, elevated liver enzymes, and low platelet count (HEL LP) syndrome.

Kidney Disease and Hypertension in Pregnancy 10.9 Acute Tubular Necrosis and Pregnancy ACUTE RENAL FAILURE IN PREGNANCY Acute tubular necrosis; hemodynamic factors, toxins, serious infection, and so o n Acute interstitial nephritis Acute fatty liver of pregnancy Preeclampsia-HELLP syndrome Microangiopathic syndromes Acute cortical necrosis: obstetric hemorrha ge HELLPhemolysis, elevated liver enzymes, and low platelet count. FIGURE 10-16 Most pregnant women with acute renal failure have acute tubular nec rosis secondary to either hemodynamic factors, toxins, or serious infection. Occ asionally, glomerulonephritis or obstructive nephropathy may be seen. Acute cort ical necrosis may complicate severe obstetric hemorrhage. Acute renal failure ma y be a complication of the rare syndrome of acute fatty liver of pregnancy, a di sorder that occurs late in gestation characterized by jaundice and severe hepati c dysfunction. This syndrome has features that overlap with the hemolysis, eleva ted liver enzymes, and low platelet count (HELLP) syndrome variant of preeclamps ia as well as microangiopathic syndromes (eg, hemolytic uremic syndrome and thro mbotic thrombocytopenic purpura). HELLP Syndrome, AFLP, TTP, and HUS DIFFERENTIAL DIAGNOSIS OF MICROANGIOPATHIC SYNDROMES DURING PREGNANCY HELLP Hypertension Renal insufficiency Fever, neurologic symptoms Onset Platelet count Liver function test results Partial thromboplastin time Antithrombin III 80% Mi ld to moderate 0 3rd trimester Low to very low High to very high Normal to high Low AFLP 2550% Moderate 0 3rd trimester Low to very low High to extremely high High Low TTP Occasional Mild to moderate ++ Any time Low to very low Usually normal Normal No rmal HUS Present Severe 0 Postpartum Low to very low Usually normal Normal Normal FIGURE 10-17 Hemolysis, elevated liver enzymes, and low platelet count (HELLP) s yndrome; acute fatty liver of pregnancy (AFLP); thrombotic thrombocytopenic purp ura (TTP); and hemolytic uremic syndrome (HUS) have similar clinical and laborat ory features [18,19]. The subtle differences are summarized. (Adapted from Salti el and coworkers [18].) AFLPacute fatty liver of pregnancy; HELLPhemolysis, elevated liver enzymes, and lo w platelet count; HUShemolytic uremic syndrome; TTPthrombotic thrombocytopenic pur pura. Adapted from Saltiel et al. [18].

10.10 Systemic Diseases and the Kidney Fertility in Women in End-Stage Renal Disease DIALYSIS AND PREGNANCY Successful outcome, 2030% High incidence of prematurity Outcome related to residu al maternal renal function Management: Increased hours on dialysis Erythropoieti n therapy Blood pressure control Therapy with low doses of heparin Continuous am bulatory peritoneal dialysis versus hemodialysis ? FIGURE 10-18 Because fertility is decreased in end-stage renal disease, pregnanc y is uncommon in women on chronic dialysis. When pregnancies occur, however, onl y about 20% to 30% are successful, with the chances of success increasing when r esidual renal function exists [20]. The overall strategy should be to maintain b lood chemistry levels as close as possible to normal by increasing the number of hours of dialysis to 20 or more. Erythropoietin may be used in pregnancy. Blood pressure control is important, and low doses of heparin should be used to preve nt bleeding. There are no apparent advantages of chronic ambulatory peritoneal d ialysis compared with hemodialysis. The incidence of worsening maternal hyperten sion and subsequent premature delivery is high. Fertility and Renal Transplantation RENAL TRANSPLANTATION AND PREGNANCY Prognosis depends on blood pressure and baseline renal function (<1.52 mg/dL; nor mal blood pressure) Controversy over whether pregnancy accelerates graft loss Pa tients are advised to wait 2 y after transplantation before pregnancy FIGURE 10-19 Fertility is restored after successful renal transplantation. Pregn ancy outcome is improved if renal function is normal and hypertension is absent. It is advisable to wait 2 years after transplantation before pregnancy so that renal function is stable and doses of immunosuppressants are lowest [21]. Cyclos porine, prednisone, and azathioprine are safe during pregnancy and are not assoc iated with fetal abnormalities. Limited experience exists with mycophenolate mof etil during pregnancy. Hypertensive Disorders in Pregnancy Developing nations Developed nations Sepsis 8% Embolism 20% Abortion 17% Hemorrhage 20% Sepsis 40% Other 25% FIGURE 10-20 Mortality and hypertension. Worldwide, hypertensive disorders are a major cause of maternal mortality, accounting for almost 20% of maternal deaths . Most deaths occur in women with eclampsia and severe hypertension (HTN) and ar e due to intracerebral hemorrhage [22]. HTN 15% Other 25% HTN 17% 100800/100,000 (deaths, births) Hemorrhage 13% 12/100,000 (deaths, births)

Kidney Disease and Hypertension in Pregnancy 10.11 FETAL CONSEQUENCES OF MATERNAL HYPERTENSION DURING PREGNANCY 3- to 6-fold increase in stillbirths 5- to 15-fold increase in intrauterine grow th restriction Premature delivery Long-term developmental and neurologic problem s CLASSIFICATION OF HYPERTENSIVE DISORDERS IN PREGNANCY Preeclampsia, eclampsia Chronic hypertension Chronic hypertension with superimpo sed preeclampsia Transient hypertension CLINICAL FEATURES OF PREECLAMPSIA Historical: Nulliparity Multiple gestations Family history Preexisting renal or vascular decrease Hypertension: 140/90 mm Hg after 20 wk or 30 mm Hg increase in systolic pressure or 15 mm Hg increase in diastolic pressure Sudden appearance of edema, especially in hands and face Rapid weight gain Headache, visual distur bances, abdominal or chest pain FIGURE 10-21 Hypertensive disorders in pregnancy are associated with increased i ncidences of stillbirth, fetal growth restriction, premature delivery, and longterm developmental problems secondary to prematurity. These complications are mo re frequent when hypertension is due to preeclampsia. FIGURE 10-22 Several classification systems exist for hypertensive disorders of pregnancy. The one used most commonly in the United States is that proposed in 1 972 by the American College of Obstetricians and Gynecologists and endorsed by t he National High Blood Pressure Education Program. The distinction is made betwe en the pregnancy-specific hypertensive disorder (preeclampsia, and the convulsiv e form, eclampsia) and chronic hypertension that precedes pregnancy, which usual ly is due to essential hypertension. Women with chronic hypertension are at grea ter risk for preeclampsia (2025%). Transient hypertension refers to late pregnanc y elevations in blood pressure, without any of the laboratory or clinical featur es of preeclampsia. This disorder may recur with each pregnancy (in contrast to preeclampsia, which usually is a disease of first pregnancy) and usually indicat es a genetic predisposition to essential hypertension. FIGURE 10-23 The diagnosis of preeclampsia is strengthened when one or more of t he risk factors are present. Hypertension develops after 20 weeks, with normal b lood pressures in the first half of pregnancy. Although edema is a feature of ma ny normal pregnancies, its sudden appearance in the face and hands in associatio n with a rapid weight gain, is suggestive of preeclampsia. Headache, visual dist urbances, and abdominal or chest pain are signs of impending eclampsia. CLINICAL FEATURES OF CHRONIC HYPERTENSION IN PREGNANCY Women are older, more likely to be multiparous Hypertension: present before 20 w k, or documented previous pregnancy Blood pressure may be significantly lower or normal in mid pregnancy Risk of superimposed preeclampsia of 1530% FIGURE 10-24 Women with chronic hypertension are usually older and may be multip arous. Although hypertension often is detectable before 20 weeks, in some women the pregnancy-mediated vasodilation is sufficient to normalize blood pressure so that women with stage 1 or 2 hypertension may have normal blood pressures by th e time of their first antepartum visit. The risk of preeclampsia is substantiall y increased in women with chronic hypertension.

10.12 Systemic Diseases and the Kidney FIGURE 10-25 Laboratory tests are helpful in making the diagnosis of preeclampsi a. In addition to proteinuria, which may occur late in the course of the disease , hyperuricemia, mild azotemia, hemoconcentration, and hypocalciuria are observe d commonly. Some women with preeclampsia may develop a microangiopathic syndrome with hemolysis, elevated liver enzymes, and low platelet counts (HELLP). The pr esence of the HELLP syndrome usually reflects severe disease and is considered a n indication for delivery. Women with uncomplicated chronic hypertension have no rmal laboratory test results unless superimposed preeclampsia or underlying rena l disease exists. LABORATORY ABNORMALITIES IN PREECLAMPSIA AND CHRONIC HYPERTENSION Chronic hypertension Renal: Creatinine Normal Preeclampsia Increased; increased blood urea nitrogen, creatinine Increased (>5.5 mg/dL) >300 mg/d <150 mg/d Increased (>38%) Decreased Increased Increased Decreased Uric acid Urinary protein Urinary calcium Heme: Hematocrit Platelets Liver funct ion tests: Aspartate aminotransferase Alanine aminotransferase Albumin Normal <300 mg/d >200 mg/d Normal Normal Normal Normal Normal Pathophysiology of preeclampsia Fetal syndrome (IUGR, IUD, prematurity) Maternal syndrome (HTN, renal, CNS) FIGURE 10-26 Preeclampsia is a syndrome with both maternal and fetal manifestati ons. Current evidence suggests that an underlying genetic predisposition leads t o abnormalities in placental adaptation to the maternal spiral arteries that sup ply blood to the developing fetoplacental unit. These abnormalities in the mater nal spiral arteries lead to inadequate perfusion of the placenta and may be the earliest changes responsible for the maternal disease. The maternal disease is c haracterized by widespread vascular endothelial cell dysfunction, resulting in v asospasm and intravascular coagulation and, ultimately, in hypertension (HTN), r enal, hepatic, and central nervous system (CNS) abnormalities. The fetal syndrom e is a consequence of inadequate placental circulation and is characterized by g rowth restriction and, rarely, demise. Premature delivery may occur in an attemp t to ameliorate the maternal condition. IUD intrauterine death; IUGRintrauterine g rowth retardation. Placental disease Abdominal implantation Placental vascular lesions Maternal disease Vasoplasm Intravascular coagulation Endothelial dysfunction Genetic susceptibility (maternal x fetal)

Kidney Disease and Hypertension in Pregnancy 10.13 GENETICS OF PREECLAMPSIA Increased incidence observed in mothers, daughters, granddaughters of probands M ode of inheritance unknown: Single recessive gene ? Shared maternal-fetal recess ive gene ? Dominant gene with incomplete penetrance ? FIGURE 10-27 A positive family history is a risk factor for preeclampsia, and th e incidence is approximately 4 times greater in first-degree relatives of index cases [23]. Cooper and coworkers [24] also noted an increased incidence in relat ives by marriage (eg, daughter-in-laws), and 10 instances in which the disease o ccurred in one but not the other monozygotic twin. These data raise the possibil ity of paternal or fetal genetic influence [24]. The mode of inheritance of pree clampsia is not known. Several possibilities have been suggested, including a re cessive gene with the possibility of a maternal-fetal genotype-by-genotype inter action or a dominant maternal gene with incomplete penetrance. Normal pregnancy Preeclampsia A Myometrium Decidua B Spiral arteries Fetus (placenta) Cytotrophoblast stem cells Cell column of anchoring villus Mother (uterus) AV Fetal Basement membrane stroma Uterine blood vessels Syncytiotrophoblast FV Maternal blood space Invasion Zone I Zone II and III Zone IV Zone V A Umbilical artery Villus (containing fetal arteriole and venule) Intervillus spac e (maternal blood) Umbilical vein

FIGURE 10-28 Uteroplacental circulation in normal pregnancy and preeclampsia. A, Normal placentation involves the transformation of the branches of the maternal uterine arteriesthe spiral arteriesfrom thickwalled muscular arteries into saclik e flaccid vessels that permit delivery of greater volumes of blood to the uterop lacental unit. B, Evidence exits that in women with preeclampsia this process is incomplete, resulting in relatively narrowed spiral arteries and decreased perf usion of the placenta [25]. FIGURE 10-29 Transformation of the spiral arteries. A, The process by which the maternal spiral arteries are transformed into dilated vessels in pregnancy is be lieved to involve invasion of the spiral arterial walls by endovascular trophobl astic cells. These cells migrate in retrograde fashion, involving first the deci dual and then the myometrial segments of the arteries and then causing considera ble disruption at all layers of the vessel wall. The mechanisms involved in this complex process are only beginning to be elucidated. These mechanisms involve a lterations in the adhesion molecules of the invading trophoblast cells, such tha t they acquire an invasive phenotype and mimic vascular endothelial cells [26]. (Continued on next page)

10.14 Systemic Diseases and the Kidney FIGURE 10-29 (Continued) B, In women destined to develop preeclampsia, trophobla stic invasion of the spiral arteries is incomplete; it may occur in the decidual but not the myometrial segments of the artery, and in some vessels the process does not occur at all. The arteries, therefore, remain thick-walled and muscular , the diameters in the myometrial segments being half those measured during norm al pregnancy. Recently, it has been reported that in preeclampsia the invading c ytotrophoblasts fail to properly express adhesion receptors necessary for normal remodeling of the maternal spiral arteries [27]. This failure of cytotrophoblas t invasion of the spiral arteries is considered to be the morphologic basis for decreased placental perfusion in preeclampsia. (a)fully modified regions. (b)parti ally modified vessel segments. (c)unmodified vessel segments in the myometrium. A Vanchoring villus; CTBscytotrophoblast cells; FVfloating villi. (From Zhou and cowo rkers [27]; with permission.) (b) (a) CTBs Endothelium Tunica media (c) Fully modified region Partially modified region Decidua Unmodified region Myometrium B Lipid peroxides Cytokines Placental ischemia Endothelial cell damage Platelet aggregation Thromboxane A2 - Serotonin, PDGF - PGI2 NO Endothelin - Mitogenic factors- (eg, PDGF) Sy stemic vasoplasm Organ flow Intravascular coagulation Thrombin FIGURE 10-30 Pathophysiology of preeclampsia. A major unresolved issue in the pa thophysiology of preeclampsia is the mechanism whereby abnormalities in placenta l modulation of the maternal circulation lead to maternal systemic disease. The current schema, which is a hypothesis, depicts a scenario whereby placental isch emia leads to the release of substances that might be toxic to maternal endothel ial cells. The resulting endothelial cell dysfunction also results in increased platelet aggregation. These events lead to the widespread systemic vasospasm, in travascular coagulation and decreased organ flow that are characteristic of pree clampsia. NOnitric oxide; PDGFplatelet-derived growth factor; PGI2prostacyclin 2.

Kidney Disease and Hypertension in Pregnancy 10.15 Central nervous sytem Visual disturbances Seizures Hyperemia, focal anemia Thrombosis, hemorrhage Cardiac Cardiac output Plasma volume - Atrial natriuretic factor Pulmonary edema Hepatic Periportal hemorrhagic necrosis Subcapsular hematoma - Aspartate aminotran sferase - Alanine aminotransferase Vasospasm Reduced flow Intravascular coagulatio n Vascular - Systemic vascular resistance - Blood pressure - Angiotensin II sensitivit y Renal Endotheliosis Proteinuria Glomerular filtration rate Renal blood flow Ur inary sodium, uric acid, and calcium excretion Plasma renin activity FIGURE 10-31 Maternal manifestations of preeclampsia. Preeclampsia is a multisys tem maternal disorder, with dramatic alterations in heart, kidney, circulation, liver, and brain. Interestingly, all of these abnormalities resolve within a few weeks of delivery.

10.16 Systemic Diseases and the Kidney of vasoconstrictors such as endothelin (ET). Compensatory suppression of the ren inangiotensin system occurs, suggesting that excess angiotensin II (AII) does no t play a major role in preeclamptic hypertension (HT). Finally, sodium retention owing to renal vasoconstriction may further increase blood pressure. cAMPcyclic adenosine monophosphate; cGMP cyclic guanosine monophosphate; 5-HT serotonin; PThr parathyroid hormone; S2serotonergic receptors; Thrthombin TX thromboxane; TXA2 throm boxane A2. (Adapted from Lscher and Dubey [28]; with permission.) Placental hormones (eg, estrogen, progesterone) The endothelium and platelet-vessel wall interaction Endothelial cells Thr PThr cGMP + Platelets + - Circulating endothelial toxins - TXA2 5-HT AII A 5-HT S NO/PGl2 1 - Sympathetic nervous system Vascular smooth muscle cells Relaxation Antiproliferation cGMP/cAMP Endothelin Contraction Proliferation S2 TX ET Compensatory responses: Plasma renin Aldosterone FIGURE 10-32 Hypertension in preeclampsia. Although the mechanism of the increas ed blood pressure in preeclampsia is not established, evidence suggests it may i nvolve multiple processes. A possible scenario involves the following: decreased placental production of estrogen and progesterone, both of which have hemodynam ic effects; increased circulating endothelial toxins, possibly released from a p oorly perfused placenta; and increased activity of the sympathetic nervous syste m. These processes may then result in alterations in platelet vascular endothelia l cell function, with decrease in vasodilators such as nitric oxide and prostacy clin and increased production Renin - Proteinuria Renal vasodilation Glomerular filtration rate Renal blood flow Urinary calcium Hypocalciuria Urate excretion FIGURE 10-33 Light microscopy of the renal lesion of preeclampsia: glomerular en dotheliosis. On light microscopy, the glomeruli from preeclamptic women are char

acterized by swelling of the endothelial and mesangial cells. This swelling resu lts in obliteration of the capillary lumina, giving the appearance of a bloodles s glomerulus. On occasion, the mesangium, severely affected, may expand. Thrombo sis and fibrinlike material and foam cells may be present, and epithelial cresce nts have been described in rare instances [2]. FIGURE 10-34 Functional renal alterations in preeclampsia. The functional conseq uences of glomerular endotheliosis and of the hormonal alterations in preeclamps ia are summarized in this schematic diagram of the nephron in preeclampsia. Supp ression of the reninangiotensin system occurs, probably in response to vasoconst riction and elevated blood pressure. The glomerular lesion leads to proteinuria, which may be heavy. Renal hemodynamic changes include modest decreases in the g lomerular filtration rate (GFR) and renal blood flow (RBF). Decreased sodium and uric acid excretion may be caused by increased proximal tubular reabsorption. T he mechanism for the marked hypocalciuria is not known.

Kidney Disease and Hypertension in Pregnancy 10.17 Trial Number of trials Antiplatelet therapy Control Odds ratio and 95% Cl (horizontal line) therapy (antiplatelet: placebo) Smaller studies (<200 women) Larger studies: EPHREDA (1990) Hauth (1993) Italian (1993) Sibai (1993) Viinikka (1993) CLASP (1994) All larger trials All trials 11 10/319 (3.1%) 5/156 5/303 12/565 69/1570 9/103) 313/4659 50/284 (17.6%) 8/74 17/303 9/477 94/1565 11/105) 352/4650 491/7174 541/7458 (7.3%) Odds ratio Overall results 25% SD 6 odds reduction (2p = 0.00002) 6 17 413/7356 423/7675 (5.5%) 0 0.5 1.0 1.5 Antiplatelet therapy better Antiplatelet therapy worse FIGURE 10-35 Prevention of preeclampsia with low-dose aspirin. Investigators hav e sought methods to prevent preeclampsia (eg, salt restriction, prophylactic diu retics, and high-protein diets). One approach that has been extensively investig ated in the last 10 years is therapy with low-dose aspirin. It was hypothesized that such therapy reversed the imbalance between prostacyclin and thromboxane th at may be responsible for some of the manifestations of the disease. Several lar ge trials now have been completed, and most have had negative results. Shown her e is an overview of the effects of aspirin on proteinuric preeclampsia reported from all trials of antiplatelet therapy (through 1994) as analyzed by the Collab orative Low-dose Aspirin in Pregnancy (CLASP) Collaborative Group [28]. Odds rat ios (area proportional to amount of information contributed) and 99% confidence interval (CI) are plotted for various trials. A black square to the left of the solid vertical line suggests a benefit (however, this indication is significant at 2p >0.01 only if the entire CI is to the left of solid vertical line). (From CLASP Collaborative Group [29]; with permission.) FIGURE 10-36 Prevention of pre eclampsia using calcium supplementation. Another preventive strategy that has be en extensively investigated, with conflicting outcomes, is calcium supplementati on. The rationale for this approach is based on the observations that low dietar y calcium intake may increase the risk for preeclampsia, and that preeclampsia i s characterized by abnormalities in calcium metabolism that suggest a calcium de ficit, eg, decreased vitamin D and hypocalciuria [31]. A recent meta-analysis of 14 trials of calcium supplementation in pregnancy concluded that calcium supple mentation during pregnancy leads to reductions in blood pressure and a lower inc idence of preeclampsia. In contrast, a large randomized trial of calcium supplem entation in 4589 low-risk women failed to demonstrate a benefit of calcium thera py [31]. CIconfidence interval; ORodds ratio. (From Bucher and coworkers [30]; wit h permission.)

Study Marya et al.,1987 Villar et al.,1987 Lopez-Jaramillo et al.,1989 Lopez-Jar amillo et al.,1990 Montanaro et al.,1990 Villar and Repke,1990 Belizan et al.,19 91 Cong et al.,1993 Sanchez-Ramos et al.,1994 Pooled estimate 0.001 0.01 Favors calcium Favors control 0.65 (0.311.38) 0.43 (0.063.14) 0.03 (0.0020.49) 0.07 (0.0041.27) 0.25 (0.061.03) 0.1 3 (0.0072.65) 0.66 (0.341.27) 0.19 (0.0094.10) 0.22 (0.070.74) 0.38 (0.220.65) 0.1 OR 1.0 10.0

10.18 Systemic Diseases and the Kidney FIGURE 10-37 Treatment of preeclampsia requires close monitoring of both the mat ernal and fetal condition to maximize chances of avoiding catastrophes such as s eizures, renal failure, and fetal demise. Close surveillance is best accomplishe d in the hospital in all but the mildest cases. Maternal hypertension should be treated to avoid cerebrovascular and cardiovascular complications. Magnesium sul fate is the treatment of choice for seizure prophylaxis and usually is institute d immediately after delivery. When the fetus is mature, delivery is indicated in all cases. When the fetus is immature, the decision to deliver is made after ca refully assessing both the maternal and fetal condition. When maternal health is in jeopardy, delivery is necessary, even with a premature fetus. TREATMENT OF PREECLAMPSIA Close monitoring of maternal and fetal conditions Hospitalization in most cases Lower blood pressure for maternal safety Seizure prophylaxis with magnesium sulf ate Timely delivery ANTIHYPERTENSIVE THERAPY IN PREECLAMPSIA Decreased uteroplacental blood flow and placental ischemia are central to the pa thogenesis of preeclampsia. Lowering blood pressure does not prevent or cure pre eclampsia and does not benefit the fetus unless delivery can be safely postponed . Lowering blood pressure is appropriate for maternal safety: maintain blood pre ssure at 130150/85100 mm Hg. FIGURE 10-38 Some controversy exists regarding when to institute antihypertensiv e therapy in women with preeclampsia. The basis for this controversy is that dec reased uteroplacental perfusion is believed to be important in the pathophysiolo gy of this disorder, and concern exists that lowering maternal blood pressure ma y compromise uteroplacental blood flow and lead to fetal distress. Furthermore, lowering maternal blood pressure does not cure preeclampsia. Thus, antihypertens ive therapy is instituted when the blood pressure reaches a level at which the p hysician considers the maternal condition to be in danger from hypertension. For most physicians, this treatment threshold is at approximately 150/100 mm Hg. Ag gressive lowering of blood pressure is not advisable. ANTIHYPERTENSIVE THERAPY IN PREECLAMPSIA Imminent delivery Hydralazine (intravenous, intramuscular) Labetalol (intravenous) Calcium channel blockers Diazoxide (intravenous) Delivery postponed Methyldopa Labetalol, other blockers Calcium channel blockers Hydralazine blocke rs Clonidine FIGURE 10-39 When blood pressure increases acutely and delivery is likely within the next 24 hours, use of a parenteral antihypertensive agent is preferable. In travenous hydralazine or labetalol are acceptable agents for pregnant women, and both have been used successfully in preeclampsia. Calcium channel blockers shou ld be used with caution because they may act synergistically with magnesium sulf ate, resulting in precipitous decreases in blood pressure. Rarely, agents such a s diazoxide may be needed; however, when hypertension is severe, maternal safety takes priority over pregnancy status. When delivery can be postponed safely for several days, an oral agent is indicated. Methyldopa is one of the safest drugs in pregnancy and has been used extensively with excellent maternal and fetal ou tcome. Labetalol and other blockers have been used successfully in preeclampsia. Calcium channel blockers also may be used as either second- or third-line agent s. Oral hydralazine is safe in pregnancy. Limited experience exists with blocker s or clonidine, although anecdotal reports suggest these agents are safe.

Kidney Disease and Hypertension in Pregnancy Treatment alogrithm for chronic hypertension 150 Systolic 140 130 120 110 100 Di astolic 90 80 70 60 Prepregnancy 10 20 28 32 38 <90 Consider careful decrease in BP medication First trimester Diastolic BP, mm Hg 90100 100 Blood pressure, mm H g Preconception 10.19 Screen for secondary hypertension (pheo, renovascular hypertension) Counseling: Increased risk of preeclampsia (25%) Lifestyle adjustments: increase rest, decre ase exercise Adjust medications: discontinue ACE inhibitors Adjust medications: Increase medication Stop ACE and angiotensin II b blockers Dec rease diuretic dose Baseline evaluation for secondary hypertension if clinically suspected Second tr imester Nonpharmacologic treatment Home BP monitoring Adequate rest <90 Consider careful decrease in BP medication Diastolic BP, mm Hg 90100 Continue treatment 1 00 Indicates significant hypertension: consider stopping work; close surveillanc e for preeclampsia Gestation, wk FIGURE 10-40 Blood pressure changes during pregnancy in women with chronic hyper tension. Women with preexisting or chronic hypertension during pregnancy have a favorable prognosis, unless preeclampsia develops. The risk of superimposed pree clampsia is about 25%. Women with this complication are at greater risk for feta l complications during pregnancy, including premature delivery, growth restricti on, and perinatal mortality. Women with chronic hypertension experience a decrea se in blood pressure during pregnancy that may permit withdrawal of some or all antihypertensive medication. In those women with uncomplicated chronic hypertens ion (solid line), blood pressure decreases in the first trimester, then may decr ease even further in the second trimester. An increase in both systolic and dias tolic blood pressure may occur during the third trimester to levels at prepregna ncy or early first trimester. In those women who develop superimposed preeclamps ia (broken lines), blood pressure often decreases in the first trimester. There is often a failure to decrease further in the second trimester, however, and blo od pressures may actually begin to increase slightly. Blood pressure then increa ses significantly when preeclampsia develops [33]. Third trimester Increased surveillance for preeclampsia Check BP every 2 weeks FIGURE 10-41 Treatment algorithm for chronic hypertension. Ideally, patients wit h chronic hypertension should be evaluated before pregnancy so that secondary hy pertension can be diagnosed and treated appropriately. Women can be counseled re garding the need for possible life-style adjustments, and medications can be adj usted. Blood pressure (BP) medications may require adjustment, depending on the magnitude of the pregnancy-related changes in blood pressure. In the latter half of pregnancy, close surveillance for early signs of preeclampsia increases the likelihood the condition will be diagnosed before it progresses to a severe stag e. ANTIHYPERTENSIVE THERAPY FOR CHRONIC HYPERTENSION DURING PREGNANCY Methyldopa blockers (labetalol) Calcium channel blockers Hydralazine Diuretics FIGURE 10-42 The overall treatment goals of chronic hypertension in pregnancy ar e to ensure a successful full-term delivery of a healthy infant without jeopardi zing maternal well-being. The level of blood pressure control that is tolerated in pregnancy may be higher, because the risk of exposure of the fetus to additio nal antihypertensive agents might outweigh the benefits to the mother (for the d

uration of pregnancy) of having a normal blood pressure. Most antihypertensive a gents have been evaluated only sporadically during gestation, and careful follow -up of children exposed in utero to many of the agents is lacking. The only anti hypertensive agent for which such follow-up exists is methyldopa. Because no adv erse effects have been documented in offspring of exposed mothers, methyldopa is considered to be one of the safest drugs during pregnancy. blockers and calcium channel blockers are acceptable second- and third-line agents. Diuretics can be used at low doses, particularly in salt-sensitive hypertensive patients on chro nic diuretic therapy. Angiotensin-converting enzyme inhibitors are contraindicat ed in pregnancy because they adversely affect fetal renal function. Angiotensin II receptor antagonists are presumed to have similar effects but have not been e valuated in human pregnancy.

10.20 Systemic Diseases and the Kidney References 1. Baylis C: Glomerular filtration and volume regulation in gravid animal models . Clin Obstet Gynaecol 1987, 1:789. 2. Lindheimer MD, Katz AI: The kidney and hy pertension in pregnancy. In The Kidney, edn 4. Edited by Brenner BM, Rector FC. Philadelphia: WB Saunders Co; 1991:15511595. 3. Davison JM, Shiells EA, Philips P R, Lindheimer MD: Serial evaluation of vasopressin release and thirst in human p regnancy: role of chorionic gonadotropin in the osmoregulatory changes of gestat ion. J Clin Invest 1988, 81:798. 4. Lindheimer MD, Richardson DA, Ehrlich EN, Ka tz AI: Potassium homeostasis in pregnancy. J Reprod Med 1987, 32:517. 5. Brown M A, Sinosich MJ, Saunders DM, Gallery EDM: Potassium regulation and progesteronealdosterone interrelationships in human pregnancy. A prospective study. Am J Obs tet Gynecol 1986, 155:349. 6. Lim VS, Katz AI, Lindheimer MD: Acid-base regulati on in pregnancy. Am J Physiol 1976, 231:1764. 7. Wilson M, Morganti AA, Zervouda kis I, et al.: Blood pressure, the reninaldosterone system and sex steroids thro ughout normal pregnancy. Am J Med 1980, 68:97. 8. August P, Mueller FB, Sealey J E, Edersheim TG: Role of reninangiotensin system in blood pressure regulation in pregnancy. Lancet 1995, 345:896897. 9. Diabetic nephropathy. Pregnancy performan ce and fetal-maternal outcome. Am J Obstet Gynecol 1988, 159:56. 10. Hayslett JP , Lynn RI: Effect of pregnancy in patients with lupus nephropathy. Kidney Int 18 :207, 1980. 11. Houser MT, Fish AJ, Tagatz GE, et al.: Pregnancy and systemic lu pus erythematosus. Am J Obstet Gynecol 1980, 138:409. 12. Fine LG, Barnett EV, D anovitch GM, et al.: Systemic lupus erythematosus in pregnancy. Ann Intern Med 1 981, 94:667. 13. Imbasciati E, Surian M, Bottino S, et al: Lupus nephropathy and pregnancy. A study of 26 pregnancies in patients with systemic lupus erythemato sus and nephritis. Nephron 1984, 36:46. 14. Jungers P, Dougodos M, Pelissier C, et al.: Lupus nephropathy and pregnancy. Report of 104 cases in 36 patients. Arc h Intern Med 1982, 142:771. 15. Lockshin MD, Druzin MC, Goel S, et al.: Antibody to cardiolipin as a predictor of fetal distress on death in pregnant patients w ith systemic lupus erythematosus. N Engl J Med 1985, 313:152. 16. Chapman AB, Jo hnson AM, Gabow PA: Pregnancy outcome and its relationship to progression of ren al failure in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 199 4, 5:11781185. 17: Lindheimer MD, Davison JM. Renal biopsy during pregnancy: To b. .. or not to b... Br J Obstet Gynecol 1987, 94:932. 18. Saltiel C, Legendre, Grun feld JP, et al.: Hemolytic uremic syndrome in association with pregnancy. In Hem olytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura. Edited by Kaplan BS, Trompeter RS, Moake JL. New York: Marcel Dekker; 1992:241254. 19. Sibai BM, Kustermann L, Velasco J: Current understanding of severe preeclampsia, pregnancy -associated hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, hemo lysis, elevated liver enzymes, and low platelet syndrome, and postpartum acute r enal failure: different clinical syndromes or just different names? Curr Opinion Nephrol Hypertens 1994, 3:436445. 20. Hou S: Peritoneal dialysis and hemodialysi s in pregnancy. Clin Obstet Gynaecol (Balliere) 1994, 8:491510. 21. Davison JM: P regnancy in renal allograft recipients: problems, prognosis, and practicalities. Clinc Obstet Gynaecol (Balliere) 1994, 8:511535. 22. Douglas KA, Redman CW: Ecla mpsia in the United Kingdom. BMJ 1994, 309:13951400. 23. Chesley LC, Annitto JE, Cosgrove RA: Pregnancy in the sisters and daughters of eclamptic women. Pathol M icrobiol 1961, 24:662. 24. Cooper DW, Brenneckes SP, Wilton AN: Genetics of preeclampsia. Hypertens Preg 1993, 12:1. 25. Khong TY, WF De, Robertson WB, Brosens I: Inadequate maternal vascular response to placentation in pregnancies complic ated by preeclampsia and small for gestational age infants. Br J Obstet Gynaecol 1986, 93:10491059. 26. Zhou Y, Fisher SJ, Janatpour M: Human cytotrophoblasts ad opt a vascular phenotype as they differentiate. A strategy for successful endova scular invasion? J Clin Invest 1997, 99:21392151. 27. Zhou Y, Damsky CH, Fisher S J: Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in thi s syndrome? J Clin Invest 1997, 99:21522164. 28. Lscher TF, Dubey RK: Endothelium

and platelet=derived vasoactive substances: role in the regulation of vascular t one and growth. In Hypertension: Pathophysiology, Diagnosis and Management, edn 2. New York: Raven Press; 1995: 609630. 29. CLASP Collaborative Group. CLASP: A r andomized trial of low-dose aspirin for the prevention and treatment of preeclam psia among 9364 pregnant women. Lancet 1994, 343:619629. 30. Bucher HC, Guyatt GH , Cook RJ, et al.: Effect of calcium supplementation on pregnancy-induced hypert ension and preeclampsia: a metaanalysis of randomized controlled trials. JAMA 19 96, 275:11131117. 31. Hojo M, August P: Calcium metabolism in normal and hyperten sive pregnancy. Semin Nephrol 1995, 15:504511. 32. Levine RJ, Hauth JC, Curet LB, et al.: Trial of calcium to prevent preeclampsia. N Engl J Med 1997, 337:6976. 3 3. August P, Lenz T, Ales KL, et al.: Longitudinal study of the renin angiotensi n system in hypertensive women: deviations related to the development of superim posed preeclampsia. Am J Obstet Gynecol 1990, 163:16121621.

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias Jo H.M. Berden Karel J.M. Assmann R enal involvement in systemic lupus erythematosus (SLE), dysproteinemias, and cer tain rheumatic diseases, namely rheumatoid arthritis, Sjgren's syndrome, and sclero derma (systemic sclerosis), is discussed. SLE is a systemic autoimmune disease t hat can lead to disease manifestations in almost every organ. SLE is characteriz ed by the formation of a wide array of autoantibodies mainly directed against nu clear autoantigens, of which antibodies against double-stranded DNA (dsDNA) are the most prominent. Although the cause is still obscure, considerable progress h as been made recently by identification of the nucleosome as the major driving a utoantigen in SLE and the possible role of disturbances in apoptosis in disease development. The section on SLE reviews the major clinical and serologic feature s of the disease, the serologic analysis, new insights into the pathophysiology of lupus nephritis, and the histologic assessment of kidney biopsies. The therap eutic options for treatment of lupus nephritis are discussed as are the results of treatment of endstage renal disease in patients with SLE. The second part of this chapter deals with the renal involvement in dysproteinemias. The renal lesi ons of these diseases, characterized by an overproduction of abnormal immunoglob ulins or their subunits, are quite heterogeneous. Because the kidney often is af fected in these disorders, it is not unusual for examination of a kidney biopsy specimen to reveal clues for the diagnosis. On immunofluorescence, the distribut ion of the light or heavy chain isotype, or both, can be detected in the tissue deposits, whereas electron microscopy can define the ultrastructural organizatio n. Incidence and types of renal involvement, the pathogenesis and risk factors f or the various types of renal lesions, the histology of the different renal mani festations, and an CHAPTER 11

11.2 Systemic Diseases and the Kidney The third part of this chapter presents a concise review of renal involvement in rheumatoid arthritis, Sjgren's syndrome, and scleroderma. overview of the therapy are given. The renal manifestations of cryoglobulinemias and fibrillary and immunotactoid glomerulonephritis also are discussed. Systemic Lupus Erythematosus CUMULATIVE INCIDENCE OF CLINICAL SYMPTOMS AND AUTOANTIBODY FORMATION IN SYSTEMIC LUPUS ERYTHEMATOSUS Percent Frequency of major clinical symptoms Musculoarticular symptoms Cutaneous manifes tations Renal involvement Neuropsychiatric disease Pulmonary and cardiac disease Hematologic abnormalities Occurrence of major autoantibody specificities Antinu clear autoantibody Antidouble-stranded DNA Antihistone Antinucleosome Anti-Sm Ant i-ribonucleoprotein (RNP) AntiSjgren's syndrome (SS-A) (Ro) Anti-SS-B (La) Anticardi olipin Antierythrocyte Antilymphocyte Antithrombocyte 6095 5580 4055 3060 2040 6085 95 6075 5070 Up to 80 1030 1030 2060 1540 1030 5060 5070 1030 EPIDEMIOLOGIC AND GENETIC CHARACTERISTICS OF SYSTEMIC LUPUS ERYTHEMATOSUS Epidemiology Prevalence: between 25 and 250 per 100,000 persons, depending on racial and geog raphic background Race: more prevalent in Asians and blacks Gender: female prepo nderance; gender ratio between 20 and 40 years; male:female, 1:9 Age: onset main ly between 2040 y Genetics Concordancy in twins Monozygotic: 5060% Dizygotic: 510% Familial aggregation in 10 % Association with the following: HLA: B7, B8, DR2, DR3, DQW1 Complement: C4A Q0 C1q or C4 deficiency Fc receptor IIA low-affinity phenotype X chromosome ? FIGURE 11-1 This overview of the major clinical symptoms illustrates the systemi c character of lupus erythematosus. Depending on patient selection, renal involv ement occurs in up to half of patients. In almost all patients, antibodies are f ormed against nuclear antigens, as detected by antinuclear antibody (ANA) testin g. These ANAs are either directed against nucleic acids (DNA), nuclear proteins (histones, Sm, ribonucleoprotein, Sjgren's syndrome-A [SS-A], and SS-B) or nucleoso mes that consist of DNA and the DNA binding proteins histones. In addition, anti bodies can be formed against the anionic phospholipid cardiolipin. This latter a ntibody specificity is characteristic for the antiphospholipid syndrome either p rimary or secondary to systemic lupus erythematosus. All these antigens recogniz ed by lupus autoantibodies share the property that they are present in apoptotic blebs at the surface of cells undergoing apoptosis. In addition to these ANAs, autoantibodies against blood cells frequently develop in lupus, giving rise to h emolytic anemia positive on Coombs testing, lymphopenia, or thrombopenia. FIGURE 11-2 The major epidemiologic characteristics of systemic lupus erythemato sus are listed. The prevalence of the disease depends on ethnic background. The highest prevalence is seen in Asians and Blacks. As in other systemic autoimmune diseases, there is a striking preponderance in women, especially during childbe aring age. This preponderance is related to hormonal status. Animal studies have shown that estrogens have a facilitating effect on disease expression, whereas androgens have a suppressive effect. The importance of estrogens is further subs tantiated by the fact that changes in the hormonal homeostasis (eg, at onset of puberty, during use of oral anticontraceptives, and during pregnancy and puerper ium) are associated with an increased frequency of lupus onset and disease flare -up. The genetic susceptibility is illustrated by the concordance of the disease in twins, occurrence of familial aggregation, and association with certain gene

s, mainly human leukocyte antigens (HLA).

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.3 THE 1982 REVISED AMERICAN RHEUMATISM ASSOCIATION CRITERIA FOR CLASSIFICATION OF SYSTEMIC LUPUS ERYTHEMATOSUS Criterion 1. Malar rash 2. Discoid rash 3. Photosensitivity 4. Oral ulcers 5. Arthritis (t wo or more joints) 6. Serositis: Pleuritis or pericarditis 7. Renal disorder: Pr oteinuria > 0.5 g/24 h or cellular casts (red, hemoglobin, granular, tubular, or mixed) 8. Neurologic disorder: Seizures or psychosis 9. Hematologic disorder: H emolytic anemia or leukopenia (<4 109/L) or lymphopenia (<1.5 109/L) or thrombop enia (<100 109/L) 10. Immunologic disorder: Positive LE cell test result or posi tive antidouble-stranded DNA or positive anti-Sm or false-positive TPI/VDRL test 11. Antinuclear antibody ANA test Negative No further evaluation unless strong clinical suspicion Positiv e Sensitivity, %* 57 18 43 27 86 56 51 Specificity, %* 96 99 96 96 37 86 94 ? Western blot test on nuclear extracts Negative Crithidia lucillae ? anti-ENA Ouchterlony immunodiffusion using ENAs Positive Farr assay 20 59 98 89 85 93 99 49 *The sensitivity was calculated as the percentage of patients with SLE who were positive for this criterion over those in whom this criterion was analyzed. The specificity was calculated as the percentage of the number of patients in the co ntrol group who were negative or normal for that criterion over those in whom th is criterion was analyzed. TPItreponemal immobilization; VDRLVenereal Disease Rese arch Laboratory. Data from Tan et al. [1]. FIGURE 11-3 These criteria were selected for their sensitivity and specificity i n classifying patients with systemic lupus erythematosus (SLE). In the selection process, these criteria were analyzed in 177 patients with SLE and 162 patients in the control group matched for age, gender, and race. Patients in the control group had a nontraumatic nondegenerative connective tissue disease, mainly rheu matoid arthritis (n = 95). The presence of four of these criteria for the diagno sis of SLE has a sensitivity of 96% and specificity of 96% in patients with SLE. For the purpose of identifying patients in clinical studies, it is determined t

hat a patient has SLE when at least four of these criteria are present, serially or simultaneously, during any interval of observation. FIGURE 11-4 Algorithm for analysis of antinuclear antibodies (ANA) in systemic l upus erythematosus. To demonstrate the presence of antinuclear antibodies the AN A test is used as a screening procedure. Details of this ANA test and the differ ent ANA patterns are given in Figure 11-5. A positive ANA test result indicates the presence of antinuclear antibodies. Although the pattern of ANA can give an indication about the specificity of the antinuclear antibody, additional tests a re needed to define this specificity. Antibody specificity to doublestranded DNA (dsDNA) can be identified by the Crithidia assay (Fig. 11-6), in which a single -celled organism is used that has purely dsDNA in the kinetoplast. When this tes t result is positive, the titer of anti-dsDNA antibodies can be determined using the Farr assay (Fig. 11-7). When these anti-dsDNA test results are negative, AN A positivity is most likely caused by antibodies directed against nuclear protei ns. Autoantibodies can be analyzed by the Western blot test on nuclear extracts (Fig. 11-8). The advantage of this technique over the Ouchterlony technique usin g extractable nuclear antigens (ENA), is that the Western blot test allows ident ification of a large number of autoantibody specificities in one test, although both tests do not completely overlap. FIGURE 11-5 Patterns of antinuclear antibody (ANA) staining. The ANA test is car ried out by incubation of the serum with either preparations of cultured cells ( eg, human cervical carcinoma cells [HeLa cells]) or sections of normal tissue (m ostly liver). Antibodies bound to the nucleus are detected by a fluorescinated a nti human immunoglobulin antibody that can reveal four distinctive staining patte rns: A, homogeneous; B, rim or peripheral; A B (Continued on next page)

11.4 Systemic Diseases and the Kidney FIGURE 11-5 (Continued) C, speckled; and D, nucleolar. Although not conclusive, these patterns can give an indication about the autoantibody specificity causing the nuclear staining. The homogeneous and peripheral patterns mainly are caused by autoantibodies directed against the nucleosome (histoneDNA complex) or double stranded DNA. The speckled pattern can be observed in antibodies against the nuc lear proteins Sm, ribonucleoprotein, Sjgren's syndrome-A [SS-A] (Ro), SS-B (La), Jo -1, topoisomerase I, and anticentromere antibodies. The nucleolar staining is as sociated with antibodies against nucleolus-specific RNA, as seen in certain limi ted forms of scleroderma. (From Maddison [2]; with permission.) FIGURE 11-6 Scre ening for antidoubled-stranded DNA (dsDNA) antibodies using the Crithidia assay. The hemoflagellate Crithidia luciliae contains in its kinetoplast pure dsDNA, no t complexed to proteins [3]. Serially diluted serum samples are added to the sli de carrying Crithidia cells. Binding of antibodies is visualized by fluorescinat ed antiimmunoglobulin G antibodies. Antibodies to dsDNA are almost pathognomonic for systemic lupus erythematosus and therefore can be regarded as marker antibod ies [4]. (From Klippel and Croft [5]; with permission.) C D Nucleus Mitochondrion Kinetoplast + dsDNA Crithidia luciliae + + Anti-dsDNA Fluorescent labeled antihuman immunoglobulin Fluorescence of kinetoplast Test serum containing anti-dsDNA FIGURE 11-7 Farr assay for quantitative measurement of anti-double-e-stranded DN A (dsDNA) antibodies. The serum to be tested is added to a tube containing radio labeled dsDNA. When antibodies to dsDNA are present, they bind to the dsDNA. Eve ntually, formed complexes are precipitated in 50% ammonium sulfate. By testing s everal dilutions of the serum and comparing them with a standard curve the resul ts can be expressed in units per milliliter. Because high salt conditions are us ed, this assay detects only high avidity anti-dsDNA antibodies [4]. Positivity a nd titer in this Farr assay are correlated with renal disease in patients with s ystemic lupus erythematosus. This titer can be used to monitor lupus disease act ivity together with complement levels and clinical parameters. In 80% to 90% of cases, disease onset or flare-up is associated with increases in anti-dsDNA tite rs in the Farr assay [6]. (From Maddison [2]; with permission.) Radiolabeled dsDNA added DNAanti-DNA complexes precipitated by ammonium sulphate Radioactivity in precipitate measured

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.5 Topo I RNP SS-B Scl-55 70,000 SS-50 A Sm B B' C Centromere CR-17 D 1 2 3 4 5 6 FIGURE 11-8 Western blot test of autoantibodies on nuclear extracts. Nuclear pro teins extracted from human cervical carcinoma cells (HeLa cells) are separated o n polyacrylamide gel and transferred to nitrocellulose. Subsequently, identical strips of the blot are incubated with various patient sera. Binding of autoantib odies can be visualized with peroxidase or alkaline phosphataselabeled antihuman immunoglobulin. Lane 1: anti-ribonucleoprotein (RNP) and centromere (CR-17) acti vity Lane 2: anti-Sm (B/B -D) Lane 3: anti-RNP and anti-Sm Lane 4: antiSjgren's synd rome (SS-B) (La) Lane 5: anticentromere Lane 6: antitopoisomerase I (Topo I) Ant ibodies against Sm are rather specific for systemic lupus erythematosus (SLE) an d can be used as marker antibody, anti-ribonucleoprotein for mixed connective ti ssue disease (MCTD), centromere (CR17) for the limited variant of scleroderma, S S-B for Sjgren's syndrome and SLE, and topoisomerase I for systemic scleroderma. Th e Western blot test is a simplified version of the currently available technique , which allows identification of autoantibodies to much more autoantigens. Refer ence 7 provides a full description of the diagnostic possibilities. (From Van Ve nrooij et al. [8]; with permission.) of patients with SLE is present in the form of oligonucleosomes [13]; the only way to generate these oligonucleosomes is by the process of apoptosis. Presently, ample evidence exists that the autoimmune response in SLE is T-celldependent and autoantigen-driven [14]. However, dsDNA is very poorly immunogenic, which is in line with the fact that antigen-presenting cells cannot present DNA-derived oligonucleotides to T cells by way of their ma jor histocompatibility complex class II molecules. However, recently it has beco me evident that the nucleosome is the driving autoantigen in SLE. In murine lupu s, T cells specific for nucleosomes have been identified. These T cells not only drive the formation of nucleosome-specific autoantibodies (ie, antibodies that react with the intact nucleosome but not with its constituent DNA and histones) but also the formation of anti-DNA and antihistone antibodies [15]. The histonederived epitopes that drive these responses recently have been identified [16]. These nucleosome-specific autoantibodies precede the emergence of anti-dsDNA and antihistone antibodies, suggesting that the loss of tolerance for nucleosomes i s an initial key event in SLE [17,18]. Both in human and murine lupus, nucleosom e-specific antibodies are detected in up to 80% of cases [1820]. Figure 11-11 ill ustrates the central role of the nucleosome in the generation of the antinuclear autoantibody repertoire. These antinucleosome and anti-DNA antibodies, after co mplex formation with the nucleosome, can localize in the glomerular basement mem brane (GBM) by way of binding to heparan sulfate (HS). This binding occurs throu gh binding of the cationic histone part of the nucleosome to the anionic HS, as demonstrated by in vivo perfusion studies [21]. The relevance of this binding me

chanism for lupus nephritis was shown by the elution of nucleosome-specific auto antibodies from glomeruli, identification of nucleosome deposits in glomeruli of patients with lupus nephritis, and presence of nucleosomeantinucleosome antibody complexes in the glomerular capillary wall in patients with lupus nephritis [18 ,2225]. The pathophysiologic significance of this nucleosome-mediated binding to the GBM was illustrated by the observation that heparin could prevent this bindi ng and inhibit the glomerular inflammation and proteinuria in lupus mice [26]. R eferences 11 and 14 provide a more detailed description of these mechanisms. Dysregulation of apoptosis Decreased phagocytosis Quantitative and qualitative c hanges in nucleosomes Persistence of autoreactive T cells Antinucleosome Ab, anti-DNA Ab In situ binding of nucleosomes to GBM (HS?) Deposition of circulating nucleosome-Ab complex Nucleosome-mediated Ab-binding to GBM Activation of complement, glomerulonephritis FIGURE 11-9 Hypothesis for the pathophysiology of lupus nephritis. In recent yea rs, evidence has emerged that the process of apoptosis is disturbed in systemic lupus erythematosus (SLE). The first indication was found in the MRL/l lupus mou se model, in which a deficiency of the Fas receptor was identified [9]. Activati on of this Fas receptor induces apoptosis. Transgenic correction of the Fas-rece ptor defect prevents development of lupus [10]. In human SLE, Fas receptor expre ssion is normal; however, a number of other observations indicate abnormalities in apoptosis [11,12] (Fig. 11-10). Alterations in apoptosis can lead to the pers istence of autoreactive T and B cells, because apoptosis is the major mechanism for the elimination of autoreactive cells. In addition, these alterations can le ad to quantitative and qualitative differences in the release of nucleosomes (Fi g. 11-10). Nucleosomes are the basic structures of chromatin. They consist of pa irs of the core histones H2A, H2B, H3, and H4 around which double-stranded DNA ( dsDNA) is wrapped twice. DNA in the circulation

11.6 Systemic Diseases and the Kidney FIGURE 11-10 On the one hand, indications exist that apoptosis is increased in h uman systemic lupus erythematosus (SLE) (eg, increased Fas expression and increa sed in vitro apoptosis). On the other hand, some findings suggest that apoptosis is decreased (eg, increased levels of soluble Fas, increased bcl-2 expression, and decreased anti-CD3induced apoptosis). Bcl-2 is a physiologic inhibitor of apo ptosis, and transgenic induction of bcl-2 overexpression leads to lupuslike auto immunity [27]. Although presently it is difficult to reconcile these findings, i t is clear that changes in the delicate balances governing apoptosis can lead to apoptosis at the wrong moment (too late) or at the wrong place (systemically in stead of locally). INDICATIONS FOR A DISTURBED APOPTOSIS IN HUMAN SYSTEMIC LUPUS ERYTHEMATOSUS Finding Increased expression of Fas receptor Circulating levels of soluble Fas Increased Normal Increased in vitro apoptosis of lymphocytes Abnormal anti-CD3induced apop tosis Apoptosis-induced alterations of autoantigens Proteolysis Study Mysler et al. [28], Lorenz et al. [29] Cheng et al. [30] Goel et al. [31], Knipp ing et al. [32] Lorenz et al. [29], Emlen et al. [33] Kovacs et al. [34] Casciol a-Rosen et al. [35], Casiano et al. [36], Rosen and Casciola-Rosen [37], Casiano [38] Utz et al. [39] Cooke et al. [40] Casciola-Rosen et al. [41], Jordan and K uebler [42] Herrmann et al. [43] Phosphorylation Reactive oxygen speciesmediated damage Apoptosis-induced surface expression of autoantigens Decreased phagocytosis of apoptotic cell Chromatin Anti-DNA B cell Anti-HMG B cell MHC II-Peptide Histonepeptide Th cell TCR Anti-nucleosome B cell CD40L Anti-Histone B cell CD40 CD4 FIGURE 11-11 Central role of T cells specific for nucleosomal histone peptides i n the generation of the antinuclear autoantibody repertoire in systemic lupus er ythematosus. The cascade begins with the uptake of nucleosomes by B cells by way of their antigen receptor. After endosomal antigen processing, these B cells pr esent histone peptides to T cells. After activation of the T cell, it provides h elp to the presenting B cell, leading to the formation of nucleosome-specific au toantibodies. Binding of B cells to other determinants on the nucleosome (B cell s specific for DNA, histones, or the nonhistone chromosomal peptides high-mobili ty group proteins [HMG]) and antigen-processing by these B cells, can generate a dditional antinuclear autoantibody responses (antidoubled-stranded DNA, antihisto ne, and anti-HMG). This intramolecular antigen-spreading owing to different endo somal antigen-processing revealing cryptic neoepitopes, is now known for a numbe r of autoimmune responses [44]. MHCmajor histocompatibility complex; TCRT-cell rec eptor. (From Datta and Kaliyaperumal [45]; with permission.)

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.7 WORLD HEALTH ORGANIZATION MORPHOLOGIC CLASSIFICATION OF LUPUS NEPHRITIS (1995 RE VISED VERSION) Class I. Normal glomeruli A. Nil (by all techniques) B. Normal on light microscopy but deposits seen on electron or immunofluorescence microscopy II. Pure mesangial a lterations (mesangiopathy) A. Mesangial widening, mild hypercellularity, or both B. Moderate hypercellularity III. Focal segmental glomerulonephritis (associate d with mild or moderate mesangial alterations) A. Active necrotizing lesions B. Active and sclerosing lesions C. Sclerosing lesions IV. Diffuse glomerulonephrit is (Severe mesangial, endocapillary, or mesangiocapillary proliferation, and/or extensive subendothelial deposits. Mesangial deposits are present invariably and subepithelial deposits often, and may be numerous.) A. Without segmental lesion s B. With active necrotizing lesions C. With active and sclerosing lesions D. Wi th sclerosing lesions V. Diffuse membranous glomerulonephritis A. Pure membranou s glomerulonephritis B. Associated with lesions of category II (A or B) VI. Adva nced sclerosing glomerulonephritis FIGURE 11-12 The various morphologic manifestations of lupus nephritis are class ified in several categories based on criteria formulated in 1974, modified in 19 82 and 1995, and designated as the World Health Organization (WHO) classificatio n of lupus nephritis [46,47]. The different forms of glomerulonephritis, as morp hologically defined by the WHO classification, also are characterized by typical patterns of deposits of several classes of immunoglobulins and complement facto rs [48]. Class I lupus nephritis has been defined by normal glomeruli by all tec hniques, or by normal glomeruli on light microscopy, with minor deposits as seen on immunofluorescence (IF) or electron microscopy (EM). Class I lupus nephritis is believed to be a rare manifestation, and its existence is challenged by many pathologists. The mildest form of lupus nephritis, class II, is characterized b y a mild or moderate increase of mesangial cells accompanied by mesangial deposi ts of immunoglobulins and complement. These mesangial deposits are regarded as t he most characteristic immunopathologic feature of lupus nephritis. The more sev ere forms of lupus nephritis not only show an increase of mesangial deposits but also deposits along the capillary loops. Dependent on the severity of the morphologic damage, the extent of immune deposits, and whether less or more than half of glomeruli a re affected, this form of proliferative lupus nephritis was divided into focal s egmental glomerulonephritis (class III) and diffuse glomerulonephritis (class IV ). The distinction between class III and class IV, however, is arbitrary; it als o is unreliable in clinical practice. Therefore, the recent modification of the WHO classification (1995) proposes a new definition of classes III and IV lupus nephritis. All more severe forms of proliferative lupus nephritis are included i n class IV and specified as mild, moderate, or severe, depending on the severity on the glomerular damage. In active lesions there occurs a large increase in me sangial cells; an influx of monocytes or granulocytes; so-called hyaline thrombi in the capillary lumina; and necrosis of the capillary loops, defined as severe mesangial proliferative or endocapillary proliferative glomerulonephritis, and sometimes with varying degrees of extracapillary proliferation. In chronic disea se, mesangiocapillary lesions are present with extensive subendothelial deposits (wire loops), duplication of the glomerular basement membrane (GBM), cellular i nterposition, and varying increases of mesangial cells and matrix. On electron m icroscopy, the deposits have a homogeneous or fine granular structure with somet imes organized fingerprint patterns. Frequently, tubuloreticular structures are pr esent in the cytoplasm of endothelial cells, inclusions also found in viral infe ctions, such as human immunodeficiency virus, and related to -interferon. Class III is now restricted to patients with active or sclerosing focal segmental necr

otizing lesions accompanied by mild increase of mesangial cells. Membranous lupu s nephritis (class V) is hardly distinguishable from the idiopathic form of lupu s nephritis. However, membranous lupus nephritis often is accompanied by a mild or moderate increase of mesangial cells or matrix, and the subepithelial deposit s contain more classes of immunoglobulins (so-called full-house) than does the i diopathic form. In addition, it is not unusual to find small subendothelial and mesangial deposits. The subepithelial deposits are either globally distributed a long the glomerular basement membrane (GBM) or more segmentally localized. The s ubepithelial deposits also are a frequent occurrence in class IV lupus nephritis . According to the most recent version of the WHO classification [47], class V i s now restricted to cases that are predominantly characterized by subepithelial immune complexes. More advanced or end-stage cases of focal and diffuse prolifer ative lupus nephritis characterized by a pronounced sclerosis and hyalinosis are classified as class VI lupus nephritis. Interstitial fibrosis, accompanied by t ubular atrophy and influx of mononuclear cells, is a frequent finding, especiall y in the chronic forms of classes III, IV, and V. Lesions resembling chronic tub ulointerstitial nephritis without glomerular alterations also have been describe d in some patients with SLE. In these cases, on immunofluorescence, it is not un usual to find granular immune complexes in the tubular basement membranes. Refer ence 47 provides additional information on the 1995 revised WHO classification. Examples of the different forms of SLE nephritis are presented in Figs. 11-14 to 11-20. (From Churg and coworkers [47]; with permission.)

11.8 Systemic Diseases and the Kidney FIGURE 11-13 The value of the analysis of lupus glomerulonephritis according to the World Health Organization (WHO) classification for prognosis and treatment c an be enhanced by including indices of activity and chronicity. These indices we re proposed in the National Institutes of Health (NIH) index [49]. The extent of the active and chronic lesions is assessed according to the scoring system here . A chronicity index of 3 or higher and an activity index of 12 or higher are as sociated with a significantly greater risk for the development of end-stage rena l disease [14]. NATIONAL INSTITUTES OF HEALTH HISTOLOGIC SCORING SYSTEM FOR ACTIVITY AND CHRONIC ITY IN LUPUS NEPHRITIS Activity index Glomerular Endocapillary hypercellularity Leukocyte infiltration Fibrinoid necro sis, karyorrhexis* Cellular crescents* Hyalin deposits, wire loops Mononuclear c ell infiltration 24 Chronicity index Glomerular sclerosis Fibrous crescents Tubulointerstitial Maximal score Fibrosis Tubular atrophy 12 Scoring per item from 0 to 3; for parameters with asterisks, the score is double d. Histology of Lupus Nephritis U L A C FIGURE 11-14 Lupus nephritis class II. A, A moderate increase of mesangial cells is seen on light microscopy. B, Immunofluorescence. Mesangial deposits of immun oglobulin G. C, Electron microscopy shows electron-dense deposits restricted to the mesangial area. Lcapillary lumen; Uurinary space. (Panel A, methenamine silver . Original magnification 400, 520, 10,000, respectively.) B

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.9 A B C deposits in a necrotizing lesion. According to the 1995 modified World Health Or ganization classification, this is a characteristic immunopathologic lesion of c lass III lupus nephritis. (Panel A, methenamine silver. Original magnification 4 00, 400, 520, respectively.) FIGURE 11-16 Lupus nephritis class IV on light micr oscopy and immunofluorescence. A and B, Diffuse endocapillary proliferative patt ern of injury with an increase of mesangial cells and an influx of mononuclear c ells and some granulocytes. Panel B shows a necrotizing lesion (arrow). C, A mes angiocapillary pattern of injury with duplication of the glomerular basement mem brane (GBM), an increase of mesangial cells and matrix, and massive subendotheli al deposits (wire loops). In addition, spikes (membranous component) can be foun d on the epithelial side of the GBM (arrow). D, Immunofluorescence. The characte ristic pattern of the immune deposits (immunoglobulin G) of class IV lupus nephr itis, predominantly localized along the capillary wall. (Panels A, B, C, methena mine silver. Original magnification 360, 360, 740, 300, respectively.) FIGURE 11-15 Lupus nephritis class III. A, Segmental necrotizing lesion surround ed by an increased number of epithelial cells. B, Immunofluorescence. Next to me sangial deposits of immuno-globulin G there also are deposits in the periphery o f some loops (arrows). C, Immunofluorescence. Fibrin A B C D

11.10 Systemic Diseases and the Kidney FIGURE 11-17 Lupus nephritis class IV. A representative electron micrograph show s diffuse lupus nephritis with subendothelial and mesangial electron-dense depos its with additional massive subepithelial deposits (asterisk). GBMglomerular base ment membrane; Uurinary space. (Original magnification 12,000.) GBM * U S S L A C FIGURE 11-18 Lupus nephritis class V. A, Discrete spikes on the epithelial side of the glomerular basement membrane (GBM) (arrows), and a moderate increase of m esangial cells. B, Immunofluorescence. Fine granular deposits of immunoglobulin G along the capillary wall in a characteristic membranous pattern. C, Electron m icrograph reveals electron-dense deposits on the epithelial side of the GBM betw een spikes. Between an increased number of mesangial cells small deposits also a re present (arrows). Lcapillary lumen; Sspikes; Uurinary space. (Panel A, methenami ne silver, original magnification 700, 400, 3100, respectively.) B

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.11 FIGURE 11-19 Lupus nephritis class VI. Sclerosing glomerulonephritis with extens ive sclerosis of most of the capillary tuft. (Methenamine silver, original magni fication 700.) FIGURE 11-20 Chronic tubulointerstitial nephritis. A, Extensive interstitial fib rosis accompanied by tubular atrophy and a mononuclear cell infiltration B, Immu nofluorescence. Granular deposits of immunoglobulin G in tubular basement membra nes. (Panel A, methenamine silver, original magnification 100, 400, respectively .) A B FIGURE 11-21 Incidence of the different forms of lupus nephritis classified acco rding to the World Health Organization (WHO) classification. The incidence of th e different forms categorized according to the WHO classification depends on pat ient selection and ethnic background. The percentages represent an average of th e data reported in the literature. Most patients have a diffuse proliferative fo rm of lupus nephritis (WHO class IV). Incidence of the different forms of lupus nephritis, % Class IV 57 Class III 15 Class II 10 Class I 1 Class VI 2 Class V 15

11.12 Systemic Diseases and the Kidney 100 Class II Class III Class IV Class V 80 60 Percentage 40 20 0 ent e a n n uri rom ctio im tein ten sed ynd un /lo An ti-d sDN A+ wC sio 3 Pro tive ic s al f Ac rot ph FIGURE 11-22 Incidence of renal manifestations and serologic abnormalities in th e different forms of lupus nephritis. The clinical manifestations of lupus nephr itis are not different from other forms of glomerulonephritis and include a neph ritic sediment (dysmorphic erythrocytes and erythrocyte casts), proteinuria or n ephrotic syndrome, impaired renal function, and hypertension. Although certain c linical manifestations are more prevalent in certain forms (nephrotic syndrome f or World Health Organization (WHO) Im class V, nephritic sediment for WHO class IV), it is clear that on the basis of clinical symptoms it is not possible to classify the form of nephritis correctly . This inability underlines the necessity for obtaining a renal biopsy specimen. In addition, listed are the occurrence of both a positive result on performing a Farr assay and a low complement 3 level for the different forms of lupus nephr itis. Anti-dsDNA antidouble-stranded DNA. (Adapted from Appel et al. [50]). pai Ne red ren Hy per

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.13 TREATMENT OF THE DIFFERENT FORMS OF LUPUS NEPHRITIS World Health Organization classification I II III, IV Treatment options Treatment guided by extrarenal lesions Corticosteroids: Cyclophosphamide pulses, oral prednisone Methylprednisolone pulses, azathioprine, low doses oral prednis one Corticosteroids (and azathioprine or cyclophosphamide) No further immunosupp ression ? Supportive treatment V VI FIGURE 11-23 Treatment options for the different forms of lupus nephritis are su mmarized. Only for World Health Organization (WHO) classes III, IV, and V are a limited number of prospective studies available. For the other forms, a balanced compilation is made from the literature and personal experience. Reference 14 s upplies a more detailed analysis of the therapeutic options. For class I lupus n ephritis, no specific renal therapy is necessary; treatment is dictated by the p resence of extrarenal symptoms. In general, patients with class II lupus nephrit is respond satisfactorily to monotherapy with oral corticosteroids. The patient, however, must be monitored for transition to a more severe form, which is generally heral ded by worsening of clinical renal symptoms. For patients with classes III and I V lupus nephritis, corticosteroid monotherapy is not sufficient (Fig. 11-24). Cy totoxic immunosuppressive therapy, either cyclophosphamide or azathioprine, shou ld be added to the treatment. The choice of one of these drugs over the other is discussed in Figures 11-24, 11-25, and 11-26. According to a recent analysis [5 1], patients with a pure membranous lupus nephritis without a proliferative comp onent (class V, according to the 1995 revised WHO classification) respond satisf actorily to corticosteroid monotherapy. Patients who have a membranous nephropat hy with a proliferative component (formerly classified as WHO class VC or VD) ha ve a much worse prognosis and should be treated as are patients with a class IV lupus nephritis. When a patient with class V (A or B) lupus nephritis does not r espond to corticosteroids, addition of azathioprine or cyclophosphamide should b e considered (as in idiopathic membranous glomerulonephritis, in which oral trea tment seems to be superior over monthly intravenous pulses [5254]). When cyclopho sphamide treatment is initiated the therapeutic response should be evaluated aft er 6 months, and the drug should be discontinued if no improvement has occurred [55]. Treatment of WHO class VI nephritis should be balanced on weighing the ris ks of intensification of immunosuppressive treatment and the expected benefits. When renal function already is strongly impaired and the renal biopsy specimen s hows predominantly chronic irreversible lesions, further deterioration of renal function may be unavoidable. Therefore, an increase in immunosuppressive therapy is questionable. This approach is strengthened by the fact that lupus disease a ctivity mostly subsides during renal replacement therapy. Results of renal trans plantation are good, and the disease rarely recurs after transplantation [14]. F IGURE 11-24 Change in chronicity index in repeat biopsies after treatment with p rednisone (PRED) alone or prednisone and cytotoxic drugs (CTD). The addition of cytotoxic drugs to the treatment regimen of patients with World Health Organizat ion (WHO) class III or IV nephritis clearly improves renal and patient survival [56,57]. The pathophysiologic basis for this beneficial effect is illustrated, d isplaying the change in chronicity index between the first and second kidney bio psies over time. As can be seen during prednisone monotherapy, there is a clear increase of the chronicity index (A); (Continued on next page)

8 6 4 Chronicity index 2 0 PRED -2 -4 0 33 66 Time interval, m 99 132 A

11.14 Systemic Diseases and the Kidney FIGURE 11-24 (Continued) whereas in patients treated with prednisone and cytotox ic drugs (B) the chronic lesions, on average, do not progress. Various studies h ave shown that this chronicity index is the strongest predictor of development o f end-stage renal disease [14]. (From Balow et al. [58]; with permission.) 8 6 Azathioprine Oral cyclophosphamide Intravenous cyclophosphamide Combined use of azathioprine and cyclophosphamide 4 Chronicity index 2 0 -2 CTD -4 0 33 66 Time interval, m 99 132 B Probability of end-stage renal disease 0 Cumulative survival, % 20 40 60 80 100 0 20 40 60 80 100 120 140 160 180 200 2 20 Months PRED IVCY AZCY POCY AZ 100 80 60 40 20 0 0 24 48 Months CPM } 72 AZA 96 120 A B FIGURE 11-25 A, The probability of end-stage renal disease in patients with prol iferative lupus nephritis treated with different drug regimens. This update of t he prospective trial by the National Institutes of Health (NIH) on the treatment of these patients clearly demonstrates that prednisone monotherapy, in a signif icantly greater proportion of patients, leads to the development of end-stage re nal disease compared with patients on regimens containing cytotoxic drugs. The r esults between azathioprine and drug regimens containing cyclophosphamide are no t significantly different. Note that in up to 7 years the results do not differ between the different treatment groups. From these studies it is clear that alth ough the therapeutic efficacy is equal for the three treatment regimens containi

ng cyclophosphamide, less side effects occurred in patients treated with intrave nous pulses of cyclophosphamide. B, Renal survival in patients with World Health Organization (WHO) class IV lupus nephritis treated with either cyclophosphamid e (CPM) or azathioprine (AZ). The NIH trial [56,59] did not reveal a significant difference between the therapeutic efficacy of cyclophosphamide and azathioprin e (A). However, the side effects of both drugs are not identical. Cyclophosphamide has a greater bone mar row toxicity, leads to amenorrhea in many patients, is teratogenic, and displays an unique urothelial toxicity (hemorrhagic cystitis and bladder carcinoma). The refore, prospective studies comparing cyclophosphamide with azathioprine are war ranted but not available. The results of the NIH trial are compared with those r eported for azathioprine [57,6062]. This analysis, carried out by Cameron [57], d oes not reveal a significant difference between cyclophosphamide and azathioprin e. A recent meta-analysis [63] again showed that monotherapy with prednisone was inferior to treatment with cytotoxic drugs in combination with steroids. Howeve r, as in the NIH trial and the analysis by Cameron, no differences were found be tween cyclophosphamide and azathioprine in preserving renal function. AZazathiopr ine; AZCY combined therapy with azathioprine and cyclophosphamide; IVCYintravenous pulses of cyclophosphamide; POCYoral cyclophosphamide. (Panel A from Steinberg a nd Steinberg [59]; with permission. Panel B from Cameron [57]; with permission.)

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.15 RISK FACTORS FOR DEVELOPMENT OF END-STAGE RENAL DISEASE IN SYSTEMIC LUPUS ERYTHE MATOSUS Clinical characteristics Elevated initial serum creatinine Nephrotic range proteinuria Low C3 Hematocrit 26% Hypertension Persistent disease activity Treatment characteristics No normalization of elevated creatinine Treatment with prednisone only Histologic characteristics World Health Organization class IV Activity index 12 Chronicity index 3 Demographic characteristics Male gender Black race Age 24 y Low socioeconomic status FIGURE 11-26 These risk factors were identified in different analyzes in differe nt patient groups. Not all these parameters were confirmed in all studies, proba bly because of differences in definitions used, composition of the cohort studie d, duration of follow-up, and so on. The most powerful predictors seem to be an elevated serum creatinine level at entry into the trial, a chronicity index of 3 or higher, and persistent or remitting renal disease activity [14,64]. 100 80 Survival, % Patients, % 60 40 20 0 0 12 24 36 48 60 Months on dialysis All patients Hemodialysis CAPD 100 80 60 40 20 0 0 110 Maximal Nonrenal SLEDAI >10 Hemodialysis CAPD FIGURE 11-27 Survival of patients with systemic lupus erythematosus (SLE) on dia lysis. Although initially dialysis treatment was not offered to patients with SL E because of the systemic nature of their illness, it later became clear that pa tients with SLE tolerate dialysis treatment as well as do patients with non-SLE renal diseases. The overall patient survival is good (90% at 5 years), and no di fferences exist in patient survival between those treated with continuous ambula tory peritoneal dialysis (CAPD) as compared with hemodialysis. (Data from Nossen t et al. [65].) FIGURE 11-28 Severity of systemic lupus erythematosus (SLE) disease activity dur ing hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). Lupus dise ase activity generally decreases during dialysis treatment. As assessed by the S LE Disease Activity Index (SLEDAI) [66], the maximal nonrenal SLEDAI decreased d uring dialysis in 49% of patients, remained stable in 42%, and showed progressio n in 9%. Despite the fact that immunosuppression was minimized, in 90% of patien ts cytotoxic drug therapy was discontinued and in 55% the dose of steroids was c onsiderably reduced [65]. In addition, in this analysis no differences were foun d in disease activity in patients treated with either hemodialysis or CAPD. The maximal nonrenal SLEDAI scores were divided in three groups: 0, no extrarenal di sease activity; 1 to 10, moderate extrarenal disease activity; over 10, high ext rarenal disease activity.

11.16 Systemic Diseases and the Kidney 25 Before dialysis During dialysis After transplantation 100 80 Actuarial Survival, % Number of patients 20 60 15 40 Patient/SLE Patient/non-SLE Graft/SLE Graft/non-SLE 10 20 5 0 0 12 24 Months after transplantation 36 0 0 110 Maximal nonrenal SLEDAI score >10 FIGURE 11-29 Graft and patient survival after renal transplantation in patients with systemic lupus erythematosus (SLE). For this analysis only patients with fi rst transplantations using a cadaveric donor kidney were included. Both graft an d patient survival were calculated for 165 patients with SLE who received transp lantation between 1984 and 1992. These data are compared with the results in 21, 726 patients with non-SLE glomerular diseases who received transplantation in th e same time period. Both graft and patient survival were not significantly diffe rent between the two groups. (From Berden [14]; with permission. Data from G. Pe rsijn, Eurotransplant, Leiden, the Netherlands.) FIGURE 11-30 Lupus disease activity after renal transplantation. Disease activit y was assessed in 28 patients with systemic lupus erythematosus (SLE) by calcula ting the maximal nonrenal SLE Disease Activity Index (SLEDAI) in the time period s before dialysis, during dialysis, and after renal transplantation. The maximal nonrenal SLEDAI scores were divided in three groups: 0, no extrarenal disease a ctivity; 1 to 10, moderate extrarenal disease activity; over 10, high extrarenal disease activity. Note that before dialysis all patients had extrarenal lupus d isease activity but that after renal transplantation no patient had high disease activity. These data illustrate that the decrease in disease activity that begi ns during dialysis treatment continues after renal transplantation. In addition, recurrence of lupus nephritis after renal transplantation is rare [67]. (From B erden [14]; with permission. Data from Nossent et al. [68].) Renal Involvement in Dysproteinemias

Heavy chains Only light chains 17% IgD/IgE 1% IgG 59% IgA 23% Light chains None 10% k 60% l 30% FIGURE 11-31 Frequency of isotypes of heavy and light chains produced by nonimmun oglobulin (Ig) M myelomas. Most paraproteins produced belong to the IgG class. N ote that in approximately 20% of myelomas only light chains are produced, of whi ch two thirds belong to the isotype and one third to the isotype [69,70]. These frequency distributions mirror those of Ig classes and light chain isotypes in t he serum.

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.17 100 90 FIGURE 11-32 Incidence of renal involvement in dysproteinemias. This incidence i s not identical for all paraproteinemias. The reason is directly related to the frequency and degree of light chain proteinuria [71]. Igimmunoglobulin. (From Pru zanski [72]; with permission.) 80 70 Cumulative incidence, % 60 50 40 30 20 10 0 IgG IgA IgD Paraproteinemia k l Tyes of renal involvement in dysproteinemias Uncontrolled proliferation of single B cell Overproduction, secretion of monoclo nal Ig or Ig fragment Monoclonal Ig deposition diseases Renal localization in di fferent forms Fibrils AL (or AH) amyloidosis Crystals Fanconi's syndrome Casts M yeloma cast nephropathy Granular precipitates LCDD LHCDD HCDD Organized structur es Tubules, fibrils Paraproteins Cryoglobulins Type I TypeII Immunotactoid GN Fi brillary GN Nonamyloidotic FIGURE 11-33 Types of renal involvement in dysproteinemias. The uncontrolled pro liferation of a B-cell clone leads to overproduction of a monoclonal immunoglobu lin (Ig), either an intact molecule or fragments thereof (light or heavy chains) . These molecules can deposit in the kidney and other vital organs, depending on the immunoglobulin cl ass, light or heavy chain isotype, and other only partly understood physiochemic al properties. The terminology used in these disorders is sometimes confusing an d inconsistent. We use the definitions proposed by Gallo and Kumar [73]. All dis eases characterized by deposits of monoclonal immunoglobulinrelated material are named monoclonal immunoglobulin deposition diseases (MIDD). These deposits can o ccur in several forms, as outlined in the figure, and are identified by specific stains (such as congo red) and on immunofluorescence and electron microscopy. T he histologic and clinical manifestations are dependent on the type of depositio n. Included in this overview are fibrillary and immunotactoid glomerulonephritis , which in certain cases also show deposits containing monoclonal immunoglobulin s. AH heavy chain amyloidosis; ALlight chain amyloidosis; GNglomerulonephritis; HCD Dheavy chain deposition disease; LCDDlight chain DD; LHCDDlight and heavy chain DD.

11.18 Systemic Diseases and the Kidney events. Because some of these light chains are relatively resistant to proteolys is, they can induce lysosomal damage. This damage can give rise to functional im pairment of the proximal tubular cell, leading to a decreased resorptive capacit y (eg, for sodium and light chains) and thereby increasing the distal delivery. When this lysosomal overload leads to intracellular crystal formation, Fanconi's s yndrome may ensue. Increased distal delivery of light chains can then induce pre cipitation of light chains together with Tamm-Horsfall protein (THP) that is sec reted in the loop of Henle. This precipitation is enhanced by an increased tubul ar fluid sodium chloride concentration. Other factors that enhance cast formatio n are listed in Figure 11-43. This intratubular cast formation leads to obstruct ion, tubular damage, and an interstitial inflammatory response with leakage of T HP in the interstitium, inducing macrophage influx and giant cell formation. Thi s entity is known as myeloma cast nephropathy. Finally, interstitial plasma cell invasion may occur in patients with myeloma, although this rarely leads to clin ical symptoms and most often is only diagnosed by kidney biopsy specimen or is s een at autopsy. CCTcortical collecting tubule; DTdistal tubule; LClight chains; PCTp roximal convoluted tubule; PRpars recta; TALthin ascending limb. (Adapted from Win earls [69].) Pathogenesis of renal lesions in dysproteinemias Deposition either as light chain, amyloid, or cryglobulins Glomerulus Toxic inju ry Reabsorption of light chains Decreased sodium and light chain reabsorption an d increased distal delivery Tubular atrophy PCT Cortex Light chains filtered DT PR Cast injury CCT Outer medulla Plasma cell invasion Giant cell infiltration interstitial infiltration TAL LC + THP = cast Inner medulla FIGURE 11-34 Pathogenesis of the different types of renal lesions in dysproteine mias. Paraproteins can deposit in the glomerular basement membrane (GBM) (and tu bular basement membrane [TBM]) either as light or heavy chains, unmodified immun oglobulins, amyloids, or cryoglobulins. Because of their size of 22 kD, light ch ains are freely filtered through the GBM. These light chains are then reabsorbed by proximal tubular cells. This process can induce a cascade of Histology of Renal Lesions in Dysproteinemias FIGURE 11-35 (see Color Plate) Light chain amyloidosis. Amyloid deposits associa ted with dysproteinemias are predominantly composed of fragments of the light ch ain variable region (AL amyloidosis) and very rarely of fragments of heavy chain variable regions (AH amyloidosis) [74]. On light microscopy, this type of amylo id is indistinguishable from amyloid of other origin. The homogeneous and amorph ous material, faintly pink-stained with eosin or sometimes brownish-stained with methenamine silver, is deposited in the mesangium and along the capillary loops of the glomeruli, in the vessels, and occasionally in the interstitium. Amyloid frequently is localized in the glomerular basement membrane (GBM) as sheaths of fibrils or spicules that are larger and more irregularly arranged than are the spikes in membranous glomerulopathy. Congo redstained sections viewed under polar

ized light reveal the specific apple-green birefringence, the gold standard for the diagnosis. Amyloid deposits are sometimes stained with commercially availabl e antisera against light chains. In addition, these deposits also are positive f or amyloid P, heparan sulfate proteoglycan, and apolipoprotein E. On electron mi croscopy, amyloid is composed of long, randomly distributed, nonbranching fibril s with diameters of 8 to 12 nm. A, Amyloid deposits in mesangium and the capilla ry wall (arrows: spicules). (Continued on next page) A

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.19 FIGURE 11-35 (Continued) B, Amyloid deposits in the renal arteries in a congo re dstained slide and viewed under polarized light. Amyloid has an apple-green color . C, Immunofluorescence. Amyloid deposits in the mesangium stained with anti- an tibodies. (Panel A, methenamine silver. Original magnification 550, 350, 400, re spectively.) B C U FIGURE 11-36 Light chain amyloidosis on electron microscopy. A, Characteristic f ibrillar pattern of amyloid deposits. Long, randomly distributed, nonbranching f ibrils with diameters of 8 to 12 nm. B, Amyloid fibrils in the capillary lumen a nd capillary wall with extension through the glomerular basement membrane (GBM) into the subepithelial space (arrow) fibrils arranged in parallel forming spicul es). (Original magnification 48,000, 20,000, respectively.) Pod GBM A B thickened, as seen in the PAS-stained sections. In the remaining cases, no renal lesions can be seen on light microscopy. On immunofluorescence, linear staining of basement membranes of glomeruli, tubuli, and vessels can be observed for one of the light chains ( > ). In most cases, the TBMs are more heavily stained tha n are the glomerular basement membranes (GBMs). Congo red staining is negative f or amyloid. On electron microscopy, fine granular electron-dense material can be found in most cases along the endothelial side of the GBM, in the mesangium, an d along the interstitial side of the TBM. A few cases of heavy chain and of ligh t and heavy chain deposition disease have been described, in most cases with ide ntical morphologic characteristics as described in light chain deposition diseas e [77,78]. A, Nodular glomerulosclerosis with nodular increase of mesangial matr ix. B, Linear staining of the GBM, mesangium, Bowman's capsule, and TBM for the li ght chain. (Continued on next page) A B FIGURE 11-37 (see Color Plate) Light chain deposition disease. In about 60% of p atients with this renal lesion, nodular expansion of the mesangium is seen that resembles nodular diabetic nephropathy [75,76]. The nodules stained purple with periodic acidSchiff (PAS) stain have a homogeneous appearance, and those stained with methenamine silver are pink-brownish in color. In a few cases, a more mesan giocapillary pattern of injury is present. The tubular basement membranes (TBMs) are

11.20 Systemic Diseases and the Kidney FIGURE 11-37 (Continued) C and D, Electron-dense granular deposits in the GBM (C ) and around the TBM (D). Lcapillary lumen; Pod podocyte. (Panel A, methenamine si lver. Original magnification 400, 400, 15,000, 6500, respectively.) Pod GBM L TBM C D A B C D FIGURE 11-38 Cast nephropathy. The casts have a homogeneous, fractured, or cryst alline appearance with sharp angular or irregular edges and are present in the d istal and collecting tubules [73]. These casts are composed of aggregated or lig ht chains mixed with Tamm-Horsfall protein (THP). Sometimes the tubular cells sh ows necrosis accompanied by disruptions of the tubular basement membrane (TBM). Proximal tubular cells show hyaline droplets or vacuoles with needlelike, tubula r, or complex crystalline material. Casts are surrounded by macrophages and mult inucleated giant cells. On electron microscopy, the casts have a granular, homog eneous, or fibrillary appearance with occasional needlelike crystals. The fibril s that surround the casts are probably THP. In most cases, a varying degree of i nterstitial fibrosis exists, accompanied by mononuclear cell infiltration and tu bular atrophy. Congo red staining for amyloid is usually negative. The glomeruli are normal. A, Low magnification with casts in the distal tubules, and intersti tial fibrosis with atrophic tubules (chronic tubulointerstitial nephritis). B, B rown-colored cast surrounded by macrophages. C, Eosinophilic homogeneous cast. D , Immunofluorescence. Casts are stained for light chains. (Panels A, B, C, methe namine silver. Original magnification 160, 400, 600, 200, respectively.)

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.21 FIGURE 11-39 Fanconi's syndrome in a patient with light chain proteinuria. A, Vacu olization of proximal tubular epithelial cells. Vacuoles contain light-brown-col ored material. B, Immunofluorescence. The granular material in tubular cells is stained for light chains. C, Low-power view of a proximal tubular epithelial cel l with vacuoles containing organized or crystalline material. D, High-power view of the vacuoles containing tubular or ladderlike crystalline structures. BBbrush border. (Panel A, methenamine silver. Original magnification 600, 400, 7000, 19 ,000, respectively.) A BB B C D

11.22 Systemic Diseases and the Kidney C A FIGURE 11-40 Glomerular deposition of immunoglobulin A- paraproteins. No parapro teins or cryoglobulins could be found in the serum of this patient. In addition, the urinary excretion of light chains was not detectable. A, A mesangiocapillar y pattern of injury with deposition of eosinophilic material in the capillary wa ll and mesangium. B, Immunofluorescence. The deposits were positive for light ch ains (and immunoglobulin A). C, Ultrastructurally, below the glomerular basement membrane, organized deposits composed of parallel arranged fibrils or gridlike structures can be seen. (Panel A, methenamine silver, original magnification 400 , 400, 25,000, respectively.) B A FIGURE 11-41 (see Color Plate) Glomerular deposition of immunoglobulin G in a pat ient with multiple myeloma. A, Glomerulus with many intracapillary protein throm bi. B, The material was composed of B closely packed tubules arranged in parallel. (Panel A, toluidine blue. Original magnification 600, 130,000, respectively.)

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.23 A B C D FIGURE 11-42 Mixed cryoglobulinemia. Of the three types of cryoglobulins, types I and II contain monoclonal immunoglobulins (Ig). Type I cryoglobulins occur in monoclonal gammopathies and lymphomas and consist of a single monoclonal immunog lobulin. Type II cryoglobulins (also called mixed cryoglobulinemia) occur in sys temic infections, autoimmune diseases, and malignancies. Type II cryoglobulins c onsist of two components, a monoclonal immunoglobulin, most frequently IgM, with rheumatoid factor activity directed to the polyclonal IgG component. Various pa tterns of glomerular injury can be found, such as a diffuse endocapillary prolif erative glomerulonephritis with a prominent influx of monocytes, or a mesangioca pillary glomerulonephritis. Less frequently, a diffuse mesangial proliferative, sclerosing glomerulonephritis, or both can be seen. Eosinophilic aggregates alon g the glomerular basement membrane (GBM) or in the lumina designated as thrombi frequently are present. Type II cryoglobulinemia is sometimes accompanied by a v asculitis. The aggregates in the glomeruli of type I, as seen on immunofluoresce nce, have a composition identical to that of the cryoglobulins in the serum. The deposits in type II contain IgG, IgM, and complement. Ultrastructurally, the de posits usually demonstrate an organized or crystalline appearance. In type I, th e deposits frequently are organized in closely packed fibrils, long tubules, or crystals. In type II, short tubulo-annular structures can be found. Sometimes ag gregates in the glomeruli composed of a single monoclonal immunoglobulin compone nt can be demonstrated in patients without evidence of a monoclonal immunoglobul in or cryoglobulins in the serum. A, Diffuse endocapillary proliferative glomeru lonephritis with prominent influx of mononuclear cells. B, Mixed pattern of inju ry in a patient with Sjgren's syndrome. Intracapillary thrombi, increase of mesangi al cells and matrix, and occasionally duplication of the GBM. C, Immunofluoresce nce with staining for IgM. D, Electron microscopy of tubular and annular structu res in the glomerular deposits. (Parts A, B, methenamine silver. Original magnif ication 400, 400, 200, 120,000, respectively.) FIGURE 11-43 Biopsy specimen of i mmunotactoid glomerulonephritis with immunoglobulin A deposits. The patient had n o signs of a monoclonal gammopathy or lymphoma. A, Mild increase of mesangial ma trix with segmental irregularity of the capillary wall. B, Immunofluorescence. T he deposits are positive for (and immunoglobulin A) C, Below the glomerular base ment membrane, seen is an accumulation of short microtubules with a diameter of about 30 nm. (Part A, methenamine silver. Original magnification 400, 400, 25,00 0, respectively.) A B (Continued on next page)

11.24 Systemic Diseases and the Kidney FIGURE 11-43 (Continued) Immunotactoid and fibrillary glomerulonephritis are com prised of lesions characterized by the deposition of immunoglobulins (and comple ment) arranged in randomly distributed fibrils or microtubules in the capillary wall and mesangium [89,90]. These lesions are thicker than are amyloid fibrils a nd are negative on congo-red staining. Although presently it is not clear whethe r these forms of glomerulonephritis are different disease entities or are differ ent morphologic expressions of one disease, some morphologic and clinical featur es exist that suggest fibrillary glomerulonephritis must be distinguished from i mmunotactoid glomerulonephritis [91]. Immunotactoid glomerulonephritis shows dep osition of microtubules with diameters of 35 to 50 nm and commonly is associated with a lymphoproliferative disease. The deposited immunoglobulins frequently ar e of monoclonal composition. In contrast, fibrillary glomerulonephritis is chara cterized by fibrils with diameters of about 18 to 20 nm. The deposited immunoglo bulins usually are polyclonal and very rarely monoclonal. An association with a lymphoproliferative disease is uncommon in contrast to immunotactoid glomerulone phritis. C A C FIGURE 11-44 Fibrillary glomerulonephritis. A, Moderate widening of mesangial ar eas by increase of matrix. B, Immunofluorescence. Heavy staining for IgG (and co mplement, and light chains). C, Ultrastructurally, randomly distributed long fib rils with diameters of 18 to 22 nm are localized in the capillary wall. (Panel A , methenamine silver. Original magnification 400, 300, 27,000, respectively.) B

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.25 CLINICAL PRESENTATION, FREQUENCY, AND CAUSES OF RENAL INVOLVEMENT IN DYSPROTEINE MIAS Acute deterioration of renal function (510%) Dehydration Hypercalcemia Cast nephr opathy Crescentic glomerulonephritis Chronic renal insufficiency (4575%) Myeloma cast nephropathy Light chain (AL) amyloidosis Interstitial plasma cell infiltrat ion (rare) Proteinuria-nephrotic syndrome (5080%) Light chain (AL) amyloidosis Li ght chain deposition disease Heavy chain deposition disease Cryoglobulinemic glo merular lesions Fanconi's syndrome (1%) Secondary lesions (2030%) Pyelonephritis Ne phrocalcinosis Hyperuricemic nephropathy RISK FACTORS FOR RENAL INVOLVEMENT IN DYSPROTEINEMIAS Factors enhancing amyloid formation Unfolding of paraprotein Light chain Factors enhancing cast nephropathy High urinary excretion of light chains Binding of li ght chain to Tamm-Horsfall protein (THP) Iso-electric point of light chain 5.1 ? (enhances binding to anionic THP (pI:3.2) Tendency to self-aggregation of light chains Light chain High levels of acute-phase proteins Resistance of light chain to urinary or macrophage-derived proteases Factors enhancing monoclonal immunog lobulin deposition Light chain Presence of hydrophobic aminoacids in CDR1 or CDR 2 of VL-chain Deletion of CH1 domain Fc part immunoglobulin Factors enhancing ac ute renal failure Hypercalcemia (1944%)* Dehydration (1065%) Urinary tract infecti on (844%) Nephrotoxic drugs (aminoglycosides; nonsteroidal anti-inflammatory drug s) (026%) Intravenous radio contrast media (011%) Loop diuretics *Percentage of pa tients in which this factor contributed to the development of acute renal failur e. From Winearls [69]; with permission. FIGURE 11-45 Renal involvement in dysproteinemias can lead to different clinical manifestations: acute renal failure; progressive deterioration of renal functio n; proteinuria, which very often is in the nephrotic range; or, seldom, Fanconi's syndrome. Furthermore, a number of secondary conditions may occur that can induc e additional renal damage. Certain features are associated with particular clini cal symptoms. The type of clinical lesion that develops is predominantly determi ned by the so-called nephrotoxic characteristics of the excreted light chains, a s demonstrated by infusion of light chains into mice. These infusions led to the same type of renal lesion as in humans [79,80]. Some of these nephrotoxic facto rs are listed in Figure 11-43. FIGURE 11-46 Factors reported in the literature to be associated with developmen t of the different renal lesions in patients with myeloma are summarized. The am yloidogenic potential is enhanced by certain amino acids that promote unfolding of the light chain and by the isotype of the light chain. In amyloidosis, the va riable regions of the light chains are deposited predominantly after metabolizat ion by macrophages. A number of factors have been characterized that enhance the binding of light chains to Tamm-Horsfall protein (THP), which is a critical eve nt in the development of cast nephropathy. In monoclonal immunoglobulin depositi on diseases, the granular deposits are composed mainly of the constant regions o f light (and seldom heavy) chains. Hypercalcemia, which frequently occurs in pat ients with myeloma and results from increased interleukin-6mediated bone resorpti on, can contribute to renal impairment by way of different mechanisms: dehydrati on (hyperemesis and nephrogenic diabetes insipidus), induction of nephrocalcinos is, and enhancement of light chain aggregation with THP. All other factors eithe r diminish tubular flow or increase distal tubular sodium concentration, thereby again enhancing cast formation.

11.26 Systemic Diseases and the Kidney TREATMENT OF RENAL LESIONS IN DYSPROTEINEMIAS Renal therapy Preventive measures: Rehydration, forced diuresis (>3 L/24 h) Correction hyperca lcemia Alkalinization of urine (pH 7) Cessation of nephrotoxic drugs Treatment of infections Colchicine ? Plasmapheresis in acute renal failure Recovery of renal function increases from 018% in the control group to 4384% with plasmapheresis Di alysis 54% survival after 1 y, and 25% after 2 y Theoretically, PD could result in a better removal of light chains Renal transplantation Light chain amyloidosi s: 29 patients; high nonrenal mortality rate, 30% recurrence rate Light chain de position disease: 12 patients; 50% recurrence rate Cryoglobulinemia: 50% recurre nce rate Multiple myeloma: 18 patients with low-grade disease; 8 alive, 5 succum bed to infection, and 5 to recurrence Antitumor therapy Melphalan-prednisone First-line therapy: 45% remission rate Vincristine-adriamycine-dexamethazone (VAD)* Second-line therapy: relapses, 40% remission; refractory cases, 25% remission High-dose chemotherapy and bone marro w transplantation Relatively good results in patients without renal involvement. No data for patients with renal involvement *VAD protocol has the advantage that drug metabolism is independent of kidney fu nction, whereas the melphalan dose must be adjusted to renal function. FIGURE 11-47 Treatment should be directed at ameliorating the renal lesion and r eduction of the production of paraproteins. In patients with myeloma it is very important to prevent situations that could precipitate acute renal failure. In t his respect, dehydration and hypercalcemia are very harmful. Measures should be taken to maintain a high fluid intake. When radiocontrast agents are necessary, hydration before the study decreases the chance of intratubular cast formation b etween light chains and the contrast agent. Alkalization of the urine can reduce the interaction between light chains and TammHorsfall protein (THP). Nephrotoxi c drugs (such as nonsteroidal anti-inflammatory drugs and gentamycin) should not be used because they further enhance tubular dysfunction. Experimental studies suggest that colchicine may be helpful in reducing cast formation either by decr easing THP secretion or modifying the interaction between THP and light chains. Presently, no data exist that document the clinical efficacy of this treatment. Plasmapheresis has the potential to remove the toxic light chains from the circu lation, although in certain patients the serum concentration can be rather low. Plasmapheresis alone does not reduce the rate of production of the paraprotein; therefore, this treatment should be combined with chemotherapy. Patients with ex tensive cast formation and interstitial changes seem to respond less well to plasmapheresis that do those without cast formation and interstitial changes [81 ]. Of two controlled studies, only one showed a beneficial effect of addition of plasmapheresis to chemotherapy [82,83]. The major determinant for success seems to be a good response to chemotherapy [83]. Furthermore, patients with extensiv e cast formation and interstitial changes seem to respond less well to chemother apy than do those without cast formation and interstitial changes [81,83]. The p atient with end-stage renal disease can be treated with dialysis, although survi val is poor and dependent on the success of chemotherapy. The experience of rena l transplantation in patients with dysproteinemias is, for obvious reasons, rath er limited. The results are rather disappointing with a high mortality rate, esp ecially in patients with multiple myeloma and amyloidosis. Patients surviving fo r more than 1 year show a high recurrence rate [8487]. Discussion of antitumor th erapy is beyond the scope of this review. Briefly, treatment with melphalan and

prednisone is considered to be the first choice, whereas more aggressive treatme nt with vincristine-adriamycin-dexamethasone is given to patients who do not res pond to or who relapse after melphalan and prednisone therapy. Recently, more en couraging results have been obtained with ablative chemotherapy and stem-cell re infusion [88]. PDperitoneal dialysis.

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.27 Renal Involvement in Rheumatic Diseases Causes of renal involvement in rheumatoid arthritis MGN 14% MesPGN 23% AA amyloidosis 18% No lesions 15% TIN 9% Vasculitis, CGN, other 21% FIGURE 11-48 Causes of renal involvement in rheumatoid arthritis. In rheumatoid arthritis, a variety of renal disorders may occur secondary to either the underl ying disease or to drugs used to treat it. The most frequent abnormality is a me sangial proliferative glomerulonephritis (MesPGN) with, in most cases, only mesa ngial immunoglobulin M (IgM) and sometimes IgA and complement 3 (C3) deposits. I gG and C1q deposits are very rare. A correlation exists with the levels of rheum atoid factor; however, the underlying mechanism is unclear. Clinically, MPGN is characterized by hematuria and proteinuria. Membranous glomerulopathy (MGN) in r heumatoid arthritis is mostly associated with gold or D-penicillamine treatment. MGN is seen more frequently in patients after therapy with D-penicillamine (714% ) than after gold therapy (39%). When a patient is positive for HLA-DR3 the risk for gold-induced MGN increases 10- to 30-fold a nd that for D-penicillamine increases 3- to 10-fold. Discontinuation of therapy leads to remission of the proteinurianephrotic syndrome in almost all cases, alt hough it may be a year before complete recovery is achieved. MGN may occur in pa tients with rheumatoid arthritis not treated with gold or D-penicillamine. The m echanism for this is not clear. Amyloidosis is associated with active joint dise ase. This type of amyloidosis is secondary to the deposition of the acute-phase reactant serum amyloid A (SAA) protein. This SAA is partly digested by macrophag es and deposited in the tissues as AA amyloid. When a patient with active rheuma toid arthritis develops a nephrotic syndrome, AA amyloidosis is the most likely cause. No good treatment options exist for AA amyloidosis, other than treating t he underlying disease. Renal transplantation in these patients is associated wit h a 3-year patient survival rate of 50% [92]. Especially in the early period aft er transplantation, there were high cardiovascular- and infection-related mortal ity rates. The rate of recurrence was approximately 20%. The development of tubu lointerstitial nephritis (TIN) in patients with rheumatoid arthritis is related to the prolonged use of analgesics, especially multicomponent analgesics and non steroidal antiinflammatory drugs. A number of other renal conditions may develop in patients with rheumatoid arthritis. Vasculitis is associated with long-stand ing and nodular rheumatoid arthritis with high levels of rheumatoid factor. This condition may be associated with a crescentic glomerulonephritis (CGN) that, on immunofluorescence, is negative for immunoglobulin and complement deposits, as in Wegener's granulomatosis. The best treatment consists of cyclophosphamide and p rednisone. References 93 and 94 provide more details on renal involvement in rhe umatoid arthritis. Because the histologic abnormalities are not specific for rhe umatoid arthritis, no histologic examples are given. They can be found elsewhere in this book. (Data from Emery and Adu [94].) FIGURE 11-49 The clinical manifes tations of the tubulointerstitial nephritis in Sjgren's syndrome can vary and depen d on localization of the functional impairment. Occasionally, symptoms of tubula r dysfunction precede development of symptoms of Sjgren's syndrome. It is unclear w hat causes these tubular dysfunctions. When the degree of tubulointerstitial dam age is not chronic, corticosteroids are beneficial. Glomerular involvement is ra re in Sjgren's syndrome. When a glomerulonephritis is present, the patient should b e evaluated for the presence of cryoglobulins and existence of systemic lupus er ythematosus. Reference 95 provides a more detailed description of this subject. RENAL MANIFESTATIONS IN SJGREN'S SYNDROME Manifestation

Interstitial nephritis with or without tubular dysfunction Tubular dysfunction ( distal > proximal) associated with interstitial infiltrates and granuloma format ion Clinical symptoms: Type 1 renal tubular acidosis Fanconi's syndrome Nephrogeni c diabetes insipidus Hypokalemia Glomerulonephritis Mesangiocapillary glomerulon ephritis Membranous glomerulonephritis Vasculitis Mostly extrarenal (skin, muscl e, nerve); occasionally in the kidney % 3060 2025 35 <5

11.28 Systemic Diseases and the Kidney RENAL INVOLVEMENT IN SCLERODERMA Incidence of renal involvement Based on autopsy studies, 6070% Based on clinical symptoms, 3050% Scleroderma rena l crisis, 1015% Risk factors for renal crisis Diffuse form of scleroderma Rapid progression of skin lesions HLA BW35, DR3, DR5 Race (Blacks > whites) Use of corticosteroids or cyclosporine A? Cold exposure ? Clinical characteristics of renal crisis Acute onset Marked to severe (malignant) hypertension (10% of patients remain no rmotensive) Features of malignant hypertension Micro-angiopathic hemolytic anemi a and thrombopenia Mostly normal urinary sediment (in cases with malignant hyper tension hematuria possible) Progressive decline of renal function Therapy for renal crisis Prevention of reduction of renal perfusion (eg, dehydration, diuretics, cyclospo rin A, nonsteroidal anti-inflammatory drugs) Angiotensin-converting enzyme inhib itors (even in patients with normotension) Renal replacement therapy FIGURE 11-50 The main features of renal involvement in scleroderma are summarize d. The major manifestation is the so-called renal crisis. Besides this often lif e-threatening manifestation, other patients may display milder forms of renal in volvement, clinically characterized by mild proteinuria or slight deterioration of kidney function. Renal involvement is more common in patients with the diffus e form of scleroderma that is serologically characterized by antibodies against topoisomerase I or RNA polymerase III. Patients with progressive skin disease sh ould be monitored carefully for hypertension and signs of renal involvement. Ear ly institution of angiotensin-converting enzyme (ACE) inhibition in patients wit h micro-albuminuria can prevent further deterioration of kidney function [96,97] . ACE inhibition is also the mainstay of treatment for patients with scleroderma renal crisis, because it will significantly reduce progression to renal failure, increase the chance of recovery if renal failure has already developed, and improve the 1-year patient survival rate. Renal replacement therapy (hemodialysis or continuous ambulatory peritoneal dialysis) should be offered to patients whose renal function does not recover. The patient survival rate, however, is lower than in patients with oth er collagen-vascular diseases such as lupus nephritis. Limited experience with r enal transplantation indicates that successful transplantation is possible, espe cially in patients with quiescent disease. Recurrence in the transplanted kidney has been reported [84]. References 96 to 98 provide more extensive reviews on t he subject. FIGURE 11-51 Scleroderma. In the acute phase, small- and medium-size d renal arteries show mucoid thickening of the intima with severe narrowing of t he lumen. Sometimes these lesions are accompanied by thrombosis and fibrinoid ne crosis of the arterioles and glomeruli. Morphologically, the vascular alteration s resemble malignant nephrosclerosis (malignant hypertension) or hemolytic-uremi c syndrome. In the chronic phase, the mucoid intimal material is replaced by fib rous tissue. A, Severe narrowing of a small-sized renal artery owing to extensiv e endothelial widening with ischemia of glomeruli. B, Accumulation of mucopolysa ccharide material in the widened endothelial layer. (Continued on next page) A B

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.29 FIGURE 11-51 (Continued) C, Severe intimal fibrosis of a medium-sized artery of a more chronic phase of scleroderma. (Panel A, methenamine silver, original magn ification 100. Panel B, alcian blue stain, original magnification 100. Panel C, cellulose acetate butyrate stain, original magnification 150.) C References 1. Tan EM, Cohen AS, Fries JF, et al.: The 1982 revised criteria for the classif ication of systemic lupus erythematosus. Arthritis Rheumatol 1982, 25:12711277. 2 . Maddison PJ: Systemic lupus erythematosus variants. In Slide Atlas of Rheumato logy. Edited by Dieppe PA, Bacon PA, Bamji AN, Watt I. London: Gower; 1984:9.19.1 4. 3. Aarden LA, De Groot ER, Feltkamp TEW: Immunology of DNA. III. Crithidia lu ciliae: a simple substrate for the detection of anti-dsDNA with the immunofluore scence technique. Ann NY Acad Sci 1975, 254:505509. 4. Smeenk RJT, Berden JHM, Sw aak AJG: dsDNA autoantibodies. In Autoantibodies. Edited by Peter JB, Shoenfeld Y. Amsterdam: Elsevier; 1996:227236. 5. Klippel JH, Croft JD: Systemic lupus eryt hematosus. In Slide Atlas of Rheumatology. Edited by Dieppe PA, Bacon PA, Bamji AN, Watt I. London: Gower; 1984:8.18.14. 6. ter Borg EJ, Horst G, Hummel EJ, et a l.: Predictive value of rises in antidouble-stranded DNA antibody levels for dise ase exacerbations in systemic lupus erythematosus: a long term prospective study . Arthritis Rheumatol 1990, 33:634643. 7. Verheyen R, Salden M, Van Venrooij WJ: Protein blotting. In Manual of Biological Markers of Disease. Edited by van Venr ooij WJ, Maini RN. Dordrecht: Kluwer; 1997:A4.1A4.25. 8. Van Venrooij WJ, De Rooi j DJ, van de Putte LBA, Habets WJ: De serologische herkenning van gedefinieerde kernantigenen bij collageenziekten: immunoblotting als nieuw diagnostisch middel . Ned Tijdschr Geneeskd 1985, 129:11241129. 9. Watanabe-Fukunaga R, Brannan CI, C opeland NG, et al.: Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 1992, 356:314317. 10. Singer GG, Car rera AC, Marshak-Rothstein A, et al.: Apoptosis, Fas and systemic autoimmunity: the MRL/lpr model. Curr Opinion Immunol 1994, 6:913920. 11. Tax WJM, Kramers C, v an Bruggen MCJ, Berden JHM: Apoptosis, nucleosomes, and nephritis in systemic lu pus erythematosus. Kidney Int 1995, 48:666673. 1. Berden JHM: Systemic lupus eryt hematosus: disturbed apoptosis? Ned Tijdschr Geneeskd 1997, 141:18481854. 13. Rum ore PM, Steinman CR: Endogenous circulating DNA in systemic lupus erythematosus. Occurrence as multimeric complexes bound to histone. J Clin Invest 1990, 86:6974 . 14. Berden JHM: Lupus nephritis. Nephrology Forum. Kidney Int 1997, 52:538558. 15. Mohan C, Adams S, Stanik V, Datta SK: Nucleosome, a major immunogen for path ogenic autoantibody-inducing T cells of lupus. J Exp Med 1993, 177:13671381. 16. Kaliyaperumal A, Mohan C, Wu W, Datta SK: Nucleosomal peptide epitopes for nephr itis-inducing T helper cells of murine lupus. J Exp Med 1996, 183:24592469. 17. B urlingame RW, Rubin RL, Balderas RS, Theofilopoulos AN: Genesis and evolution of anti-chromatin autoantibodies in murine lupus implicates T-dependent immunizati on with self antigen. J Clin Invest 1993, 91:16871696. 18. Amoura Z, Chabre H, Ko utouzov S, et al.: Nucleosome-restricted antibodies are detected before anti-dsD NA and/or antihistone antibodies in serum of MRL-Mp lpr/lpr and +/+ mice, and ar e present in kidney eluates of lupus mice with proteinuria. Arthritis Rheumatol 1994, 37:16841688. 19. Burlingame RW, Boey ML, Starkebaum G, Rubin RL: The centra l role of chromatin in autoimmune responses to histones and DNA in systemic lupu s erythematosus. J Clin Invest 1994, 94:184192. 20. Chabre H, Amoura Z, Piette JC , et al.: Presence of nucleosomerestricted antibodies in patients with systemic lupus erythematosus. Arthritis Rheumatol 1995, 38:14851491. 21. Kramers C, Hylkem a MN, van Bruggen MCJ, et al.: Anti-nucleosome antibodies complexed to nucleosom al antigens show anti-DNA reactivity and bind to rat glomerular basement membran e in vivo. J Clin Invest 1994, 94:568577. 22. van Bruggen MCJ, Kramers C, Hylkema MN, et al.: Significance of antinuclear and anti-extra cellular matrix auto-ant

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1. Goel N, Ulrich DT, St.Clair EW, et al.: Lack of correlation between serum sol uble Fas/APO-1 levels and autoimmune disease. Arthritis Rheumatol 1995, 38:173817 43. 32. Knipping E, Krammer PH, Onel KB, et al.: Levels of soluble Fas/APO1/CD95 in systemic lupus erythematosus and juvenile rheumatoid arthritis. Arthritis Rh eumatol 1995, 38:17351737. 33. Emlen W, Niebur J, Kadera R: Accelerated in vitro apoptosis of lymphocytes from patients with systemic lupus erythematosus. J Immu nol 1994, 152:36853692. 34. Kovacs B, Vassilopoulos D, Vogelgesang SA, Tsokos GC: Defective CD3mediated cell death in activated T cells from patients with system ic lupus erythematosus: role of decreased intracellular TNF- . Clin Immunol Immu nopathol 1996, 81:293302. 35. Casciola-Rosen LA, Anhalt G, Rosen A: DNA-dependent protein kinase is one of a subset of autoantigens specifically cleaved early du ring apoptosis. J Exp Med 1995, 182:16251634. 36. Casiano CA, Martin SJ, Green DR , Tan EM: Selective cleavage of nuclear autoantigens during CD95(Fas/APO-1)-medi ated T cell apoptosis. J Exp Med 1996, 183:765770. 37. Rosen A, Casciola-Rosen LA : Macromolecular substrates for the ICElike proteases during apoptosis. J Cell B iochem 1997, 64:5054. 38. Casiano C, Tan EM: Recent developments in the understan ding of antinuclear autoantibodies. Int Arch Allergy Immunol 1996, 111:308313. 39 . Utz P, Hottelet M, Schur PH, Anderson P: Proteins phosphorylated during stress -induced apoptosis are common targets for autoantibody production in patients wi th systemic lupus erythematosus. J Exp Med 1997, 185:843854. 40. Cooke MS, Mistry N, Wood C, et al.: Immunogenicity of DNA damaged by reactive oxygen species. Im plications for anti-DNA antibodies in lupus. Free Rad Bio Med 1997, 22:151159. 41 . Casciola-Rosen LA, Anhalt G, Rosen A: Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptoti c keratinocytes. J Exp Med 1994, 179:13171330. 42. Jordan P, Kuebler D: Autoimmun e diseases: nuclear autoantigens can be found at the cell surface. Mol Biol Rep 1996, 22:6366. 43. Hermann M, Voll RE, Zoller RM, et al.: Impaired phagocytosis o f apoptotic cell material by monocyte-derived macrophages from patients with sys temic lupus erythematosus. Arthritis Rheum 1998, 41:12411250. 44. Mamula MJ: Lupu s autoimmunity: from peptides to particles. Immunol Rev 1995, 144:301314. 45. Dat ta SK, Kaliyaperumal A: Nucleosome-driven autoimmune response in lupus. Pathogen ic T helper cell epitopes and co-stimulatory signals. In B Lymphocytes and Autoi mmunity. Edited by Chiorazzi N, Lahita RG, Pavelka K, Ferrarini M. New York: New York Academy of Sciences; 1997:155170. 46. Churg J, Sobin LH: Lupus nephritis. I n Renal Diseases. Classification and Atlas of Glomerular Diseases. Edited by Chu rg J. Tokyo: IgakuShoin; 1982:127149. 47. Churg J, Bernstein J, Glassock RJ: Lupu s nephritis. In Renal Diseases. Classification and Atlas of Glomerular Diseases, edn 2. Edited by Churg J, Bernstein J, Glassock RJ. New York: Igaku-Shoin; 1995 :151180. 48. D'Agati VD: Systemic lupus erythematosus. In Renal Biopsy Interpretati on. Edited by Silva FG, D'Agati VD, Nadasdy T. New York: Churchill Livingstone; 19 96:181220.

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 72. Pruzanski W: Clinical manifestations of multiple myeloma: relation to class and type of the M component. Can Med Assoc J 1976, 114:896897. 73. Gallo G, Kumar V: Hematopoietic disorders. In Renal Biopsy Interpretation. Edited by Silva FG, D'Agati VD, Nadasdy T. New York: Churchill Livingstone; 1996:259282. 74. Enlitz M, Weiss DT, Solomon A: Immunoglobulin heavy-chain-associated amyloidosis. Proc Na tl Acad Sci USA 1990, 87:65426546. 75. Preudhomme JL, Aucouturier P, Touchard G, et al.: Monoclonal immunoglobulin deposition disease (Randall type). Relationshi p with structural abnormalities of immunoglobulin chains. Kidney Int 1994, 46:96 5972. 76. Sanders PW, Herrera GA: Monoclonal immunoglobulin light chainrelated re nal diseases. Semin Nephrol 1993, 13:324341. 77. Buxbaum JN, Chuba JV, Hellman GC , et al.: Monoclonal immunoglobulin deposition disease: light chain and light an d heavy chain deposition diseases and their relation to light chain amyloidosis: clinical features, immunopathology, and molecular analyses. Ann Intern Med 1990 , 112:455464. 78. Autocouterier P, Khamlichi AA, Touchard G, et al.: Brief report : heavychain deposition disease. Nucl Acids Res 1993, 329:13891393. 79. Solomon A , Weiss DT, Kattine AA: Nephrotoxic potential of Bence Jones proteins. N Engl J Med 1991, 324:18451851. 80. Sanders PW, Booker BB: Pathobiology of cast nephropat hy from human Bence Jones proteins. J Clin Invest 1992, 89:630639. 81. Johnson WJ , Kyle RA, Pineda AA, et al.: Treatment of renal failure associated with multipl e myeloma. Plasmapheresis, hemodialysis and chemotherapy. Arch Intern Med 1990, 150:863869. 82. Zucchelli P, Pasquali S, Cagnoli L, Ferrari G: Controlled plasma exchange trial in acute renal failure due to multiple myeloma. Kidney Int 1988, 33:11751180. 83. Misiani R, Tiraboschi G, Mingardi G, Mecca G: Management of myel oma kidney: an antilight chain approach. Am J Kidney Dis 1987, 10:2833. 84. Ramos EL, Tisher CC: Recurrent disease in the kidney transplant. Am J Kidney Dis 1994, 24:142154. 11.31 85. Harrison KL, Alpers CE, Davis CL: De novo amyloidosis in a renal allograft: a case report and review of the literature. Am J Kidney Dis 1993, 22:468476. 86. Sammett D, Dagher F, Abbi R, et al.: Renal transplantation in multiple myeloma. Transplantation 1996, 62:15771580. 87. Gerlag PGG, Koene RAP, Berden JHM: Renal t ransplantation in light chain nephropathy: case report and review of the literat ure. Clin Nephrol 1986, 25:101104. 88. Varet B, Choukroun G, Grunfeld JP: Multipl e myeloma. Part II: treatment. Nephron 1995, 70:1820. 89. Iskander SS, Falk RJ, J enette JC: Clinical and pathologic features of fibrillary glomerulonephritis. Ki dney Int 1992, 42:14011407. 90. Fogo A, Qureshi N, Horn RG: Morphologic and clini cal features of fibrillary versus immunotactoid glomerulonephritis. Am J Kidney Dis 1993, 22:367377. 91. Alpers CE: Fibrillary glomerulonephritis and immunotacto id glomerulopathy. Curr Opinion Nephrol Hyperts 1994, 3:349355. 92. Pasternack A, Ahonen J, Kuhlback B: Renal transplantation in 45 patients with amyloidosis. Tr ansplantation 1986, 42:598601. 93. Helin H, Korpela M, Mustonen J, Pasternack A: Rheumatoid arthritis and ankylosing spondylitis. In The Kidney in Collagen-Vascu lar Diseases. Edited by Grishman E, Churg J, Needle MA, Vankataseshan VS. New Yo rk: Raven Press; 1993:149166. 94. Emery P, Adu D: The patient with rheumatoid art hritis, mixed connective tissue disease or polymyositis. In Oxford Textbook of C linical Nephrology, edn 2. Edited by Davison AM, Cameron JS, Grunfeld JP, et al. Oxford: Oxford University Press; 1998:975993. 95. Winer RL: Sjgren's syndrome. In T he Kidney in Collagen-Vascular Diseases. Edited by Grishman E, Churg J, Needle M A, Venkataseshan VS. New York: Raven Press; 1993:179187. 96. Donohue JF: Sclerode rma and the kidney. Kidney Int 1992, 41:462477. 97. Steen VD: Scleroderma renal c risis. Rheumatol Dis Clin North Am 1996, 22:861878. 98. D'Agati VD, Cannon PJ: Scle roderma (systemic sclerosis). In The Kidney in Collagen-Vascular Diseases. Edite d by Grishman E, Churg J, Needle MA, Venkataseshan VS. New York: Raven Press; 19 93:121147.

Principles of Dialysis: Diffusion, Convection, and Dialysis Machines Robert W. Hamilton C hronic renal failure is the final common pathway of a number of kidney diseases. The choices for a patient who reaches the point where renal function is insuffi cient to sustain life are 1) chronic dialysis treatments (either hemodialysis or peritoneal dialysis), 2) renal transplantation, or 3) death. With renal failure of any cause, there are many physiologic derangements. Homeostasis of water and minerals (sodium, potassium, chloride, calcium, phosphorus, magnesium, sulfate) , and excretion of the daily metabolic load of fixed hydrogen ions is no longer possible. Toxic end-products of nitrogen metabolism (urea, creatinine, uric acid , among others) accumulate in blood and tissue. Finally, the kidneys are no long er able to function as endocrine organs in the production of erythropoietin and 1,25-dihydroxycholecalciferol (calcitriol). Dialysis procedures remove nitrogeno us end-products of catabolism and begin the correction of the salt, water, and a cid-base derangements associated with renal failure. Dialysis is an imperfect tr eatment for the myriad abnormalities that occur in renal failure, as it does not correct the endocrine functions of the kidney. Indications for starting dialysi s for chronic renal failure are empiric and vary among physicians. Some begin di alysis when residual glomerular filtration rate (GFR) falls below 10 mL/min /1.7 3 m2 body surface area (15 mL/min/1.73 m2 in diabetics.) Others institute treatm ent when the patient loses the stamina to sustain normal daily work and activity . Most agree that, in the face of symptoms (nausea, vomiting, anorexia, fatigabi lity, diminished sensorium) and signs (pericardial friction rub, refractory pulm onary edema, metabolic acidosis, foot or wrist drop, asterixis) of uremia, dialy sis treatments are urgently indicated. CHAPTER 1

1.2 Dialysis as Treatment of End-Stage Renal Disease FUNCTIONS OF THE KIDNEY AND PATHOPHYSIOLOGY OF RENAL FAILURE Function Salt, water, and acid-base balance Water balance Sodium balance Potassium balanc e Bicarbonate balance Magnesium balance Phosphate balance Excretion of nitrogeno us end products Urea Creatinine Uric acid Amines Guanidine derivatives Endocrine -metabolic Conversion of vitamin D to active metabolite Production of erythropoi etin Renin Dysfunction Salt, water, and acid-base balance Fluid retention and hyponatremia Edema, conge stive heart failure, hypertension Hyperkalemia Metabolic acidosis, osteodystroph y Hypermagnesemia Hyperphosphatemia, osteodystrophy Excretion of nitrogenous end products ?Anorexia, nausea, pruritus, pericarditis, polyneuropathy, encephalopa thy, thrombocytopathy Endocrine-metabolic Osteomalacia, osteodystrophy Anemia Hypertension FIGURE 1-1 Functions of the kidney and pathophysiology of renal failure. FIGURE 1-2 Statue of Thomas Graham in George Square, Glasgow, Scotland. The phys icochemical basis for dialysis was first described by the Scottish chemist Thoma s Graham. In his 1854 paper On Osmotic Force he described the movements of various solutes of differing concentrations through a membrane he had fashioned from an ox bladder. (From Graham [1].) Blood Membrane Dialysate Na+ K+ Ca2+ HCO3 Creatinine Urea Na+ K+ Ca2+ HCO3 Creatinine Urea FIGURE 1-3 Membrane fluxes in dialysis. Dialysis is the process of separating el ements in a solution by diffusion across a semipermeable membrane (diffusive sol ute transport) down a concentration gradient. This is the principal process for removing the end-products of nitrogen metabolism (urea, creatinine, uric acid), and for repletion of the bicarbonate deficit of the metabolic acidosis associate d with renal failure in humans. The preponderance of diffusion as the result of gradient is shown by the displacement of the arrow.

Principles of Dialysis: Difusion, Convection, and Dialysis Machines 1.3 Acidified concentrate Water Pump Heater Bicarbonate concentrate Air embolus detector Membrane unit Patient Conductivity monitor Volume balance s ystem Blood pump Pump Mix 1 Mix 2 Deaerator Spent dialysate Heat exchanger Ultrafiltrate pump Spent dialysate pump Blood leak detector Drain Heparin pump FIGURE 1-4 Simplified schematic of typical hemodialysis system. In hemodialysis, blood from the patient is circulated through a synthetic extracorporeal membran e and returned to the patient. The opposite side of that membrane is washed with an electrolyte solution (dialysate) containing the normal constituents of plasm a water. The apparatus contains a blood pump to circulate the blood through the system, proportioning pumps that mix a concentrated salt solution with water purified by reverse osmos is and/or deionization to produce the dialysate, a means of removing excess flui d from the blood (mismatching dialysate inflow and outflow to the dialysate comp artment), and a series of pressure, conductivity, and air embolus monitors to pr otect the patient. Dialysate is warmed to body temperature by a heater. FIGURE 1 -5 The hemodialysis membrane. Most membranes are derived from cellulose. (The ea rliest clinically useful hemodialyzers were made from cellophane sausage casing. ) Other names of these materials include cupraphane, hemophan, cellulose acetate . They are usually sterilized by ethylene oxide or gamma irradiation by the manu facturer. They are relatively porous to fluid and solute but do not allow large molecules (albumin, vitamin B12) to pass freely. There is some suggestion that c upraphane membranes sterilized by ethylene oxide have a high incidence of biosen sitization, meaning that the patient may have a form of allergic reaction to the membrane. Polysulfone, polyacrylonitrile, and polymethylmethacrylate membranes are more biocompatible and more porous (high flux membranes). They are most ofte n formed into hollow fibers. Blood travels down the center of these fibers, and dialysate circulates around the outside of the fibers but inside a plastic casin g. Water for dialysis must meet critical chemical and bacteriologic standards. T hese are listed in Figures 1-6 and 1-7. Dialysate Blood

Blood Dialysate Blood Dialysate

1.4 Dialysis as Treatment of End-Stage Renal Disease FIGURE 1-6 Association for the Advancement of Medical Instrumentation (AAMI) che mical standards for water for hemodialysis. Before hemodialysis can be performed , water analysis is performed. Water for hemodialysis generally requires reverse osmosis treatment and a deionizer for polishing the water. Organic materials, chl orine, and chloramine are removed by charcoal filtration. (From Vlchek [2]; with permission.) ASSOCIATION FOR THE ADVANCEMENT OF MEDICAL INSTRUMENTATION CHEMICAL STANDARD FOR WATER FOR HEMODIALYSIS Substance Aluminum Arsenic Barium Cadmium Calcium Chloramine Chlorine Chromium Copper Fluo ride Lead Magnesium Mercury Nitrate Potassium Selenium Silver Sodium Sulfate Zin c Concentration (mg/L) 0.01 0.005 0.1 0.001 2.0 0.1 0.5 0.014 0.1 0.2 0.005 4.0 0.0002 2.0 8.0 0.009 0. 005 70 100 0.1 ASSOCIATION FOR THE ADVANCEMENT OF MEDICAL INSTRUMENTATION BACTERIOLOGIC STANDAR DS FOR DIALYSIS WATER AND PREPARED DIALYSATE Colony-forming units/mL Dialysis water Prepared dialysate <200 <2000 FIGURE 1-7 Association for the Advancement of Medical Instrumentation (AAMI) bac teriologic standards for dialysis water and prepared dialysate. Excess bacteria in water can lead to pyrogen reactions. Treated water supply systems are designe d so that there are no dead-end connections. Because the antiseptic agents (chlo rine and chloramine) have been removed in water treatment, the water is prone to develop such problems if stagnation is allowed. (From Bland and Favero [3]; wit h permission.) dn dc = DA dt dx FIGURE 1-8 Factors that govern diffusion, where dn/dt = the rate of movement of molecules per unit time; D = Fick's diffusion coefficient; A = area of the boundary through which molecules move; dc = concentration gradie nt; and dx = distance through which molecules move. Hemodialysis depends on the process of diffusion for removal of solutes. The amount of material removed depe nds on the magnitude of the concentration gradient, the distance the molecule tr avels, and the area through which diffusion takes place. For this reason those d ialyzers that have a large surface area, thin membranes, and are designed to max imize the effect of concentration gradient (countercurrent design) are most effi cient at removing solutes.

Principles of Dialysis: Difusion, Convection, and Dialysis Machines kT 6ph 3 1.5 D= 4pN 3Mu FIGURE 1-9 Fick's diffusion constant, where D = Fick's diffusion coefficient, k = Bo ltzman's constant; T = absolute temperature; = viscosity; N = Avogadro's number; M = molecular weight; and = partial molal volume. The diffusion constant is proport ional to the temperature of the solution and inversely proportional to the visco sity and the size of the molecule removed. FIGURE 1-10 Effect of blood flow on c learance of various solutes, Fresenius F-5 membrane. The amount of solute cleare d by a dialyzer depends on the amount delivered to the membrane. The usual blood flow is 300400 mL/min, which is adequate to deliver the dialysis prescription. O n institution of dialysis to a very uremic patient the blood flow is decreased t o 160 to 180 mL/min to avoid disequilibrium syndrome. As time goes on, blood flo w can be increased to standard flows as the patient adjusts to dialysis. Most pa tients require hemodialysis at least thrice weekly. From this graph it is also e vident that small molecules such as urea (molecular weight 60 D) are cleared mor e easily than large molecules such as vitamin B12 (molecular weight 1355 D). 250 200 Clearance, mL/min 150 100 50 0 0 Urea Creatinine Phosphate Vitamin B12 100 200 300 Blood flow, mL/min 400 200 100 0 Pressure, mmHg 100 FIGURE 1-11 Hydrostatic ultrafiltration also takes place during hemodialysis. Be cause the spent dialysate effluent pump (see Fig. 1-4) creates negative pressure on the dialysate compartment of the membrane unit and the blood pump creates po sitive pressure in the blood compartment, there is a net hydrostatic pressure gr adient between the compartments. This causes a flow of water and dissolved subst ances from blood to the dialysate compartment. The process of solute transfer as sociated with this flow of water is called convective transport. In hemodialysis, the amount of lowmolecular weight solute (eg, urea) removed by convection is negl igible. In the continuous renal replacement therapies, this is a major mechanism for solute transport. 200 300 400 Blood compartment Dialysate Net transmembrane compartment pressure

1.6 35 30 UFR, mL/h/mmHg 25 20 15 10 5 0 F5 Dialysis as Treatment of End-Stage Renal Disease FIGURE 1-12 Dialysis membranes differ in their ability to remove fluid. Differen ces in ultrafiltration coefficient (UFR) are shown for two different membranes, F-5 and F-50. The F-50 is considered a high-flux membrane. F50 References 1. 2. Graham T: The Bakerian lectureon osmotic force. Philos Trans R Soc Lond 185 4, 144:177228. Vlchek DL: Monitoring a hemodialysis water treatment system. In AA MI Standards and Recommended Practices, vol. 3. Arlington, VA: Association for t he Advancement of Medical Instrumentation; 1993:267277. 3. Bland LA, Favero MS: M icrobiologic aspects of hemodialysis systems. In AAMI Standards and Recommended Practices, vol. 3. Arlington, VA: Association for the Advancement of Medical Ins trumentation; 1993:257265. Daniels F, Alberty RA: Physical Chemistry. New York : John Wiley & Sons; 1955. 4.

Dialysate Composition in Hemodialysis and Peritoneal Dialysis Biff F. Palmer T he goal of dialysis for patients with chronic renal failure is to restore the co mposition of the body's fluid environment toward normal. This is accomplished prin cipally by formulating a dialysate whose constituent concentrations are set to a pproximate normal values in the body. Over time, by diffusional transfer along f avorable concentration gradients, the concentrations of solutes that were initia lly increased or decreased tend to be corrected. When an abnormal electrolyte co ncentration poses immediate danger, the dialysate concentration of that electrol yte can be set at a nonphysiologic level to achieve a more rapid correction. On a more chronic basis the composition of the dialysate can be individually adjust ed in order to meet the specific needs of each patient. Dialysate Composition for Hemodialysis In the early days of hemodialysis, the dialysate sodium concentration was delibe rately set low to avoid problems of chronic volume overload such as hypertension and heart failure. As volume removal became more rapid because of shorter dialy sis times, symptomatic hypotension emerged as a common and often disabling probl em during dialysis. It soon became apparent that changes in the serum sodium con centrationand more specifically changes in serum osmolality were contributing to t he development of this hemodynamic instability. A decline in plasma osmolality d uring regular hemodialysis favors a CHAPTER 2

2.2 Dialysis as Treatment of End-Stage Renal Disease erbate hemodynamic instability during the dialysis procedure [21]. In this regar d, the intradialysis drop in blood pressure noted in patients dialyzed against a low-calcium bath, while statistically significant, is minor in degree [22,23]. Nevertheless, for patients who are prone to intradialysis hypotension avoiding l ow calcium dialysate concentration may be of benefit. On the other hand, the use of a lower calcium concentration in the dialysate allows the use of increased d oses of calcium-containing phosphate binders and lessens dependence on binders c ontaining aluminum. In addition, use of 1,25-dihydroxyvitamin D can be liberaliz ed to reduce circulating levels of parathyroid hormone and, thus, the risk of in ducing hypercalcemia. With dialysate calcium concentrations below 1.5 mmol/L, ho wever, patients need close monitoring to ensure that negative calcium balance do es not develop and that parathyroid hormone levels remain in an acceptable range [24]. fluid shift from the extracellular space to the intracellular space, thus exacer bating the volume-depleting effects of dialysis. With the advent of high-clearan ce dialyzers and more efficient dialysis techniques, this decline in plasma osmo lality becomes more apparent, as solute is removed more rapidly. Use of dialysat e of low sodium concentration would tend further to enhance the intracellular sh ift of fluid, as plasma tends to become even more hyposmolar consequent to the m ovement of sodium from plasma to dialysate. The use of a higher sodium concentra tion dialysate (>140 mEq/L) has been among the most efficacious and best tolerat ed therapies for episodic hypotension [13]. The high sodium concentration prevent s a marked decline in the plasma osmolality during dialysis, thus protecting the extracellular volume by minimizing osmotic fluid loss into the cells. In the ea rly 1960s acetate became the standard dialysate buffer for correcting uremic aci dosis and offsetting the diffusive losses of bicarbonate during hemodialysis. Ov er the next several years reports began to accumulate that linked routine use of acetate with cardiovascular instability and hypotension during dialysis. As a r esult, dialysate containing bicarbonate began to re-emerge as the principal dial ysate buffer, especially as advances in biotechnology made bicarbonate dialysate less expensive and less cumbersome to use. For the most part, the bicarbonate c oncentration used consistently in most dialysis centers is 35 mmol/L. Emphasis i s now being placed on individually adjusting the dialysate bicarbonate concentra tion so as to maintain the predialysis tCO2 concentration above 23 mmol/L [1216]. Increasing evidence suggests that correction of chronic acidosis is of clinical benefit in terms of bone metabolism and nutrition. Dialysis assumes a major rol e in the maintenance of a normal serum potassium concentration in patients with end-stage renal disease. Excess potassium is removed by using a dialysate with a lower potassium concentration, so that a gradient is achieved that favors movem ent of potassium. In general, one can expect only up to 70 to 90 mEq of potassiu m to be removed during a typical dialysis session. As a result, one should not o verestimate the effectiveness of dialysis in the treatment of severe hyperkalemi a. The total amount removed varies considerably and is affected by changes in ac id-base status, in tonicity, in glucose and insulin concentration, and in catech olamine activity [1720]. The concentration of calcium in the dialysate has implic ations for metabolic bone disease and hemodynamic stability. Like the other cons tituents of the dialysate, the calcium concentration should be tailored to the i ndividual patient [21]. Some data suggest that lowering the dialysate calcium co ncentration would exacDialysate Composition for Peritoneal Dialysis To meet the ultrafiltration requirements of patients on peritoneal dialysis, the peritoneal dialysate is deliberately rendered hyperosmolar relative to plasma, to create an osmotic gradient that favors net movement of water into the periton eal cavity. In commercially available peritoneal dialysates, glucose serves as t he osmotic agent that enhances ultrafiltration. Available concentrations range f

rom 1.5% to 4.25% dextrose. Over time, the osmolality of the dialysate declines as a result of water moving into the peritoneal cavity and of absorption of dial ysate glucose. The absorption of glucose contributes substantially to the calori e intake of patients on continuous peritoneal dialysis. Over time, this carbohyd rate load is thought to contribute to progressive obesity, hypertriglyceridemia, and decreased nutrition as a result of loss of appetite and decreased protein i ntake. In addition, the high glucose concentrations and high osmolality of curre ntly available solutions may have inhibitory effects on the function of leukocyt es, peritoneal macrophages, and mesothelial cells [25]. In an attempt to develop a more physiologic solution, various new osmotic agents are now under investiga tion. Some of these may prove useful as alternatives to the standard glucose sol utions. Those that contain amino acids have received the most attention. The sod ium concentration in the ultrafiltrate during peritoneal dialysis is usually les s than that of extracellular fluid, so there is a tendency toward water loss and development of hypernatremia. Commercially available peritoneal dialysates have a sodium concentration of 132 mEq/L to compensate for this tendency toward dehy dration. The effect is more pronounced with increasing frequency of exchanges an d with increasing dialysate glucose concentrations. Use of the more hypertonic s olutions and frequent cycling can result in significant dehydration and hypernat remia. As a result of stimulated thirst, water intake and weight may increase, r esulting in a vicious cycle. Potassium is cleared by peritoneal dialysis at a ra te similar to that of urea. With chronic ambulatory peritoneal dialysis and 10 L of drainage per day, approximately 35 to 46 mEq of potassium is removed per day . Daily potassium intake is usually greater than this, yet significant hyperkale mia is uncommon in these patients. Presumably potassium balance is maintained by increased colonic secretion of potassium and by some residual

Dialysate Composition in Hemodialysis and Peritoneal Dialysis renal excretion. Given these considerations, potassium is not routinely added to the dialysate. The buffer present in most commercially available peritoneal dia lysate solutions is lactate. In patients with normal hepatic function, lactate i s rapidly converted to bicarbonate, so that each mM of lactate absorbed generate s one mM of bicarbonate. Even with the most aggressive peritoneal dialysis there is no appreciable accumulation of circulating lactate. The rapid metabolism of lactate to bicarbonate maintains the high dialysate-plasma lactate gradient nece ssary for continued 2.3 absorption. The pH of commercially available peritoneal dialysis solutions is pu rposely made acidic by adding hydrochloric acid to prevent dextrose from caramel izing during the sterilization procedure. Once instilled, the pH of the solution rises to values greater than 7.0. There is some evidence that the acidic pH of the dialysate, in addition to the high osmolality, may impair the host's peritonea l defenses [25,26]. To avoid negative calcium balanceand possibly to suppress cir culating parathyroid hormonecommercially available peritoneal dialysis solutions evolved to have a calcium concentration 150 Baseline Interstitial space Cell Cell Intravascular space BUN Low-sodium dia lysate High-sodium dialysate Step Linear Exponential BUN H2O Decreased osmolality H2O BUN H2O Na concentration, mEq/L Stable osmolality 145 BUN Less vascular refilling Peripheral vasoconstriction Exacerbated autonomic insuffici ency -inhibits afferent sensing - CNS efferent outflow Venous pooling secondary to - PGE2 Na H2O 140 Hypotension 1 2 Time, h 3 4 of 3.5 mEq/L (1.75 mmol/L). This concentration is equal to or slightly greater t han the ionized concentration in the serum of most patients. As a result, there is net calcium absorption in most patients treated with a conventional chronic a mbulatory peritoneal dialysis regimen. As the use of calcium-containing phosphat e binders has increased, hypercalcemia has become a common problem when utilizin g the 3.5 mEq/L calcium dialysate. This complication has been particularly commo n in patients treated with peritoneal dialysis, since they have a much greater i

ncidence of adynamic bone disease than do hemodialysis patients [27]. In fact, t he continual positive calcium balance associated with the 3.5-mEq/L solution has been suggested to be a contributing factor in the development of this lesion. T he low bone turnover state typical of this disorder impairs accrual of administered calcium, contributing to the development of hypercalcemia. As a result, there has been increased interest in using a strategy similar to that em ployed in hemodialysis, namely, lowering the calcium content of the dialysate. T his strategy can allow increased use of calcium-containing phosphate binders and more liberal use of 1,25-dihydroxyvitamin D to effect decreases in the circulat ing level of parathyroid hormone. In this way, development of hypercalcemia can be minimized. Dialysate Na in Hemodialysis

2.4 Dialysis as Treatment of End-Stage Renal Disease FIGURE 2-1 Use of a low-sodium dialysate is more often associated with intradial ysis hypotension as a result of several mechanisms [4]. The drop in serum osmola lity as urea is removed leads to a shift of water into the intracellular compart ment that prevents adequate refilling of the intravascular space. This intracell ular movement of INDICATIONS AND CONTRAINDICATIONS FOR USE OF SODIUM MODELING (HIGH/LOW PROGRAMS) Indications Intradialysis hypotension Cramping Initiation of hemodialysis in set ting of severe azotemia Hemodynamic instability (eg, intensive care setting) Con traindications Intradialysis development of hypertension Large interdialysis wei ght gain induced by high-sodium dialysate Hypernatremia Dialysate Buffer in Hemodialysis Acid concentrate NaCl CaCl KCL MgCl Acetic acid Dextrose NaHCO3 concentrate NaHC O3 Final dialysate Na Cl Ca Acetate K HCO3 Mg Dextrose 137 mEq/L 105 mEq/L 3.0 mEq/ L 4.0 mEq/L 2.0 mEq/L 33 mEq/L 0.75 mEq/L 200 mg/dl water, combined with removal of water by ultrafiltration, leads to contraction o f the intravascular space and contributes to the development of hypotension. Hig h-sodium dialysate helps to minimize the development of hypo-osmolality. As a re sult, fluid can be mobilized from the intracellular and interstitial compartment s to refill the intravascular space during volume removal. Other potential mecha nisms whereby low-sodium dialysate contributes to hypotension are indicated. Naso dium; BUNblood urea nitrogen; PGE2prostaglandin E2. FIGURE 2-2 There has been inte rest in varying the concentration of sodium (Na) in the dialysate during the dia lysis procedure so as to minimize the potential complications of a high-sodium s olution and yet retain the beneficial hemodynamic effects. A high sodium concent ration dialysate is used initially and progressively the concentration is reduce d toward isotonic or even hypoPure H2O H 2O MECHANISMS BY WHICH ACETATE BUFFER CONTRIBUTES TO HEMODYNAMIC INSTABILITY Directly decreases peripheral vascular resistance in approximately 10% of patien ts Stimulates release of the vasodilator compound interleukin 1 Induces metaboli c acidosis via bicarbonate loss through the dialyzer Produces arterial hypoxemia and increased oxygen consumption ?Decreased myocardial contractility tonic levels by the end of the procedure. The concentration of sodium can be red uced in a linear, exponential, or step pattern. This method of sodium control al lows for a diffusive sodium influx early in the session to prevent a rapid decli ne in plasma osmolality secondary to efflux of urea and other small-molecular we ight solutes. During the remainder of the procedure, when the reduction in osmol ality accompanying urea removal is less abrupt, the dialysate is sodium level is set lower, thus minimizing the development of

Dialysate Composition in Hemodialysis and Peritoneal Dialysis 2.5 hypertonicity and any resultant excessive thirst, fluid gain, and hypertension i n the interdialysis period. In some but not all studies, sodium modeling has bee n shown to be effective in treating intradialysis hypotension and cramps [5-11]. FIGURE 2-3 Indications and contraindications for use of sodium modeling (high/l ow programs). Use of a sodium modeling program is not indicated in all patients. In fact most patients do well with the dialysate sodium set at 140 mEq/L. As a result the physician needs to be aware of the benefits as well as the dangers of sodium remodeling. 5.0 Start hemodialysis 4.5 Plasma potassium, mM 4.0 3.5 3.0 End hemodialysis 2.5 0 1 2 Time, h 3 4 5 FACTORS RELATED TO DIALYSIS THAT AFFECT DISTRIBUTION OF POTASSIUM BETWEEN CELLS AND THE EXTRACELLULAR FLUID Dialysis membrane Dialysis membrane K+ Factors that enhance cell potassium uptake Insulin 2-adrenergic receptor agonist s Alkalemia Factors that reduce cell potassium uptake or increase potassium effl ux 2-adrenergic receptor blockers Acidemia (mineral acidosis) Hypertonicity -adr energic receptor agonists K+ B K+ K+ Less K removal A Glucose-containing dialysate Correction of metabolic acidosis during hemodialysi s Pre-dialysis treatment with b-stimlants FIGURE 2-4 The current utilization of a bicarbonate dialysate requires a special ly designed system that mixes a bicarbonate and an acid concentrate with purifie d water. The acid concentrate contains a small amount of lactic or acetic acid a nd all the calcium and magnesium. The exclusion of these cations from the bicarb onate concentrate prevents the precipitation of magnesium and calcium carbonate that would otherwise occur in the setting of a high bicarbonate concentration. D

uring the mixing procedure the acid in the acid concentrate reacts with an equimolar amount of bicarbonate to generate carbonic acid and carbon dioxide. The generation of carbon dioxide causes the pH of the f inal solution to fall to approximately 7.07.4. The acidic pH and the lower concen trations in the final mixture allow the calcium and magnesium to remain in solut ion. The final concentration of bicarbonate in the dialysate is approximately 333 8 mmol/L.

2.6 Dialysis as Treatment of End-Stage Renal Disease FIGURE 2-5 Step 1: Control serum phosphate Low-phosphate diet (8001000 mg/d) Phophate binder s Step 2: Normalize serum calcium If calcium is still low after control of phospha te, treat with 1,25-(OH)2 vitamin D Use calcium-containing phosphate binders 1.01 .5 g dietary calcium Step 3: Control secondary hyperparathyroidism Treat with 1,25(OH)2 vitamin D Mechanisms by which acetate buffer contributes to hemodynamic instability. Altho ugh bicarbonate is the standard buffer in use today, hemodynamically stable pati ents can be dialyzed safely using as acetate-containing dialysis solution. Since muscle is the primary site of metabolism of acetate, patients with reduced musc le mass tend to be acetate intolerant. Such patients include malnourished and el derly patients and women. Dialysate Potassium in Hemodialysis Individualize dialysate calcium Low-calcium dialysate Helps prevent hypercalcemia secondary to high-dose calcium containing phosphate binders and vitamin D Monitor for negative calcium balance Low-calcium dialysate High-calcium dialysate Promotes positive calcium balance S uppresses parathyroid hormone levels Better hemodynamic stability Risk of hyperc alcemia ? Risk of adynamic bone disease

Dialysate Composition in Hemodialysis and Peritoneal Dialysis 2.7 FIGURE 2-6 ADVANTAGES AND DISADVANTAGES OF INDIVIDUALIZING VARIOUS COMPONENTS OF HEMODIALYS ATE Dialysate component and adjustment Sodium: Increased Decreased (rarely used) Calcium: Increased Decreased Potassium : Increased Decreased Bicarbonate: Increased Decreased Magnesium: Increased Decr eased Advantages More hemodynamic stability, less cramping Less interdialytic weight gain Suppres sion of PTH, promotes hemodynamic stability in HD Permits greater use of vitamin D and calcium containing phosphate binders Less arrhythmias in setting of digox in or coronary heart disease ? improved hemodynamic stability Permits greater di etary intake of potassium with less hyperkalemia ? improvement in myocardial con tractility Corrects chronic acidosis thereby benefits nutrition and bone metabol ism Less metabolic alkalosis ? Less arrhythmias, ? hemodynamic benefit Permits g reater use of magnesium containing phosphate binders which in tum permits reduce d dose of calcium binders and results in less hypercalcemia Disadvantages Dipsogenic effect, increased interdialytic weight gain, ? chronic hypertension I ntradialytic hypotension and cramping more common Hypercalcemia with vitamin D a nd high-dose calcium-containing phosphate binders, ? contribution to adynamic bo ne disease in PD Potential for negative calcium balance, stimulation of PTH, sli ght decrease in hemodynamic stability Limited by hyperkalemia Increased arrhythm ias, may exacerbate autonomic insufficiency Post-dialysis metabolic alkalosis Potential for chronic acidosis Potential for h ypermagnesemia Symptomatic hypomagnesemia Plasma potassium concentration can be expected to fall rapidly in the early stag es of dialysis, but as it drops, potassium removal becomes less efficient [17,18 ]. Since potassium is freely permeable across the dialysis membrane, movement of potassium from the in tracellular space to the extracellular space appears to be the limiting factor t hat accounts for the smaller fractional decline in potassium concentration at lo wer plasma potassium concentrations. Presumably, the movement of potassium out o f cells and into the extracellular space is slower than the removal of potassium from the extracellular space into the dialysate, so a disequilibrium is created . The rate of potassium removal is largely a function of its predialysis concent ration. The higher the initial plasma concentration, the greater is the plasma-d ialysate gradient and, thus, the more potassium is removed. After the completion of a standard dialysis treatment there is an increase in the plasma concentrati on of potassium secondary to continued exit of potassium from the intracellular space to the extracellular space in an attempt to re-establish the intracellular -extracellular potassium gradient. FIGURE 2-7 COMPOSITION OF A COMMERCIALLY AVAILABLE PERITONEAL DIALYSATE Solute Sodium, mEq/L Potassium, mEq/L Chloride , mEq/L Calcium , mEq/L Magnesium, mEq/L D, L-Lactate, mEq/L Glucose, g/dL Osmolality pH Dianeal PD-2 132 0 96 3.5 0.5 40 1.5, 2.5, 4.25 346, 396, 485 5.2

2.8 Dialysis as Treatment of End-Stage Renal Disease The total extracellular potassium content is only about 50 to 60 mEq/L. Without mechanisms to shift potassium into the cell, small potassium loads would lead to severe hyperkalemia. These mechanisms are of particular importance in patients with end-stage renal disease since the major route of potassium excretion is eli minated from the body by residual renal clearance and enhanced gastrointestinal excretion. FIGURE 2-8 During a typical dialysis session approximately 80 to 100 mEq/L of potassium is removed from the body. A, Potassium (K) flux from the extr acellular space across the dialysis membrane exceeds the flux of potassium out o f the intracellular space. B, The movement of potassium between the intra- and e xtracellular spaces is controlled by a number of factors that can be modified du ring the dialysis procedure [17,18]. As compared with a glucose-free dialysate, a bath that contains glucose is associated with less potassium removal [19]. The presence of glucose in the dialysate stimulates insulin release, which in turn has the effect of shifting potassium into the intracellular space, where it beco mes less available for removal by dialysis. Dialysis in patients who are acidoti c is also associated with less potassium removal since potassium is shifted into cells as the serum bicarbonate concentration rises. Finally, patients treated w ith inhaled stimulants, as for treatment of hyperkalemia, will have less potassi um removed during dialysis since stimulation causes a shift of potassium into th e cell [20].

High-Efficiency and High-Flux Hemodialysis Sivasankaran Ambalavanan Gary Rabetoy Alfred K. Cheung H emodialysis remains the major modality of renal replacement therapy in the Unite d States. Since the 1970s the drive for shorter dialysis time with high urea cle arance rates has led to the development of high-efficiency hemodialysis. In the 1990s, certain biocompatible features and the desire to remove amyloidogenic 2mi croglobulin has led to the popularity of high-flux dialysis. During the 1990s, t he use of high-efficiency and high-flux membranes has steadily increased and use of conventional membrane has declined [1]. In 1994, a survey by the Centers for Disease Control showed that high-flux dialysis was used in 45% and high-efficie ncy dialysis in 51% of dialysis centers (Fig. 3-1) [1]. Despite the increasing u se of these new hemodialysis modalities the clinical risks and benefits of highperformance therapies are not welldefined. In the literature published over the past 10 years the definitions of high-efficiency and high-flux dialysis have bee n confusing. Currently, treatment quantity is not only defined by time but also by dialyzer characteristics, ie, blood and dialysate flow rates. In the past, wh en the efficiency of dialysis and blood flow rates tended to be low, treatment q uantity was satisfactorily defined by time. Today, however, treatment time is no t a useful expression of treatment quantity because efficiency per unit time is highly variable. CHAPTER 3

3.2 Dialysis as Treatment of End-Stage Renal Disease Dialyzers 50 40 HIGH-PERFORMANCE EXTRACORPOREAL THERAPIES FOR END-STAGE RENAL DISEASE High-efficiency hemodialysis High-flux hemodialysis Hemofiltration, intermittent Hemodiafiltration, intermittent FIGURE 3-2 The four highperformance extracorporeal therapies for end-stage renal disease are listed [2]. Centers, % 30 20 10 0 1986 1988 1990 Year 1992 1994 1996 FIGURE 3-1 Centers using high-flux dialyzers have increased threefold from 1986 to 1996 because of their ability to remove middle molecules. (From Tokars and co workers [1]; with permission.) FIGURE 3-3 Definitions of flux, permeability, and efficiency. The urea value KoA, as conventionally defined in hemodialysis, is a n estimate of the clearance of urea (a surrogate marker of low molecular weight uremic toxins) under conditions of infinite blood and dialysate flow rates. The following equation is used to calculate this value: 1-Kd/Qb QbQd KoA= ln Qb-Qd 1 -Kd/Qd where Ko = mass transfer coefficient A = surface area Qb = blood flow rat e Qd = dialysate flow rate ln = natural log Kd = mean of blood and dialysate sid e urea clearance As conventionally defined in hemodialysis, flux is the rate of water transfer across the hemodialysis membrane. Dissolved solutes are removed b y convection (solvent drag effect). Permeability is a measure of the clearance r ate of molecules of middle molecular weight, sometimes defined using 2-microglob ulin (molecular weight, 11,800 D) as the surrogate [3,4]. Dialyzers that permit 2-microglobulin clearance of over 20 mL/min under usual clinical flow and ultraf iltration conditions have been defined as highpermeability membrane dialyzers. B ecause of the general correlation between water flux and the clearance rate of m olecules of middle molecular weight, the term high-flux membrane has been used c ommonly to denote high-permeability membrane. DEFINITIONS OF FLUX, PERMEABILITY, AND EFFICIENCY Flux Measure of ultrafiltration capacity Low and high flux are based on the ultr afiltration coefficient (Kuf) Low flux: Kuf <10 mL/h/mm Hg High flux: Kuf >20 mL /h/mm Hg Permeability Measure of the clearance of the middle molecular weight mo

lecule (eg, General correlation between flux and permeability Low permeability: 2-microglobulin clearance <10 mL/min High permeability: 2-microglobulin clearanc e >20 mL/min Efficiency Measure of urea clearance Low and high efficiency are ba sed on the urea KoA value Low efficiency: KoA <500 mL/min High efficiency: KoA > 600 mL/min Komass transfer coefficient; Asurface area. 2-microglobulin)

High-Efficiency and High-Flux Hemodialysis 1000 High flux 3.3 100 KOA, mL/min 10 Low flux FIGURE 3-4 Theoretic KoA profile of high- and low-flux dialyzers and highand low -efficiency dialyzers. Note that here the definition of KoA applies to the produ ct of the mass transfer coefficient and surface area for solutes having a wide r ange of molecular weights, and is not limited to urea. Note also the logarithmic scales on both axes [3]. Komass transfer coefficient; Asurface area. (From Cheung and Leypoldt [3]; with permission.) 1 High efficiency Low efficiency 0.1 0.01 10 100 1000 10,000 100,000 Solute molecular weight, D CLASSIFICATION OF HIGHPERFORMANCE DIALYSIS High-efficiency low-flux hemodialysis High-efficiency high-flux hemodialysis Low -efficiency high-flux hemodialysis FIGURE 3-5 Classification of high-performance dialysis. Some authors have define d high-efficiency hemodialysis as treatment in which the urea clearance rate exc eeds 210 mL/min. High-flux dialysis, arbitrarily defined as a 2-microglobulin cl earance of over 20 mL/min, is achieved using high-flux membranes [3,4]. 400 350 Urea clearance rate, mL/min 300 250 200 150 100 50 0 0 50 150 250 350 45 0 500 Blood flow rate, mL/min KOA=500 KOA=1000 CHARACTERISTICS OF HIGH-EFFICIENCY DIALYSIS Urea clearance rate is usually >210 mL/min Urea KoA of the dialyzer is usually > 600 mL/min Ultrafiltration coefficient of the dialyzer (Kuf) may be high or low Clearance of middle molecular weight molecules may be high or low Dialysis can b e performed using either cellulosic or synthetic membrane dialyzers Komass transf er coefficient; Asurface area. FIGURE 3-6 Comparison of urea clearance rates between low- and high-efficiency h emodialyzers (urea KoA = 500 and 1000 mL/min, respectively). The urea clearance rate increases with the blood flow rate and gradually reaches a plateau for both types of dialyzers. The plateau value of KoA is higher for the high-efficiency dialyzer. At low blood flow rates (<200 mL/min), however, the capacity of the hi gh-efficiency dialyzer cannot be exploited and the clearance rate is similar to that of the low-flux dialyzer [3,6]. Komass transfer coefficient; Asurface area. ( From Collins [6]; with permission.) FIGURE 3-7 Characteristics of high-efficiency dialysis. High-efficiency dialysis is arbitrarily defined by a high clearance rate of urea (>210 mL/min). High-eff iciency membranes can be made from either cellulosic or synthetic materials. Dep ending on the membrane material and surface area, the removal of water (as measu

red by the ultrafiltration coefficient or Kuf) and molecules of middle molecular weight (as measured by 2-microglobulin clearance) may be high or low [3,4,6,7].

3.4 Dialysis as Treatment of End-Stage Renal FIGURE 3-8 Differences between high- and al hemodialysis refers to low-efficiency lar modality before the 1980s [3,6]. Low <500 <350 <500 Optimal Disease low-efficiency hemodialysis. Convention low-flux hemodialysis that was the popu efficiency, mL/min

DIFFERENCES BETWEEN HIGH- AND LOW-EFFICIENCY HEMODIALYSIS High efficiency, mL/min Dialyzer KoA Blood flow Dialysate flow Bicarbonate dialysate 600 350 500 Necessary Komass transfer coefficient; Asurface area. TECHNICAL REQUIREMENTS FOR HIGH-EFFICIENCY DIALYSIS High-efficiency dialyzer Large surface area (A) High mass transfer coefficient ( Ko) Both (high KoA) High blood flow (350 mL/min) High dialysate flow (500 mL/min) Bicarbonate dialysate CONCENTRATION OF DIALYSATE IN HIGH-EFFICIENCY DIALYSIS Dialysate Sodium Potassium Acetate Bicarbonate Magnesium Calcium Glucose FACTORS INFLUENCING BLOOD FLOW IN HIGH-EFFICIENCY HEMODIALYSIS Type of access Native arteriovenous fistulae, polytetrafluoroethylene grafts, tw in catheter systems: high blood flow rate, >350 mL/min Permanent catheters, temp orary intravenous catheters: low blood flow rate, <350 mL/min Needle design: siz e, thickness, and length Blood tubing Pump design Concentration 139145 mEq/L 04 mEq/L 2.54.5 mEq/L 3540 mEq/L 1 mEq/L 2.53.5 mEq/L 0200 mg/dL FIGURE 3-9 Technical requirements for high-efficiency dialysis. The KoA is the t heoretic value of the urea clearance rate under conditions of infinite blood and dialysate flow. High blood and dialysate flow rates are necessary to achieve op timal performance of high-efficiency dialyzers. Bicarbonate-containing dialysate is necessary to prevent symptoms associated with acetate intolerance (ie, nause a, vomiting, headache, and hypotension), worsening of metabolic acidosis, and ca rdiac arrhythmia [6,8,9]. Komass transfer coefficient; Asurface area. FIGURE 3-10 Concentration of dialysate in high-efficiency dialysis. Although the concentration of other ions is variable, high bicarbonate concentration, relati ve to that of acetate, is essential for high-efficiency dialysis in order to min imize the transfer of acetate into the patient. FIGURE 3-11 Factors influencing blood flow in high-efficiency hemodialysis. Arte riovenous fistulae often have blood flow rates of over 1000 mL/min, as measured by current noninvasive devices. Polytetrafluoroethylene grafts and the newly int roduced twin catheter systems also are capable of providing the blood flow rates necessary for high-efficiency hemodialysis. In contrast, most other temporary o r semipermanent catheters cannot provide sufficient blood flow reliably enough f or adequate dialysis delivery in a short time period. Needles, blood tubing diam eter, and blood pumps may also contribute to this problem [8,9].

High-Efficiency and High-Flux Hemodialysis 3.5 CAUSES OF HIGH-EFFICIENCY DIALYSIS FAILURE Access-related Low blood flow rate High recirculation rate Time-related Patient not adherent to prescribed time Staff not adherent to prescribed time Failure to adjust time for conditions such as alarm, dialysate bypass, and hypotension BENEFITS OF HIGHEFFICIENCY DIALYSIS Higher clearance of small solutes, such as urea, compared with conventional dial ysis without increase in treatment time Better control of chemistry Potentially reduced morbidity Potentially higher patient survival rates LIMITATIONS OF HIGHEFFICIENCY DIALYSIS Hemodynamic instability Low margin of safety if short treatment time is prescrib ed Potential vascular access damage Dialysis disequilibrium syndrome FIGURE 3-12 Causes of high-efficiency dialysis failure. The maintenance of a hig h blood flow rate (>350 mL/min) is essential for high-efficiency hemodialysis. F istula recirculation, regardless of the blood flow rate, compromises achievement of the urea Kt/V goal. Interruptions during the prescribed short treatment time further compromise the overall delivery of the prescribed Kt/V [6,7]. Kurea clea rance; ttime of therapy; Vvolume of distribution. FIGURE 3-13 Benefits of high-efficiency dialysis. With improved control of bioch emical parameters (such as potassium, hydrogen ions, phosphate, urea, and other nitrogenous compounds) the potential exists for reduced morbidity and mortality without increasing dialysis treatment time [5,7]. FIGURE 3-14 Limitations of high-efficiency dialysis. Removal of a large volume o f fluid over a short time period (22.5 h) increases the likelihood of hypotension , especially in patients with poor cardiac function or autonomic neuropathy. The loss of a fixed amount of treatment time has a proportionally greater impact du ring a short treatment time than during a long treatment time. Thus, the margin of safety is narrower if a short treatment time is used in conjunction with high -efficiency dialysis compared with conventional hemodialysis with a longer treat ment time. Although unproved, high blood flow rates may predispose patients to v ascular access damage. Rapid solute shifts potentially precipitate the dialysis disequilibrium syndrome in those patients with a very high blood urea nitrogen c oncentration, especially during the first treatment [3,7,9]. CHARACTERISTICS OF HIGH-FLUX DIALYSIS Dialyzer membranes are characterized by a high ultrafiltration coefficient (Kuf > 20 mL/h/mm Hg) High clearance of middle molecular weight molecules occurs (eg, 2-microglobulin) Urea clearance can be high or low, depending on the urea KoA o f the dialyzer Dialyzers are made of either synthetic or cellulosic membranes Hi gh-flux dialysis requires an automated ultrafiltration control system FIGURE 3-15 Characteristics of high-flux dialysis. Because of the high ultrafilt ration coefficients of high-flux membranes, high-flux dialysis requires an autom ated ultrafiltration control system to avoid accidental profound intravascular v olume depletion. Because high-flux membranes tend to have larger pores, clearanc e of middle molecular weight molecules is usually high. Urea clearance rates for high-flux dialyzers are still dependent on urea KoA values, which can be either high (ie, high-flux high-efficiency) or low (ie, high-flux lowefficiency) [3,4, 10]. Komass transfer coefficient; Asurface area.

3.6 Dialysis as Treatment of End-Stage Renal Disease TECHNICAL REQUIREMENTS FOR HIGH-FLUX DIALYSIS High-flux dialyzer Automated ultrafiltration control system POTENTIAL BENEFITS OF HIGH-FLUX DIALYSIS Delayed onset and risk of dialysis-related amyloidosis because of enhanced 2-mic roglobulin clearance [11,12] Increased patient survival resulting from higher cl earance of middle molecular weight molecules [12,13,15,16] Reduced morbidity and hospital admissions [14,16] Improved lipid profile [16,17] Higher clearance of aluminum [18] Improved nutritional status [19,20] Reduced risk of infection [16, 21] Preserved residual renal function [22] LIMITATIONS OF HIGH-FLUX DIALYSIS Enhanced drug clearance, requiring supplemental dose after dialysis High cost of dialyzers FIGURE 3-16 Technical requirements for high-flux dialysis. Because of the potent ial for reverse filtration (movement of fluid from dialysate to the blood compar tment) to occur, use of a pyrogen-free dialysate is preferred but not mandatory. Bicarbonate concentrate used to prepare dialysate is particularly prone to bact erial overgrowth when stored for more than 2 days [5,8]. FIGURE 3-18 Limitations of high-flux dialysis. The enhanced clearance of drugs d epends on the physicochemical characteristics of the specific drug and dialysis membrane. Because of their relative high costs, highflux dialyzers are usually r eused. FIGURE 3-17 Potential benefits of high-flux dialysis. Data are accumulating that support many potential benefits of high-flux dialysis. Large-scale randomized p rospective trials, however, are unavailable. FIGURE 3-19 Examples of commonly us ed dialyzers. Efficiency refers to the capacity to remove urea; flux refers to the c apacity to remove water, and indirectly, the capacity to remove molecules of mid dle molecular weight. Cellulosic membranes can be either low flux or high flux. Similarly, synthetic membranes can be either low flux or high flux. Highefficien cy membranes usually have large surface areas. EXAMPLES OF COMMONLY USED DIALYZERS Dialyzer type Low-flux low-efficiency CA90 CF12 Low-flux high-efficiency CA150 T150 High-flux low-efficiency F50 PAN 150P High-flux high-efficiency CT190 F80 Material Cellulose acetate Cuprammonium Cellulose acetate Cuprammonium Polysulfone Polyac rylonitrile Cellulose triacetate Polysulfone Surface area, m2 0.9 0.7 1.5 1.5 0.9 1.0 1.9 1.8 KoA (in vitro), mL/min 410 418 660 730 520 420 920 945 Komass transfer coefficient; Asurface area. Adapted from Leypoldt and coworkers [4 ] and Van Stone [22].

High-Efficiency and High-Flux Hemodialysis 3.7 Solutes Cb Cb Cb Postdilution Ultrafiltrate Solute flux Fluid flux Cd Blood Membrane Ultrafiltrate Blood Membr ane Solute flux Predilution Ultrafiltrate Blood FIGURE 3-20 Solute transport in hemodialysis. The primary mechanism of solute tr ansport in hemodialysis is diffusion, although convective transport is also cont ributory. Solutes small enough to pass through the dialysis membrane diffuse dow n a concentration gradient from a higher plasma concentration (Cb) to a lower di alysate concentration (Cd). The arrow represents the direction of solute transpo rt. FIGURE 3-21 Solute clearance in hemofiltration. Hemofiltration achieves solute c learance by convection (or the solvent drag effect) through the membrane. In con trast to diffusive hemodialysis, fluid flux is a prerequisite for the removal of solutes during hemofiltration, whereas the concentration gradient is not. For s mall solutes (eg, urea) that traverse the membrane unimpeded, concentrations in the blood compartment (Cb) and ultrafiltrate compartment (Cuf) are equivalent. F or some molecules of middle molecular weight whose movement across the membrane is partially restricted, Cuf is lower than is Cb (ie, the sieving coefficient, d efined as Cuf/Cb, is less than 1.0). FIGURE 3-22 Fluid replacement in hemofiltration. Because hemofiltration achieves substantial solute clearance by removing large volumes of plasma water (which c ontains the dissolved solutes), the removed fluid must be replaced. The replacem ent fluid can be infused into the extracorporeal circuit before the blood enters the filter (predilution, or replacement before expenditure) or after the blood leaves the filter (postdilution). More replacement fluid is required when it is given before filtration rather than after to provide equivalent solute clearance because the plasma in the filter (and therefore the ultrafiltrate) is diluted i n the predilution mode. Postdilution Ultrafiltrate Dialysate FIGURE 3-23 Addition of diffusive transport in hemodiafiltration. In hemodiafilt ration, diffusive transport is added to hemofiltration to augment the clearance of solutes (usually small solutes such as urea and potassium). Solute clearance is accomplished by circulating dialysate in the dialysate-ultrafiltrate compartm ent. Hemodiafiltration is particularly useful in patients who have hypercataboli sm with large urea generation. Predilution Blood

3.8 Dialysis as Treatment of End-Stage Renal Disease Membranes Bacteria Macrophage ET FIGURE 3-24 Backfiltration, or reverse filtration, of endotoxins (ET) from dialy sate to blood. Reverse filtration of ET is particularly prone to occur when high -flux membranes are used and the dialysate is heavily contaminated with bacteria (>2000 CFU/mL) and may result in pyrogenic reactions. The dialysis membranes ar e impermeable to intact ET; however, their fragments (some of which still are py rogenic) may be small enough to traverse the membrane. Although the membrane is impermeable to bacteria and blood cells, a mechanical break in the membrane coul d result in bacteremia. ET fragments Dialysate Membrane Blood H 2O H 2O H 2O H 2O H 2O FIGURE 3-25 Dialysis membranes with small and large pores. Although a general co rrelation exists between the (water) flux and the (middle molecular weight molec ule) permeability of dialysis membranes, they are not synonymous. A, Membrane wi th numerous small pores that allow high water flux but no 2-microglobulin transp ort. B, Membrane with a smaller surface area and fewer pores, with the pore size sufficiently large to allow 2-microglobulin transport. The ultrafiltration coef ficient and hence the water flux of the two membranes are equivalent. A H 2O H 2O H 2O H 2O B A FIGURE 3-26 Scanning electron microscopy of a conventional low-flux-membrane hol low fiber (panel A) and a synthetic high-flux-membrane hollow fiber (panel B). T he low-flux membrane consists of a single layer of relatively homogenous materia l. The high-flux membrane has a three-layer structure, ie, finger, sponge, and s kin. The skin is a thin semipermeable layer that functions as the selective barr ier; it is mechanically supported by the sponge and finger layers. (Magnificatio n: finger, 14,000; sponge 17,000; skin 85,000.) (Courtesy of Goehl H, Gambrogrou p). B

High-Efficiency and High-Flux Hemodialysis 3.9 Dialysate flow rate 300 280 Urea clearance rate, mL/min 260 240 220 200 180 160 140 120 100 200 250 300 350 400 Blood flow rate, mL/min 450 500 Qd=800 Qd=500 FIGURE 3-27 Effect of the dialysate flow rate (Qd) on the urea clearance rate by a high-efficiency dialyzer with a urea KoA value of 800 mL/min. At low blood fl ow rates (<200 mL/min), no difference exists in urea clearance rates between the two different Qd conditions, because equilibrium in urea concentrations between blood and dialysate is readily achieved. When the blood flow rate is high (>300 mL/min), the higher Qd maintains a higher concentration gradient for diffusion of urea, and therefore, the urea clearance rate is higher. Recent studies have s hown that the KoA value of dialyzers also increases with higher dialysate flow r ates [4], presumably because of more uniform distribution of dialysate flow. The refore, the actual urea clearance rate may increase further (red line). Komass tr ansfer coefficient; Asurface area. Backfiltration Blood flow Blood /Dialysate inlet outlet Pbi Dialysate flow Blood /Dialysate out let inlet 150 Pressure, mm Hg 140 130 120 Pdi Ultrafiltrate x Back filtrate Pdo FIGURE 3-28 Pressure inside the blood compartment (dark colored arrow) and the d ialysate compartment (light colored arrow) with a fixed net zero ultrafiltration rate. The pressure gradually decreases in the blood compartment as blood travel s from the inlet toward the outlet. Beyond a certain point along the dialyzer le ngth (x, where the two pressure lines intersect), the pressure in the dialysate compartment exceeds that in the blood compartment, forcing fluid to move from th e dialysate to the blood compartment. This movement of fluid in the direction op posite to that of the designed ultrafiltration is called backfiltration. Backfil tration may carry with it contaminants (eg, endotoxins) from the dialysate. Incr easing the net ultrafiltration rate shifts the pressure intersection point to th e right and diminishes backfiltration. 110 100 Pbo

3.10 Dialysis as Treatment of End-Stage Renal Disease References 1. Tokars JI, Alter MJ, Miller E, et al.: National surveillance of dialysis asso ciated disease in the United States: 1994. ASAIO J 1997, 43:108119. 2. United Sta tes Renal Data System, 97: Treatment modalities for ESRD patients. Am J Kidney D is 1997, 30:S54S66. 3. Cheung AK, Leypoldt JK: The hemodialysis membranes: a hist orical perspective, current state and future prospect. Sem Nephrol 1997, 17:19621 3. 4. Leypoldt JK, Cheung AK, Agodoa LY, et al.: Hemodialyzer mass transferarea c oefficients for urea increase at high dialysate flow rates. Kidney Int 1997, 51: 20132017. 5. Collins AJ, Keshaviah P: High-efficiency, high flux therapies in cli nical dialysis. In Clinical Dialysis, edn 3. Edited by Nissenson AR. 1995:848863. 6. Collins AJ: High-flux, high-efficiency procedures. In Principles and Practic e of Hemodialysis. Edited by Henrich W. Norwalk, CT: Appleton & Large; 1996:7688. 7. von Albertini B, Bosch JP: Short hemodialysis. Am J Nephrol 1991, 11:169173. 8. Keshaviah P, Luehmann D, Ilstrup K, Collins A: Technical requirements for rap id high-efficiency therapies. Artificial Organs 1986, 10:189194. 9. Shinaberger J H, Miller JH, Gardner PW: Short treatment. In Replacement of Renal Function by D ialysis, edn 3. Edited by Maher JF. Norwell, MA: Kluwer Academic Publishers; 198 9:360381. 10. Barth RH: High flux hemodialysis: overcoming the tyranny of time. C ontrib Nephrol 1993, 102:7397. 11. Van Ypersele, De Strihou C, Jadoul M, et al.: The working party on dialysis amyloidosis: effect of dialysis membrane and patie nt's age on signs of dialysis-related amyloidosis. Kidney Int 1991, 39:10121019. 12 . Koda Y, Nishi S, Miyazaki S, et al.: Switch from conventional to highflux memb rane reduces the risk of carpal tunnel syndrome and mortality of hemodialysis pa tients. Kidney Int 1997, 52:10961101. 13. Chandran PKG, Liggett R, Kirkpatrick B: Patient survival on PAN/AN 69 membrane hemodialysis: a ten year analysis. J Am Soc Nephrol 1993, 4:11991204. 14. Hornberger JC, Chernew M, Petersen J, Garber AM : A multivariate analysis of mortality and hospital admissions with high-flux di alysis. J Am Soc Nephrol 1992, 3:12271236. 15. Hakim RM, Held PJ, Stannard DC, et al.: Effect of the dialysis membrane on mortality of chronic hemodialysis patie nts. Kidney Int 1996, 50:566570. 16. Churchill DN: Clinical impact of biocompatib le dialysis membranes on patient morbidity and mortality: an appraisal of eviden ce. Nephrol Dial Trans 1995, 10(suppl):5256. 17. Seres DS, Srain GW, Hashim SA, e t al.: Improvement of plasma lipoprotein profiles during high flux dialysis. J A m Soc Nephrol 1993, 3:14091415. 18. Mailloux LU: Dialysis modality and patient ou tcome. UpToDate Med 1995. 19. Parker TF III, Wingard RL, Husni L, et al.: Effect of the membrane biocompatibility on nutritional parameters in chronic hemodialy sis patients. Kidney Int 1996, 49:551556. 20. Ikizler TA, Hakim RM: Nutrition in end-stage renal disease. Kidney Int 1996, 50:343357. 21. Hakim RM, Wingard RL, Pa rker RA, et al.: Effects of biocompatibility on hospitalizations and infectious morbidity in chronic hemodialysis patients. J Am Soc Nephrol 1994, 5:450. 22. Va n Stone JC: Hemodialysis apparatus. In Handbook of Dialysis, edn 2. Edited by Da ugirdas JT, Ing TS. Boston/New York: Little, Brown & Co.; 1994:3152.

Principles of Peritoneal Dialysis Ramesh Khanna Karl D. Nolph P eritoneal dialysis is a technique whereby infusion of dialysis solution into the peritoneal cavity is followed by a variable dwell time and subsequent drainage. Continuous ambulatory peritoneal dialysis (CAPD) is a continuous treatment cons isting of four to five 2-L dialysis exchanges per day (Fig. 4-1A). Diurnal excha nges last 4 to 6 hours, and the nocturnal exchange remains in the peritoneal cav ity for 6 to 8 hours. Continuous cyclic peritoneal dialysis, in reality, is a co ntinuous treatment carried out with an automated cycler machine (Fig. 4-1B). Mul tiple short-dwell exchanges are performed at night with the aid of an automated cycler machine. Other peritoneal dialysis treatments consist of intermittent reg imens (Fig. 4-2A-C). During peritoneal dialysis, solutes and fluids are exchange d between the capillary blood and the intraperitoneal fluid through a biologic m embrane, the peritoneum. The three-layered peritoneal membrane consists of 1) th e mesothelium, a continuous monolayer of flat cells, and their basement membrane s; 2) a very compliant interstitium; and 3) the capillary wall, consisting of a continuous layer of mainly nonfenestrated endothelial cells, supported by a base ment membrane. The mesothelial layer is considered to be less of a transport bar rier to fluid and solutes, including macromolecules, than is the endothelial lay er [1]. The capillary endothelial cell membrane is permeable to water through aq uaporins (radius of approximately 0.2 to 0.4 nm) [2]. In addition, small solutes and water are transported through ubiquitous small pores (radius of approximate ly 0.4 to 0.55 nm). Sparsely populated large pores (radius of approximately 0.25 nm, perhaps mainly venular) transport macromolecules passively. Diffusion and c onvection move small molecules through the interstitium with its gel and sol pha ses, which are restrictive owing to the phenomenon of exclusion [3,4]. The splan chnic blood flow in the normal adult ranges from 1.0 to 2.4 L/min, arising from celiac and mesenteric arteries [5]. The lymphatic vessels located primarily in t he subdiaphragmatic region drain fluid and solutes from the peritoneal cavity th rough bulk transport. CHAPTER 4

4.2 Dialysis as Treatment of End-Stage Renal Disease fraction of glucose absorbed from the dialysate at specific times can be determi ned by the ratio of dialysate glucose concentrations at specific times to the in itial level in the dialysis solution. Tests are standardized for the following: duration of the preceding exchange before the test; inflow volume; positions dur ing inflow, drain, and dwell; durations of inflow and drain; sampling methods an d processing; and laboratory assays [7]. Creatinine and urea clearance rates are the most commonly used indices of dialysis adequacy in clinical settings. Contr ibutions of residual renal clearances are significant in determining the adequac y of dialysis. The mass-transfer area coefficient (MTAC) represents the clearanc e rate by diffusion in the absence of ultrafiltration and when the rate of solut e accumulation in the dialysis solution is zero. Peritoneal clearance is influen ced by both blood and dialysate flow rates and by the MTAC [8]. Therefore, the m aximum clearance rate can never be higher than any of these parameters. At infin ite blood and dialysate flow rates, the clearance rate is equal to the MTAC and is mass-transferlimited. Large molecular weight solutes are mass-transferlimited; therefore, their clearance rates do not increase significantly with high dialysa te flow rates [9]. In CAPD, blood flow and MTAC rates are higher than is the max imum achievable urea clearance rate. However, the urea clearance rate approximat ely matches the dialysate flow rate, suggesting that the dialysate flow rate lim its CAPD clearances. The extent of lymph drainage from the peritoneal cavity is a subject of controve rsy owing to the lack of a direct method to measure lymph flow. Dialysis solutio n contains electrolytes in physiologic concentrations to facilitate correction o f acid-base and electrolyte abnormalities. High concentrations of glucose in the dialysis solution generate ultrafiltration in proportion to the overall osmotic gradient, the reflection coefficients of small solutes relative to the peritone um, and the peritoneal membrane hydraulic permeability. Removal of solutes such as urea, creatinine, phosphate, and other metabolic end products from the body d epends on the development of concentration gradients between blood and intraperi toneal fluid, and the transport is driven by the process of diffusion. The amoun t of solute removal is a function of the degree of its concentration gradient, t he molecular size, membrane permeability and surface area, duration of dialysis, and charge. Ultrafiltration adds a convective component proportionately more im portant as the molecular size of the solute increases. The peritoneal equilibrat ion test is a clinical tool used to characterize the peritoneal membrane transpo rt properties [6]. Solute transport rates are assessed by the rates of their equ ilibration between the peritoneal capillary blood and dialysate (see Fig. 4-8). The ratio of solute concentrations in dialysate and plasma at specific times dur ing the dwell signifies the extent of solute transport. The Peritoneal Dialysis Regimens Day Night Day Night Left 2.0 1.0 0.0 FIGURE 4-1 Continuous peritoneal dialysis regimens. A, Continuous ambulatory per itoneal dialysis (CAPD); B, continuous cyclic peritoneal dialysis (CCPD) is show n. Multiple sequential exchanges are performed during the day and night so that dialysis occurs 24 hours a day, 7 days a week. A Day Night

Day Night Right 2.0 1.0 0.0 B Exchanges, n

Principles of Peritoneal Dialysis 4.3 Day Left 2.0 1.0 0.0 Night Day Night A FIGURE 4-2 Intermittent peritoneal dialysis regimens. Peritoneal dialysis is per formed every day but only during certain hours. A, In daytime ambulatory periton eal dialysis (DAPD), multiple manual exchanges are performed during the waking h ours. B, Nightly peritoneal dialysis (NPD) is also performed while patients are asleep using an automated cycler machine. One or two additional daytime manual e xchanges are added to enhance solute clearances. Left 2.0 1.0 0.0 Day Night Day Night B Solute Removal 24 Blood urea nitrogen, mg/dL 100 Creatinine, mg/dL 80 60 40 20 0 0 80 160 240 3 20 400 480 Dialysate Blood 20 16 12 8 4 0 0 40 80 120 160 200 Time, min 240 280 Dialysate Blood 20 560 A Time, min B 320 360 FIGURE 4-3 Solute removal. Solute concentration gradients are at maximum at the beginning of dialysis and diminish gradually as dialysis progresses. As the grad ients diminish, the solute removal rates decrease. Solute removal can be enhance d by increasing the dialysate flow

rate by either increasing the intraperitoneal dialysate volume per exchange or i ncreasing the frequency of exchange. By convection or enhanced diffusion, solute s are able to accompany the bulk flow of water. (From Nolph and coworkers [10]; with permission.)

4.4 1.0 0.9 Dialysis as Treatment of End-Stage Renal Disease 1.0 0.9 Dialysate to plasma ratio 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 100 200 300 500 400 Dwell time, min Urea Creatinine Uric acid Phosphorus Inulin Calcium Dialysate to plasma ratio 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 100 200 300 500 400 Dwell time, min Urea Creat inine Uric acid Phosphorus Inulin Calcium A B FIGURE 4-4 Solute removal. The rates of change of solute concentrations are simi lar for 1.5% dextrose dialysis solutions (panel A) and 4.25% dextrose dialysis s olutions (panel B). Hypertonic exchanges enhance solute removal owing to larger drain volumes. Net solute diffusion ceases at equilibration when the dialysate t o plasma solute ratio (D/P) is near 1.0. Smaller size solutes (ie, urea and creatinine) diffuse across the m embrane faster, equilibrate sooner, and are influenced more by exchange frequenc y as compared with larger size solutes (ie, uric acid, phosphates, inulin, and p roteins). (From Nolph and coworkers [10]; with permission.) Total dialysate volume (V) Creatnine dialysate to plasma ratio (D/P) Creatinine clearance per exchange (Ccr) High transport 1.0 0.5 0 2600 2300 2000 1700 0 NIPD DAPD NTPD CCPD (NE) CAPD CCPD (DE) Low transport 2 1 D/P=1 Ccr=V Ccr=V D/P 1 2 3 4 5 6

7 0 1 2 A Dwell time, h B 3 4 5 Dwell time, h 6 7 1 2 C 3 4 5 Dwell time, h 6 7 FIGURE 4-5 Solute removal. In a highly permeable membrane, smaller molecules (ie , urea and creatinine) are transported at a faster rate from the blood to dialys ate than are larger molecules, enhancing solute removal. Similarly, glucose (a s mall solute used in the peritoneal dialysis solution to generate osmotic force f or ultrafiltration across the peritoneal membrane) is also transported faster, b ut in the opposite direction. This high transporter dissipates the osmotic force more rapidly than does the low transporter. Both osmotic and glucose equilibriu ms are attained eventually in both groups, but sooner in the high transporter gr oup. Intraperitoneal volume peaks and begins to diminish earlier in the high tra nsporter group. When the membrane is less permeable, solute removal is lower, ul trafiltration volume is larger at 2 hours or more, and glucose equilibriums are attained later. Consequently, intraperitoneal volume peaks later. Ultrafiltration in a low trans porter peaks late during dwell time. Therefore, a low transporter continues to g enerate ultrafiltration even after 8 to 10 hours of dwell. The solute creatinine dialysate to plasma ratio (D/P) increases linearly during the dwell time. Patie nts with average solute transfer rates have ultrafiltration and mass transfer pa tterns between those of high and low transporters. NIPDnightly intermittent perit oneal dialysis; NTPDnighttime tidal peritoneal dialysis; DAPDdaytime ambulatory pe ritoneal dialysis; CAPDcontinuous ambulatory peritoneal dialysis; CCPD (NE)continu ous cyclic peritoneal dialysis (night exchange); CCPD (DE)continuous cyclic perit oneal dialysis (day exchange). (From Twardowski [11]; with permission.)

Principles of Peritoneal Dialysis 4.5 150 140 130 120 110 100 90 Inflow 0 Sodium, mLq/L Serum and dialysate 1.5% dextrose dialysis solutions A 100 200 300 400 500 Dwell time, min 150 140 130 120 110 100 90 Inflow 0 Sodium, mLq/L Serum and dialysate 4.25% dextrose dialysis solutions B 100 200 300 400 Dwell time, min 500 FIGURE 4-6 Solute sieving. A, Dialysate sodium concentration is initially reduce d and tends to return to baseline later during a long dwell exchange of 6 to 8 h ours. B, Dialysate sodium concentration decreases, particularly when using 4.25% dextrose dialysis solution, because of the sieving phenomenon. Removal of water during ultrafiltration unaccompanied by sodium, in proportion to its extracellu lar concentration, is called sodium sieving [7,12]. The peritoneum offers greate r resistance to the movement of solutes than does water. This probably relates t o approximately half the ultrafiltrate being generated by solute-free water move ment through aquaporins channels. Therefore, ultrafiltrate is hypotonic compared with plasma. Dialysate chloride is also reduced below simple Gibbs-Donnan equil ibrium, particularly during hypertonic exchanges. Patients with a low peritoneal membrane transport type tend to reduce dialysate sodium concentration more than do other patients. Therefore, during a short dwell exchange of 2 to 4 hours, ne t electrolyte removal per liter of ultrafiltrate is well below the extracelluar fluid concentration. As a result, severe hypernatremia, excessive thirst, and hy pertension may develop. This hindrance can be overcome by lowering the dialysate sodium concentration to 132 mEq/L. In patients who use cyclers with short dwell exchanges and who generate large ultrafiltration volumes, lower sodium concentr ations may need to be used (such as 118 mEq/L for 2.5% glucose solutions or 109 mEq/L for 4.25% solutions). In continuous ambulatory peritoneal dialysis with lo ng dwell exchanges of 6 to 8 hours, significant sieving usually does not occur, whereas in automated peritoneal dialysis with short dwell exchanges, sieving may occur. Sieving predisposes patients to thirst and less than optimum blood press ure control, especially in those who have low-normal serum sodium levels, those with low peritoneal membrane transporter rates, or both. (From Nolph and coworke rs [10]; with permission.) FIGURE 4-7 Fluid removal by ultrafiltration. During p eritoneal dialysis, hyperosmolar glucose solution generates ultrafiltration by t he process of osmosis. Water movement across the peritoneal membrane is proporti onal to the transmembrane pressure, membrane area, and membrane hydraulic permea bility. The transmembrane pressure is the sum of hydrostatic and osmotic pressur e differences between the blood in the peritoneal capillary and dialysis solutio n in the peritoneal cavity. Net transcapillary ultrafiltration defines net fluid movement from the peritoneal microcirculation into the peritoneal cavity primar ily in response to osmotic pressure. Net ultrafiltration would equal the resulti

ng increment in intraperitoneal fluid volume if it were not for peritoneal reabs orption, mostly through the peritoneal lymphatics. Peritoneal reabsorption is co ntinuous and reduces the intraperitoneal volume throughout the dwell. A, The net transcapillary ultrafiltration rate decreases exponentially during the dwell ti me, owing to dissipation of the glucose osmotic gradient secondary to peritoneal glucose absorption and dilution of the solution glucose by the ultrafiltration. Later in the exchange net, ultrafiltration ceases when the transcapillary ultra filtration is reduced to a rate equal to the peritoneal reabsorption. B, When th e transcapillary ultrafiltration rate decreases below that of the peritoneal rea bsorption rate, the net ultrafiltration rate becomes negative. Consequently, the intraperitoneal volume begins to diminish. Thus, peak ultrafiltration and intra peritoneal volumes are observed before osmotic equilibrium during an exchange. ( Continued on next page) Transcapillary ultrafiltration Lymphatic absorption 600 500 400 mL/h 300 Peak ultrafiltration volume 200 100 A 0 1 2 Dwell time, h 3 2800 Intraperitoneal Peak intraperitoneal volume Dialysate 2600 2400 0 1 2 Dwell time, h 3 4 B

4.6 360 Dialysis as Treatment of End-Stage Renal Disease FIGURE 4-7 (Continued) C, Osmotic equilibrium most likely precedes glucose equil ibrium because of both solute sieving and the higher peritoneal reflection coeff icient of glucose compared with other dialysate solutes, allowing net transcapil lary ultrafiltration to continue at a low rate even after osmotic equilibrium. D , Ultrafiltration can be maximized by measures that delay osmotic equilibrium, w hich can be accomplished by using hypertonic glucose solutions, larger volumes, or both, during an exchange. More frequent exchanges shorten dwell times and inc rease the dialysate flow rate and thus avert attaining osmotic equilibrium. Addi tionally, potential exists for enhancing ultrafiltration by measures that reduce the peritoneal reabsorption rate. (From Mactier and coworkers [13]; with permis sion.) Osmolality, mOsm/L Dialysate Serum 340 320 300 Osmotic equilibrium C 0 1 2 3 Dwell time, h 4 Glucose, mOsm/L 2000 Dialysate Serum Hypothetical glucose equilibrium 1000 0 1 D 2 3 Dwell time, h 4 STANDARDIZED 4-HOUR PERITONEAL EQUILIBRATION TEST 1. Perform an overnight 8- to 12-h preexchange. 2. Drain the overnight exchange (drain time not to exceed 25 min) with patient in the upright position. 3. Infus e 2 L of dialysis solution over 10 min with patient in the supine position. Roll the patient from side to side after every 400-mL infusion. 4. After the complet ion of infusion (0 time) and at 120 min, drain 200 mL of dialysate. Take a 10-mL sample, and reinfuse the remaining 190 mL into the peritoneal cavity. 5. Positi on the patient upright, and allow patient ambulation if able. 6. Obtain a serum sample at 120 min. 7. At the end of study (240 min), drain the dialysate with th

e patient in the upright position (drain time not to exceed 20 min). 8. Measure the drained volume, and take a 10-mL sample from the drained volume after a good mixing. 9. Analyze the blood and dialysate samples for creatinine and glucose c oncentrations. 10. Correct the serum and dialysate creatinine concentrations for high glucose level (correction factor 0.000531415). 11. Calculate the dialysate to plasma ratios for creatinine, and so on, and calculate the Dt/D0 glucose. FIGURE 4-8 Standardized 4-hour peritoneal equilibration test. Dt/D0 glucosefinal to initial dialysate glucose ratio. Correction of creatinine levels Corrected creatinine (mg/dL) = Observed creatinine (mg/dL) (glucose [mg/dL] x 0. 000531415) FIGURE 4-9 Equation to correct the creatinine levels in dialysate and serum. The creatinine levels in dialysate and serum need to be corrected for high glucose levels, which contribute to formation of noncreatinine chromogens during the cre atinine assay. The correction factor may vary from one laboratory to another. In our laboratory at the University of MissouriColumbia, the correction factor is 0 .000531415. Accordingly, the corrected creatinine is calculated as in the equati on. The correction in the serum is minimal due to low blood sugar levels; howeve r, it is significant in dialysate, especially during the early phase of dwell (0 - and 2-hour dialysate samples).

Principles of Peritoneal Dialysis 4.7 Intraperitoneal residual volume R= Vin(S3 S2) (S1 S3) FIGURE 4-10 Equation to calculate the intraperitoneal residual volume. Residual volume is the volume of dialysate remaining in the peritoneal cavity after drain age over 20 minutes. The residual volume can be determined by knowing the diluti on factor for solutes such as potassium, urea, and creatinine during the next in stillation. The calculation of residual volumes is based on the assumption that the mixing of fluid in the peritoneal cavity is instantaneous and complete. This equation is used for the calculation, where Vin is instillation volume; S1 is s olute concentration in pretest exchange dialysate; S2 is solute concentration in instilled dialysis solution; and S3 is solute concentration immediately after i nstillation (0 dwell time). The residual volumes by urea, creatinine, glucose, p otassium, and protein are calculated and averaged for accuracy. The measurement of residual volumes is of limited clinical usefulness; however, it is of great v alue in a research setting in which accurate determination of intraperitoneal vo lume is required. FIGURE 4-11 Classification of peritoneal transport function. B ased on the peritoneal equilibrium test results, peritoneal transport function m ay be classified into average, high (H), and low (L) transport types. The averag e transport group is further subdivided into high-average (HA) and low-average ( LA) types. For the population studied by Twardowski and coworkers [6], the trans port classification is based on means; standard deviations (SDs); and minimum an d maximum dialysate to plasma ratio (D/P) values over 4 hours for urea, creatini ne, glucose, protein, potassium, sodium, and corrected creatinine (panels AG). (C ontinued on next page) 1.1 0.9 Dialysis to plasma ratio 0.7 0.5 0.3 0.1 0 1.1 Urea Creatinine 0.9 Dialysis to plasma ratio 0.7 0.5 0.3 0.1 1/ 2 1 2 Hours 3 4 0 1/ 2 1 2 Hours 3 4

A B 1.1 Final to initial dialysate glucose ratio 0.9 0.7 0.5 0.3 0.1 0 Glucose 35 Dialysate to plasma ratio 1000 30 25 20 15 10 5 0 Protein C 1/ 2 1 2 Hours 3 4 0 1/ 2 1 D 2 Hours 3 4

4.8 1.1 Potassium Dialysis as Treatment of End-Stage Renal Disease FIGURE 4-11 (Continued) The volume of drainage correlates positively with dialys ate glucose and negatively with D/P creatinine values at 4-hour dwell times (pan el H). (From Twardowski and coworkers [6]; with permission.) 1.00 Sodium 0.9 Dialysate to plasma ratio Dialysate to plasma ratio 0.7 0.90 0.5 0.80 H HA LA L 0.70 0.3 Max +SD SD Min 0.1 0 E 0 1/ 2 1 2 Hours 3 4 0 F 1/ 2 1 2 Hours 3 4 ADK vol05 ch p04 fig11F 1.1 Corrected creatinine 3000 0.9 2500 3500

Max +SD x SD Min Dialysate to plasma ratio 0.7 mL 0.5 2000 1500 1000 0.3 H HA LA L 500 0 0.1 0 G 0 1/ 2 1 2 Hours 3 4 H Drain volume Residual pre-eq Volume post-eq CLINICAL APPLICATIONS OF THE PERITONEAL EQUILIBRATION TEST Peritoneal membrane transport classification 1. Choose peritoneal dialysis regim en. 2. Monitor peritoneal membrane function. 3. Diagnose acute membrane injury. 4. Diagnose causes of inadequate ultrafiltration. 5. Diagnose causes of inadequa te solute clearance. 6. Estimate dialysate to plasma ratio of a solute at time t . 7. Diagnose early ultrafiltration failure. 8. Predict dialysis dose. 9. Assess influence of systemic disease on peritoneal membrane function. FIGURE 4-12 In clinical practice it is customary to perform the baseline standar dized peritoneal equilibrium test (PET) approximately 3 to 4 weeks after cathete r insertion. The PET is repeated when complications occur. The standardized test for clinical use measures dialysate creatinine and glucose levels at 0, 2, and 4 hours of dwell time and serum levels of creatinine and glucose at any time dur ing the test. The extensive unabridged test, as originally proposed by Twardowsk i and coworkers [6], has become a very important research tool.

Principles of Peritoneal Dialysis 4.9 Baseline peritoneal equilibrium test High transporter D/P creatinine 16% High av erage transporter D/P creatinine 68% Low average transporter D/P creatinine Low transporter D/P creatinine 16% FIGURE 4-13 Population distribution of peritoneal membrane transport types. Base line peritoneal equilibrium test results of patients on long-term peritoneal dia lysis in the United States suggest that approximately 68% have average transport rates, 16% have high transport rates, and another 16% have low transport rates [6]. Similar distributions of transport types have been documented worldwide [141 6]. D/Pdialysate to plasma ratio. Baseline peritoneal equilibrium test High NIPD DAPD High average NIPD CAPD Low a verage High-dose CAPD High-dose CCPD Low High-dose CCPD only when significant re sidual renal function is present FIGURE 4-14 Using transport type to select a peritoneal dialysis regimen. Becaus e clearance rates continue to increase with time, patients with low transport ra tes are treated with long dwell exchanges, ie, continuous cyclic peritoneal dial ysis (CCPD). Owing to the low rate of increase in the dialysate to plasma ratio (D/P), the clearance rate per unit of time is augmented relatively little by rap id exchange techniques such as nightly intermittent peritoneal dialysis (NIPD). On the contrary, the clearance per exchange rate over long dwell exchanges would be less in patients with high transport rates. During the short dwell time, pat ients with high transport rates capture maximum ultrafiltration and small solute s are completely equilibrated. Therefore, these patients are best treated with t echniques using short dwell exchanges, ie, NIPD or daytime ambulatory peritoneal dialysis (DAPD). Patients with average transport rates can be effectively treat ed with either short or long dwell exchange techniques. CAPDcontinuous ambulatory peritoneal dialysis. 1.0 0.97 Dialysate to plasma ratio 0.92 0.9 0.88 0.85 0.8 High High average Low average Low 0.80 FIGURE 4-15 Diagnosis of early ultrafiltration failure. The dialysate to plasma ratio (D/P) curve of sodium, during the unabridged peritoneal equilibrium test ( 2.5% dextrose dialysis solution), typically shows an initial decrease owing to t he high ultrafiltration rate. Because of sodium sieving, the ultrafiltrate is lo w in sodium. Consequently, the dialysate sodium is lowered, resulting in a lower D/P ratio of sodium. Later, during the dwell when ultrafiltration ceases, dialy sate sodium tends to equilibrate with that of capillary blood, returning the D/P ratio of sodium to baseline. Absence of the initial decrease of the D/P of sodi um is an indication of ultrafiltration failure and is typically seen in the earl y phase of sclerosing encapsulating peritonitis. (From Dobbie and coworkers [17] ; with permission.) 0.7 0.0 1.0 2.0 3.0

4.0

4.10 C= Dialysis as Treatment of End-Stage Renal Disease FIGURE 4-16 Creatinine and urea clearances rates. These rates are estimated by d ividing the amount of solute removed per unit of time by the plasma solute conce ntration. Alternatively, clearance also can be estimated by multiplying the solu te equilibration rate per unit of time by the volume of dialysate into which equ ilibration occurred over the same unit of time. By convention, the creatinine cl earance rate is normalized to body surface area. The urea clearance is normalize d to total body water (volume of urea distribution in the body) and is expressed as Kt/V. The Kt/Vvalue is a number without a unit ([mL/min min]/ mL). During in termittent dialysis, with a dialysate flow rate of 30 mL/min, the typical urea c learance is about 18 to 20 mL/min [18]. Increasing the dialysate flow rates to 3 .5 to 12 L/h by rapid exchanges increases the urea clearance rate to a maximum o f 30 to 40 mL/min. Beyond this maximum rate, the clearance rate begins to decrea se owing to the loss of membrane-fluid contact time with infusion and drainage; inadequate mixing may also occur [1922]. Clearance could be enhanced by increasin g the membrane-solution contact [23]. Continuous dialysate flow techniques using either two catheters or double-lumen catheters also have enhanced the urea clea rance rate to a maximum of 40 mL/min. At these high flow rates, poor mixing, cha nneling, abdominal pain, and poor drainage limit successful application. Maintai ning a fluid reservoir in the peritoneal cavity (called tidal peritoneal dialysi s) and then replacing only a fraction of the intraperitoneal volume rapidly, inc reases clearance rates by about 30% compared with the standard technique using t he same doses owing to maintaining fluid-membrane contact at higher dialysis-sol ution flow rates [2429]. During continuous ambulatory peritoneal dialysis (CAPD) in adults, the optimum volume that ensures complete membrane-solution contact is about 2 L [30,32]. Successful use of 2.5and 3.0-L volumes has been reported in adult patients undergoing CAPD; however, hernial complications are increased [32 ,33]. FIGURE 4-17 The mass-transfer area coefficient (MTAC). The MTAC represents the clearance rate by diffusion in the absence of ultrafiltration and when the solute accumulation in the dialysis solution is zero [3439]. MTAC is equal to the product of peritoneal membrane permeability (P) and effective peritoneal membra ne surface area (S). Thus, when both capillary blood and dialysate flows are inf inite, the clearance rate is directly proportional to the effective peritoneal s urface area and inversely proportional to the overall membrane resistance. Howev er, infinite blood and dialysate flows cannot be achieved, and the maximum clear ance rate is unattainable. The closest measurable value, the MTAC, was introduce d. The MTAC represents an instantaneous clearance without being influenced by ul trafiltration and solute accumulation in the dialysate. The MTAC is measured ove r a test exchange during which at least two blood and dialysate samples are obta ined at different dwell times. The precision of the measurement is enhanced with more data points. The MTAC is seldom used clinically; however, it is a very use ful research tool. (DxV) P where C = clearance in mL/min: DxV = dialysate solute removed per minute ; D = dialysate solute concentration; V = volume of dialysate in mL/min; and P = plasma solute concentration or C=(D/P) x V where C = clearance in mL/exchange a t time t; D/P = solute equilibrium rate at time t; and V = volume of dialysate a t time t A Kt/V where K = urea clearance in mL/min; t = minutes of therapy; and V = volume of urea distribution or total body water B Mass-transfer area coefficient

The diffusive mass transfer is estimated by M=I A (C C ) R P D A where M = diffusive mass transfer: A = effective membrane surface area; I = coef ficient of proportionality; R = sum of all resistances; Cp = solute concentratio n in the potential capillary blood; and CD = solute concentration in the dialysa te Dividing both sides of the equation by solute concentration in peripheral blood (CB) will yield instantaneous clearance or the MTAC; M A CP CD =K=I CB R CB CB ( ( B If the peritoneal capillary blood flow is infinite, Cp will equal Cb and A C Ki= I 1 D R CB ( ( C If the dialysate flow is also infinite, then Co will equal 0, and A Ki=Kmax=I R

Principles of Peritoneal Dialysis 4.11 References 1. Clough G, Michel CC: Quantitative comparisons of hydraulic permeability and e ndothelial intercellular cleft dimensions in single form capillaries. J Physiol 1988, 405:563576. 2. Pannekeet MM, Mulder JB, Weening JJ, et al.: Demonstration o f aquaporin-CHIP in peritoneal tissue of uremic and CAPD patients. Peritoneal Di al Int 1996, 16(suppl 1):S54. 3. Flessner MF, Dedrick RL, Schultz JS: Exchange o f macromolecules between peritoneal cavity and plasma. Am J Physiol 1985, 248:H1 5. 4. Flessner MF, Fenstermacher JD, Blasberg RG, Dedrick RL: Peritoneal absorpt ion of macromolecules studied by quantitative autoradiography. Am J Physiol 1985 , 248:H26. 5. Wade OL, Combes B, Childs AW, et al.: The effect of exercise on th e splanchnic blood flood and splanchnic blood volume in normal man. Clin Sci 195 6, 15:457. 6. Twardowski ZJ, Nolph KD, Khanna R, et al.: Peritoneal equilibratio n test. Peritoneal Dial Bull 1987, 7:138147. 7. Ahearn DJ, Nolph KD: Controlled s odium removal with peritoneal dialysis. Trans Am Soc Artif Intern Organs 1972, 2 8:423. 8. Popovich RP, Moncrief JW: Kinetic modeling of peritoneal transport: In Today's Art of Peritoneal Dialysis. Edited by Trevino-Bacerra A, Boen FST. Basel, Switzerland: Karger; 1979:5972. [Contributions to Nephrology, 1.] 9. Twardowski ZJ: Physiology of peritoneal dialysis. In Clinical Dialysis. Edited by Nissenson AR, Fine RN, Gentile DE, edn 3. Norwalk, CT: Appleton & Lange; 1995:322. 10. No lph KD, Twardowski ZJ, Popovich RP, et al.: Equilibration of peritoneal dialysis solutions during long dwell exchanges. J Lab Clin Med 1979, 93:246256. 11. Tward owski ZJ: Nightly peritoneal dialysis (why? who? how? and when?). Trans Am Soc A rtif Intern Organs 1990, 36:816. 12. Nolph KD, Hano JE, Teschan PE: Peritoneal so dium transport during hypertonic peritoneal dialysis: physiologic mechanisms and clinical implications. Ann Intern Med 1969; 70:931. 13. Mactier RA, Khanna R, T wardowski ZJ, et al.: Contribution of lymphatic absorption to loss of ultrafiltr ation and solute clearances in continuous ambulatory peritoneal dialysis. J Clin Invest 1987, 80:13111316. 14. Zabetakis PM, Krapf R, DeVita MV, et al.: Determin ing peritoneal dialysis prescriptions by employing a patient-specific protocol. Peritoneal Dial Int 1993, 13:189193. 15. Wolf CJ, Polsky J, Ntoso KA, et al.: Ade quacy of dialysis in CAPD and cycler PD; the PET is enough. Peritoneal Dial Bull 1992, 8:208211. 16. Struijk DG, Krediet RT, Koomen GCM, et al.: A prospective st udy of peritoneal transport in CAPD. Kidney Int 1994, 17391744. 17. Dobbie JW, Kr ediet RT, Twardowski ZJ, et al.: A 39-year-old man with loss of ultrafiltration. Peritoneal Dial Int 1994, 14:384394. 18. Nolph KD, Popovich RP, Ghods AJ, et al. : Determinants of low clearances of small solutes during peritoneal dialysis. Ki dney Int 1978, 13:117123. 19. Boen ST: Kinetics of Peritoneal Dialysis. Baltimore , MD: Medicine; 1961:243287. 20. Penzotti SC, Mattocks AM: Effects of dwell time, volume of dialysis fluid, and added accelerators on peritoneal dialysis of urea . J Pharm Sci 1971, 60:15201522. 21. Pirpasopoulos M, Lindsay RM, Rahman M, et al .: A cost-effectiveness study of dwell time in peritoneal dialysis. Lancet 1972, 2:11351136. 22. Tenckhoff H, Ward G, Boen ST: The influence of dialysate volume and flow rate on peritoneal clearance. Proc Eur Dial Transplant Assoc 1965, 2:11 3117. 23. Trivedi HS, Twardowski ZJ: Long-term successful nocturnal intermittent peritoneal dialysis: a ten-year case study. In Advances in Peritoneal Dialysis. Edited by Khanna R. Toronto, Canada: Peritoneal Dialysis Publications; 1994:8184. 24. Di Paolo N: Semicontinuous peritoneal dialysis. Dial Transplant 1978, 7:8398 42. 25. Finkelstein FO, Kliger AS: Enhanced efficiency of peritoneal dialysis us ing rapid, small-volume exchanges. ASAIO J 1979, 2:103106. 26. Twardowski ZJ, Nol ph KD, Khanna R, et al.: Tidal peritoneal dialysis. In Ambulatory Peritoneal Dia lysis: Proceedings of the IVth Congress of the International Society for Periton eal Dialysis, Venice, Italy, June 1987. Edited by Avram MM, Giordano C. New York : Plenum; 1990:145149. 27. Twardowski ZJ, Prowant BF, Nolph KD, et al.: Chronic n ightly tidal peritoneal dialysis (NTPD). ASAIO Trans 1990, 36:M584M588. 28. Tward owski ZJ: Tidal peritoneal dialysis: acute and chronic studies. Eur Dial Transpl ant Nurses Assoc Eur Renal Care Assoc September 1990, 15:49. 29. Twardowski ZJ: T

idal peritoneal dialysis. In Dialysis Therapy. Edited by Nissenson AR, Fine RN. Philadelphia: Hanley & Belfus; 1993:153156. 30. Twardowski ZJ, Nolph KD, Prowant BF, et al.: Efficiency of high volume low frequency continuous ambulatory perito neal dialysis (CAPD). ASAIO Trans 1983, 29:5357. 31. Krediet RT, Boeschoten EW, Z uyderhoudt FMJ, et al.: Differences in the peritoneal transport of water, solute s and proteins between dialysis with two- and with three-litre exchanges [thesis ]. In Peritoneal Permeability in Continuous Ambulatory Peritoneal Dialysis Patie nts. Edited by Krediet RT. Amsterdam, Holland: University of Amsterdam; 1986:1291 46. 32. Twardowski Z, Janicka L: Three exchanges with a 2.5 liter volume for con tinuous ambulatory peritoneal dialysis. Kidney Int 1981, 20:281284. 33. Twardowsk i ZJ, Prowant BF, Nolph KD, et al.: High volume, low frequency continuous ambula tory peritoneal dialysis. Kidney Int 1983, 23:6470. 34. Randerson DH: Continuous ambulatory peritoneal dialysis-a critical appraisal [thesis]. Sydney, Australia: University of New South Wales; 1980. 35. Pyle WK: Mass transfer in peritoneal d ialysis [thesis]. Austin: University of Texas; 1981. 36. Farrell PC, Randerson D H: Mass transfer kinetics in continuous ambulatory peritoneal dialysis. In Proce edings of the First International Symposium on Continuous Ambulatory Peritoneal Dialysis. Edited by Legrain M. Amsterdam, Holland: Excerpta Medica; 1980:3441. 37 . Pyle WK, Moncrief JW, Popovich RP: Peritoneal transport evaluation in CAPD. In CAPD Update. Edited by Moncrief JW, Popovich RP. New York: Masson; 1981:3552. 38 . Pyle WK, Popovich RP, Moncrief JW: Mass transfer in peritoneal dialysis. In Ad vances in Peritoneal Dialysis. Edited by Gahl GM, Kessel M, Nolph KD. Amsterdam, Holland: Excerpta Medica; 1981:4146. 39. Garred LF, Canaud B, Farrell PC: A simp le kinetic model for assessing peritoneal mass transfer in continuous ambulatory peritoneal dialysis. ASAIO J 1983, 6:131137.

Dialysis Access and Recirculation Toros Kapoian Jeffrey L. Kaufman John Nosher Richard A. Sherman S ince its inception, hemodialysis has been bedeviled by problems of vascular acce ss. Access, from the time of creation and throughout a patient's dialysis life, co nsumes significant time, effort, and expense and creates much anxiety and risk f or patient and family. Vascular access complications remain the single leading c ause of hospitalization and expense for dialysis patients. Some, such as infecte d access sites, are potentially life threatening. It is common for an access pro blem to precipitate a crisis related to the end of a patient's dialysis life. Desp ite the advances made in hemodialysis technology, the same vascular access probl ems that plagued dialysis pioneers continue today to confound patient care teams . CHAPTER 5

5.2 Dialysis as Treatment of End-Stage Renal Disease Arteriovenous Dialysis Access: Evaluation and Placement EVALUATION FOR HEMODIALYSIS VASCULAR ACCESS History Surgical cutdown Multiple peripheral catheters Peripherally inserted cen tral catheter line placement Transvenous pacemaker Axillary dissection Intraveno us drug use Obesity Peripheral vascular disease Atherosclerotic disease Physical examination Asymmetry of pulse Asymmetry of blood pressure Abnormal capillary r efill Abnormal Allen test Presence of surgical or other scars FIGURE 5-1 Evaluation for hemodialysis access. The creation of optimal vascular access requires an integrated approach among patient, nephrologist, and surgeon. The preoperative evaluation includes a thorough history and physical examinatio n. A history of arterial and venous line placements should be sought. The upper extremities are examined for edema and asymmetry of pulse and blood pressure. Ac cess should be placed at the wrist only after it is verified that the radial art ery is not the dominant arterial conduit to the hand. The classic study is the A llen test, in which an observer compresses both the radial and ulnar arteries, h as the patient exercise the hand by opening and closing to cause blanching, then releases one vessel to be certain that the fingers become perfused. An alternat ive, and perhaps more precise, test is to verify by Doppler imaging that flow to all digits is maintained despite occlusion of the radial artery. If indicated, vascular imaging studies should be used to delineate the vascular anatomy and ru le out arterial or venous disease. Clinically silent stenosis involving the cent ral veins is becoming increasingly common with the improved survival of critical ly ill patients for whom central vein catheters are commonplace. FIGURE 5-2 Crea tion of a Brescia-Cimino (radial-cephalic) fistula. The native vein arteriovenou s fistula is the preferred choice for hemodialysis access. This simple and effec tive procedure, in which an artery is connected to an adjacent vein to provide a large volume of blood flow into the superficial venous system, has become less common in recent years. The ideal artery has minimal wall calcification, so that dilation can occur with time and allow unimpeded flow. In addition, the artery should not be affected by proximal stenosis, the most common site being an ostia l lesion in the subclavian artery. Ideally, the outflow vein is subjected to min imal dissection or manipulation during the surgical procedure. Forcible distensi on of veins and rough handling of arteries leads to formation of neointimal fibr ous hyperplasia and localized stenosis. The first autogenous access site describ ed was radial-cephalic at the level of the radial styloid process. These can be constructed endvein to side-artery, A and B, or side-to-side, C, between the two vessels. The exposure is conveniently obtained using a transverse incision at t he wrist, just proximal to the radial styloid process, where the artery and ceph alic vein lie close to one another. In general, the two vessels are just far eno ugh apart so that an end-to-side technique is best. When the vessels overlie eac h other, some surgeons prefer the side-to-side technique, which allows reversal of blood flow into the dorsum of the hand and then via collaterals into the fore arm, theoretically leading to better flow volume over time.

Dialysis Access and Recirculation 5.3 FIGURE 5-3 The Brescia-Cimino (radial-cephalic) fistula. The radial-cephalic fis tula offers many advantages. It is simple to create and preserves more proximal vessels for future access construction. The lower incidence of steal is likely the result of the lower flow rate associated with t hese accesses. Additionally, such accesses have low rates of thrombosis and infe ction. The photograph shows a mature Brescia-Cimino fistula in a patient with lo ngstanding diabetes. The fistula outflow vein has numerous aneurysmal segments, and, although they are associated with some tendency toward flow stagnation, the y are of no harm to the patient's dialysis life. They do, however, become obvious targets for the dialysis technical staff, who have a tendency to puncture them r epeatedly rather than to utilize new needle insertion sites. The patients arm al so demonstrates marked muscle atrophy secondary to advanced diabetic neuropathy, which particularly involves the thenar eminence and the interosseus muscle grou ps. Complaints of weakness and loss of grip strength in the arm are common and m ay represent symptoms of steal. In this case, however, the symptoms are due to t he intrinsic loss of muscle mass, rather than to steal. A FIGURE 5-4 The brachial-cephalic vein fistula. If a radial-cephalic vein fistula cannot be constructed, the next best choice for vascular access is the brachial -cephalic vein fistula. Accesses that utilize the brachial artery have the advan tage of higher blood flow rates than those that use the radial artery. Although this may improve the efficiency of hemodialysis, it is also associated with incr eased risk of arm edema and steal. A, The native anatomy of the antecubital vein s somewhat resembles the letter M. A more complete depiction is seen in B. The m edial volar venous flow enters the basilic system; lateral volar flow enters the cephalic system; and the central connector, which includes a deep tributary, co nnects the brachial (venae comitantes) system at the brachial artery bifurcation . To create an antecubital autogenous site, there are two general approaches; th e surgeon either mobilizes the cephalic vein directly into the brachial artery ( C) or anastomoses the deep connector between the median antecubital vein and the b rachial veins directly to the adjacent artery. It is also possible to prepare a native vein arteriovenous fistula in the antecubital fossa by transposing brachi al or basilic veins from the deeper compartment of the brachium to the subcutane ous tissue. C

5.4 Dialysis as Treatment of End-Stage Renal Disease during manufacture. The process of healing after implantation involves ingrowth of fibroblasts into the pore structure, giving a final graft-tissue amalgam that is incorporated when encountered by the surgeon for revision. There is virtually no neovascularization through the pores, which are too small for capillary ingro wth. In humans, neointima grow along the graft for no more than 3 cm from the an astomosis. In animal models, neointima can be much more robust, growing along mo st of the length of the graft and providing it with greater resistance to thromb osis. Typical layouts for the construction of a PTFE access site are A, the fore arm loop, and B, linear forearm graft, respectively. Alternative sites include u pper arm loop grafts, groin grafts, axillary arteryto-vein grafts, and a variety of other constructions. The sites of choice are limited by the requirements of hemodialysis: delivery of a high rate of blood flow and accessibility to the dia lysis staff for cannulation with an adequate length of graft to keep the needles sufficiently separated and allow rotation of cannulation sites. FIGURE 5-5 Polytetrafluoroethylene (PTFE) vein graft. The most common synthetic material used for dialysis access construction is the PTFE conduit. This materia l replaced bovine heterografts; alternative materials such as the umbilical vein graft have not yet made much headway. Because of the infection risk, Dacron byp ass grafts have never functioned well for dialysis. PTFE is an inert material th at is formed into a pliable conduit. Its ultramicroscopic structure is a series of nodes connected by tiny filaments, leaving pores whose size can be varied FIGURE 5-6 Trends in dialysis access sites. Despite our understanding of hemodia lysis access and the advantages and disadvantages of the various options availab le, there is an alarming trend away from the use of native vein fistulas. Of eve n more concern is the increasing number of patients who begin dialysis without a permanent vascular access in place and the increasing prevalence of central vei n catheters. It is not clear whether these trends are the result of age, comorbi d conditions such as diabetes and peripheral vascular disease, or simply the unt oward effect of late nephrology referral. Although central vein catheters were i nitially designed for temporary use while an arteriovenous vascular access was b eing constructed, improvements in design have led to their being used for perman ent dialysis access. Nevertheless, central vein catheters, while popular with pa tients because they obviate being stuck, are the source of a variety of access com plications, including infection, central vein stenosis, and thrombosis.

Dialysis Access and Recirculation 5.5 Complications of Arteriovenous Dialysis Access Placement A FIGURE 5-7 Arteriovenous fistula anastomotic stenosis. Arteriovenous hibit better long-term patency compared with polytetrafluoroethylene ts. A, This arteriogram, performed by injecting the brachial artery, s an end-to-side arteriovenous fistula involving the brachial artery halic vein. The arrow indicates an area of narrowing adjacent to the , the fistulas ex (PTFE) graf demonstrate and the cep anastomosis

B most common site for a stenotic lesion in native vein fistulas. B, Angioplasty s uccessfully eliminated the anastomotic stenosis. Limitations on balloon size are often encountered when treating lesions in arteriovenous fistulas because a por tion of the balloon must often extend into the donor artery, which typically is of smaller diameter than the outflow vein. FIGURE 5-8 Exposed polytetrafluoroeth ylene (PTFE) graft. Proper placement of a PTFE graft is crucial for its long-ter m survival. The graft cannot be too short, as it will deteriorate quickly from p uncture limited to only a few sites; if it is too long, however, it will have a greater impedance to flow and a tendency toward thrombosis. The graft should be neither too deep to the skin nor too shallow. When the graft is too shallow, pun cture by the dialysis staff is easier, but the skin may be eroded with scarring from repeated use. This photograph shows a linear forearm graft with a segment o f exposed PTFE. An exposed graft is a serious problem for several reasons. First , exposure of actual puncture holes eventually leads to hemorrhage. Second, an e xposed graft is, by definition, infected. Although some cases have been treated successfully with rotational skin flaps and a long course of antibiotics, the ma jority do not heal. The ideal treatment is removal of the segment of exposed gra ft, splicing a segment of new PTFE away from the site of exposure, and allowing secondary wound healing.

5.6 Dialysis as Treatment of End-Stage Renal Disease A FIGURE 5-9 Extravasation injury to the access site. A, A relatively fresh segmen t of polytetrafluoroethylene graft was removed during a revision procedure. Ther e is virtually no fibrosis or calcification (associated with repeated puncture). The luminal surface displays the results of multiple sites of puncture and heal ing. Among the most dramatic and troublesome complications of dialysis is access infiltration. In most cases the infiltration is minor and usually results from either inadequate hemostasis at the end of dialysis or needle perforation throug h the access site. Extravasation injury to the access is more likely when a need le errantly transfixes a graft or vein or when it accidentally becomes dislodged into the subcutaneous tissue. The venous return needle presents the biggest pro blem. In the face of typical pump speeds of 400 to 500 mL/min a B potentially huge volume of fluid can enter the soft tissue before the pump stops in response to the alarm for elevated venous pressure. In many cases, the graft is unusable for weeks after such an episode. Continued use of the access in thi s setting may result in loss of the access site. B, In this example, the infiltr ation was composed of approximately 400 mL of priming crystalloid and blood, loc ated both deep and superficial to the investing fascia of the arm. The access re mained patent and was eventually restored to function; however, a series of perc utaneous drainage procedures and open drainage were necessary. Compartment syndr ome, with loss of distal motor function or sensation in the arm, is another conc ern in this setting, and drainage must be performed to treat this surgical emerg ency. FIGURE 5-10 Outflow vein stenosis. Stenotic lesions are most often found a t a polytetrafluoroethylene (PTFE) graft's venous anastomotic site or within its o utflow vein. A, Radiograph depicting an angioplasty balloon inflated across an o utflow vein with a stenotic lesion. The waist in the balloon (arrow) indicates the location of the stenosis. With increasing inflation pressure the waist disappea rs, an indication of successful angioplasty. Failure to eliminate the waist in t he balloon indicates incomplete dilatation of the lesion. Occasionally, outflow vein stenoses are very resistant to dilatation and require high inflation pressu res. This is not surprising given the amount of scarring and intimal hyperplasia that can develop in a dialysis access site. B, Resected graft-venous anastomosi s from a one-year-old PTFE graft. The vein wall seen here is enormously thickene d. Angioplasty of lesions such as these is often unsuccessful, as this rigid mat erial is likely to rebound to its stenotic state with any manipulation. A B

Dialysis Access and Recirculation 5.7 A B C D be necessary to permit removal of this material under direct visualization. Fail ure to remove this meniscus invariably leads to rethrombosis. B, This type of cl ot is demonstrated in an arteriogram performed through the brachial artery follo wing thrombolytic therapy. The arterial end of this polytetrafluoroethylene (PTF E) graft demonstrates a residual intraluminal thrombus (arrow), which is typical of the platelet-rich plug or arterial type thrombus. A third type of clot (not shown) consists of a white laminar material that lines the graft over time, espe cially in sites of repeated puncture. This material can create a stenosis along the body of the graft and may be removed by curettage at the time of thrombectom y using an atherectomy catheter. Failure to remove this material decreases blood flow through the graft and may lead to rethrombosis. According to Poiseuille's la w, if blood pressure remains constant, a 6-mm graft with 1 mm of circumferential laminar clot accommodates only 20% of the flow originally present, since flow i s inversely related to the fourth power of the radius. Eighty percent of thrombo sed accesses have an associated stenotic lesion. C, An eccentric focal stenosis is demonstrated at the anastomosis of a PTFE forearm graft and its outflow vein (arrow), which did not respond to percutaneous transluminal angioplasty. The les ion was subsequently resected using a Simpson atherectomy catheter, which consis ts of a concealed cutting chamber that is deflected into contact with the stenot ic lesion of the vessel wall by inflating the associated balloon. With the lesio n projecting into the cutting chamber, a high-speed cylindrical cutting blade re sects tissue into a collecting chamber. This chamber is rotated sequentially unt il the circumference of the lesion has been treated. D, The Simpson atherectomy catheter is placed across the stenotic lesion. E, The postprocedure venogram sho ws that the lesion was successfully resected. E FIGURE 5-11 Graft thrombosis due to outflow vein stenosis requiring use of an at herectomy catheter. Thrombectomy of a dialysis access site involves removal of t hree types of clot. A, The body of a thrombosed access contains a red or purplis h thrombus that is often gelatinous. It is easily removed with a balloon-tipped thrombectomy/embolectomy catheter. This photograph also demonstrates the small m eniscus of firm, laminar, platelet-rich clot that usually obstructs arterial inf low. On occasion, it is also found at the venous end. This type of clot can be t enacious and may not be removed with thrombolytic therapy or the balloon cathete r. A cutdown at the arterial end of the graft may

5.8 Dialysis as Treatment of End-Stage Renal Disease FIGURE 5-12 Pulse spray catheter. To increase the efficiency of drug thrombolysi s, pulse spray catheters are often used. The technique involves embedding the ca theter within the clot and intentionally obstructing the catheter end hole with a guidewire. When the fibrinolytic agent is injected, it is forced out through t he catheter sideholes in jets and permeates the clot. With this method, a larger surface area of clot is exposed to the fibrinolytic agent. FIGURE 5-13 Thrombectomy brush. Several types of mechanical thrombectomy devices have been developed as alternatives to pharmaceutical fibrinolysis. All mechani cally macerate or disrupt clot into small fragments that embolize into the centr al veins and, eventually, the pulmonary vascular bed. This photograph demonstrat es a brush attached to a motor drive that imparts high-speed rotary motion to di srupt the thrombus. The danger of most mechanical devices is the risk of vascula r injury. A B C FIGURE 5-14 Outflow vein stenosis with stenting. A, Arteriography in this patien t with a Brescia-Cimino fistula demonstrates stenosis of the outflow vein approx imately 15 cm central to the fistula (arrow). B, Percutaneous transluminal angio plasty was performed in this patient; however, because of immediate elastic reco il, the lesion looks no different after angioplasty. C, Following stent placemen t (arrow), there is no residual stenosis, and good flow through the stent is app arent. Stents have proven controversial in access sites. Although they may impro ve patency in central vein stenoses (vide infra), in the periphery they may be a hindrance. Some patients D develop vigorous fibrosis at the venous site of a stent. D, This photograph demo nstrates what had occurred only 1 month after stent placement. Stents can be a p roblem when dealing with subsequent vascular access dysfunction. During thrombec tomy, the tiny wires of a stent can puncture balloon catheters. When stented seg ments restenose, it is impossible to perform open patch angioplasty over such se gments, and it becomes necessary to jump to a different venous outflow site. It is not clear whether stents in or adjacent to dialysis grafts are cost effective in maintaining graft patency.

Dialysis Access and Recirculation 5.9 A FIGURE 5-15 Intragraft stenosis. A, This arteriogram demonstrates a forearm loop polytetrafluoroethylene (PTFE) graft with an intragraft stenosis (arrow). Steno tic lesions in this site are less common than those involving either the venous anastomosis or the outflow vein. B, These lesions can be treated successfully wi th percutaneous transluminal angioplasty (arrow). In cases where angioplasty is unsuccessful, intragraft stenoses can also be treated using percutaneous B atherectomy or surgical revision. Since this region of the access is subject to needle cannulation, the placement of a stent would be inadvisable. Intragraft st enoses may be located between the sites of the arterial and venous needle placem ents during dialysis. If so, the most common screening studies, namely venous pr essure measurements and recirculation, do not have abnormal findings and the les ion may remain undetected until access thrombosis develops. A B FIGURE 5-16 Aneurysmal degeneration. Severe aneurysmal degeneration poses a sign ificant surgical problem for both patient and surgeon. A, Photograph demonstrati ng an anastomotic aneurysm in a loop forearm polytetrafluoroethylene (PTFE) graf t. This aneurysm is an example of the type of degenerative changes that occasion ally occur in both arteries and veins subjected to turbulence and high tangentia l wall stress. This is common in the native circulation in areas of poststenotic dilatation. The PTFE graft with high flow volumes manifested the enlargement of the venous outflow. This bulge, which constitutes a segment of flow stagnation, is associated with increased risk of thrombosis over time. Since this would jeo pardize the long-term function of the access, the area was revised by interposin g a short segment of PTFE to a new venous outflow adjacent to the aneurysmal seg ment. B, Radiograph demonstrating a pseudoaneurysm in the midportion of a forear m loop PTFE graft (arrow). This lesion represents a communication between the gr aft and a confined space in the tissue surrounding the graft and is a common fin ding in dialysis patients. C, A pseudoaneurysm in a patient with a 3-year-old le ft groin PTFE graft. Because of the patient's severe phobia of central vein cathet ers, this access was revised in two separate procedures to maintain dialysis con tinuity. The lateral area of the loop was initially replaced, and when this was healed and functioning well the medial segment was replaced. C

5.10 Dialysis as Treatment of End-Stage Renal Disease FIGURE 5-17 Vascular steal. Vascular steal is a common problem of dialysis acces s sites. The principle of steal is related to two phenomena: 1) calcification or stenosis in the inflow arterial segment proximal to an access site (so that the native artery cannot dilate to meet the increasing demands for flow volume); 2) and an outflow arterial bed in parallel to the fistula origin with higher net v ascular resistance than the fistula conduit. If both of these are present, blood flow is diverted to the access site in association with a drop in perfusion pre ssure to the most acral tissues, the fingers. When steal is severe, trauma to th e digits leads to gangrene. Several treatment strategies are available to the su rgeon. The access can be banded, or purposefully stenosed at its origin to divert flow to the ischemic site. The access can be revised using a tapered graft or th e point of origin of the access can be moved more proximally in the arterial tre e, in the hope of allowing full flow without diverting distal perfusion pressure . Additionally, one can perform a variety of bypass procedures to divert higherpressure proximal blood to increase distal perfusion pressure. In severe cases, either the access or the distal digits may be sacrificed to preserve the other. FIGURE 5-18 Vascular access screening methods. Dialysis grafts have a high incid ence of thrombosis, the risk of which increases when graft flow rates (A) fall b elow 600 to 700 mL/min, particularly with stenotic lesions in or near the graft. Most often, stenoses occur just distal to the graft-vein anastomosis (B) but th ey can occur proximal to the graft-artery anastomosis (C) or within the graft it self (D). Various screening methods may help detect grafts at high risk for thrombosis at a point where graft revision (surgical or radiologic) may increase its longevity. Measur ement of graft blood flow (using Doppler imaging, ultrasound dilution, or anothe r method) is increasingly available and may be the best screening method. When g raft flow declines below dialyzer blood flow (E), blood flows between the needle s (F) in a retrograde direction. This development is called recirculation, since it results in repeated uptake and dialysis of blood that has just been dialyzed . Recirculation can be detected by finding evidence that blood from the venous c annula is being taken up by the arterial cannula. This is most often recognized by the finding of an arterial blood urea nitrogen value below that in blood ente ring the graft. A stenotic lesion in an outflow vein tends to increase the press ure in the vein and graft (G) between the stenosis and the venous needle. This p ressure usually ranges from 25 to 50 mm Hg but may increase to more than 70 mm H g in the presence of stenosis. This pressure can be measured directly or can be estimated from the venous pressure monitor on the dialysis machine at zero blood flow (adjusting for the difference in height between the graft and the transduc er). To increase accuracy, this pressure can be normalized by dividing it by the mean arterial pressure. More commonly, this intragraft pressure is determined i ndirectly by using the dialysis machine's pressure transducer and a pump speed of 200 mL/min. In this case the measured pressure often exceeds 100 mm Hg in a norm al graft, owing to the resistance in the venous needle.

Dialysis Access and Recirculation 5.11 Central Venous Dialysis Access FIGURE 5-19 Right internal jugular vein catheters. The use of central vein cathe ters has grown significantly over the past several years. These catheters were a t one time used only on a temporary basis and served as a bridge to permanent vasc ular access. Improvements in catheter design and function combined with ease of insertion have increased use of central vein catheters in dialysis units. To min imize the risk of central vein stenosis and subsequent thrombosis, central vein catheters should be inserted preferentially into the right internal jugular vein , regardless of whether they are being used for temporary or more permanent purp oses. The typical positioning of a double-lumen catheter, A, is with its tip at the junction of the right atrium and the superior vena cava. The catheter has be en tunneled underneath the skin so that the exit site (large arrow) is located jus t beneath the right clavicle and distant from the insertion site (small arrow). This catheter also has a cuff into which endothelial cells will grow and produce a biologic barrier to bacterial migration. B, Chest radiograph showing a dialys is central vein catheter that is composed of two separate single-lumen catheters that have been inserted into the right internal jugular vein. The distal tip of the venous catheter is positioned just above the right atrium. Care must be tak en, however, to ensure proper placement of catheters with this type of design, b ecause the two single lumens are radiographically indistinguishable. B FIGURE 5-20 Central vein stenosis. A, Venogram of the central outflow veins perf ormed in a patient with a left upper extremity polytetrafluoroethylene graft and arm edema, B. (Continued on next page) A B

5.12 Dialysis as Treatment of End-Stage Renal Disease FIGURE 5-20 (Continued) The angiogram (Panel A) demonstrates complete occlusion of the innominate vein (arrow) with collateral filling in the neck and the chest . The most common cause for stenosis or thrombosis of the central venous system is previous injury from indwelling central vein catheters. Central vein stenosis may not become apparent until an arteriovenous anastomosis is created. This inc reases blood flow in the outflow veins and may overwhelm a compromised central v ein, resulting in the appearance of superficial collateral veins on the neck and chest wall in addition to ipsilateral arm edema. In this example, the occlusion was crossed using an angiographic catheter, and thrombolytic therapy was admini stered. C, Venography performed after thrombolysis demonstrates severe stenosis of the innominate vein and the superior vena cava (arrow). C A B FIGURE 5-21 Stent deployment. When angioplasty fails, metal stents are introduce d to treat outflow vein occlusion. These stents are either balloon expandable or self-expanding. The stages of deployment of the selfexpanding Wallstent (Schnei der, Inc, Division of Pfizer Hospital Products, Minneapolis, MN) are seen in the se radiographs. A, The radiopaque stent is positioned across the lesion to be tr eated. B, As the deployment envelope is gradually withdrawn, the stent begins to expand (arrow). These stents shorten during deployment, and this factor must be taken into consideration for proper placement. C, An angioplasty balloon (arrow ) is placed in the proximal portion of this completely deployed stent to achieve further expansion. (Continued on next page) C

Dialysis Access and Recirculation 5.13 FIGURE 5-21 (Continued) D, To improve central vein patency following angioplasty , metal stents have been placed in the innominate vein and the superior vena cav a. E, A postprocedure venogram demonstrates no residual stenosis. D E FIGURE 5-22 Central vein catheter complications. A, This radiograph demonstrates the tip of this dialysis catheter abutting the wall of the left innominate vein at its junction with the superior vena cava. To maintain adequate dialysis flow rates and minimize fibrin sheath formation, it is important for the catheter ti p to be in the superior vena cava, near or in the right atrium. B and C, Injecti on of contrast through these dialysis catheters demonstrates the contrast outlin ing the outside of the distal portion of the catheter (arrows). This finding is characteristic of a fibrin sheath with contrast medium trapped between the fibri n sheath and the outer wall of the catheter. Fibrin sheaths are associated with a reduction (often severe) in the achievable blood flow rate and, as a result, i nadequate dialysis delivery. They can be lysed by instilling large doses of urok inase (typically 250,000 units) through the catheter ports. If thrombolytic ther apy is unsuccessful, the fibrin sheath can be stripped using a snare loop. Altho ugh these catheters can function remarkably well, they are prone to thrombosis. (Continued on next page) A B C

5.14 Dialysis as Treatment of End-Stage Renal Disease FIGURE 5-22 (Continued) D, The clot is typical of one that is remarkably tenacio us. Before replacement of this catheter, a variety of manipulations were perform ed, including attempted thrombolysis with localized infusion of urokinase. A new catheter was placed in the same site in a same-day procedure using local anesth esia. D FIGURE 5-23 Translumbar catheter placement. Patients receiving chronic hemodialy sis may exhaust potential sites for permanent vascular access. Additionally, aft er long-term use of central vein catheters, these sites also develop irreversibl e occlusion. In most cases, these patients are trained for peritoneal dialysis; however, some patients cannot tolerate this modality. This patient failed all at tempts at arteriovenous and central vein access placement, including those invol ving the vessels of the lower extremity. Peritoneal dialysis was not possible ow ing to recurrent disabling pleural effusions. Translumbar placement of tunneled catheters (arrow) into the inferior vena cava can provide a long-term solution f or the patient with no apparent remaining access sites.

The Dialysis Prescription and Urea Modeling Biff F. Palmer H emodialysis is a life-sustaining procedure for the treatment of patients with en d-stage renal disease. In acute renal failure the procedure provides for rapid c orrection of fluid and electrolyte abnormalities that pose an immediate threat t o the patient's well-being. In chronic renal failure, hemodialysis results in a dr amatic reversal of uremic symptoms and helps improve the patient's functional stat us and increase patient survival. To achieve these goals the dialysis prescripti on must ensure that an adequate amount of dialysis is delivered to the patient. Numerous studies have shown a correlation between the delivered dose of hemodial ysis and patient morbidity and mortality [14]. Therefore, the delivered dose shou ld be measured and monitored routinely to ensure that the patient receives an ad equate amount of dialysis. One method of assessing the amount of dialysis delive red is to calculate the Kt/V. The Kt/V is a unitless value that is indicative of the dose of hemodialysis. The Kt/V is best described as the fractional clearanc e of urea as a function of its distributional volume. The fractional clearance i s operationally defined as the product of dialyzer clearance (K) and the treatme nt time (t). Recent guidelines suggest that the Kt/V be determined by either for mal urea kinetic modeling using computational software or by use of the Kt/V nat ural logarithm formula [5]. The delivered dose also may be assessed using the ur ea reduction ratio (URR). A number of factors contribute to the amount of dialys is delivered as measured by either the Kt/V or URR. Increasing blood flow rates to 400 mL/min or higher and increasing dialysate flow rates to 800 mL/min are ef fective ways to increase the amount of delivered dialysis. When increases in blo od and dialysate flow rates are no longer effective, use of a high-efficiency me mbrane can further increase the dose of dialysis (KoA >600 mL/min, where KoA is the constant indicating the efficiency of dialyzers in removing urea). Eventuall y, increases in blood and dialysate flow rates, even when combined with a high-e fficiency membrane, result in no further increase in the urea clearance rate. At this point the most important determinant affecting the dose of dialysis is the amount of time the patient is dialyzed. CHAPTER 6

6.2 Dialysis as Treatment of End-Stage Renal Disease that has been used as a marker of biocompatibility is evidence of complement act ivation. Cellulosic membranes generally tend to be bioincompatible, whereas nonc ellulosic or synthetic membranes have more biocompatible characteristics. Whethe r any clinical difference exists in acute or chronic outcomes between biocompati ble and bioincompatible membranes is still a matter of debate. Trials designed t o address this issue have been mostly uncontrolled, limited in sample size, and often retrospective in nature. Nevertheless, some evidence exists to suggest tha t bioincompatible membranes may have a greater association with 2 microglobulininduced amyloidosis, susceptibility to infection, enhanced protein catabolism, a nd increased patient mortality [59]. Another aspect of the dialysis prescription is the composition of the dialysate. The concentrations of sodium, potassium, ca lcium, and bicarbonate in the dialysate can be individualized such that ionic co mposition of the body is restored toward normal during the dialytic procedure. T his topic is discussed in detail in chapter 2. Although hemodialysis is effectiv e in removing uremic toxins and provides adequate control of fluid and electroly te abnormalities, the procedure does not provide for the endocrine or metabolic functions of the normal kidney. Therefore, the dialysis prescription often inclu des medications such as erythropoietin and 1,25(OH)2 vitamin D. The dose of eryt hropoietin should be adjusted to maintain the hematocrit between 33% and 36% (he moglobin of 11 g/dL and 12 g/dL, respectively) [10]. Vitamin D therapy is often used in patients undergoing dialysis to help limit the severity of secondary hyp erparathyroidism. Dosages usually range from 1 to 2 g given intravenously with ea ch treatment. Ultrafiltration during dialysis is performed to remove volume that has accumulat ed during the interdialytic period so that patients can be returned to their dry weight. Dry weight is determined somewhat crudely, being based on clinical find ings. The patient's dry weight is the weight just preceding the development of hyp otension. The patient should be normotensive and show no evidence of pulmonary o r peripheral edema. A patient's dry weight frequently changes over time and theref ore must be assessed regularly to avoid hypotension or progressive volume overlo ad. During ultrafiltration the driving force for fluid removal is the establishm ent of a pressure gradient across the dialysis membrane. The water permeability of a dialysis membrane is a function of membrane thickness and pore size and is indicated by its ultrafiltration coefficient (KUf). During ultrafiltration addit ional solute removal occurs by solvent drag or convection. Because of increased pore size, high-flux membranes (KUf >20 mL/h/mm Hg) are associated with much hig her clearances of average to high molecular weight solutes such as 2 microglobul in. Because blood flow rates over 50 to 100 mL/min result in little or no furthe r increase in the clearance of these molecules, clearance is primarily membranelimited. In contrast, clearance values for urea are not significantly greater wi th a high-flux membrane compared with a high-efficiency membrane because the blo od flow rate, and not the membrane, is the principal determinant of small solute clearance. The biocompatibility of the dialysis membrane is another considerati on in the dialysis prescription. A biocompatible dialysis membrane is one in whi ch minimal reaction occurs between the humoral and cellular components of blood as they come into contact with the surface of the dialyzer [6]. One such reactio n Treatment Diffusion Blood Urea, 100 mg/dL Dialysate Urea, 0 mg/dL Potassium, 5.0 mEq/L Potassium, 2.0 mEq/L Bicarbonate, 20 mEq/L

Bicarbonate, 35 mEq/L FIGURE 6-1 Diffusional and convective flux in hemodialysis. Dialysis is a proces s whereby the composition of blood is altered by exposing it to dialysate throug h a semipermeable membrane. Solutes are transported across this membrane by eith er diffusional or convective flux. A, In diffusive solute transport, solutes cro ss the dialysis membrane in a direction dictated by the concentration gradient e stablished across the membrane of the hemodialyzer. For example, urea and potass ium diffuse from blood to dialysate, whereas bicarbonate diffuses from dialysate to blood. At a given temperature, diffusive transport is directly proportional to both the solute concentration gradient across the membrane and the membrane s urface area and inversely proportional to membrane thickness. (Continued on next page) A Dialysis membrane

The Dialysis Prescription and Urea Modeling Ultrafiltration Blood 90 mm Hg Dialysate 150 mm Hg H 2O H 2O H 2O 6.3 TREATMENT OF HEMODYNAMIC INSTABILITY Exclude nondialysis-related causes (eg, cardiac ischemia, pericardial effusion, infection) Set the dry weight accurately Optimize the dialysate composition Use a sodium concentration of 140 mEq/L Use sodium modeling Use a bicarbonate buffer Avoid low magnesium dialysate Avoid low calcium dialysate Optimize the method of ultrafiltration Use volume-controlled ultrafiltration Use ultrafiltration model ing Use sequential ultrafiltration and isovolemic dialysis Use cool temperature dialysate Maximize cardiac performance Have patients avoid food on day of dialys is Have patients avoid antihypertensive medicines on day of dialysis Pharmacolog ic prevention Erythropoietin therapy to keep hematocrit >30% Experimental (eg,ca ffeine, midodrine, ephedrine, phenylephrine, carnitine) B Dialysis membrane FIGURE 6-1 (Continued) B, During hemodialysis water moves from blood to dialysat e driven by a hydrostatic pressure gradient between the blood and dialysate comp artments, a process referred to as ultrafiltration. The rate of ultrafiltration is determined by the magnitude of this pressure gradient. Movement of water tend s to drag solute across the membrane, a process referred to as convective transp ort or solvent drag. The contribution of convective transport to total solute tr ansport is only significant for average-to-high molecular weight solutes because they tend to have a smaller diffusive flux. FIGURE 6-2 The common treatments for hemodynamic instability of patients undergo ing dialysis. It is important to begin by excluding reversible causes associated with hypotension because failure to recognize these abnormalities can be lethal . Perhaps the most common reason for hemodynamic instability is an inaccurate se tting of the dry weight. Once these conditions have been dealt with, the use of a high sodium dialysate, sodium modeling, cool temperature dialysis, and perhaps the administration of midodrine may be attempted. All of these maneuvers are ef fective in stabilizing blood pressure in dialysis patients. FIGURE 6-3 Acceptabl e methods to measure hemodialysis adequacy as recommended in the Dialysis Outcom es Quality Initiative (DOQI) Clinical Practice Guidelines. These guidelines may change as new information on the benefit of increasing the dialysis prescription becomes available. For the present, however, they should be considered the mini mum targets. ACCEPTABLE METHODS TO MEASURE HEMODIALYSIS ADEQUACY* Formal urea kinetic modeling (Kt/V) using computational software Kt/V = -LN (R 0 .008 t) + (4-3.5 R) Uf/wt Urea reduction ratio *Recommended by the National Kidney Foundation Dialysis Outcomes Quality Initiative Clinical Practice Guidelines, which suggest a prescribed minimum Kt/V of 1.3 and a minimum urea reduction ratio of 70%. tLN is the natural logarithm; R is postdialysis blood urea nitrogen (BUN)/predialysis BUN; t is time in hours , Uf is ultrafiltration volume in liters; w is postdialysis weight in kilograms.

6.4 Dialysis as Treatment of End-Stage Renal Disease Considerations in Choice of Membranes 400 KoA 900 High-efficiency dialyzer KoA 650 KoA 300 Conventional dialyzer 300 200 e-lim Membran ited 100 0 0 100 200 300 Blood flow rate, mL/min 400 FIGURE 6-4 Relationships between membrane efficiency and clearance and blood flo w rates in hemodialysis. When prescribing the blood flow rate for a hemodialysis procedure the following must be considered: the relationship between the type o f dialysis membrane used, blood flow rate, and clearance rate of a given solute. For a small solute such as urea (molecular weight, 60) initially a linear relat ionship exists between clearance and blood flow rates. Small solutes are therefo re said to be flow-limited because their clearance is highly flow-dependent. At higher blood flow rates, increases in clearance rates progressively decrease as the characteristics of the dialysis membrane become the limiting factor. The eff iciency of a dialyzer in removing urea can be described by a constant referred t o as KoA, which is determined by factors such as surface area, pore size, and me mbrane thickness. Use of a high-efficiency membrane (KoA >600 mL/min) can result in further increases in urea clearance rates at high blood flow rates. In contr ast, at low blood flow rates no significant difference exists in urea clearance between a conventional and a high-efficiency membrane because blood flow, and no t the membrane, is the primary determinant of clearance. FIGURE 6-5 Water permea bility of a membrane and control of volumetric ultrafiltration in hemodialysis. The water permeability of a dialysis membrane can vary considerably and is a fun ction of membrane thickness and pore size. The water permeability is indicated b y its ultrafiltration coefficient (KUf). The KUf is defined as the number of mil liliters of fluid per hour that will be transferred across the membrane per mm H g pressure gradient across the membrane. A high-flux membrane is characterized b y an ultrafiltration coefficient of over 20 mL/h /mm Hg. With such a high water permeability value a small error in setting the transmembrane pressure can resul t in excessively large amounts of fluid to be removed. As a result, use of these membranes should be restricted to dialysis machines that have volumetric ultraf iltration controls so that the amount of ultrafiltration can be precisely contro lled. Urea clearance, mL/min 2000 1800 1600 1400 Ultrafiltration, mL/h 1200 1000 800 600 400 200 0 0 100 500 200 300 400 Transmembrane pressure, mm Hg 600 KUf=3 mL/h/mm Hg KUf=60 mL/h/mm Hg KUf=4 mL/h/mm Hg Flo wlim ite d

The Dialysis Prescription and Urea Modeling 6.5 High-efficiency dialyzer High-flux dialyzer Normal kidney 150 Clearance, mL/min 100 FIGURE 6-6 High-efficiency and high-flux membranes in hemodialysis. These membra nes have similar clearance values for low molecular weight solutes such as urea (molecular weight, 60). In this respect both types of membranes have similar KoA values (over 600 mL/min), where KoA is the constant indicating the efficiency o f the dialyzer in removing urea. As a result of increased pore size, use of high flux membranes can lead to significantly greater clearance rates of high molecul ar weight solutes. For example, 2-microglobulin is not removed during dialysis u sing low-flux membranes (KUf <10 mL/h/mm Hg, where KUf is the ultrafiltration co efficient). With some high-flux membranes, 400 to 600 mg/wk of 2-microglobulin c an be removed. The clinical significance of enhanced clearance of 2-microglobuli n and other middle molecules using a high-flux dialyzer is currently being studi ed in a national multicenter hemodialysis trial. 50 0 0 10 (m Urea w= 60) 100 1000 10,000 100,000 Solute molecular weight, Daltons Vit (m amin b - w=1 B1 2 m 35 2 (m icrog 5) w= lob 11, ulin 800 ) 80 Patients recovering renal function, % 60 Polymethyl methacrylate 40 Cuprophane 20 0 0 5 10 15 20 25 Number of hemodialysis treatments 30 FIGURE 6-7 Effects of membrane biocompatibility in hemodialysis. Another conside ration in the choice of a dialysis membrane is whether it is biocompatible. In c hronic renal failure some evidence exists to suggest that long-term use of bioco mpatible membranes may be associated with favorable effects on nutrition, infect ious risk, and possibly mortality when compared with bioincompatible membranes [

59]. In the study results shown here, the effect of biocompatibility on renal out come in a group of patients with acute renal failure who required hemodialysis w as examined. Patients received dialysis with a cuprophane membrane (a bioincompa tible membrane known to activate complement and neutrophils) or a synthetic memb rane made of polymethyl methacrylate (a biocompatible membrane associated with m ore limited complement and neutrophil activation). The two groups of patients we re similar in age, degree of renal failure, and severity of the underlying disea se as defined by the Acute Physiology and Chronic Health Evaluation (APACHE) II score. As compared with the bioincompatible membrane, those patients treated wit h the synthetic biocompatible membrane had a significantly shorter duration of r enal failure in terms of number of treatments and duration of dialysis. In the s etting of acute renal failure, particularly in patients after transplantation, a biocompatible membrane may be the preferred dialyzer. (From Hakim and coworkers [11]; with permission.)

6.6 300 280 260 240 Clearance, mL/min 220 200 180 160 140 120 100 200 250 Dialysis as Treatment of End-Stage Renal Disease FIGURE 6-8 Dialysate flow rate in hemodialysis. The clearance of urea also is in fluenced by the dialysate flow rate. Increased flow rates help maximize the urea concentration gradient along the entire length of the dialysis membrane. Increa sing the dialysate flow rate from 500 to 800 mL/min can be expected to increase the urea clearance rate on the order of 10% to 15%. This effect is most pronounc ed at high blood flow rates and with use of high KoA dialyzers. KoA constant indi cating the efficiency of the dialyzer in removing urea; QDdialysate flow rate. QD=800 Dialyzer KoA=800 QD=500 QD=800 QD=500 Dialyzer KoA=400 300 350 400 450 Blood flow rate, mL/min 500 Prescription for Dose Delivery 1. Dialyzer urea clearance rate KoA of membrane Blood flow Dialysate flow Convec tive urea flux 2. Treatment time 3. Volume of distribution 1. Urea generation rate Protein catabolic rate 2. Volume of distribution 3. Resi dual renal function FIGURE 6-9 Delivering an adequate dose of dialysis in hemodialysis. Providing an adequate amount of dialysis is an important part of the dialysis prescription. During the dialytic procedure a sharp decrease in the concentration of urea occu rs followed by a gradual increase during the interdialytic period. The decrease in urea during dialysis is determined by three main parameters: dialyzer urea cl earance rate (K), dialysis treatment time (t), and the volume of urea distributi on (V). The dialyzer urea clearance rate (K) is influenced by the characteristic s of the dialysis membrane (KoA), blood flow rate, dialysate flow rate, and conv ective urea flux that occurs with ultrafiltration. The gradual increase in urea during the interdialytic period depends on the rate of urea generation that, in an otherwise stable patient, reflects the dietary protein intake, distribution v olume of urea, and presence or absence of residual renal function. Urea concentration Dialysis time Interdialytic time Time on Time off Time on (next dialysis)

The Dialysis Prescription and Urea Modeling 6.7 FACTORS RESULTING IN A REDUCTION OF THE PRESCRIBED DOSE OF HEMODIALYSIS DELIVERE D Compromised urea clearance Access recirculation Inadequate blood flow from the v ascular access Dialyzer clotting during dialysis (reduction of effective surface area) Blood pump or dialysate flow calibration error Reduction in treatment tim e Premature discontinuation of dialysis for staff or unit convenience Premature discontinuation of dialysis per patient request Delay in starting treatment owin g to patient or staff tardiness Time on dialysis calculated incorrectly Laborato ry or blood sampling errors Dilution of predialysis BUN blood sample with saline Drawing of predialysis BUN blood sample after start of the procedure Drawing po stdialysis BUN >5 minutes after the procedure BUNblood urea nitrogen. FIGURE 6-10 Each of the factors listed may play a major role in the reduction of delivered dialysis dose. Particular attention should be paid to the vascular ac cess and to a reduction in the effective surface area of the dialyzer. Perhaps t he most important cause for reduction in dialysis time has to do with premature discontinuation of dialysis for the convenience of the patient or staff. Delays in starting dialysis treatment are frequent and may result in a significant loss of dialysis prescription. Finally, particular attention should be paid to the c orrect sampling of the blood urea nitrogen level and the site from which the sam ple is drawn. Increasing ultrafiltation 0.1 0.0 0 0.0 8 0.0 6 4 1.80 0.02 0.00 1.60 Kt/v by formal urea kinetic modeling 1.40 FIGURE 6-11 Monitoring the delivered dose in hemodialysis. Use of the urea reduc tion ratio (URR) is the simplest way to monitor the delivered dose of hemodialys is. However, a shortcoming of this method compared with formal urea kinetic mode ling is that the URR does not account for the contribution of ultrafiltration to the final delivered dose of dialysis. During ultrafiltration, convective transf er of urea from blood to dialysate occurs without a decrease in urea concentrati on. As a result, with increasing ultrafiltration volumes the Kt/V, as determined by formal urea kinetic modeling, progressively increases at any given URR. For example, a URR of 65% may correspond to a Kt/V as low as 1.1 in the absence of u ltrafiltration or as high as 1.35 when ultrafiltration of 10% of body weight occ urs. 1.20 1.00 0.80 0.60 0.40 0.50 0.60 0.70 Urea reduction ratio, % 0.80

6.8 45 Dialysis as Treatment of End-Stage Renal Disease MAJOR COMPONENTS OF DIALYSIS PRESCRIPTION 500 U/kg 150 U/kg 40 35 Hematocrit, % 30 50 U/kg 25 15 U/kg 20 15 0 2 4 12 6 8 10 Weeks of rHuEpo therapy 14 16 Choose a biocompatible membrane Prescribe a Kt/V 1.3 or a URR 70% Rigorously ensur e that the delivered dose equals the amount prescribed When the delivered dose i s less than that prescribed do the following: Exclude factors listed in Figure 6 -10 Increase blood flow rate 400 mL/min Increase dialysate flow rate to 800 mL/min Use a high-efficiency dialyzer Increase treatment time Choose dialysate composi tion: sodium, potassium, bicarbonate, and calcium Adjust ultrafiltration rate to achieve patients' dry weight (assess dry weight regularly) Adjust recombinant ery thropoietin to maintain hematocrit between 33% and 36% When indicated, use 1,25( OH)2 vitamin D for treatment of secondary hyperparathyroidism Use normal saline, hypertonic saline, or mannitol for treatment of intradialytic hypotension URRure a reduction ratio. FIGURE 6-12 Correction of anemia in chronic renal failure. Anemia is a predictab le complication of chronic renal failure that is due partly to reduction in eryt hropoietin production. Use of recombinant erythropoietin to correct the anemia i n patients with chronic renal failure has become standard therapy. The rate of i ncrease in hematocrit is dose-dependent. The indicated doses were given intraven ously three times per week. Current guidelines for the initiation of intravenous therapy suggest a starting dosage of 120 to 180 U/kg/wk (typically 9000 U/wk) a dministered in three divided doses. Administration of erythropoietin subcutaneou sly has been shown to be more efficient than is intravenous administration. That is, on average, any given increment in hematocrit can be achieved with less ery thropoietin when it is given subcutaneously as compared with intravenously. In a dults, the subcutaneous dosage of erythropoietin is 80 to 120 U/kg/wk (typically 6000 U/wk) in two to three divided doses. rHuEporecombinant human erythropoietin . Data from Eschbach and coworkers [12]; with permission. FIGURE 6-13 All these components are important as contributors to a successful d ialysis prescription. The Dialysis Outcomes Quality Initiative (DOQI) recommenda tions should be followed to achieve an adequate dialysis prescription, and the t ime on dialysis should be monitored carefully. When the delivered dialysis dose is less that prescribed, the reversible factors listed in Figure 6-10 should be addressed first. Subsequently, an increase in blood flow to 400 mL/min should be attempted. Increases in dialyzer surface area and treatment time also may be at tempted. In addition, attention should be paid to the correct dialysis compositi on and to the ultrafiltration rate to make certain that patients achieve a weigh t as close as possible to their dry weight. Hematocrit should be sustained at 33

% to 36%. Finally, vitamin D supplementation to prevent secondary hyperparathyro idism and use of normal saline or other volume expanders are encouraged to treat hypotension during dialysis. KoAconstant indicating the efficiency of the dialyz er in removing urea. References 1. Owen WF, Lew NL, Liu Y, Lowrie EG: The urea reduction ratio and serum albumin concentration as predictors of mortality in patients undergoing hemodialysis. N Engl J Med 1993, 329:10011006. Hakim RM, Breyer J, Ismail N, Schulman G: Effects of dose of dialysis on morbidity and mortality. Am J Kidney Dis 1994, 23:661669. Held PJ, Port FK, Wolfe RA, et al.: The dose of hemodialysis and patient mortal ity. Kidney Int 1996, 50:550556. Parker TF III, Husni L, Huang W, et al.: Surviva l of hemodialysis patients in the United States is improved with a greater quant ity of dialysis. Am J Kidney Dis 1994, 23:670680. Hemodialysis Adequacy Work Grou p: Dialysis Outcomes Quality Initiative (DOQI). Am J Kidney Dis 1997, 30(suppl 2 :S22S31. Hakim, RM: Clinical implications of hemodialysis membrane biocompatibili ty. Kidney Int 1993, 44:484494. 7. Vanholder R, Ringoir S, Dhondt A, et al.: Phag ocytosis in uremic and hemodialysis patients: a prospective and cross sectional study. Kidney Int 1991, 39:320327. 8. Gutierrez A, Alvestrand A, Bergstrom J: Mem brane selection and muscle protein catabolism. Kidney Int 1992, 42:S86S90. 9. Hor nberger JC, Chernew M, Petersen J, Garber AM: A multivariate analysis of mortali ty and hospital admissions with high-flux dialysis. J Am Soc Nephrol 1992, 3:122 71237. 10. Hemodialysis Adequacy Work Group: Dialysis Outcomes Quality Initiative (DOQI). Am J Kidney Dis 1997, 30(suppl 3:S199S201. 11. Hakim RM, Wingard RL, Par ker RA: Effect of the dialysis membrane in the treatment of patients with acute renal failure. N Engl J Med 1994, 331:13381342. 12. Eschbach JW, Egrie JC, Downin g MR, et al.: Correction of the anemia of end-stage renal disease with recombina nt human erythropoietin. N Engl J Med 1987, 316:7378. 2. 3. 4. 5. 6.

Complications of Dialysis: Selected Topics Robert W. Hamilton C omplications observed in end-stage renal disease may be due to the side effects of treatment or to the alterations of pathophysiology that go with kidney failur e. CHAPTER 7

7.2 Dialysis as Treatment of End-Stage Renal Disease Complications of Hemodialysis COMPLICATIONS OF HEMODIALYSIS Complication Fever Hypotension Differential diagnosis Bacteremia, water-borne pyrogens, overheated dialysate Excessive ultrafiltration , cardiac arrhythmia, air embolus, pericardial tamponade; hemorrhage (gastrointe stinal, intracranial, retroperitoneal); anaphylactoid reaction Inadequate remova l of chloramine from dialysate, failure of dialysis concentrate delivery system Incomplete removal of aluminum from dialysate water, prescription of aluminum an tacids Excessive urea clearance (first treatment), failure of dialysis concentra te delivery system Excessive heparin or other anticoagulant Excessive ultrafiltr ation Hemolysis Dementia Seizure Bleeding Muscle cramps FIGURE 7-1 Complications associated with hemodialysis. FIGURE 7-2 (see Color Plate) Dialyzer hypersensitivity. This patient was switche d from a cellulose acetate dialysis membrane to a cuprammonium cellulose one. Wi thin 8 minutes of starting hemodialysis he developed apprehension, diaphoresis, pruritus, palpitations, and wheezing. This eruption was seen over the arm used f or arteriovenous access for dialysis. (From Caruana and coworkers [1]; with perm ission.) FIGURE 7-3 Thrombosis of the left innominate vein. Thrombosis can be a complicat ion of reliance on subclavian catheters for vascular access for hemodialysis. Th is was discovered during investigation of edema of the left arm. FIGURE 7-4 Dilation of a stricture of the left innominate vein using balloon ang ioplasty in the patient shown in Figure 7-3.

Complications of Dialysis: Selected Topics FIGURE 7-5 (see Color Plate) Ischemia of the index finger. Occasionally the arte riovenous fistula results in radial-tobrachiocephalic steal, leaving inadequate blood supply to the fingers. This risk is especially common in diabetic patients . 7.3 FIGURE 7-6 Dialysis-associated amyloidosis. Multiple carpal bone cysts without j oint space narrowing in a patient treated with dialysis for 11 years. This pheno menon has been attributed to inadequate clearance of -2microglobulin using low-p ermeability, cellulose dialysis membranes. (From van Ypersele de Strihou and cow orkers [2]; with permission.) Complications of Peritoneal Dialysis FIGURE 7-7 Perforation of the bladder on insertion of peritoneal catheter. Bladd er perforation can be a complication of blind insertion of a peritoneal catheter . It is recognized by the sudden appearance of glucose-positive urine on instillat ion of the first bag of dialysate. Instillation of radiographic contrast medium confirms the diagnosis.

7.4 Dialysis as Treatment of End-Stage Renal Disease FIGURE 7-8 (see Color Plate) Peritonitis. In continuous ambulatory peritoneal di alysis (CAPD) peritonitis can easily be recognized by the fact that drained peri toneal fluid becomes opacified. The inability to read the writing on the opposit e side of the drained bag (or a newspaper through the bag) correlates with a per itoneal leukocyte count of more than 100 cells per microliter. FIGURE 7-9 (see Color Plate) Tunnel abscess in patient undergoing continuous amb ulatory peritoneal dialysis. Pericatheter infections are a common source of peri tonitis. Sometimes, the findings are more subtle than in this case. Prompt treat ment with antibiotics is indicated. If the infection fails to respond, removal o f the catheter is indicated. FIGURE 7-10 Sclerosing encapsulating peritonitis. T his patient had several bouts of peritonitis during the course of her treatment on peritoneal dialysis. She developed partial small bowel obstruction. Abdominal computed tomography revealed a homogeneous mass filling the anterior peritoneum . At laparotomy the mesentery was encased in a marblelike fibrotic mass. The patie nt required long-term home parenteral hyperalimentation for recovery. (From Pusa teri and coworkers [3]; with permission.)

Complications of Dialysis: Selected Topics 7.5 Complications of Renal Failure Pericardial effusion Ventricular septum Right ventricle Left ventricle FIGURE 7-11 Pericardial tamponade. Narrow pulse pressure and a pericardial frict ion rub suggest pericarditis (a frequent complication of uremia) especially in p atients with chest pain. Pericardial tamponade may present as dialysis-induced hypotension. (Courte sy of T. Pappas, MD, Medical College of Ohio.) FIGURE 7-12 (see Color Plate) Perforating folliculitis. The skin of uremic patie nts can be intensely pruritic. Earlier, it was attributed to deposition of calci um and phosphorus in the skin. Today, we know that is the result of repeated tra uma to the skin associated with scratching. FIGURE 7-13 Acquired cystic disease of the kidney. Abdominal computed tomography demonstrates cystic disease in this patient, who had focal segmental glomerulos clerosis complicated by protein C deficiency and renal vein thrombosis. Eleven y ears after the initial diagnosis, he developed renal failure requiring hemodialy sis. Two years after starting dialysis, he developed hematuria, and these cysts were found. The appearance and clinical course are consistent with acquired cyst ic disease of the kidney. These cysts carry some risk of malignant transformatio n.

7.6 15 Dialysis as Treatment of End-Stage Renal Disease FIGURE 7-14 Malnutrition. Malnutrition is an important risk factor for dialysis patients, as reflected in this graph depicting the relation of death to serum al bumin values. Albumin may have antioxidant properties. Low concentrations of ser um albumin may favor oxidation of lipids, which renders them more atherogenic. ( Data from Owens and coworkers [4]. Risk of death 10 5 0 >4.5 4.04.4 3.53.9 3.03.4 2.52.9 <2.5 Serum albumin, g/dL Radiologic Manifestations of Renal Osteodystrophy FIGURE 7-15 Radiograph of a shoulder t demonstrates diffuse osteoporosis. A small amount of calcification can oclavicular ligament. These findings involved by osteoporosis. The shoulder join There is distal resorption of the clavicle. be seen on the clavicular side of the corac are suggestive of osteitis fibrosa cystica.

FIGURE 7-16 Diffuse bone demineralization as demonstrated in skull radiograph. T his radiograph demonstrates the generalized granular appearance that is characte ristic of the diffuse demineralization seen in renal osteodystrophy.

Complications of Dialysis: Selected Topics 7.7 10 min 30 30 FIGURE 7-17 Radiograph of the hands of a patient who has renal osteodystrophy. T he hands demonstrate diffuse bilateral osteoporosis. The resorption of the dista l phalanges is best seen in the first and second digits of the right hand. The r adial side of the middle phalanges of the second and third digits bilaterally de monstrates subperiosteal bone resorption. Soft tissue calcification is present o n the radial side of the proximal interphalangeal joint of the second digit of t he left hand. 50 1 hr 2 hr FIGURE 7-18 Parathyroid scan. The patient was injected with 24.6 mCi of 99m Tc C ardiolite. Hyperfunction of four parathyroid glands is seen. This technique is o ften useful to determine the location and number of parathyroid glands before pe rforming subtotal parathyroidectomy. At operation, diffuse hyperplasia of four p arathyroid glands was found. (From Ishibashi and coworkers [5].) References 1. 2. Caruana RJ, Hamilton RW, Pearson FC: Dialyzer hypersensitivity syndrome: p ossible role of allergy to ethylene oxide. Am J Nephrol 1985, 5:271274. van Ypers ele de Strihou C, Jadoul M, Malghem J, et al.: Effect of dialysis membrane and p atient's age on signs of dialysis-related amyloidosis. The working party on dialys is amyloidosis. Kidney Int 1991, 39:10121019. Pusateri R, Ross R , Marshall R, et al.: Sclerosing encapsulating peritonitis: report of a case with small bowel ob struction managed by long-term home parenteral hyperalimentation and a review of the literature. Am J Kidney Dis 1986, 8:5660. 4. 5. Owens WF, Lew NL, Liu L, et al.: The urea reduction ratio and serum albumin concentration as predictors of m ortality in patients undergoing hemodialysis. N Engl J Med 1993, 329:10011006. Is hibashi M, Nishida H, Hiromatsu Y, et al.: Localization of ectopic parathyroid g lands using technetium-99m sestamibi imaging: comparison with magnetic resonance and computed tomographic imaging. Eur J Nuclear Med 1997, 24:197201. 3.

Histocompatibility Testing and Organ Sharing Lauralynn K. Lebeck Marvin R. Garovoy H istocompatibility and its current application in kidney transplantation are disc ussed. Both theoretic and clinical aspects of human leukocyte antigen testing ar e described, including antigen typing, antibody detection, and lymphocyte crossm atching. Living related, living unrelated, and cadaveric donor-recipient matchin g algorithms are discussed with regard to mandatory organ sharing and graft outc omes. CHAPTER 8

8.2 Chromosome 6 (short arm) Glyoxylase DP Transplantation as Treatment of End-Stage Renal Disease Class II DQ DR Class III Class I B C A HLA complex DZ DO Cyp21 TNF A Class II 0 1000 Class III 2000 Class I 3000 4000 DQB2 DQA2 DQB1 DQA1 LMP 2 TAP 1 LMP 7 TAP 2 DPA1 DPA2 DPB1 DPB2 DMB DMA DNA DRB DRA H G J A C X E B 500 3000 CYP 21-B C4B CYP 21-A C4A HSP 70 B 1500 FIGURE 8-1 The major histocompatibility complex (MHC) is a group of closely link

ed genes that was first appreciated because it was found to contain the structur al genes for transplantation antigens. A, The MHC, located on the short arm of c hromosome 6, is now recognized to include many other genes important in the regu lation of immune responses. B, Regions of the MHC classes I, II, and III. The MH C can be divided into three regions, of which the class I and II regions contain the loci for the human histocompatibility antigen or human leukocyte antigen (H LA). Genes in the class I region encode the or heavy chain of the class I antigens, HLA-A, B, and C. The c lass I region is composed of other genes, most of which are pseudogenes and are not expressed. The MHC class II region is more complex, with structural genes fo r both the and chains of the class II molecules. The class II region includes fo ur DP genes, one DN gene, one DO gene, five DQ genes, and a varying number of DR genes (two to 10), depending on the halotype. Many other immune response genes are coded within the class III region. TNFtumor necrosis factor. FIGURE 8-2 Nomen clature of human leukocyte antigen (HLA) specificities. HLA nomenclature may be confusing to the newcomer, but the format is logical. The prefix HLA precedes al l antigens or alleles to define the major histocompatibility complex (MHC) of th e species. The designation, A, B, C, DR, and so on, is next and defines the locu s. The locus is followed by a number that denotes the serologically defined anti gen or a number with an asterisk that denotes the molecularly defined allele. In some cases the letter w is placed before the serologic antigen, indicating it i s a workshop designation and the specific assignment is provisional. Specific locus HLA C w 8 The major histocompatibility complex in humans Locus HLA DRB1 * Provisional specificity Specific antigen Allele designation 04 03 Corresponding antigen Specific allele TNF a TNF b BF C2 F

Histocompatibility Testing and Organ Sharing 8.3 PRETRANSPLANTATION TESTING FOR RENAL PATIENTS HLA phenotype Patient cells tested with known antisera HLA antibody screen Known cells tested with patient sera HLA crossmatch Donor cells tested with patient s era FIGURE 8-3 In an immunogenetics and transplantation laboratory, three major type s of renal pretransplantation testing are performed routinely. The human leukocy te antigen (HLA) assignments are assigned by serologic methods (ie, complement-d ependent cytotoxicity); however, molecular-based methodologies are becoming wide ly accepted. Most laboratories now have the capability of reporting at least low -resolution molecular class II types. The sera of patients awaiting cadaveric do nor kidney transplantation are tested for the degree of alloimmunization by dete rmining the percentage of panel reactive antibodies (PRAs). Current federal regu lations require that the serum screening test use lymphocytes as targets; howeve r, because these same regulations no longer mandate monthly screening, assays us ing soluble antigens may be used as adjuncts to the classic lymphocytotoxic assa ys. The purpose of cross-match testing is to detect the presence of antibodies i n the patients' serum that are directed against the HLA antigens of the potential donor. When present, the antibodies indicate that the immune system of the recip ient has been sensitized to the donor antigens. The various test methods differ in sensitivity, including the multiple variations of the lymphocytotoxicity text , flow cytometry, and enzyme-linked immunosorbent assay (ELISA). The degree of a cceptable risk is one factor to be considered in selecting a method of appropria te sensitivity. For example, when the only risk considered unacceptable is that of hyperacute rejection, a technique having lower sensitivity is adequate. A sec ond approach may be to consider the degree to which an individual patient or typ e of patient is at risk for graft rejection. The patient having a repeat graft i s at higher risk for graft rejection than is the patient receiving a primary gra ft. Because patients differ in their degree of risk, it is appropriate to use di fferent techniques to offset that risk. FIGURE 8-4 Human leukocyte antigens (HLA s) are heterodimeric cell-surface glycoproteins. HLAs are divided into two class es, according to their biochemical structure and respective functions. Class I a ntigens (A, B, and C) have a molecular weight of approximately 56,000 D and cons ist of two chains: a glycoprotein heavy chain ( ) and a light chain ( 2-microglo bulin). The chain is attached to the cell membrane, whereas 2-microglobulin is a ssociated with the chain but is not covalently bonded. The HLA class I molecules are found on almost all cells; however, only vestigial amounts remain on mature erythrocytes. Class II antigens (HLA-DR, DQ, and DP) have a molecular weight of approximately 63,000 D and consist of two dissimilar glycoprotein chains, desig nated and , both of which are attached to the membrane. Each chain consists of t wo extramembranous amino acid domains, and the outer domains of each molecule co ntain the variable regions corresponding to class II alleles. Although class I a ntigens are expressed on all nucleated cells of the body, the expression of clas s II antigens is more restricted. Class II antigens are found on B lymphocytes, activated T lymphocytes, monocyte-macrophages, dendritic cells, and early hemato poietic cells, and of importance in transplantation, endothelial cells. MHC I AND II CHARACTERISTICS Class I Composed of HLA-A, -B, and -C Ubiquitous distribution Autosomal codominant Targe t for immune effector mechanism Serologic and molecular detection Heterodimer no ncovalently linked Heavy chain ( ): Contains variable regions Confers human leuk ocyte antigen specificity Light chain ( 2-microglobulin): Invariant Class II Composed of HLA-DR, -DQ, and -DP Restricted distribution Autosomal codominant Ma

jor role in immune response induction Serologic, molecular, and cellular detecti on Heterodimer noncovalently linked Chain: Nonvariable in HLA-DR Contains variab le regions in HLA-DQ and -DP Chain: Contains variable regions Confers most of HL A-DR specificity

8.4 Transplantation as Treatment of End-Stage Renal Disease MHC protein T-cell receptor a chain Processed antigen b chain FIGURE 8-5 Biology of the major histocompatibility complex (MHC). A, The biologi c function of MHC antigens is to present antigenic peptides to T lymphocytes. In fact, it is an absolute requirement of T-lymphocyte activation for the T cells to see the antigenic peptide bound to an MHC molecule. This MHC restriction has be en defined on a molecular basis with the elucidation of the crystalline structur es of classes I and II MHC molecules. B, The N-terminal domains of the MHC molec ules are formed by the folding of portions of their component chains in -pleated sheets and helices. C, The sheet portions form a floor, and the helices form th e sides of a peptide-binding groove. A a1 a2 b2m a3 B C Peptide Peptide Hev subunit b2m subunit a subunit b subunit A B FIGURE 8-6 The structure of class I and II molecules. Comparison of the crystall ine structures of classes I and II molecules has revealed overall structural sim ilarity, with a few significant differences. A, Class I molecules have a groove with deep anchor pockets at each end (a pita pocket). These pockets restrict the b inding of peptides to those of eight to nine amino acid residues in length. B, T he peptide-binding groove of class II molecules is more flexible and relatively open at one end, more like a hotdog bun, permitting larger peptides from 13 to 25 amino acid residues in length to bind.

Histocompatibility Testing and Organ Sharing 8.5 HLA SPECIFICITIES A A1 A2 A203 A210 A3 A9 A10 A11 A19 A23(9) A24(9) A2403 A25(10) A26(10) A28 A29(19 ) A30(19) A31(19) A32(19) A33(19) A34(10) A36 A43 A66(10) A68(28) A69(28) A74(19 ) A80 B B5 B7 B703 B8 B12 B13 B14 B15 B16 B17 B18 B21 B22 B27 B2708 B35 B37 B38(16) B39( 16) B3901 B3902 B40 B4005 B41 B42 B44(12) B45(12) B46 B47 B48 B49(21) B50(21) B B51(5) B5102 B5103 B52(5) B53 B54(22) B55(22) B56(22) B57(17) B58(17) B59 B60(40 ) B61(40) B62(15) B63(15) B64(14) B65(14) B67 B70 B71(70) B72(70) B73 B75(15) B7 6(15) B77(15) B7801 B81 Bw4 Bw6 C Cw1 Cw2 Cw3 Cw4 Cw5 Cw6 Cw7 Cw8 Cw9(w3) Cw10(w3) DR DR1 DR103 DR2 DR3 DR4 DR5 DR6 DR7 DR8 DR9 DR10 DR11(5) DR12(5) DR13(6) DR14(6) D R1403 DR1404 DR15(2) DR16(2) DR17(3) DR18(3) DR51 DR52 DR53 DQ DQ1 DQ2 DQ3 DQ4 DQ5(1) DQ6(1) DQ7(3) DQ8(3) DQ9(3) DP DPw1 DPw2 DPw3 DPw4 DPw5 DPw6 FIGURE 8-7 Allelic polymorphism. Allelic polymorphism is a hallmark of the human leukocyte antigen (HLA) system. The extreme polymorphism of the HLA system is s een in the large numbers of different alleles that exist for the multiple major histocompatibility complex (MHC) loci. At any given locus, one of several altern ative forms or alleles of a gene can exist. Because so many alleles are possible for each HLA locus, the system is extremely polymorphic. The currently accepted World Health Organization serologically defined alleles are shown here. Establi shed HLA antigens are designated by a number following the letter that denotes t he HLA locus (eg, HLA-A1 and HLA-B8). For example, by serologic techniques, 28 d istinct antigens are recognized at the HLA-A locus, and 59 defined antigens at t he HLA-B locus. Sequencing studies of the HLA-DRB1 gene have identified over 100 distinct alleles, and preliminary analysis indicates that this level of polymor phism will be as high for other loci such as HLA-B. MHC polymorphism ensures eff ective antigen presentation of most pathogens; however, clinically, MHC polymorp hism complicates attempts to find histocompatible donors for solid organ transpl antation. Antigens listed in parentheses are the broad antigens, antigens followed by broa d antigens in parentheses are the antigen splits.

8.6 Transplantation as Treatment of End-Stage Renal Disease Father a b A1 A3 Mother c d A2 A9 Stage 1 Incubate cells and serum Wash 3 Cw7 B8 Cw7 B7 Cw7 B12 Cw4 B35 30 min RT Add AHG 2 min DR3 DR2 DR5 DR3 Stage 2 Children a A1 c A2 A1 a d A9 A3 b c A2 A3 b d A9 60 min RT Add rabbit serum (complement) Cw7 B8 Cw7 B12 Cw7 B8 Cw4 B35 Cw7 B7 Cw7 B12 Cw7 B7 Cw4 B35 Stage 3 Visualize membrane injury (Eosin-y, AO/EB, etc.) DR3 DR5 DR3 DR3 DR2 DR5 DR2 DR3 FIGURE 8-8 Genetic principles of the major histocompatibility complex (MHC). The MHC demonstrates a number of genetic principles. Each person has two chromosome

s and thus two MHC haplotypes, each inherited from one parent. Because the human leukocyte antigen (HLA) genes are autosomal and codominant, the phenotype repre sents the combined expression of both haplotypes. Each child receives one chromo some and hence one haplotype from each parent. Because each parent has two diffe rent number 6 chromosomes, four different combinations of haplotypes are possibl e in the offspring. This inheritance pattern is an important factor in finding c ompatible related donors for transplantation. Thus, an individual has a 25% chan ce of having an HLA-identical or a completely dissimilar sibling and a 50% chanc e of having a sibling matched for one haplotype. The genes of the HLA region occ asionally ( 1%) demonstrate chromosomal crossover. These recombinations are then transmitted as new haplotypes to the offspring. FIGURE 8-9 Complement-dependent technique. The standard technique used to detect human leukocyte antigen (HLA)-A, -B, -C, -DR, and -DQ antigens has been the mic rolymphocytotoxicity test. This assay is a complement-dependent cytotoxicity (CD C) in which lymphocytes are used as targets because the HLA antigens are express ed to varying degrees on lymphocytes and a relatively pure suspension of cells c an be obtained from anticoagulated peripheral blood. Lymphocytes obtained from l ymph nodes or the spleen also may be used. HLA antisera of known specificity are placed in wells on a Terasaki microdroplet tray. A concentrated suspension of lym phocytes is added to each well. If the target lymphocytes possess the antigen co rresponding to the antibody present in the antiserum, the antibody will affix to the cells. Rabbit complement is then added to the wells and, when sufficient an tibody is bound to the lymphocyte membranes, complement is activated. Complement activation injures the cell membranes (lymphocytotoxicity) and increases their permeability. Cell injury is detected by dye exclusion: cells with intact membra nes (negative reactions) exclude vital dyes; cells with permeable membranes (pos itive reactions) take up the dye. Sensitivity of the CDC assay is increased by w ash techniques or the use of AHG reagents prior to the addition of complement. B ecause HLA-DR and -DQ antigens are expressed on B cells and not on resting T cel ls, typing for these antigens usually requires that the initial lymphocyte prepa ration be manipulated before testing to yield an enriched B-cell preparation. AH Gantiglobulinaugmented lymphocytotoxicity; RTroom temperature. FIGURE 8-10 Scoring of complement-dependent cytotoxicity. In an effort to standardize interpretatio n of complement-dependent cytotoxicity (CDC) reactions, a uniform set of scoring criteria have been established. When most of the cells are alive, visually refr actile on microscopic examination, a score of 1 is assigned. Conversely, when mo st of the cells are dead, a score of 8 is assigned. This method of interpretatio n for CDC reactions is universally used in cross-match testing, antibody screeni ng, and antigen phenotyping for serologically defined HLA-A, -B, -C, -DR, and -D Q. (Adapted from Gebel and Lebeck [1]; with permission.) SCORING OF COMPLEMENT-DEPENDENT CYTOTOXICITY REACTIONS Dead cells, % 010 1120 2150 5180 80100 Unreadable Assigned value 1 2 4 6 8 0 Interpretation Negative Borderline negative Weak positive Positive Strong positive No cells, co ntamination, bubble

Histocompatibility Testing and Organ Sharing 8.7 6 7 10 8 2 9 1 5 11 4 3 FIGURE 8-11 The United Network for Organ Sharing (UNOS) regions. UNOS is a not-f or-profit corporation within the United States organized exclusively for charita ble, educational, and scientific purposes related to organ procurement and trans plantation. Its formation established a national Organ Procurement and Transplan tation Network with the mandate to improve the effectiveness of the nation's renal and extrarenal organ procurement, distribution, and transplantation systems by increasing the availability of and access to donor organs for patients with endstage organ failure. Additionally, the UNOS maintains quality assurance activiti es and systematically gathers and analyzes data and regularly publishes the resu lts of the national experience in organ procurement and preservation, tissue typ ing, and clinical organ transplantation. Functionally, the United States is divi ded into UNOS regions as detailed on this map. Additional geographic divisions ( ie, local designation) defined by the individual organ procurement organizations and the transplantation centers they service comprise the working system for ca daveric renal allocation. UNITED NETWORK FOR ORGAN SHARING: NUMBER OF PATIENT REGISTRATIONS ON THE NATIONA L TRANSPLANT WAITING LIST AS OF OCTOBER 31, 1997 Kidney number by blood type (%) Type O: 19,654(52.04) Type A: 10,612(28.10) Type B: 6579(17.42) Type AB: 923(2.4 4) Total: 37,768 Kidney number by race (%) White: 18,353(48.59) Black: 13,290(35.19) Hispanic: 3441(9.11) Asian: 2200(5.83) Other: 484(1.28) Total: 37,768 Kidney number by gender (%) Female: 16,269(43.08) Male: 21,499(56.92) Total: 37,768 Kidney number by transplantation center region (%) Region 1: 1738(4.60) Region 2: 6060(16.05) Region 3: 3844(10.18) Region 4: 2191( 5.80) Region 5: 7361(19.49) Region 6: 855(2.26) Region 7: 3826(10.13) Region 8: 1559(4.13) Region 9: 3936(10.42) Region 10: 3121(8.26) Region 11: 3277(8.68) Tot al: 37,768 Kidney number by age (%) 05: 76(0.20) 610: 119(0.32) 1117: 429(1.14) 1849: 21,102(55.87) 5064: 12,942(34.27) 6 5+: 3100(8.21) Tota: 37,768 FIGURE 8-12 The United Network for Organ Sharing (UNOS) patient waiting list. Th e UNOS patient waiting list is a computerized list of patients waiting to be mat ched with specific donor organs in the hope of receiving a transplantation. Pati ents on the waiting list are registered on the UNOS computer by UNOS member tran splantation centers, programs, or organ procurement organizations. The UNOS Matc

h System is an algorithm used to prioritize patients waiting for organs. The system eliminates potential recipients whose si ze or ABO type is incompatible with that of a donor and then ranks those remaini ng potential recipients according to a UNOS board-approved system. As indicated here, nearly 40,000 patients are awaiting kidney transplantation in the United S tates. (Adapted from the United Network for Organ Sharing [2]).

8.8 Transplantation as Treatment of End-Stage Renal Disease FIGURE 8-13 Point system for kidney allocation. Kidneys that cannot be allocated to a human leukocyte antigen (HLA)matched patient are distributed locally to can didates who are ranked according to waiting time, with additional points for deg rees of HLA mismatch and antibody sensitization. Pediatric patients, medically u rgent cases, and previous donors (living related donors, and so on) also are giv en a point advantage. POINT SYSTEM FOR KIDNEY ALLOCATION Time of waiting The time of waiting begins when a patient is listed and meets the minimum established criteria on the United Network for Organ Sharing Patient Wai ting List. One point will be assigned to the patient waiting for the longest per iod, with fractions of points being assigned proportionately to all other patien ts according to their relative time of waiting. Quality of HLA mismatch 10 point s if there are no A, B, or DR mismatches. 7 points if there are no B or DR misma tches. 5 points if there is one B or DR mismatch. 2 points if there is a total o f two mismatches at the B and DR loci. Panel reactive antibody Patients will be assigned 4 points if they have a panel reactive antibody level of 80% or more. M edical urgency No points will be assigned to patients based on medical urgency f or regional or national allocation of kidneys. Locally, the patient's physician ha s the authority to use medical judgment in assignment of points for medical urge ncy. When there is more than one local renal transplantation center, a cooperati ve medical decision is required before assignment of points for medical urgency. Pediatric kidney transplantation candidates 4 points if the patient is under 11 years of age. 3 points if the patient is over 11 and under 18 years of age. CROSSMATCH METHODS Lymphocytotoxicity: Autocrossmatch vs allocrossmatch T or B cell Short/long/wash/A HG methods IgG vs IgM Flow cytometry Enzyme-linked immunosorbent assay FIGURE 8-14 Crossmatch methods. Early reports correlating a positive crossmatch between recipient serum and donor lymphocytes with hyperacute rejection of trans planted kidneys led to establishing tests of recipient sera as the standard of p ractice in transplantation. However, controversy remains regarding 1) the level of sensitivity needed for crossmatch testing; 2) the relevance of B-cell crossma tches, a surrogate for class II incompatibilities; 3) the relevance of immunoglo bulin class and subclass of donor-reactive antibodies; 4) the significance of hi storical antibodies, ie, antibodies present previously but not at the time of tr ansplantation; 5) the techniques and type of analyses to be performed for serum screening; and 6) the appropriate frequency and timing of serum screening. Despi te a number of variables, when the data from reported studies are considered col lectively, several observations can be made. Human leukocyte antigendonor-specifi c antibodies present in the recipient at the time of transplantation are a serio us risk factor that significantly diminishes graft function and graft survival. Antibodies specific for human leukocyte antigen class II antigens (HLA-DR and -D Q) are as detrimental as are those specific for class I antigens (HLA-A, -B, and -C). The degree of risk resulting from HLA-specific antibodies varies among imm unoglobulin classes, with immunoglobulin G antibodies representing the most seri ous risk. AHGantiglobulinaugmented lymphocytotoxicity.

Histocompatibility Testing and Organ Sharing 250 200 150 100 50 0 0 50 100 R1 8.9 250 200 CD3 PE 150 100 50 0 150 FSC 200 250 0 50 100 R2 A B 150 FSC 200 250 200 T cell 100 90 80 70 60 M1 Neg (n = 508) Neg (n = 75) Pos (n = 106) Pos (n = 43) 160 Counts 120 80 40 0 0 50 40 First C 50 100 150 200 Human IgG-Fc-FITC 250 30 Regraft D 0 6 12 0 6 12 Months after transplantation FIGURE 8-15 Techniques of crossmatch testing. Early crossmatch testing provided a means to prevent most but not all hyperacute rejections. These early tests wer e performed with a technique of rather low sensitivity. Subsequently, more sensi tive techniques were employed in an attempt to not only prevent all hyperacute r ejections but also improve graft survival rates. Techniques that have been used include variations of the lymphocytotoxicity test that incorporate wash steps, c hange in incubation times or temperatures, or both, or add an antiglobulin reage nt. Flow cytometry and an array of other methods such as antibodydependent cellular cytotoxicity also have been tried. Two of the most sensitive techniques are the antiglobulin-augmented lymphocytotoxicity (AHG) and flow cyto metric crossmatching. A, The use of flow cytometry to define the lymphocyte popu lation by light scatter parameters, followed by a specific marker for T lymphocy tes, ie, CD3 (B) allows this technique to be highly specific for human leukocyte

antigen (HLA) class Ipositive cells. The donor lymphocytes have been preincubate d with recipient serum, washed, and subsequently stained with AHG-Fluorescsin is othiocyanate (FITC), a fluorochrome-labeled antihuman globulin. C, Results of fl ow cytometric cross-matching are evaluated as shifts in the fluorescence from ne gative sera and are interpreted as positive or negative based on independently d efined cutoffs above the negative. D, Multiple studies in renal transplantation have shown correlations between positive AHG or flow cytometric cross-matches an d decreased graft survival at 1 year or more. The largest differences are seen w hen patients are grouped as primary grafts versus repeat grafts. In some instanc es the effect of using a more sensitive cross-match technique only can be seen i n patients having repeat grafts or those with a higher immunologic risk. CD3 PEmo noclonal antibody to CD3 fluorescent labelled with phycoerythrin; FCconstant frag ment of IgG molecule; FITCfluorescent labelled with fluorescein isothiocynate; FS Cforward scatter; R1region 1; R2region 2; SSCside scatter. (Panel D adapted from Coo k [3]; with permission.) SSC ALTERNATIVE APPROACHES TO HLA MATCHING Associated human leukocyte antigen gene products A1,3,9,10,11,28,29,30,31,32,33 A2,9,28, B17 B5,15,17,18,35,53,70,49 B7,13,22,274 0,41,47,48 B8,14,16,18 B12,13,21,40,41 A24,25,32,34, Bw4 Bw6, Cw1,3,7 CREG* 1C 2C 5C 7C 8C 12C 4C 6C Approximate epitope frequency, % 80 66 59 64 37 44 85 87 C refers to major public epitope or cross-reactive groups (CREG). FIGURE 8-16 Alternative approaches to human leukocyte antigen (HLA) matching. Be cause completely mismatched kidney transplantations function well over long peri ods, an alternative approach might begin with the hypothesis that six-antigen mis matched transplantations were not completely mismatched. Interest in reevaluating the potential roles of cross-reactive groups (CREGs) in transplantation is one such approach. In the early days of serologic HLA testing, a high panel reactive antibody sera was considered to be composed of many antiHLA antibodies. It was later noted, however, that sera of highly sensitized patients awaiting solid org an transplantation were generally composed of a small number of antibodies direc ted at public antigens, also called CREGs, rather than multiple antibodies, each reacting with a specific conventional HLA antigen. Furthermore, the frequency o f the CREGs was much higher, eg, 35% to 88%, than that of even the most common H LA-A and -B antigens. By inference, therefore, matching for donor and recipient antigens included in the same CREG, ie, CREG matching, could result in a higher number of matched transplantations and a lower level of sensitization in patient s having repeat grafts. In addition, because of the inclusion of several private HLA-A and -B antigens within a single CREG, a number of relatively rare antigen s can be matched more easily, offering the possibility of improved graft surviva l for a greater number of both white and nonwhite patients. (Adapted from Thelan and Rodey [4]; with permission.)

8.10 100 80 Graft survival (log), % Transplantation as Treatment of End-Stage Renal Disease 100 80 Graft survival (log), % 60 40 30 20 ABDR MM 0 1 2 3 4 5 6 n 301 255 970 2459 3251 2078 739 T 12 7 7 6 6 6 6 6 60 40 30 20 ABDR MM n 0 3023 1 1305 2 3 4 5 6 3736 6312 6414 3641 1209 T 12 14 12 12 12 11 11 10 White 1st cadaver UNOS (19911996) Black 1st cadaver UNOS (19911996) 10 0 1 2 10 3 4 5 6 7 Years after transplantation 8 9 10 0 1 2 A B 3 4 5 6 7 Years after transplantation 8 9 10 FIGURE 8-17 The role of human leukocyte antigen (HLA) matching in the United Sta tes in whites (A) and blacks (B). Recent large registry analyses of the role for HLA matching in renal transplantation consistently have shown a stepwise decrea se in long-term graft survival rates with increasing antigen mismatches. Based o n these results the United Network of Organ Sharing (UNOS) incorporated the leve l of HLA match into its algorithm used nationally for kidney allocation. The UNO S initially determined that transplantations for which all six HLA-A, -B, and -D R antigens matched in the donor and recipient should be performed. Each cadaveri c donor type was compared by a computer search with the HLA types of all patient s awaiting kidney transplantation. When a patient with six antigen matches was identified in an ABO-compatible recipient, the kidney was offered for that patie nt, and if accepted by the transplantation center, was shipped for transplantati on. (Normally, kidneys from a patient with blood type O are allocated only to pa tients with type O blood, except in the case of patients with six antigen matche s.) The UNOS policy regarding mandatory sharing of HLA-matched kidneys has been liberalized twice. The first time was in 1990 to include phenotypically matched pairs with fewer than six antigens. The policy was changed for a second time in 1995 to include zero-mismatched pairs in which the donor could have fewer antige ns than the recipient, provided none were mismatched. (Adapted from Cecka [5]; w ith permission.) FIGURE 8-18 Serologic testing and antigen assignment. Most of t he published transplantation outcome data is based on serologic testing and assi gnment of antigens. These data include algorithm matching based on broad human leu kocyte antigen (HLA) specificities such as HLA-DR6 that includes HLA-DR13 and HL A-DR14 and their many alleles. The question has now become one of what level of HLA testing is useful clinically for matching purposes in renal transplantation. Although this issue has not been resolved, recent data published from the Europ ean Registry upholds the positive effect that correct HLA matching has had on rena l graft outcome. Serology (antibody defined)

versus (Low Molecular Intermediate High resolution) HLA-DR13 *1301*1312 *1314*1330 HLA-DR6 HLA-DR14 DR1403 DR1404 *1401, *1402, *1405*1429

Histocompatibility Testing and Organ Sharing 100 90 Graft survival, % 80 70 60 50 40 0 3 6 Time, mo 9 12 DNA: DR >0 mm (n = 22) DNA: DR 0 mm (n = 64) 8.11 A 100 90 Graft survival, % 80 70 60 50 0 0 3 DNA: A+B 0 mm (n = 183) FIGURE 8-19 Classes II and I mismatches in supposed 0 mm shared renal transplant ations. The effect on graft survival of shared human leukocyte antigen (HLA) 0mm organs when defined by serologic typing and then confirmed by molecular typing. A strong effect of HLA matching is seen at even 1 year on the graft survival. A , Eighty-six first cadaveric kidney transplantations that were reported by serol ogic typing as HLA-A, -B, -DR identical-compatible were tested by molecular method s. Sixty-four transplantations were confirmed to be HLA-DR compatible; however, mismatches were found in the remaining 22 transplantations. Transplantations in which HLA compatibility was confirmed had a functional success rate of 90% at 1 year compared with 68% for transplantations in which the DNA typing revealed HLA -DR mismatches (P < 0.02). B, An analysis of the influence of HLA-class I DNA ty ping on kidney graft survival is shown. A total of 183 cadaveric transplantation s were confirmed to be HLA-A and B compatible after DNA typing, whereas mismatch es were found in the remaining 32 cases. Transplantations in which compatibility was confirmed had a functional success rate of 86.9% at 1 year compared with a 71.9% rate for those in which DNA typing revealed HLA-A or -B mismatches (P = 0. 033.) (Panel A adapted from Opelz and coworkers [6]; panel B adapted from Mytili neous and coworkers [7]; with permission.) DNA: A+B >0 mm (n = 32) B 6 Time, mo 9 12 100 90 80 Graft survival, % 70 60 50 40 30 20 10 0 0 1 2 88 89 90 91 n 1809 1895 2086 2385 t 12 12.5 14.3 14.9 14.6 92 93 94 95 n 2527 282 8 2914 3117 t 12 17.0 16.3 17.5 8.8 Living donor 60 1988 50 40 % 30 20 10 0 3 4 5 Years after transplantation 6 7 8 Parent Offspring Sibl ing 1996 A B Other relative Spouse/other unrelated

FIGURE 8-20 Living donor kidney transplantation graft survival rates (A) and don or sources (B). The high graft survival rates reported for recipients of living donor kidneys improved from 89% in 1988 to 93% in 1991 (P < 0.001), even though a substantial increase has occurred in both the number of living donors and cent ers performing these transplantations. Some of the increase in living donations has been due to a growing acceptance of so-called unconventional donors, ie, spouses and other genetically unrelated donors, as we ll as distant relatives and half-siblings. In 19881989, unrelated donors accounte d for 4% of living donor transplantations and distant relatives for 2%. These nu mbers have tripled and are now at 12% and 6%, respectively. (Panel A from Cecka [8]; panel B adapted from the United Network for Organ Sharing [9]; with permiss ion.)

8.12 Transplantation as Treatment of End-Stage Renal Disease References 1. 2. 3. 4. 5. Gebel HM, Lebeck LK: Crossmatch procedures used in organ transpla ntation. Clin Lab Med 1991, 11:609. United Network for Organ Sharing: UNOS Bulle tin 1997, 2. Cook DJ, et al.: An approach to reducing early kidney transplant fa ilure by flow cytometry crossmatching. Clin Transpl 1987, 1:25. Thelan D, Rodey G: American Society of Histocompatibility and Immunogenetics Laboratory Manual, edn 3. Lenexa, KS: ASHI. Cecka JM: The role of HLA in renal transplantation. Hum an Immunology 1997, 56:616. 6. 7. 8. Opelz et al.: Transplantation 1998, 55:782785 . Mytilenous et al.: Tissue Antigens 1997, 50:355358. Cecka JM: UNOS Scientific R enal Transplant Registry. In Clinical Transplant Registry. Edited by Cecka JM, T erasaki P. Los Angeles: UCLA; 1996:114. United Network for Organ Sharing: UNOS Bu lletin 1997, 2. 9.

Transplant Rejection and Its Treatment Laurence Chan R ejection is the major cause of graft failure, and if the injury to the tubules a nd glomeruli is severe, the kidney may not recover. It is therefore important to diagnose acute rejection as soon as possible to institute prompt antirejection therapy. Generally, the success with which rejection can be reversed by immunosu ppressive agents determines the chance of long-term success of the transplant [1 ,2]. CHAPTER 9

9.2 Transplantation as Treatment of End-Stage Renal Disease Mechanisms of Renal Allograft Rejection Immune response cascade CD2 TCR CD4 HLAclass II CD4 CD58 CD2 TCR CD3 Allograft HLAclass I HLAclass II T cells CD3 HLAclass I CD58 CD8 TCR CD2 CD3 APC IL-1 CD4 T cells Cytokines IL-2R IFN-g etc. IL-2 CD4 CD8 T cells TCR CD8 CD3 B cells NK cells Clonal expansion HLAclass I HLAclass II CD8 T cells CD2 IL-2R A Graft destruction B. OVERVIEW OF REJECTION EVENTS Antigen-presenting cells trigger CD4 and CD8 T cells Both a local and systemic i mmune response develop Cytokines recruit and activate nonspecific cells and accu mulate in graft, which facilitates the following events: Development of specific T cells, natural killer cells, or macrophage-mediated cytotoxicity Allograft de struction FIGURE 9-1 Aspects of the rejection response. A, The immune response cascade. Re jection is a complex and redundant response to grafted tissue. The major targets of this response are the major histocompatibility complex (MHC) antigens, which are designated as human leukocyte antigens (HLAs) in humans. The HLA region on the short arm of chromosome 6 encompasses more than 3 million nucleotide base pa irs. It encodes two structurally distinct classes of cell-surface molecules, ter med class I (HLA-A, -B, and -C) and class II (-DR, -DQ, -DP). B, Overview of rej

ection events. T cells recognize foreign antigens only when the antigen or an im munogenic peptide is associated with a self-HLA molecule on the surface of an ac cessory cell called the antigen-presenting cell (APC). Helper T cells (CD4) are activated to proliferate, differentiate, and secrete a variety of cytokines. The se cytokines increase expression of HLA class II antigens on engrafted tissues, stimulate B lymphocytes to produce antibodies against the allograft, and help cy totoxic T cells, macrophages, and natural killer cells develop cytotoxicity agai nst the graft. C, Possible mechanisms for allorecognition by host T cells. In th e direct pathway, T cells recognize intact allo-MHC on the surface of donor cell s. The T-cell response that results in early acute cellular rejection is caused mainly by direct allorecognition. In the indirect pathway, T cells recognize pro cessed alloantigens in the context of self-APCs. Indirect presentation may be im portant in maintaining and amplifying the rejection response, especially in chro nic rejection. IFN- interferon gamma; IL-1interleukin-1; IL-2Rinterleukin-2 recepto r; NKnatural killer. (Panel A adapted from [3]; with permission; panel C adapted from [4]; with permission.) Indirect allorecognition CD8+ cytotoxic cell Direct allorecognition CD8+ cytoxic cell I Allogeneic cell Th cell Th cell Shed allogeneic MHC IL-2 IL-2 II (Class Iderived peptide presented by responder class II molecule) I Allogeneic (stimulator) antigen presenting cell II Taken up and processed by host antigen-presenting cell Peptide derived from allogeneic MHC presented on host MHC C Responder antigen-presenting cell Class I stimulator Class II haplotype Class III responder haplotype b2 microglobul in

Transplant Rejection and its Treatment 9.3 Classification of Rejection A. VARIETIES OF REJECTION Types of rejection Time taken Hyperacute Accelerated Acute Chronic Minutes to hours Days Days to weeks Months to years B. IMMUNE MECHANISMS OF RENAL ALLOGRAFT REJECTION Type Hyperacute Accelerated Acute Cellular Vascular Chronic Cause Preformed antidonor antibodies and complement Reactivation of sensitized T cells Primary activation of T cells Both immunologic and nonimmunologic factors Humoral +++ ++ + +++ ++ Cellular + +++ + +? FIGURE 9-2 Varieties of rejection (panel A) and immune mechanisms (panel B). On the basis of the pathologic process and the kinetics of the rejection response, rejection of renal allografts can be commonly divided into hyperacute, accelerated, acute, and chronic types. A FIGURE 9-3 (See Color Plate) Histologic features of hyperacute rejection. Hypera cute rejection is very rare and is caused by antibody-mediated damage to the gra ft. The clinical manifestation of hyperacute rejection is a failure of the kidne y to perfuse properly on release of the vascular clamps just after vascular anas tomosis is completed. The kidney initially becomes firm and then rapidly turns b lue, spotted, and flabby. The presence B of neutrophils in the glomeruli and peritubular capillaries in the kidney biopsy confirms the diagnosis. A, Hematoxylin and eosin stain of biopsy showing inters titial hemorrhage and extensive coagulative necrosis of tubules and glomeruli, w ith scattered interstitial inflammatory cells and neutrophils. B, Immunofluoresc ence stain of kidney with hyperacute rejection showing positive staining of fibr ins.

9.4 Transplantation as Treatment of End-Stage Renal Disease A FIGURE 9-4 Histologic features of acute accelerated rejection. A and B, Photomic rographs showing histologic features of acute accelerated vascular rejection. Gl omerular and vascular endothelial infiltrates and swelling are visible. An accel erated rejection, which may start on the second or third day, tends to occur in the previously sensitized patient in B whom preformed anti-HLA antibodies are present. This type of rejection occurs in patients who have had a previous graft and presents with a decrease in renal fu nction; the clinical picture is similar to that for hyperacute rejection. A FIGURE 9-5 Histologic features of acute cellular rejection. A, Mild tubulitis. B , Moderate to severe tubulitis. Acute rejection episodes may occur as early as 5 to 7 days, but are generally seen between 1 and 4 weeks after transplantation. The classic acute rejection episode of the earlier era (ie, azathioprine-prednis olone) was accompanied by swelling and tenderness of the kidney and the onset of oliguria with an associated rise in serum creatinine; these symptoms were usual ly accompanied by a significant fever. However, in patients who have been treate d with cyclosporine, the clinical features of an acute rejection are really quit e minimal in that there is perhaps some swelling of the kidney, usually no tende rness, and there may be a minimal to moderate degree of fever. Because such an a cute rejection may occur at a time when there is a distinct possibility of B acute cyclosporine toxicity, the differentiation between the two entities may be extremely difficult. The differential diagnosis of acute rejection, acute tubul ar necrosis, and cyclosporine nephrotoxicity may be difficult, especially in the early posttransplant period when more than one cause of dysfunction can occur t ogether [2]. Knowledge of the natural history of several clinical entities is ex tremely helpful in limiting the differential diagnosis. Reversible medical and m echanical causes should be excluded first. Percutaneous biopsy of the renal allo graft using real-time ultrasound guide is a safe procedure. It provides histolog ic confirmation of the diagnosis of rejection, aids in the differential diagnosi s of graft dysfunction, and allows for assessment of the likelihood of a respons e to antirejection treatment.

Transplant Rejection and its Treatment 9.5 A C. CHRONIC ALLOGRAFT REJECTION Typical clinical presentation Gradual increase in creatinine (months) Non-nephro ticrange proteinuria No recent nephrotoxic events Key pathologic features Interst itial fibrosis Arterial fibrosis and intimal thickening B Hypothetical schema for chronic rejection Acute rejection Antibody deposition Ox idized LDL Infection T cells Macrophages Platelet aggregates Cytokines/ growth factors Cell proliferation Fibrosis Tubulointerstitial injury Glomerular sclerosis Vascular injury Arteriosclerosis Reduced nephron mass D Graft loss FIGURE 9-6 Features of chronic rejection. A, Arterial fibrosis and intimal thick ening. B. Interstitial fibrosis and tubular atrophy. C, Typical presentation and pathologic features. Chronic rejection occurs during a span of months to years. It appears to be unresponsive to current treatment and has emerged as the major problem facing transplantation [5]. Because chronic rejection is thought to be the end result of uncontrolled repetitive acute rejection episodes or a slowly p rogressive inflammatory process, its onset may be as early as the first few week s after transplantation or any time thereafter. D, The likely sequence of events in chronic rejection and potential mediating factors for key steps. Progressive azotemia, proteinuria, and hypertension are the clinical hallmarks of chronic r ejection. Immunologic and nonimmunologic mechanisms are thought to play a role i n the pathogenesis of this entity. Immunologic mechanisms include antibody-media ted tissue destruction that occurs possibly secondary to antibodydependent cellu lar cytotoxicity leading to obliterative arteritis, growth factors derived from macrophages and platelets leading to fibrotic degeneration, and glomerular hyper tension with hyperfiltration injury due to reduced nephron mass leading to progr essive glomerular sclerosis. Nonimmunologic causes can also contribute to the de cline in renal function. Atheromatous renovascular disease of the transplant kid ney may also be responsible for a significant number of cases of progressive gra ft failure. (Continued on next page)

9.6 Transplantation as Treatment of End-Stage Renal Disease FIGURE 9-6 (Continued) E, Diagnostic and therapeutic approach to chronic rejecti on. ATGantithymocyte globulin; ATNacute tubular necrosis; BP blood pressure; CsAcycl osporine; LDLlow-density lipoprotein. Diagnostic and therapeutic approach to chronic rejection Slowly rising creatinin e Check CsA level High Lower CsA dose and repeat creatinine Improved No improvemen t Ultrasound Obstruction No obstruction Biopsy Rejection Acute on chronic ATN Gl omerulonephritis Recurrent GN de novo GN Chronic Low Acute Adjust immunosuppressant Steroid bolus OKT3 or ATG Temporizing measures Control BP Avoid nephrotoxins E BANFF CLASSIFICATION OF RENAL ALLOGRAFT REJECTION Normal Patchy mononuclear cell infiltrates without tubulitis is not uncommon Bor derline changes No intimal arteritis; mild tubulitis and endocapillary glomeruli tis Acute rejection Grade I: tubulitis ++ Grade II: tubulitis with glomerulitis Grade III: intimal arteritis, interstitial hemorrhage, fibrinoid, thrombosis FIGURE 9-7 The Banff classification of renal allograft rejection. This schema is an internationally agreed on standardized classification of renal allograft pat hology that regards intimal arteritis and tubulitis as the main lesions indicati ve of acute rejection [6].

Transplant Rejection and its Treatment 9.7 New techniques FIGURE 9-8 Fine-needle aspiration cytology technique for the transplanted kidney . A 23- or 25-gauge spinal needle is used under aseptic conditions. A 20-mL syri nge containing 5 mL of RPMI-1640 tissue culture medium is connected to the needl e. Ultrasound guidance may be used on the rare occasions when the graft is not e asily palpable [8]. Monitoring of other products of inflammation such as neopter in and lymphokines continues to be explored. It has been shown that acute reject ion is associated with elevated plasma interleukin (IL)-1 in azathioprine-treate d patients and IL-2 in cyclosporine-treated patients. IL-6 is also increased in the serum and urine immediately after transplantation and during acute rejection episodes. The major problem, however, is that infection, particularly viral, ca n also elevate cytokine levels. Recently, polymerase chain reaction (PCR) has al so been used to detect mRNA for IL-2 in fine-needle aspirate of human transplant kidney [7,8]. Using the PCR approach, IL-2 could be detected 2 days before reje ction was apparent by histologic or clinical criteria. Reverse transcriptasePCR h as also been used to identify intrarenal expression of cytotoxic molecules (gran zyme B and perforin) and immunoregulatory cytokines (IL-2, -4, -10, interferon g amma, and transforming growth factor- 1) in human renal allograft biopsy specime ns [9]. Molecular analyses revealed that intragraft display of mRNA encoding gra nzyme B, IL-10, or IL-2 correlates with acute rejection, and intrarenal expressi on of transforming growth factor (TGF)- 1 mRNA is associated with chronic reject ion. These data suggest that therapeutic strategies directed at the molecular co rrelates of rejection might refine existing antirejection regimens. Constant (but not excessive) suction 25-G needle Transplanted kidney Wound Inguinal ligament Treatment IMMUNOSUPPRESSION PROTOCOLS Induction protocols Maintenance protocols Early posttransplantation Late posttra nsplantation Antirejection therapy FIGURE 9-9 Immunosuppressive therapy protocols. Standard immunosuppressive thera py in renal transplant recipient consists of 1) baseline therapy to prevent reje ction, and 2) short courses of antirejection therapy using high-dose methylpredn isolone, monoclonal antibodies or polyclonal antisera such as antilymphocyte glo bulin (ALG) and antithymocyte globulin (ATG). Antilymphocyte globulin is prepare d by immunizing rabbits or horses with human lymphoid cells derived from the thy mus or cultured B-cell lines. Disadvantages of using polyclonal ALS include lotto-lot variability, cumbersome production and purification, nonselective targeti ng of all lymphocytes, and the need to administer the medication via central ven ous access. Despite these limitations, ALG has been used both for prophylaxis ag ainst and for the primary treatment of acute rejection. A typical recommended do se for acute rejection is 10 to 15 mg/kg daily for 7 to 10 days. The reversal ra te has been between 75% and 100% in different series. In contrast to murine mono clonal antibodies (eg, OKT3), ALS does not generally induce a host antibody resp onse to the rabbit or horse serum. As a result, there is a greater opportunity f or successful readministration.

9.8 Transplantation as Treatment of End-Stage Renal Disease FIGURE 9-10 Induction (panel A) and maintenance (panel B) immunosuppression prot ocols. These immunosuppressive protocols differ from center to center. There are numerous variations, but the essential features are 1) the prednisone dosage is high initially and then reduced to a maintenance dose of 10 to 15 mg/d over 6 t o 9 months, and 2) the cyclosporine dosage is 8 to 12 mg/kg/d given as a single or twice daily dose, and dosage is adjusted according to trough plasma and serum blood levels. To maintain immunosuppression provided by cyclosporine and to red uce the incidence of cyclosporine side effects, azathioprine or mycophenolate ha s also been used with lower dosages of cyclosporine. The results of this triple therapy are excellent, with first-year graft survival greater than 85% reported in most instances and with a substantial number of patients having no rejection at all. Although this type of regimen was the most common, there have been a num ber of exceptions [2,10]. Recently, mycophenolate mofetil has been approved by t he US Food and Drug Administration for prophylaxis of renal transplant rejection [11]. This agent was developed as a replacement to azathioprine for maintenance immunosuppression. FK506 is a new immunosuppressive agent that has been approve d by the FDA. FK506 is similar to cyclosporine in its mode of action, efficacy, and toxicity profile. The drug has been used in kidney transplantation. FK506 ma y be beneficial in renal transplantation as rescue therapy in patients taking cy closporine who have recurrent or resistant rejection episodes [1214]. A. INDUCTION PROTOCOLS Standard induction Corticosteroids Azathioprine or mycophenolate Cyclosporine or FK506 Antibody induction OKT3 or antithymocyte gamma globulin B. MAINTENANCE IMMUNOSUPPRESSION Cyclosporine or FK506 Mycophenolate Prednisolone ATG OKT3 Postantigenic differentiation CD4 ATG OKT3 Allogeneic cell Class II HLA antigen IL-1 Steroids CD4 Macrophage CsA FK506 RPM IL-2 ATG OKT3 MPA AZA CD4 Prolife ration CD4 IL-2 B lymphocyte MPA Ant ibod y ATG OKT3 TNF-a Stimulated macrophage ine ATG OKT3 Class I HLA antigen IL-1 CD8 CD8 AZA MPA ATG OKT3 ATG OKT3 Cy to k CD8 Steroids s

CD8 ration Prolife ATG OKT3 A FIGURE 9-11 Mechanism of action of immunusuppressive drugs. A, The sites of ac tion of the commonly used immunosuppressive drugs. Immunosuppressive drugs inter fere with allograft rejection at various sites in the rejection pathways. Glucoc orticoids block the release of g-Interferon interlekin (IL)-1 by macrophages, cyclosporine (CsA) and FK506 interfere with I L-2 production from activated helper T cells, and azathioprine (AZA) and mycophe nolate mofetil (MPA) prevent proliferation of cytotoxic and helper T cells. (Con tinued on next page)

Transplant Rejection and its Treatment 9.9 TCR signal TCR signal IL-2R TCR signal Nucleus TCR Cyclosporin A FK506 Nucleus TCR T lymphocyte LKR signal IL-2R LKR signal TCR Nucleus IL-2R Il-2 LKR signal Rapamycin Nucleus TCR B Cell differentiation Cell proliferation FIGURE 9-11 (Continued) B, Mechanism of action of CsA, FK506, and rapamycin (RPM ). CsA and FK506 block the transduction of the signal from the Tcell receptor (T CR) after it has recognized antigen, which leads to the production of lymphokine s such as IL-2, whereas RPM blocks the lymphokine receptor signal, eg, IL-2 plus IL-2 receptor (IL-2R), which leads to cell proliferation. The addition of a pro phylactic course of antithymocyte globulin (ATG) or OKT3 with delay of the admin istration of CsA or FK506 during the initial postoperative periods has been advo cated by some groups. OKT3 prophylaxis was associated with a lower rate of early acute rejection and fewer rejection episodes per patient. Prophylactic use of t hese agents appears to be most effective in high-risk cadaver transplant recipie nts, including those who are sensitized or who have two HLA-DR mismatches or a p rolonged cold ischemia time [2,10]. IFN- interferon gamma; TNF- tumor necrosis fac tor- . A. ANTIREJECTION THERAPY REGIMENS Intravenous methylprednisolone, 0.5 or 1 g x 3 d OKT3 Antithymocyte gamma globul in Rabbit antithymocyte globulin Humanized anti-CD25 (IL-2 receptor) intravenous ly every 2 wk AntiICAM-1 and antiLFA-1 antibodies Treatment algorithm for acute rejection Acute rejection Mild Steroid bolus Resol ves Rising creatinine OKT3 or polyplonal antibodies x 10 d Resolves Persistent a cute rejection on repeat biopsy Evaluate OKT3 antibody titer Low High Severe FIGURE 9-12 Treatment of acute rejection. A, Typical antirejection therapy regim ens. B, Treatment algorithm. A biopsy should be performed whenever possible. The first-line treatment for acute rejection in most centers is pulse methylprednis olone, 500 to 1000 mg, given intravenously daily for 3 to 5 days. The expected r

eversal rate for the first episode of acute cellular rejection is 60% to 70% wit h this regimen [1517]. Steroid-resistant rejection is defined as a lack of improv ement in urine output or the plasma creatinine concentration within 3 to 4 days. In this setting, OKT3 or polyclonal antiT-cell antibodies should be considered [ 18]. The use of these potent therapies should be confined to acute rejections wi th acute components that are potentially reversible, eg, mononuclear interstitia l cell infiltrate with tubulitis or endovasculitis with acute inflammatory endot helial infiltrate [19,21]. ATGantithymocyte globulin; ICAM-1intercellular adhesion molecule-1; LFA-1leukocyte function-associated antigen-1. B ATG or OKT3 ATG

9.10 Transplantation as Treatment of End-Stage Renal Disease A. MAJOR SIDE EFFECTS OF IMMUNOSUPPRESSIVE AGENTS Mycophenolate mofetil + + 0 0 ? Cyclosporine Nephrotoxicity Neurotoxicity Hirsutism Gingival hypertrophy ????? Hypertension + ++ + +++ ++ 0 +++ FK506 ++ ++ 0 0 + + Infection Marrow suppression Hepatic dysfunction Megaloblastic ane mia Hair loss ? Neoplastic Azathioprine ++ ++ + ++ + +? FIGURE 9-13 Side effects of immunosuppressive agents. A, The major side effects of several immunosuppressive agents. The major complication of pulse steroids is increased susceptibility to infection. Other potential problems include acute h yperglycemia, hypertension, peptic ulcer disease, and psychiatric disturbances i ncluding euphoria and depression. B, Vasoconstriction of the afferent arteriole (AA) caused by cyclosporine. (From English et al. [22]; with permission.) B Spleen Lymph nodes Washed white cells Thymus Subcutaneous injection Intravenous infusion Globulin extracted Vial FIGURE 9-14 The making of a polyclonal antilymphocyte preparation. Antilymphocyt e globulin (ALG) or antithymocyte globulin (ATG) are polyclonal antisera derived from immunization of lymphocytes, lymphoblasts, or thymocytes into rabbits, goa ts, or horses. These agents have been used prophylactically as induction therapy during the early posttransplantation period and for treatment of acute rejectio n. Most centers reduce concomitant immunosuppression (eg, stop cyclosporine and lower azathioprine dose) to decrease infectious complications. Antithymocyte gam ma globulin (ATGAM) is the only FDA-approved Horse serum polyclonal preparation. Two rabbit immunoglobulin preparations, raised by immuni zation with thymocytes or with a human lymphoblastoid line, are scheduled for ph ase III multicenter testing versus ATGAM or OKT3, respectively. Potential side e ffects include fever, chills, erythema, thrombocytopenia, local phlebitis, serum sickness, and anaphylaxis. The potential for development of host anti-ALG antib odies has not been a significant problem because of the use of less immunogenic preparations and probably because ALG suppresses the immune response to the fore ign protein itself [2,10].

Transplant Rejection and its Treatment Fuse with polyethylene glycol 9.11 Spleen cells Myeloma cells Assay hybrid cells Select desired hybrids Propagate desired clones Grow in mass culture Freeze Thaw Produce in animals Antibody Antibody FIGURE 9-15 The making of a monoclonal antibody. OKT3 is a mouse monoclonal anti body directed against the CD3 molecule of the T lymphocyte. OKT3 has been used e ither from the time of transplantation to prevent rejection or to treat an acute rejection episode. It has been shown in a randomized clinical trial to reverse 95% of primary rejection episodes compared with 75% with high-dose steroids in p atients who received azathioprineprednisone immunosuppression. In patients recei ving triple therapy (cyclosporineazathioprine-prednisone), 82% of primary reject ion episodes were successfully reversed by OKT3 versus 63% with high-dose steroi ds. Like antilymphocyte globulin (ALG), reduction of concomitant immunosuppressi on (discontinuation of cyclosporine and reduction of azathioprine or mycophenola te mofetil dose) decreases the incidence of infectious complications. Side effec ts include fever, rigors, diarrhea, myalgia, arthralgia, aseptic meningitis, dys pnea, and wheezing, but these rarely persist beyond the second day of therapy. R elease of tumor necrosis factor (TNF), interleukin-2, and interferon gamma in se rum are found after OKT3 injection. The acute pulmonary compromise due to a capi llary leak syndrome rarely has been seen because patients are brought to within 3% of dry weight before initiation of OKT3 treatment. Infectious complications, particularly infection with cytomegalovirus, are increased after multiple course s of OKT3. A. RECOMMENDED PROTOCOL FOR OKT3 TREATMENT Evaluation and treatment before administration Physical examination Laboratory t ests including complete blood count Monitor intake and output; record weight cha nges Chest radiograph Hemodialysis or ultrafiltration for volume overload Premed ication on day 0 and 1 Methylprednisolone, 250500 mg IV given 1 h prior to dose M ethylprednisolone or hydrocortisone sodium succinate, 250500 mg IV given 30 min a fter the dose Diphenhydramine, 50 mg IV 30 min prior to dose daily Acetaminophen , 650 mg PO 30 min prior to dose Discontinue cyclosporine, maintain azathioprine at 25 mg/d Administer OKT3, 5 mg/d IV, days 013 Monitor clinical course Check CD 3 level on day 3 Increase OKT3 dosage to 10 mg/d if either: Anti-OKT3 antibody i s high OKT3 level is low CD3 level is not low FIGURE 9-16 Treatment with OKT3. A, Recommended protocol for OKT3 treatment. The development of host anti-OKT3 antibodies is a potential problem for the reuse o f this drug in previously treated patients. About 33% to 100% of patients develo p antimouse antibodies after the first exposure to OKT3, depending on concomitan t immunosuppression. Anti-OKT3 titers of 1:10,000 or more usually correlate with lack of clinical response. If anti-OKT3 antibodies are of low titer, retreatmen t with OKT3 is almost always successful. If retreatment is attempted with antimo use titers of 1:100 or more, then certain laboratory parameters, including the p eripheral lymphocyte count, CD3 T cells, and trough free circulating OKT3 should

be monitored. If the absolute CD3 T-lymphocyte count is greater than 10 per mic roliter or free circulating trough OKT3 level is not detected, it may be indicat ive of an inadequate dose of OKT3. The dose of OKT3 can be increased from 5 to 1 0 mg/d [21]. (Continued on next page)

9.12 Transplantation as Treatment of End-Stage Renal Disease FIGURE 9-16 (Continued) B, Monitoring of peripheral blood T cells in a patient r eceiving OKT3 treatment. The absence of CD3+ cells from the circulation is the b est parameter for monitoring the effectiveness of OKT3. Failure of the CD-positi ve percentage to fall or a fall followed by a rapid rise indicates the appearanc e of blocking antibodies. Approximately 50% to 60% of patients who receive OKT3 will produce human antimouse antibodies (HAMA), generally in low titers (< 1:100 ). Low antibody titers do not affect the response to retreatment (reversal rate almost 100%) if the rejection episode occurs within 90 days after transplantatio n. Conversely, titers above 1:100 or recurrent rejection beyond 90 days is assoc iated with a reversal rate of less than 25%. The reversal rate is essentially ze ro when both high HAMA titers and late rejection are present. POorally; IVintraven ous. AntiOKT3 antibodies 80 70 60 %CD+cells 50 OKT3 treatment CD3 40 30 20 10 0 0 1 2 5 Hours 9 13 16 Days 22 CD4 CD8 B Chimeric antibody Mouse antibody Mouse determinants } Human determinants A IgG1 depleting Reshaped antibody IgG4 nondepleting TCR/CD3 MHC/Ag APC Signal 1 T-cell FIGURE 9-17 New immunosuppressive agents. New agents such as mycophenolate mofet il, FK506, and rapamycin are currently under evaluation for refractory acute rej ection. In addition, both mycophenolate and rapamycin prevent chronic allograft rejection in experimental animals. Whether this important observation is reprodu cible in humans remains to be determined by long-term study. A, Humanized monocl onal antibodies. The development of genetically engineered humanized monoclonal antibodies will largely eliminate the anti-antibody response, thereby increasing the utility of antiT-cell antibodies in the treatment of recurrent rejection. Ex perimental antibody therapies are now being designed to directly target the CD4 molecule, the interleukin-2 receptor, the CD3 molecule by a humanized form of mo noclonal anti-CD3, and adhesion molecules such as intercellular adhesion molecul e-1 or leukocyte functionassociated antigen-1 [23]. Humanized monoclonal antibod ies are essentially human immunoglobulin G (IgG), nonimmunologic with a long hal f-life, and potentially can be administered intravenously about every 2 weeks. H umanized anti-CD25 (IL-2 receptor chain) monoclonal antibodies has been shown to be effective in lowering the incidence of acute renal allograft rejection. Its role in the treatment of rejection, however, has not been explored. With increas ing specificity for lymphocytes, these new agents are likely to have fewer toxic ities and better efficacy. B, Therapeutic application of CTLA41g to transplant r ejection. APCantigen-presenting cell; MHCmajor histocompatibility complex; TCRT-cel l receptor.

B7-1 B7-2 CD28 X CTLA4 Signal 2 Signal 1 without signal 2 results in: T-cell anergy Th2>Th1 Apoptosis B CTLA41g

Transplant Rejection and its Treatment 9.13 References 1. Terasaki PI, Cecka JM, Gjertson DW, et al.: Risk rate and long-term kidney tr ansplant survival. Clin Transpl 1996, 443. 2. Chan L, Kam I: Outcome and complic ations of renal transplantation. In Diseases of the Kidney, edn 6. Edited by Sch rier RW, Gottschalk CW: 1997. 3. J Clin Immunol 1995, 15:184. 4. Nephrol Dial Tr anspl 1997, 12 [editorial comments]. 5. Shaikewitz ST, Chan L: Chronic renal tra nsplant rejection. Am J Kidney Dis 1994, 23:884. 6. Solez K, Axelsen RA, Benedik tsson H, et al.: International standardization of criteria for the histologic di agnosis of renal allograft rejection: the Banff working classification on renal transplant pathology. Kidney Int 1993, 44:411. 7. Helderman JH, Hernandez J, Sag alowsky A, et al.: Confirmation of the utility of fine needle aspiration biopsy of the renal allograft. Kidney Int 1988, 34:376. 8. Von Willebrand E, Hughes D: Fine-needle aspiration cytology of the transplanted kidney. In Kidney Transplant ation, edn 4. Edited by Morris PJ. 1994:301. 9. Suthanthiran M: Clinical applica tion of molecular biology: a study of allograft rejection with polymerase chain reaction. Am J Med Sci 1997, 313:264. 10. Halloren PF, Lui SL, Miller L: Review of transplantation 1996. Clin Transpl 1996. 11. Sollinger HW for the US Renal Tr ansplant Mycophenolate Mofetil Study Group: Mycophenolate mofetil for prevention of acute rejection in primary cadaveric renal allograft recipients. Transplanta tion 1995, 60:225. 12. Jordan ML, Shapiro R, Vivas SA, et al.: FK506 rescue for re sistant rejection of renal allografts under primary cyclosporine immunosuppressi on. Transplantation 1994, 57:860. 13. Woodle ES, Thistlethwaite JR, Gordon JH, e t al.: A multicenter trial of FK506 (tacrolimus) therapy in refractory acute ren al allograft rejection. Transplantation 1996, 62:594. 14. Jordan ML, Naraghi R, Shapiro R, et al.: Tacrolimus rescue therapy for renal allograft rejection: five year experience. Transplantation 1997, 63:223. 15. Gray D, Shepherd H, Daar A, et al.: Oral versus intravenous high dose steroid treatment of renal allograft r ejection. Lancet 1978, 1:117. 16. Chan L, French ME, Beare J, et al.: Prospectiv e trial of high dose versus low dose prednisone in renal transplantation. Transp l Proc 1980, 12:323. 17. Auphan N, DiDonato JA, Rosette C, et al.: Immunosuppres sion by glucocorticoids: inhibition of NF-kB activation through induction of IkB a. Science 1995, 270:286. 18. Ortho Multicenter Study Group: A randomized trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants. N Engl J Med 1985, 313:337. 19. Norman DJ, Shield CF, Henell KR, et al.: Effecti veness of a second course of OKT3 monoclonal anti-T cell antibody for treatment of renal allograft rejection. Transplantation 1988, 46:523. 20. Schroeder TJ, We iss MA, Smith RD, et al.: The efficacy of OKT3 in vascular rejection. Transplant ation 1991, 51:312. 21. Schroeder TJ, First MR: Monoclonal antibodies in organ t ransplantation. Am J Kidney Dis 1994, 23:138. 22. English J, et al.: Transplanta tion 1987, 44:135. 23. Strom TB, Ettenger RB: Investigational immunosuppressants : biologics. In Primer on Transplantation. Edited by Norman D, Suki W.

Post-transplant Infections Connie L. Davis A lthough the rates are markedly decreased from previous decades, infection is the most important cause of early morbidity and mortality following transplantation . Infection is closely linked to the degree of immunosuppression and thus to the frequency and intensity of rejection and its therapy. The potential sources of infection in the transplant patient are multiple, including organisms from the a llograft itself and from the environment. Patients should be advised to be sensi ble to possible exposures and to wash their hands thoroughly when exposed to inf ected individuals or human excrement, specifically, exposures in daycare and occ upational settings as well as during gardening and pet care. In those taking imm unosuppressive agents, signs and symptoms of infections are frequently blunted u ntil disease is far advanced. Therefore, due to the unusual nature of the infect ions and the lack of timely symptom development, the key to patient survival is the prevention of infection. Infections may be prevented by pretransplant vaccin ations, along with prophylactic medications, preemptive monitoring and behavior modification. Currently, the most common infectious problems within the first mo nth following transplantation are bacterial infections of the wound, lines, and lungs. Additionally, herpetic stomatitis is common. Beyond 1 month following tra nsplantation, infections are related to more intense immunosuppression and inclu de viral, fungal, protozoal, and unusual bacterial infections. Although hepatiti s may occasionally cause fulminate and fatal disease if acquired peritransplanta tion, the manifestations of hepatitis B or hepatitis C infections occur years fo llowing transplantation. CHAPTER 10

10.2 Transplantation as Treatment of End-Stage Renal Disease Conventional Viral HSV Unconventional CMV onset EBV VZV papova adenovirus CMV chorioretinitis CLASSIFICATION OF INFECTIONS OCCURRING IN TRANSPLANT PATIENTS Infections related to technical complications* Transplantation of a contaminated allograft, anastomotic leak or stenosis, wound hematoma, intravenous line conta mination, iatrogenic damage to the skin, mismanagement of endotracheal tube lead ing to aspiration, infection related to biliary, urinary, and drainage catheters Infections related to excessive nosocomial hazard Aspergillus species, Legionel la species, Pseudomonas aeruginosa, and other gramnegative bacilli, Nocardia ast eroides Infections related to particular exposures within the community Systemic mycotic infections in certain geographic areas Histoplasma capsulatum, Coccidio ides immitis, Blastomyces dermatitidis, Strongyloides stercoralis Community-acqu ired opportunistic infection resulting from ubiquitous saphrophytes in the envir onment Cryptococcus neoformans, Aspergillus species, Nocardia asteroides, Pneumoc ystis carinii Respiratory infections circulating in the community Mycobacterium tuberculosis, influenza, adenoviruses, parainfluenza, respiratory syncytial viru s Infections acquired by the ingestion of contaminated food/water Salmonella spe cies, Listeria monocytogenes Viral infections of particular importance in transp lant patients Herpes group viruses, hepatitis viruses, papillomavirus, HIV *All lead to infection with gram-negative bacilli, Staphylococcus species, and/or Can dida species. The incidence and severity of these infections and, to a lesser ext ent, the other infections listed, are related to the net state of immunosuppress ion present in a particular patient. Fungal TB Pneumocystis Listeria Aspergillus, nocardia, toxoplasma CNS Bacterial Cryptococcus Wound Pneumonia line-related Hepatitis Hepatitis B Onset of non-A, non-B hepatitis UTI: bacteremia, pyelitis, relapse U TI: Relatively benign 0 Transplant 1 2 3 4 Time, mo 5 6 FIGURE 10-1 Timetable for the occurrence of infection in the renal transplant pa

tient. Exceptions to this chronology are frequent. CMV cytomegalovirus; CNScentral nervous system; EBVEpsteinBarr virus; HSVherpes simplex virus; UTIurinary tract in fection; VZVvaricella-zoster virus. (Adapted from Rubin and coworkers. [1]; with permission.) FIGURE 10-2 Classifications of infections occurring in transplant patients. (Ada pted from Rubin [2]; with permission.) FIGURE 10-3 Timing of infections followin g kidney/pancreas transplantation at a single transplantation center using antiv iral (ganciclovir IV followed by acyclovir) and antibacterial (trimethoprim-sulf amethoxazole) prophylaxis. CMVcytomegalovirus. (From Stratta [3]; with permission .) 50 40 Patients, n 30 20 10 0 1 2 3 Months after transplant 46 712 Period of prophy laxis Timing of infection Bacterial (mean 60 days) CMV (mean 70 days) Non-CMV viral (mean 145 days) Fungal (mean 163 days)

Post-transplant Infections 10.3 Preventive Strategies INFECTIOUS DISEASE HISTORY TO BE TAKEN PRIOR TO TRANSPLANTATION 1. Past immunizations. 2. Past infections or exposures to infections. A. Bacteri al Rheumatic fever, sinusitis, ear infections, urinary tract infections, pyelone phritis, pneumonia, diverticulitis, tuberculosis B. Viral Measles, mumps, varice lla, rubella, hepatitis 3. Chronic or recurrent infections, such as pneumonia, s inusitis, urinary tract infection, or diverticulitis 4. Surgical history, such a s splenectomy 5. Transfusion or previous transplant history and dates 6. Past tr avel history, including military service 7. Past immunosuppressive drug treatmen t (eg, for asthma, renal disease, or rheumatologic disease) 8. Lifestyle A. Smok ing, drinking, illicit drug use, marijuana smoking B. Sexual partners, orientati on, unprotected contact and date, safety practices used, sexually transmitted di seases, genital warts C. Food, consumption of raw fish or meat, consumption of u npasteurized products, such as milk, cheese, fruit juices, or tofu D. Avocationga rdening and the use of gloves, cleaning sheds, hiking, camping, water sources, b athing pets, cleaning pet litter and cages, hunting practices E. Vocationjobs tha t require exposure to possible infectious agents, such as daycare, ministry, sma ll closed offices, garbage collections or dump workers, construction workers, fo restry workers, health care, veterinarians, farmers FIGURE 10-4 Infectious disease history to be taken prior to transplantation. PRETRANSPLANT VACCINATIONS OR BOOSTERS TO BE GIVEN TO ALL TRANSPLANT RECIPIENTS UNLESS RECENT ADMINISTRATION CAN BE DOCUMENTED 1. Td (Tetanus toxoid, diphtheria) 2. Pneumococcal vaccine 3. Hepatitis B 4. Inf luenza FIGURE 10-5 Pretransplant vaccinations or boosters to be given to all transplant recipients unless recent administration can be documented. PRETRANSPLANT VACCINATIONS TO BE GIVEN IF SERONEGATIVE OR PAST INFECTION BY HIST ORY CANNOT BE DOCUMENTED 1. Measles-mumps-rubella vaccine 2. Polio 3. Varicella (0.5 mL subcutaneously fo llowed by booster of 0.5 mL in 48 weeks) 4. Haemophilus influenza type B FIGURE 10-6 Pretransplant vaccinations to be given if seronegative or past infec tion by history cannot be documented.

10.4 Transplantation as Treatment of End-Stage Renal Disease INACTIVATED VACCINES THAT ARE CONSIDERED SAFE AND MAY BE GIVEN AS NEEDED POST-TR ANSPLANT FOR ANTICIPATED EXPOSURE 1. Anthrax 2. Cholera 3. Rabies vaccine absorbed 4. Human diploid cell rabies va ccine 5. Inactivated typhoid vaccine, capsular polysaccharide parenteral vaccine , or heat phenol-treated parenteral vaccine 6. Japanese encephalitis virus vacci ne 7. Meningococcal vaccine 8. Plague vaccine VACCINES THAT MAY NOT BE GIVEN (LIVE ATTENUATED VACCINES) 1. Bacille Calmette-Gurin (BCG) 2. Measles 3. Mumps 4. Rubella 5. Oral polio 6. O ral typhoid 7. Yellow fever FIGURE 10-8 Vaccines that may not be given include live attenuated vaccines. FIG URE 10-7 Inactivated vaccines that are considered safe and may be given as neede d post-transplant for anticipated exposure. A. DOSAGE AND ADMINISTRATION GUIDELINES FOR VACCINES AVAILABLE IN THE UNITED STA TES Vaccine DT Td DTP DTaP (Acel-Imune) DTP-HbOC (Tetramune) Dosage 0.5 mL 0.5 mL 0.5 mL 0.5 mL 0.5 mL Route of administration IM IM IM IM IM Type Toxoids Toxoids Diphtheria and tetanus toxoids with killed B. pertussis organism s Diphtheria and tetanus toxoids with acellular pertussis Diphtheria and tetanus toxoids with killed B. pertussis organisms and Haemophilus b conjugate (diphthe ria CRM197 protein conjugate) Polysaccharide (diphtheria toxoid conjugate) Oligo saccharide (diphtheria CRM protein conjugate) Polysaccharide (meningococcal prot ein conjugate) Yeast recombinantderived inactivated viral antigen Haemophilus B, conjugate vaccine ProHIBit (PRP-D), manufactured by Connaught Lab oratories HibTITER (HbOC), manufactured by Praxis Biologicals PedvaxHib (PRP-OMP ), manufactured by MSD Hepatitis B 0.5 mL 0.5 mL 0.5 mL 0.5 mL IM IM IM IM IM in the anterolateral thigh or in the upper arm; SC in individuals at risk of hemorrhage Infants born to HBsAg-negative mothers and children < y[ ] Recombivax HB (MSD) E ngerix-B (SKF) 2.5 g (0.25 mL) 10 g (0.5 mL) FIGURE 10-9 AD, General immunization guidelines. HBOChaemophilus B influenzaediphth eria protein conjugate vaccine, oligosaccharide; IDintradermal; IMintramuscularly; DTdiphtheria tetanus; DTPdiphtheria tetanus pertussis; MMRmeasles mumps rubella; M Rmeasles rubella; MSDMerck Sharpe & Dohme; PRP-Dhaemophilus Bdiphtheria toxoid conjugate vaccine, polysaccharide; PRP-OMPhaemo philus influenzae type bmeningococcal protein conjugate vaccine; SCsubcutaneous; S KFSmithKline and French; Tdtetanus, diphtheria. (From Isada and coworkers [4]; wit

h permission.) (Continued on next page)

Post-transplant Infections 10.5 B. DOSAGE AND ADMINISTRATION GUIDELINES FOR VACCINES AVAILABLE IN THE UNITED STA TES Infants born to HBsAg-positive mothers (immunization and administration of 0.5 m L hepatitis B immune globulin is recommended for infants born to HBsAg mothers u sing different administration sites) within 12 hours of birth; administer vaccin e at birth; repeat vaccine dose at 1 and 6 months following the initial dose Vaccine Recombivax HB (MSD) Engerix-B (SKF) Children 1119 y Recombivax HB (MSD) Engerix-B (SKF) Adults > 19 y Recombivax HB (MSD) Engerix-B (SKF) Dialysis patients and i mmunosuppressed patients Recombivax HB (MSD) Engerix-B (SKF)

Dosage 5 g (0.5 mL) 10 g (0.5 mL) 5 g (0.5 mL) 20 g (1 mL) 10 g (1 mL) 20 g (1 mL) <11 y, 20 (0.5 mL); 11 y, 40 g, (1 mL) using special dialysis formulation <11 y, 20 g (1 mL) ; 11 y, 40 g (2 mL), give as two 1 mL doses at different sites C. DOSAGE AND ADMINISTRATION GUIDELINES FOR VACCINES AVAILABLE IN THE UNITED STA TES Vaccine Influenza Split virus only in pediatric patients 635 mo 38 y 9 y Measles Dosage Route of administration IM (2 doses 4+ weeks apart in children <9 years of age not previously immunized; only 1 dose needed for annual updates) Type Inactivated virus subvirion (split) (contraindicated in patients allergic to chi cken eggs) 0.25 mL (1 or 2 doses) 0.5 mL (1 or 2 doses) 0.5 mL (1 dose) 0.5 mL SC Live virus (contraindicated in patients with anaphylactic allergy to neomycin) Most areas: Two doses (1st dose at 12 months with MMR; 2nd dose at 46 years or 111 2 years, depending on local school entry requirements). High-risk area: Two dose s (1st dose at 12 months with MMR; 2nd dose as above). Children 615 months in epi demic situations: Dose is given at the time of first contact with a health care provider; children<1 year of age should receive single antigen measles vaccine. If vaccinated before 1 year, revaccinate at 15 months with MMR. A 3rd dose is ad ministered at 46 years or 1112 years, depending on local school entry requirements . FIGURE 10-9 (Continued) (Continued on next page)

10.6 Transplantation as Treatment of End-Stage Renal Disease D. DOSAGE AND ADMINISTRATION GUIDELINES FOR VACCINES AVAILABLE IN THE UNITED STA TES Children 615 months in epidemic situations: Dose is given at the time of first co ntact with a health care provider; children<1 year of age should receive single antigen measles vaccine. If vaccinated before 1 year, revaccinate at 15 months w ith MMR. A 3rd dose is administered at 46 years or 1112 years, depending on local school entry requirements. Vaccine Meningococcal MMR MR Mumps Pneumococcal polyvalent Poliovirus (OPV) trivalent Po liovirus (IPV) trivalent Rabies Rubella Tetanus (adsorbed) Tetanus (fluid) Yello w fever Dosage, mL 0.5 0.5 0.5 0.5 0.5 (2 y) 0.5 0.5 1 0.5 (12mo) 0.5 0.5 0.5 Route of administration SC SC SC SC IM or SC (IM preferred) Oral SC IM , ID SC IM IM, SC SC Type Polysaccharide Live virus Live virus Live virus Polysaccharide Live virus Inacti vated virus Inactivated virus Live virus Toxoid Toxoid Live attenuated virus FIGURE 10-9 (Continued) PRETRANSPLANT VIRAL SEROLOGIES TO CHECK AT THE PRETRANSPLANT VISIT Viral serology Herpes simplex virus 1, 2 Epstein-Barr virus Varicella-zoster virus Cytomegalovi rus HBsAg FIGURE 10-10 Pretransplant viral serologies to check at the pretransplant visit. Treatment, work-up modification or change in post-transplant treatment If positive, treat early post-transplant with acyclovir, famciclovir, or gancicl ovir If negative, consider post-transplant ganciclovir. Test donor due to risk o f post-transplant lymphoma with primary infection Consider vaccination with Oka strain live attenuated virus if negative or treatment with acyclovir following c linical exposure If the recipient is positive or donor positive, consider prophy lactic or preemptive antiviral treatment If positive, check HBeAg and HBDNA and biopsy. If HBDNA positive, consider pretransplant antiviral treatment with inter feron if biopsy allows. Consult hepatologist regarding other treatment options I f positive, check HCV RNA status by polymerase chain reaction. If positive biops y even with normal transaminase values and consider pretransplant treatment with interferon Consider safety of transplantation if true positive. More data are r equired to make an informed decision Hepatitis C virus HIV

Post-transplant Infections FIGURE 10-11 Pretransplant bacterial serologies. 10.7 PRETRANSPLANT BACTERIAL SEROLOGIES Serology RPR (Rapid plasma reagin) Modification If positive, check with a treponemal specific testFluorescent treponemal antibody absorbed test (FTA-ABS) or microhemagglutination assay for treponema pallidum ( MHA-TP) If positive the general recommendation without documented previous treat ment after first evaluating a chest radiograph is isoniazid 300 mg/d to continue for 6 months or 9 to 12 months post-transplant PPD EFFECT AND POSSIBLE EFFECTS OF PROPHYLACTIC ANTIVIRAL STRATEGIES No treatment Risk: - HSV - CMV - VZV - EBV - Adenovirus - HHV6 - HHV8 Acyclovir orally 3M Ganciclovir IV acyclovir PO HSV Slight CMV VZV EBV ? Adenovirus Slight HHV6 Slight HHV8 3M CMVIgG ? Effect Slight CMV ? Effect ? Effect ? Effect ? Effect ? Effect 5 doses Ganciclovir 3M PO HSV Slight CMV VZV Slight EBV No change in adenovirus Slight HHV6 Slight HHV8 HSV CMV VZV EBV ? Slight in adenovirus ? HHV6 ? HHV8 FIGURE 10-12 Effect and possible effects of prophylactic antiviral strategies. C MV cytomegalovirus; EBVEpstein-Barr virus; HHV6human herpes virus 6; HHV8human herpes virus 8; HSVherpes simplex; VZV varicella zoster. Questio n mark indicates question as to the effect. FIGURE 10-13 Prophylactic antibacter ial/ antiprotozoal strategies. PROPHYLACTIC ANTIBACTERIAL AND ANTIPROTOZOAL STRATEGIES Type of infection Wound Treatment perioperatively or postoperatively Against uropathogens and staphylococci, eg, ampicillin-sulbactam, cefazolin plus aztreonam 24 to 48 hours adjusted for renal function Risk - urinary leak, hematom a, lymphocele Common choices Trimethoprim sulfamethoxazole Ciprofloxacin Cephazo lin Ampicillin Duration of treatment varies An important factor is the presence

of the urinary catheter Trimethoprim sulfamethoxazole Trimethoprim sulfamethoxaz ole Trimethoprim sulfamethoxazole Trimethoprim sulfamethoxazole Trimethoprim sul famethoxazole Urinary tract Legionella Pneumocystis Toxoplasmosis Nocardia Listeria monocytogenes

10.8 Transplantation as Treatment of End-Stage Renal Disease Prevention Strategies PREVENTION OF RESPIRATORY INFECTIONS IN THE IMMUNOSUPPRESSED PATIENT Infection Pneumococcal pneumonia Influenza illness Haemophilus influenzae Tuberculosis Myc obacterium avium complex illness Pneumocystis carinii pneumonia CMV pneumonia Le gionella pneumonia Aspergillosis Candida illness Cryptococcosis Histoplasmosis C occidioidomycosis Strongyloidiasis Options for prevention Pneumococcal vaccination; oral penicillin prophylaxis; passive prophylaxis with immune globulin Annual influenza vaccination; amantadine or rimantadine prophyla xis (for influenza A virus only) H. influenza type B vaccination Case finding an d early treatment; infection control procedures; preventive therapy with isoniaz id Rifabutin prophylaxis Prophylaxis with oral trimethoprim-sulfamethoxazole or aerosolized pentamidine Use of CMV-seronegative organs and blood products for CM V-seronegative recipients; passive prophylaxis with CMV immune globulin; prophyl axis with antiviral agents (acyclovir, ganciclovir) Identification of source; in stitution of control measures associated with potable water, such as hyperchlori nation, maintenance of hot water temperature above 50C (122F) Use of HEPA filter t o minimize airborne spores; avoidance of decaying leaves and vegetation Prophyla xis with antifungal agents Avoidance of pigeons and pigeon droppings; prophylaxi s with antifungal agents Complete travel history to identify patients at risk; a voidance of areas of high exposure to Histoplasma; formalin treatment of infecte d soil Complete travel history to identify patients at risk; avoidance of areas of high exposure to Coccidioides immitis Complete travel history to identify pat ients at risk; ova and parasite analysis of stool specimen in patients at risk; thiabendazole prophylaxis FIGURE 10-14 Prevention strategies for the prevention of pulmonary infection. CM Vcytomegalovirus; HEPAhigh-efficiency particulate air. (Adapted from Maguire and W ormser [5]; with permission.)

Post-transplant Infections 10.9 PASSIVE IMMUNIZATION AGENTSIMMUNE GLOBULINS Immune globulin Hepatitis B (H-BIG*) Percutaneous inoculation Perinatal Sexual exposure Immune g lobulin (IG) Hepatitis A prophylaxis Dosage 0.06 mL/kg/dose (within 24 h) (5 mL max) 0.5 mL/dose (within 12 h of birth) 0.06 mL/kg/dose (within 14 d of contact) (5 mL max) Route IM IM* 0.02 mL/kg/dose (as soon as possible or within 2 wk after exposure) (single exposure) 0.06 mL/kg/dose (>3 mo or continuous exposure) repeat every 46 mo 0.06 mL/kg/dose (H-BIG should be used) 0.06 mL/kg/dose (percutaneous exposure) 0.25 m L/kg/dose (max 15 mL/dose) (within 6 d of exposure) 0.5 mL/kg/dose (max 15 mL/do se) (immunocompromised children) 20 IU/kg/dose (within 3 d) 250500 units/dose Wit hin 48 hours but not later than 96 hours after exposure 010 kg 125 units = 1 vial 10.120 kg 250 units = 2 vials 20.130 kg 375 units = 3 vials 30.140 kg 500 units = 4 vials >40 kg 625 units = 5 vials Hepatitis B Hepatitis C Measles Rabies Tetanus (serious, contaminated, wounds; <3 previous tetanus vaccine doses) Varicella-zoster (VZIG) IM IM *Deep IM in the gluteal region for large doses only. Deltoid muscle or the anter olateral aspect of the thigh are preferred sites for injection. No greater than 5 mL/site in adults or large children; 13 mL/site in small children and infants. Maximum dose: 20 mL at one time. IG prophylaxis may not be indicated in a patient who has received IGIV within 3 weeks of exposure. 1/2 of dose used to infiltrate the wound with the remaining 1/2 of dose given IM Rabies immune globulin is not recommended in previously HDCV immunized patients. No greater than 2.5 mL of VZI G/one injection site. Doses >2.5 mL should be divided and administered at differ ent sites. FIGURE 10-15 Passive immunization agents for prevention postexposure. HBIGhepatit is B immune globulin; HDCVhuman diploid cell rabies vaccine; IGimmune globulin; IG IVintravenous immune globulin; IMintramuscularly; VZIGvaricella zoster immune globulin. (From Is ada and coworkers [4]; with permission.)

10.10 Transplantation as Treatment of End-Stage Renal Disease FIGURE 10-16 Live virus vaccinations generally not given to transplant patients. IGimmune globulin; OPVpoliovirus vaccine live oral. (From Isada and coworkers [4] ; with permission.) GUIDELINES FOR SPACING THE ADMINISTRATION OF IMMUNE GLOBULIN (IG) PREPARATIONS A ND VACCINES Immunobiologic combinations Simultaneous administration IG and killed antigen IG and live antigen None. May be given simultaneously at different sites or at any time between doses. Should generally not be given simultaneously. If unavoidable to do so, give at differen t sites and revaccinate or test for seroconversion in 3 months. Example: MMR sho uld not be given to patients who have received immune globulin within the previo us 3 months. Recommended minimum interval between doses Nonsimultaneous administration First IG Killed antigen IG Live antigen Second Ki lled antigen IG Live antigen IG None None 6 wk, and preferably 3 mo 2 wk *The live virus vaccines, OPV, and yellow fever are exceptions to these recommen dations. Either vaccine may be administered simultaneously or any time before or after IG without significantly decreasing antibody response. O N H2N O N N O HN H 2N O N HN HN N N N HN N H O (CH3)CH C C O NH+Cl 3 Valacyclovir Acyclovir 54% 100% liver/GI 23 h 0.71 h HSV/V2V/EBV H 2N N N HO N O OH N HO Acyclovir 15% 100%* R 23 h 0.71 h N O CH3COO CH3COO Famciclovir Penciclovir Oral bioavailability: Excretion: Plasma t1/2: Intracellu lar t1/2: Antiviral spectrum: 77% 100%* R 23 h 720 h HSV/V2V/EBV Ganciclovir 2%7% 91% unchanged urine 23 h 6 h3 wk HHV8, CMV, adeno, HBV NH2 A

HSV/V2V/EBV 3Na + O O O O N N O OCH2P(OH)22H2O HOCH2 S O O N N P C 6H2O O O Phosphonoformicacid Foscarnet Administration: t1/2: Tissue t1/2: Metabolism: IV 26 h 87.541.8 h 100% renal excretion OH Cidofuvir IV 34 h 1765 h 85% renal excretion Lamivudine 86% oral bioavailability 57 h 1015 h 70%90% renal excretion B FIGURE 10-17 Antiviral agents. Asterisk indicates excreted unchanged in the urin e; all antivirals are subject to changes in t1/2 with changing renal function. A denoadenovirus; CMVcytomegalovirus; EBVEpstein-Barr virus; HHV8human herpesvirus 8; HSVherpes simple x virus; VZVvaricella-zoster virus.

Post-transplant Infections 10.11 Acyclovir Valacyclovir Famciclovir R1 viral thymidine kinase Drug-P1 cell kinase Drug P2 cell kinase R2 Drug P3 viral DNA Polymerase R2 R1 Ganciclovir cell car v UL97 GP1 kinase gene product autophosphorylating protein kinase cellu lar enzymes GP2 cell kinase GP3 cell kinase viral DNA Polymerase Cidofovir CP2 (no viral enzymes needed) FIGURE 10-18 Antiviral activation and action (acyclovir, valacyclovir, famciclov ir, ganciclovir). Resistance (R) to antivirals has been found at the level of vi ral thymidine kinase (R1) and DNA polymerase (R2). Ganciclovir is monophosphoryl ated in cytomegalovirus (CMV)-infected cells by the CMV UL97 gene product. Acycl ovir, valacyclovir, and famciclovir are not easily phosphorylated in CMV-infecte d cells. Cidofovir does not require viral enzymes to be phosphorylated to the ac tive diphosphonate. FIGURE 10-19 Drug interactions between antivirals, antifunga ls, antibacterials, antimycobacterials, and antiprotozoals with cyclosporine and FK506. (From Lake [6] and Yee [7]; with permission.) DRUG INTERACTIONS BETWEEN ANTIVIRALS, ANTIFUNGALS, ANTIBACTERIALS, ANTIMYCOBACTE RIALS, AND ANTIPROTOZOALS WITH CYCLOSPORINE AND FK506 Drug Antifungals Amphotericin B Clotrimazole troches (more in FK506) Ketoconazole (ke to>itra>fluconazole) Griseofulvin Antibacterial Clarithromycin Doxycycline Eryth romycin Gentamicin Nafcillin Rifampin Rifabutin Sulfamethoxazole/trimethoprim Ti

carcillin Antimycobacterial Isoniazid Pyrazinamide Antiparasitic Chloroquine Effect on CSA/FK506 Nephrotoxicity of combination -- - -- - - -- - INFECTIONS TRANSMITTED TO TRANSPLANT RECIPIENTS VIA THE DONOR ORGAN Virus Bacteria Fungi Parasitic FIGURE 10-20 Infections transmitted to transplant recipients via the donor organ . HIV, cytomegalovirus, Aerobe (gram positive), herpes simplex virus, aerobe (gram negative), Epstein-Barr virus, anaerobes, Mycobacterium hepatitis B virus, tube rculosis, atypical hepatitis C virus, mycobacteria hepatitis D virus, ? hepatiti s G virus, adenovirus (?), parvovirus (?), papillomavirus, rabies, Creutzfeldt-J akob Candida albicans, Malaria toxoplasmosis, Histoplasma capsulatum, trypanosomiasis , Cryptococcus neoformans, strongyloidiasis Marosporium apiospermum

10.12 Transplantation as Treatment of End-Stage Renal Disease Cytomegalovirus Envelope Tegument Attachment and penetration Capsid Egress Cytoplasm Uncoating Nucleus Release of viral DNA IE E L Transcription Protein synthesis Replication DNA Scaffold Assembly Packaging FIGURE 10-21 The lifecycle of cytomegalovirus (CMV). The envelope binds with the cell membrane, and the DNA is uncoated and transferred into the nucleus, where cell protein synthesis machinery is used to manufacture new DNA and capsid. The DNA is packaged into the capsid and returns to the cytoplasm, where the tegument and envelope are assembled around the capsid and the whole virus transported to the cellular surface and released. CMV is a double-stranded DNA virus that causes disease following transplantation after primary infection, reinfection, or reactivation of latent infections. CMV disease is seen most frequently within the first 4 to 6 months of transplantati on if no antiviral prophylaxis is used; however, in the presence of antiviral pr ophylaxis and new immunosuppressive agents, the onset of CMV disease may be shif ted to longer intervals from transplantation. There also may be a slight increas e in the occurrence of CMV enteritis with the use of some of the newer combinati ons of immunosuppressive agents. When the recipient is CMV positive and receives an organ from a CMV-positive donor, reactivation of the latent infection in the recipient is responsible for 15% to 30% of the infections seen, and reinfection with the virus from the donor is responsible for 70%. CMV disease prevention ma y be accomplished by administering prophylactic antiviral agents or by the use o f routine surveillance testing. Variables to be considered in an individual's risk of CMV disease development are the use of antilymphocyte medications, and the d onor and recipient, CMV serostatus. The highest risk group for CMV disease is th e group at risk for primary CMV exposure and those given antilymphocyte preparat ions. Specifically, increased CMV disease is seen during situations that trigger viral replication. High levels of tumor necrosis factor alpha, such as levels o ccurring during infections or after OKT3 administration, activate the CMV promot er, thus stimulating the conversion from the latent to the reactivated state. Al l of the prophylactic strategies for the prevention of CMV disease have shown so me benefit in different studies; currently, however, the most effective approach is oral ganciclovir. A more bioavailable oral ganciclovir may even increase the effectiveness and is now under investigation. Oral ganciclovir is started when the patient is able to take oral medications within the first week following tra nsplantation and is administered at a dose of 1 g 3 times a day for 3 months fol lowing transplantation adjusted for renal function. The protective effect is als o seen in those who have received antilymphocyte preparations. The most desirabl e solution would be a vaccine that induced natural immunity mechanisms. Vaccines targeted against the structural glycoproteins of CMV are currently continuing u

nder development but are not yet available; their ultimate effectiveness is not known at this time. As patients who already have had natural infections are not immune to reinfection or reactivation, a vaccine solution may not be possible.

Post-transplant Infections 10.13 MANIFESTATIONS OF CMV DISEASE IN RENAL TRANSPLANT RECIPIENTS CMV disease A. Syndrome: fever, leukopenia, malaise, lack of another cause B. Or gan specific: hepatitis, enteritisduodenum, colon; pancreatitis; pneumonitis; int erstitial nephritis, retinitis C. Risk of CMV disease by donor Recipient serosta tus without antiviral prophylaxis D/R D+RD+R+ D-R+ D-RInfection* 70%100% 50%80% Di sease 56%80% 27%39% 0%27% <5% FIGURE 10-22 Manifestations of cytomegalovirus (CMV) disease in renal transplant recipients. *Infection determined by new anti-CMV antibody development or a greater than fou rfold rise in anti-CMV titers. FIGURE 10-23 (see Color Plates) Endoscopic aspects of cytomegalovirus (CMV) infe ction. A, CMV esophageal ulcers. B, CMV duodenal ulcers. A B FIGURE 10-24 (see Color Plate) Histologic lesion in cytomegalovirus infection.

10.14 Transplantation as Treatment of End-Stage Renal Disease RANDOMIZED TRIALS EVALUATING CMV PROPHYLACTIC STRATEGIES ADMINISTERED DURING THE TIME OF GREATEST RISK FOR CMV DISEASE Control Drug IgG Treated n 19 16 18 24 11 53 Author Metsellar Steinmuller Teuschert Snydman* Boland Balfour Induction or Rejection Antilymphocyte ATG-rej ALG/OKT3 None Some None ALG Serostatus All patients R+ D+RD+RD+RAll patients Subgroups D+RD+R+ n 20 18 18 35 11 51 CMV Disease 30% 39% 100% 60% 18% 29% CMV Disease 37% 13% 20% 21% 27% 8% Dosing Cytotec, 6 doses Sandoglobulin, 5 doses Cytotec, 11 doses Cytotec Cytotec, 5 dos es Acyclovir 800 mg po qid x 3 months AcyclovirPO 7 8 15 18 49 23 204 100% 38% 73% 56% 33% 61% 10.8% 6 9 17 22 64 19 204 17% 11% 47% 9% 14% 21% 0% Ganciclovir 5 mg/kg bid IV d1428 Ganciclovir with antil ymphocyte drug 2.5 mg/kg/IV bid Ganciclovir 2.5 mg/kg/d during ALG Oral ganciclo vir 1 g tid 2 g qid Ganciclovir Rondeau Conti Hibberd Brennan ATG/OKT3 Antilymphocyte OKT3 ATG NA D+RR+ R+ D+or R+ R+ Valacyclovir Squillet *Antilymphocyte serum was given to two globulin and eight control patients as in duction therapy and four globulin and seven control patients as antirejection th

erapy. FIGURE 10-25 Randomized trials evaluating cytomegalovirus (CMV) prophylactic str ategies administered during the time of greatest risk for CMV disease.

Post-transplant Infections 10.15 The "prevention" of CMV disease CMV D+ CMV R+ FIGURE 10-26 The prevention of cytomegalovirus (CMV) disease. This figure shows th e different strategies for the management of CMV-positive transplant recipients or recipients of CMVpositive organs. Preemptive treatment CMV antigenemia testing or PCR testing weekly starting the third or fourth postoperative week ()* or low titer positive-depending on the laboratory threshold (+) Treat with IV ganciclovir 5 mg/kg bid adjusted for renal function 1014 d Antiviral prophylaxis For all CMV D+ R, D+ R+, D R+ the following have been employ ed a. po ganciclovir 1 g tid 3 months b. IV ganciclovir post transplant only or f ollowed by oral acyclovir for 3 months c. Oral high dose acyclovir 800 mg po qid 3 months d. Pooled IV IgG or CMV hyperimmune globulin No testing or antiviral therapy Wait for infection * Different laboratories have different thresholds for clinically significant po sitive tests. Continue surveillance The most costly approach. The most convenient and effective. Both ganciclovir an d acyclovir are adjusted for renal function. DETECTION OF CMV DISEASE AND INFECTION Antibodies: the development of IGM anti-CMV antibodies, a four fold or greater i ncrease in IgG titers Culture: A. Standard culture in a fibroblast monolayer Res ults may require up to 6 wk B. Shell vial culturesthe buffy coat is centrifuged o nto fibroblasts increasing fibroblast infection. Viral infection is detected by applying a monoclonal antibody directed against the 72-Kd major immediate early protein of CMV. RBCs in the buffy coat may be toxic to the monolayer resulting i n a false-negative test. Urine and BAL specimens may be positive without predict ing disease. Results are available in 16 to 36 h. Other: A. AntigenemiaGranulocyt es and monocytes are isolated and stained with a monoclonal antibody against a m atrix, tegument protein pp65 (structural late protein). Culture is not required, granulocytes and monocytes from the buffy coat are stained, testing results are available in 4 to 6 h. It may be argued that the positivity may not be due to r eplicating virus in the WBCs but due to exogenous acquisition from infected endo thelial cells. The number of antigen positive cells per unit number of WBC count ed that determines the onset of symptomatic diseases depends upon the individual laboratory; however, usually over 10 positive cells per 105 WBC precede the ons et of symptoms by approximately 1 week. B. Polymerase chain reactionFor the detec tion of CMV DNA in whole blood or serum. CMV DNA is amplified from whole blood o r serum. The sensitivity and predictive value depend on the laboratory. FIGURE 10-27 Detection of cytomegalovirus (CMV) disease and infection. BALbroncho alveolar lavage; RBCred blood cell; WBCwhite blood cell.

10.16 Transplantation as Treatment of End-Stage Renal Disease Tuberculosis SOME ANTITUBERCULOSIS DRUGS Drug Primary antituberculous therapy Isoniazid* (I.N.H., and others) Rifampin*(Rifadin, Rimactane) Pyrazinamide Ethambutol(Myambutol) Other Drugs Capreomycin (Capastat) Kanamycin (Kantrex, and others) Streptomycin** Cycloserine (Seromycin, and other s) Ethionamide (Trecator-SC) Ciprofloxacin (Cipro) Ofloxacin (Floxin) Adult dosage (daily) 300 mg 600 mg 1530 mg/kg 15 mg/kg (about 1 g) 15 mg/kg IM or IV 15 mg/kg IM 250500 m g bid 250500 mg bid 500750 mg bid 200400 mg q12h or 400800 mg/day Pediatric dosage (daily) 1020 mg/kg (max. 300 mg) 1020 mg/kg (max. 600 mg) same as adult same as adult 1530 mg/kg 1530 mg/kg 2040 mg/kg IM 1520 mg/kg 1520 mg/kg Not recommended Not recommended Main adverse effects Hepatic toxicity Hepatic toxicity, flu-like syndrome Hepatic toxicity, hyperuric emia Optic neuritis Auditory and vestibular toxicity, renal damage Auditory toxi city, renal damage Vestibular toxicity, renal damage Psychiatric symptoms, seizu res Gastrointestinal and hepatic toxicity Nausea Nausea *Rifamate (containing rifampin 300 mg plus isoniazid 150 mg) is also available Ca n be given orally or parenterally. Pyridoxine should be given to prevent neuropa thy in malnourished or pregnant patients and those with alcoholism or diabetes. For intermittent use after a few weeks to months of daily dosage, the dosage is 15 mg/kg twice/wk (max. 900 mg). Availale orally or intravenously. For intermitt ent use after a few weeks to months of daily dosage, the dosage is 600 mg twice/ wk. For intermittent use after a few weeks to months of daily dosage, the dosage is 4050 mg/kg twice/wk (max. 3 g). Daily dosage should be 25 mg/kg/d if organism i soniazid-resistant or during first 1 to 2 months; decrease dosage if renal funct ion diminished. For intermittent use after a few weeks to months of daily dosage , the dosage is 50 mg/kg twice/wk. **Temporarily not available in the United Sta tes. For patients > 40 years old, 500 to 750 mg/d or 20 mg/kg twice/wk; decrease d osage if renal function is diminished. Some clinicians change to lower dosage at 60 rather than 40 years of age. Some authorities recommend pyridoxine 50 mg for e very 250 mg of cycloserine to decrease the incidence of adverse psychiatric effe cts. FIGURE 10-28 The treatment of tuberculosis (TB) depends on the clinical presenta tion. Pretransplant prophylaxis for a positive purified protein derivative, if g iven, is with isoniazid 300 mg/d up to, or following, transplantation. Post-tran splant treatment is more accepted, but due to the possible high rate of hepatoto xicity, many centers have chosen not to administer prophylaxis. Treatment of pul monary disease should include at least two to three drugs (depending on resistan ce patterns in the area) for 6 to 9 months. Treatment of disseminated disease or extrapulmonary disease should include three or four drug s for 12 to 18 months. When starting treatment with isoniazid and rifampicin, ca re should be taken to increase the glucocorticoid dose twofold and the cyclospor ine by threefold to fivefold. This is because rifampicin (and somewhat isoniazid ) induces the metabolism of steroids and cyclosporine and FK506 through the P450 cytochrome system. (Adapted from Med Lett Drugs Ther [8]; with permission.)

Post-transplant Infections 10.17 Protozoal/Parasitic Infections DIAGNOSTIC TECHNIQUES FOR PNEUMOCYSTIS CARINII INFECTION Technique Routine sputum Induced sputum Transtracheal aspiration Gallium scan Bronchoalveo lar lavage (BAL) BAL/brushing BAL/transbronchial biopsy Open lung biopsy Needle aspirate Yield Poor 30%75% Fair (with experience) Nonspecific >50% (>95% in AIDS) As for BAL alo ne Over 90% (all patients) Over 95% (all patients) Up to 60% Complications Rare Rare Common: bleeding; subcutaneous air Injection site Bleeding, aspiration fever, bronchospasm As for BAL See BAL; pneumothorax Anesthesia, air leakage, a ltered respiration, wound infection Pneumothorax, bleeding Comments* Cultures needed First choice; excellent in AIDS Rarely worthwhile Positive in >9 5% of infected patients Wedged terminal BAL with immunofluorescence Not useful f or P. carinii Impression smears; cultures/pathology Gold standard noninfectious/in fectious processes; large sample Best in localized disease *All samples should be cultured and stained for bacteria (including mycobacteria ), fungi, viruses, and examined for protozoa. Optimal procedures depend on the l ocally available expertise. FIGURE 10-29 Diagnostic techniques for Pneumocystis carinii infection. (Adapted from Fishman [9]; with permission.) FIGURE 10-30 The treatment of Pneumocystis c arinii infection. (Adapted from Fishman [9]; with permission.) Options Treat through rash: reduce TMP or SMZ by one half; desensitize Lower dose (23 mg/ kg); IM not advised Methemoglobinemia; G6PD; may be tolerated in sulfadiazine al lergy Methemoglobinemia; diarrhea (pyrimethamine for primaquine) Leukopenia, ane mia; thrombocytopenia; relapse common Not studied fully Maximum 4 g in two doses ; up to 8 g Variable absorbance, improved with fatty food; rash THE TREATMENT OF PNEUMOCYSTIS CARINII Agent(s) (route) Trimethoprim and sulfamethoxazole (TMP-SMZ) (IV/po) Pentamidine isethionate (IV) Dapsone (po) with TMP (po/IV) Clindamycin (IV/po) and primaquine Trimetrexate ( IV) with folinic acid (po) (leucovorin) Pyrimethamine (po) with sulfadiazine Ato vaquone (po) Dose 15 mg/kg/d TMP (to 20) 75 mg/kg/d SMZ (to 100) 4 mg/kg/d 300 mg/d maximum 100 mg /d 1520 mg/kg/d (900 mg) 600900 mg q 6 h 1530 mg base po qd 3045 mg/m2/d 80100 mg/m2/ d Load 50 mg bid x 2 d, then 2550 mg qd Load 75 mg/kg, then 100 mg/kg/qd 750 mg p o tid *Adjunctive therapies (see text); corticosteroids (high dose with rapid taper); possibly interferon gamma; granulocyte-macrophage colony-stimulating factor. Base d on clinical judgment of physicians; some agents are not approved by the Food a nd Drug Administration for this indication.

10.18 Transplantation as Treatment of End-Stage Renal Disease FIGURE 10-31 Antibiotic therapy for Toxoplasma gondii infection. (Adapted from F ishman [9]; with permission.) ANTIBIOTIC THERAPY FOR TOXOPLASMA GONDII INFECTION Drug Pyrimethamine Dose 100 mg po x 2 (then) 25 mg50 mg po, qd, or qod Sulfadiazine 4 g po (then 11.5 g po qid or tri-sulfapyridine; (75100 mg/kg/d) 6001200 mg IV or 600 mg po q6h 1 g po t id or qid Duration Load 36 wk Comments Bone marrow suppression; may give folinic acid 5 mg po/im qod except leukemia De crease dose for neutropenia; sulfa allergy common Slower resolution than with su lfa; C. difficile colitis In pregnancy or sulfa allergy with pyrimethamine; CNS data limited Sulfonamide 36 wk Clindamycin Spiramycin 36 wk 36 wk *Active infection: twice weekly blood counts are necessary to detect bone marrow suppression resulting from therapy. Lifelong prophylaxis after acute infection is recommended in transplant and AIDS patients. Investigational: trimetrexate, at ovaquone, macrolides, gamma interferon. Yeast and Fungal Infections FIGURE 10-32 (see Color Plate) Candida esophagitis seen on esophagogastroduodeno scopy. FIGURE 10-33 (see Color Plate) Endoscopic view of severe esophagitis.

Post-transplant Infections 10.19 FIGURE 10-34 (see Color Plate) Displayed are Aspergillus as fungus balls, which are proliferating masses of fungal hyphae. The hyphae are septute, 5 to 10 m thic k, and branch at acute 40 angles. Aspergillus frequently invades blood vessels, c ausing hemorrhage and necrotizing inflammation with downstream infarction. This image shows three fungus balls in the lung (Gomori-Ammon stain for fungi). TREATMENT OF FUNGAL INFECTIONS IN THE SOLID-ORGAN TRANSPLANT RECIPIENT BY CATEGO RY OF INFECTION Category of infection Mucocutaneous candidiasis Candiduria Invasive candidiasis Life-threatening Cathe ter-associated Less-ill, sensitive organism Aspergillosis Mucormycosis, Phaeohyph omycosis, Hyalohyphomycosis Cryptococcosis Prophylactic Nystatin (oral) Preemptive Fluconazole* Definitive Fluconazole Amphotericin B bladder irrigation; Fluconazole Amphotericin B (0.51.0 mg/kg) +/ flucytosine Amphotericin B Fluconazole in selected cases Fluconazole Amp hotericin B (1.01.5 mg/kg)** Amphotericin B (1.0-1.5 mg/kg)** FIGURE 10-35 Treatment of fungal infections in the solidorgan transplant recipie nt by category of infection. TMP/SMXtrimethoprimsulfamethoxazole. (Adapted from H adley and Karchmer [10]; with permission.) Itraconazole Fluconazole Histoplasmosis, Coccidioidomycosis, Blastomycosis Pneumocystis carinii ?Itraconazole Itraconazole T P/S X Amotericin B + flucytosine x 2 wk, then Fluconazole x 410 wk if clinical and mi crobiologic response Amphotericin B; itraconazole may be useful as primary thera py TMP/SMX *Asymptomatic candiduria in renal transplant recipients Not T. glabrata or other resistant species Removal of catheter Less ill, sensitive organism, nephrotoxicity owing to amphotericin B and proven microbiologic and clinical response Pulmonary colonization immediately before or after transplantation **Surgical dbridement w here possible Excision of focal pulmonary nodule due to C. neoformans or H. capsul atum For coccidioidomycosis in endemic areas

10.20 Transplantation as Treatment of End-Stage Renal Disease Hepatitis B 100 90 80 Cumulative survival, % 70 60 50 40 30 20 10 0 0 2 4 6 8 Years followin g detection of HBsAg 10 31 22 19 18 6 15 13 13 1 11 9 9 6 5 24 20 17 12 9 7 Dialysis Transplant FIGURE 10-36 Survival of hepatitis B virus (HBV)infected patients with end-stage renal disease treated with either dialysis or transplantation. Patients infected with HBV (hepatitis B surface antigen [HBsAg] positive) on hemodialysis were ma tched for age with 22 previously transplanted HBsAg-positive patients. This stud y shows the reason for concern and investigation as to the safety of transplanta tion in HBV-infected patients. Although there are other studies showing a signif icantly decreased survival in patients transplanted with HBV infection, most cur rently show equivalent survival of over 10 years. The cause of death in the HBVinfected group, however, may more often be from infection and liver failure than from cardiac disease. The safety of transplantation in HBsAg-positive patients has been debated for ov er 25 years. Increased mortality, if seen, is usually seen beyond 10 years follo wing transplantation and is often secondary to liver failure or sepsis. The acqu isition of hepatitis B infections post-transplant, however, does carry a worse p rognosis. Virtually all patients with severe chronic active hepatitis, and 50% t o 60% of those with mild chronic active hepatitis on liver biopsy prior to trans plantation, will progress to cirrhosis. Patients with chronic persistent hepatit is usually do not show histologic progression over 4 to 5 years of follow-up, al though mild lesions do not guarantee preservation of hepatic function over longe r periods. The complete natural history of hepatitis B following transplantation is not known, as biopsies have been performed largely in those who have abnorma l liver function tests; however, one recent study, that included analyses of all individuals who were HBsAg positive around the time of transplantation, has sho wn histologic progression in 85.3% of those who were rebiopsied with the develop ment of hepatocellular carcinoma in eight of 35 patients who developed cirrhosis . A key to management of patients who were HBsAg positive following transplantat ion is to periodically monitor the liver by ultrasound and to perform a serum al pha-fetoprotein level to detect hepatocellular carcinoma at the earliest possibl e stage. The key to minimizing the effects of hepatitis B infections following t ransplantation, however, is to administer the hepatitis B vaccine as early as po ssible in the treatment for end-stage renal disease. It is noted that 60% will d evelop antihepatitis B titers when vaccinated while on dialysis compared with on ly 40% of those who have already been transplanted. Co-infection with hepatitis C may result in more aggressive liver disease but so far has not led to a marked decrease in patient survival. Because of the high risk of acute renal failure o r rejection with the use of interferon post-transplant, treatment of hepatitis B with interferon following renal transplantation is not advised. Lamivudine or o ther experimental antihepatitis agents may be used pretransplant for patients wi th hepatitis B infection. (Figure adapted from Harnett and coworkers. [11]; with permission.)

Post-transplant Infections 10.21 POST-TRANSPLANT SURVIVAL IN HEPATITIS BINFECTED PATIENTS Patients evaluated, n Author Pirson Hillis Touraine Dhar Roy Pfaff 1 y, % HBsAg + 94 55 94 92 100 88.8 3 y, % HBsAg + HBsAg 28 80 91 88 75 77.6 95 90 93 98 100 91.8 60 5 y, % HBsAg + HBsAg 80 88 93 75 80.6 87 66 61.6 10 y, % HBsAg + HBsAg Year 1977 1979 1989 1991 1994 1997 HBsAg + 61 16 140 51 85 781 HBsAg 60 149 869 541 172 13,287 HBsAg 82 68 (8 y) 65.8 +HBsAg positive; HBsAg negative. Later studies have usually shown comparable patien t and graft survival in HBsAg-positive patients compared with HBsAg-negative pat ients. There may only be a slight 3% to 4% difference overall in long-term graft and patient survival in favor of HBsAg-negative patients. FIGURE 10-37 Post-transplant survival in hepatitis Binfected patients. Later stud ies have shown comparable patient and graft survival in hepatitis B surface anti gen (HBsAg)positive patients compared with HBsAgnegative patients. There may only be a slight 3% to 4% difference overall (in favor of HBsAg-negative patients) in long-term graft and patient sur vival. (Data from Pirson and coworkers [12], Hillis and coworkers [13], Touraine and coworkers [14], Dhar and coworkers [15], Roy and coworkers [16], and Pfaff and Blanton [17].) FIGURE 10-38 Chronic hepatitis B infection in hepatitis B sur face antigen (HBsAg)positive renal transplant recipients. Results of liver biopsi es performed peritransplant and a median of 66 months later in 131 of 151 HBsAg+ patients. Histologic determination was seen in 85.3% of patients rebiopsied, wi th hepatocellular carcinoma seen in eight of 35 patients with cirrhosis. Patient s had not been treated with anti-hepatitis B virus agents. With a median age of 46, 151 patients were HBsAg positive (35 female, 116 male). Immunosuppression in 124 patients was with prednisone and azathioprine, and in 27 patients was with cyclosporine, azathioprine, and prednisone. (From Fornairon and coworkers [18]; with permission.) CHRONIC HEPATITIS B INFECTION IN HBsAg-POSITIVE RENAL TRANSPLANT RECIPIENTS: RES ULTS OF LIVER BIOPSIES PERFORMED PERITRANSPLANT AND A MEDIAN OF 66 MONTHS LATER First Biopsy n = 131 Histology Normal Chronic persistent Chronic active Cirrhosis Miscellaneous % 39%

25% 25% 0% 11% 66 months Second biopsy n = 101 % 6% 18% 42% 28% 6% Histologic deterioration was seen in 85.3% of those rebiopsied with hepatocellul ar carcinoma seen in 8/35 with cirrhosis. Patients had not been treated with ant i-HBV agents. 151 patients were HBsAg positive, median age 46, 35 females, 116 m ales. Immunosuppression in 124 was prednisone and azathioprine and in 27 cyclosp orine, azathioprine, and prednisone. The median follow-up was 125 months (range 1 to 320). Median time of HBsAg positively was 176 months with 20% acquiring HBV infection post-transplant.

10.22 Transplantation as Treatment of End-Stage Renal Disease FIGURE 10-39 Chronic hepatitis B infection. Causes of death in 151 hepatitis B s urface antigen (HBsAg)positive patients over 125 months. Death following transpla ntation is more frequently due to sepsis and liver failure in patients with hepa titis than in patients without chronic hepatitis. (From Fornairon and coworkers [18]; with permission.) CHRONIC HEPATITIS B INFECTION: CAUSES OF DEATH IN 151 HBSAG-POSITIVE PATIENTS OV ER 125 MONTHS Liver related (n = 15) Spontaneous bacterial peritonitis Hepatocellular carcinoma Liver failure Fibrosi ng cholestatic hepatitis 6 4 5 2 Not liver related (n = 26) Cancer Sepsis Cardiovascular Stroke Other 6 8 5 3 4 Death following transplantation in patients with hepatitis is more frequently ca used by sepsis and liver failure than in patients with chronic hepatitis. Hepatitis B virus screening in renal transplant candidates Hepatitis B virus Scr een by HBsAg Cumulative survival, % 1.0 0.9 0.8 0.7 0.6 0.5 0 12 24 36 48 HCV+HBV (n=189) HCV+HBV+ (n=46) (+) eAg HBV DNA ()No further testing except by routine dialysis schedule () DNA indicates lack of viral replication (+) DNA/eAg (+) Biopsy Cirrhosis 60 72 Months 84 96 108 120 ? Biopsy ? Use antiviral Consult hepatology Mild to severe hepatitis (CPH, CAH) No renal transplant alone Referral to Liver transplant center (if appropriate) t hat transplants HBV DNA(+) candidates Consider treatment FDA approved interferon Lamividine Famacyclovir Labucovir Adefovir

In trials FIGURE 10-41 Patient survival in 235 hepatitis C virus (HCV)-positive patients. Patients coinfected with HCV and hepatitis B virus (HBV) had comparable survival 12 years after transplant as those infected with HCV alone although fibrosis wa s more common in dually infected patients. Results were based on 27 biopsies in patients who were both HCV positive and HBV positive and 81 biopsies in patients who were both HCV positive and HBV negative. Over time, liver failure occurred more frequently in patients who were both HCV and HBV positive (17%) than in pat ients who were both HCV positive and HBV negative (7%). (From Pouteil-Noble and coworkers [19]; with permission.) FIGURE 10-40 Hepatitis screening in renal transplant candidates. CAH chronic acti ve hepatitis; CPHchronic persistent hepatitis; HBsAghepatitis B surface antigen; H BVhepatitis B virus.

Post-transplant Infections 10.23 Hepatitis C Other high risk 30% 16% Drug-related 4% STD history 1% Prison 9% Low SES Injection drug use 43% Sexual 15% Transfusions 4% Occupation/hemodialysis 4% Unknown 1% Household 3% FIGURE 10-42 Risk factors associated with reported cases of acute hepatitis C in the United States (1991 to 1995). Hepatitis C transplant infection prior to tra nsplantation has not been definitively shown in most studies to markedly affect survival for at least 5 years following renal transplantation. Furthermore, hepa titis Cpositive individuals who are otherwise good transplant candidates appear t o have increased survival when transplanted, compared with staying on dialysis. Liver biopsies performed prior to transplantation have usually shown mild histol ogical changes or chronic persistent hepatitis, but sequential biopsies have not been performed for a long enough period of time and compared with survival to o utline the natural history. Transaminase levels do not help to predict histology or outcome. Death in hepatitis Cpositive individuals is more often related to in fection than in hepatitis Cnegative transplant recipients. Post-transplant treatm ent with interferon alpha has led to an unacceptably high rate of both rejection and acute renal failure secondary to severe interstitial edema without tubuliti s. Additionally, except for a few individuals, interferon has not resulted in lo ng-term viral clearance. Most studies show the return of hepatitis C viremia wit hin 1 month following cessation of interferon. At this point it appears that hep atitis G infections (also caused by an RNA virus) in renal transplant recipients , although occasionally associated with slight increases in chronic hepatitis, a re not associated with decreased survival. E2/NS1 glycoprotein Hepatitis C virus screening in renal transplant candidates Hepatitis C virus Scr een for HCV by EIA-2 or 3 HCV (Ab) (+) 55 nm RNA 33 nm core HCV Ab () no further testing unless high-risk behavior + PCR E1 glycoprotein Lipoprotein envelope Cirrhosis Liver biopsy Cleared infection Repeat PCR in high-risk group in 6 months FIGURE 10-43 Proposed structure of the hepatitis C virus. Referral for liver and kidney transplant Mild changes CPH (mild hepatitis) CAH (moderate to severe hepatitis)

Transplant Monitor clinically for the onset of cirrhosis Monitor carefully for i nfection Referral for Interferon treatment Currently unknown sustained response Transplant FIGURE 10-44 Hepatitis screening in renal transplant candidates. CAHchronic activ e hepatitis; CPHchronic persistent hepatitis; HCV(ab) hepatitis C virus antibody; PCRpolymerase chain reaction.

10.24 1.0 Fraction of patients surviving 0.9 0.8 0.7 0.6 0.5 0 Transplantation as Treatment of End-Stage Renal Disease FIGURE 10-45 The survival of hepatitis C virus (HCV)infected patients after trans plant group 1 or while awaiting transplantation group 2. Patients who are transp lanted have an increased survival. A small biopsy study of dialysis (n = 14) and transplant (n = 14) patients showed no difference in histologic progression in transplant recipients. The amount of fibrosis, however, was slightly increased. (Adapted from Knoll and coworkers. [20]; with permission.) Group I Group II 12 24 Time, mo 36 48 100 80 Survival, % 60 40 20 0 HCV + HCV FIGURE 10-46 Five-year patient (panel A) and graft (panel B) survival in hepatit is C virus (HCV)positive and HCV-negative patients from recent reports from Unite d States centers. There is no significant difference over 5 years in patient or kidney graft survival. MCWMedical College of Wisconsin; MiamiUniversity of Miami; NEOBNew England Organ Bank; UCSF CAD University of California, San Francisco with cadaveric donors; UCSF LRDUniversity of California, San Francisco, with living re lated donors; UWUniversity of Washington. MCW Miami UCSF LRD UCSF CAD NEOB UW 3 yr 100 80 Survival, % 60 40 20 0 HCV + HCV MCW Miami UCSF LRD UCSF CAD NEOB

UW 3 yr

Post-transplant Infections 10.25 RENAL AND HEPATIC OUTCOME IN PATIENTS TREATED WITH INTERFERON ALPHA FOLLOWING RE NAL TRANSPLANT FOR HCV INFECTION Author Year Number treated HCV + HBV + Dose mU, SC, TIW Normalization of ALT Dis continued treatment Number with cirrhosis PCR +PCR RelapsePCR + Acute renal failur e Rejection Lost transplant New proteinuria Thervet 1994 13 4 35 1 7 8 NA NA 2 0 0 NA Magnone 1995 11 1 1.55 NA 7 NA NA NA 0 7 6 NA Rostaing 1995 14 0 3 10 7 1 4 4 5 0 1 2 Rostaing* 1996 16 NA 3 NA 9 NA NA NA 6 0 3 NA Yasumura 1997 6 0 6 6 0 0 2 0 0 1 0 1 FIGURE 10-47 Renal and hepatic outcome in patients treated with interferon alpha post-renal transplant for hepatitis C virus (HCV) infection. Interferon treatme nt results in a high rate of transplant acute renal failure or rejection. Transp lant biopsies in those with acute renal failure show severe diffuse edema. Acute renal failure is not very responsive to steroids. Virologic clearing is rare, a s HCV-RNA is detectable, on average, 1 month after discontinuing interferon if t he polymerase chain reaction (PCR) became negative during treatment. ALT alanine aminotransferase; SCsubcutaneously; TIWthree times a week. (Data from Thervet and coworkers [21], Magnone and coworkers [22], Rostaing and coworkers [23,24], and Yasumura and coworkers [25].) *Most are overlapping patients with the 1995 study. Hepatitis G HEPATITIS G VIRUS IN RENAL TRANSPLANTATION: PREVALENCE OF INFECTION AND ASSOCIAT ED FINDINGS Author Year Location % infection % with HCV infection % with chronic ALT elevati on Rejection rate % with HBsAg Survival versus HGV negative Dussol 1997 Marseill e 28% 12.5% 12.5% Unchanged 8% NA Murthy* 1997 NEOB 18% 28% 35% Unchanged NA Unc hanged Fabrizi 1997 Milan 36% 91% 18% NA 18% NA *One patient may have acquired HGV through the donor organ. Five of 10 pretransp lant positive patients became HGV RNA negative post-transplant. FIGURE 10-48 Hepatitis G virus (HGV) in renal transplantation: prevalence of inf ection and associated findings. Hepatitis G virus is an RNA virus of the flavivi ridae family. Hepatitis G virus was isolated independently by two different grou ps of investigators and called hepatitis GB viruses by Simmons and colleagues, a nd hepatitis G virus by Lenin and colleagues. It now appears that GB virus-A and GB virus-B are tamarin viruses and GBV-C is a human virus with sequence homology of more than 95% with the hepatitis GV sequence. The virus has been shown to be transmitted by transfusions, including plasma products, by fre quent parenteral exposure, including intravenous (IV) drug abuse, by sexual expo sure, and by mother to child transmission. In the United States, the prevalence of hepatitis G virus is 1.7% among healthy volunteer blood donors, 8.3% among ca daveric organ donors, and 33% among IV drug abusers. Among chronic hemodialysis patients, the prevalence of hepatitis G virus RNA has been variable, ranging fro m 3.1% in Japan to 55% in Indonesia and some areas in France. Likewise, the repo rted incidence of co-infection with hepatitis B virus (HBV) and hepatitis C viru s (HCV) is extremely variable. Hepatitis G virus RNA is detected by reverse tran scriptase polymerase chain reaction (PCR). The development of reliable serologic assays for hepatitis G has been difficult due to the lack of linear epitopes ex pressed by hepatitis G virus. The risk for pretransplant hepatitis G infection i s associated with increasing numbers of blood transfusions and with longer durat ion of dialysis. Post-transplantation, most patients with hepatitis G virus rema in viremic; however, patients have been shown to clear the virus post-transplant

. At this time, hepatitis G virus does not appear to invoke a poor outcome after transplantation, either in the form of severe liver disease or increased mortal ity; however, the long-term studies needed to provide a firm conclusion about th is have not been performed. The question of transmission of hepatitis G virus vi a transplantation is still under investigation. NAnot available; NEOB New England Organ Bank. (Data from Dussol and coworkers [26], Murthy and coworkers [27], and Fabrizi and coworkers [28].)

10.26 1.0 0.8 0.6 0.4 Transplantation as Treatment of End-Stage Renal Disease FIGURE 10-49 Kaplan-Meier estimate of graft survival among recipients with GBV-C RNA and without GBV-C RNA before transplantation. Death with a functioning graf t is included as a cause of graft loss. The relative risk of graft loss among re cipients with pretransplantation GBV-C RNA (and 95% CI of the risk) was calculat ed using a proportional hazards model. The number of patients at risk at the beg inning of each 12-month interval is provided. (Adapted from Murthy and coworkers [27]; with permission.) Relative risk: 0.88 (0.37, 2.09) GBV-C negative GBV-C positive Probability of graft survival 0.2 0.0 0 12 63 12 24 58 10 36 54 10 48 60 Time, mo 50 10 46 10 72 35 9 84 26 9 96 14 4 108 0 0 GBV-C neg. 79 GBV-C pos. 16 Value of Pretransplant Liver Biopsy HEPATITIS MARKERS AND HISTOPATHOLOGIC DIAGNOSIS FROM LIVER BIOPSIES PRIOR TO TRA NSPLANT CAH HbsAg (+) Anti-HCV (+) HBsAg and anti-HCV (+) Anti-HBs and anti-HCV (+) Anti-HBs (+) Total 2 11 1 8 22 CPH 2 4 2 8 CIRH 1 1 2 Normal 1 10 1 9 13 34 HSTAS 2 1 3

Other 1 3 1 5 Total 7 30 2 22 13 74 FIGURE 10-50 Liver biopsy in the evaluation of hemodialysis patients who are ren al transplant candidates. Seventy-four patients were biopsied. Forty-six percent of patients had normal or nonspecific changes in their liver biopsies, 30% CAH, 11% CPH, and 3% cirrhosis. Liver enzymes are poor predictors of histology in ES RD. Although with current management HBV-positive and HCV-positive recipients ca n enjoy comparable 10-year survival to noninfected patients, those with moderate to severe hepatitis more frequently progress histologically and may develop sep sis or liver failure. Liver biopsy aids in the long-term plan for the individual patients' immunosuppression and hepatic and infection monitoring. Furthermore, pr etransplant antiviral medications may be beneficial, especially interferon, wher e post-transplant administration is not advisable because of markedly increased rates of acute renal failure and rejection.(Adapted from zdogan and coworkers. [2 9]; with permission.) Hepatitis A infections are associated with acute hepatitis and, on occasion, wit h acute renal failure. Hepatitis A infections can be prevented by either using i mmunoglobulin injections or, more currently, a hepatitis A vaccine that is given as a two-dose series. This is an inactivated virus that is produced in human fi broblast cell culture and is given to adults as an initial and second dose 6 to 12 months later. The effectiveness of this vaccination has not yet been tested i n renal transplant recipients, nor are there specific guidelines on the administ ration prior to transplantation, but given the lack of toxicity, it may very wel l be advised in the future to give this to patients with end-stage renal disease and, specifically, to patients who are considering transplantation. CAHchronic a ctive hepatitis; CPHchronic persistent hepatitis; CIRHcirrhosis; HSTAS hepatic stea tosis.

Post-transplant Infections 10.27 Viral Interstitial Nephritis VIRAL INTERSTITIAL NEPHRITIS Adenovirus BK virus Cytomegalovirus Epstein-Barr virus Herpes simplex virus 1, 2 , 6 Varicella-zoster virus Hantavirus Hepatitis C viruspossible HIV FIGURE 10-51 Viruses that cause interstitial nephritis in renal transplant recip ients. Consider this condition when nonspecific inflammation is seen on biopsy o r unexplained rejection occurs. Viruses may cause renal disease by direct infect ion of the glomerular and/or tubular cells or by the immune response directed ag ainst virally infected cells. Most commonly nonspecific interstitial inflammatio n is seen but severe tubular injury by mononuclear cells, peritubular inflammati on, and interstitial fibrosis may also be seen. The presentation of virally medi ated interstitial nephritis may be acute or subacute. In addition to routine lig ht microscopy, occasionally evaluation by immunofluorescence, electron microscop y, or special stains for light microscopy are necessary to make the diagnosis. HIV 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 No cyclosporine treatment (n=13) Cyclosporine treatment (n=40) P=0.001 6 12 18 24 30 36 42 48 54 60 Months since transplantation-related HIV-1 infectio n 66 FIGURE 10-52 The occurrence of AIDS in HIV-infected transplant recipients accord ing to immunosuppressive treatment. Immunosuppression included cyclosporine in 4 0 individuals and no cyclosporine in 13 individuals. The precise natural history of HIV infection following renal transplantation is still not well delineated. The largest single series from Pittsburgh analyzed 11 patients who were HIV posi tive prior to transplantation and 14 patients who developed HIV infections follo wing transplantation. Of the 11 patients infected before transplantation, six we re alive an average of 3.3 years following transplantation. Five patients had di ed, however; three of AIDS-related complications. Of the 14 patients infected pe ritransplantation, seven patients were alive at follow-up an average of 4.8 year s later. There had been seven deaths, three due to AIDS. Complications seemed to correlate with increased immunosuppression for rejection. Another report evaluating 53 patients infected with HIV around the time of transplantation found that patients treated with cyclosporine appeared to have a better long-term prognosis than those who were treated with prednisone and aza thioprine. In summary, although there are no firm conclusions, it appears that t here is not much difference between pre- or post-transplant acquisition of HIV i nfection, although some authors, based on small numbers of patients, have conclu ded that the age of the patient and the duration of the infection are both progn ostic factors. It also appears that approximately 25% of HIV-infected individual s do poorly within the first 6 months of transplantation, especially following a ntirejection treatment (Rubin, unpublished data). Another 25% of individuals app ear to do very well 6 years and beyond following transplantation. The remainder of the individuals seem to develop AIDS within 3 to 3.5 years after transplantat ion, with an average survival of about 3 months after the onset of AIDS. It has also been noted that cytomegalovirus or other infections that may increase HIV p roliferation may influence this outcome, and that prophylactic antimicrobial str ategies may alter the natural history. Currently, it is advised that all transplan

t candidates be screened for the presence of HIV antibody and counseled about th e possible consequences of further immunosuppression, but not be categorically d enied transplantation if they are otherwise asymptomatic. Patient management fol lowing transplantation should be focused on the avoidance of large increases in immunosuppression and opportunistic infections, with special attention to the vi ral, pneumocystic, and mycobacterial infections that these individuals may devel op. Antiretroviral strategies in transplantation require study. (Adapted from Sc hwarz and coworkers [30]; with permission.) Proportion of patients with AIDS

10.28 Transplantation as Treatment of End-Stage Renal Disease Herpes Simplex Virus FIGURE 10-53 (see Color Plate) Linear esophageal ulcers caused by herpes simplex virus (HSV) and Candida. Infection with HSV-1 and -2 leads to stomatitis and es ophagitis post-transplantation without acyclovir prophylaxis. Additionally, paro nychia, corneal ulcers, encephalitis, genital lesions, disseminated involvement of the gastrointestinal tract, pancreas, and liver, and interstitial nephritis h as been seen. HSV-6 causes exanthem subitum in children, mononucleosis, and hepa titis. There has been some evidence that reactivation infections may be associat ed with rejection in transplant recipients. Both reactivation and reinfection ma y occur. HSV-8 is associated with Kaposi's sarcoma. Prevention of these infections has been achieved using prophylactic acyclovir following transplantation. If cl inical symptoms occur from HSV, they usually are treated with acyclovir adjusted for renal function. 94% of adults have evidence of a prior VZV infection. In th ose patients previously infected, antibody titers increase following transplanta tion. Pretransplant screening is recommended to advise the patient on treatment of post-transplant exposures. Post-transplant exposures to zoster or chickenpox in the nonimmune individual should be treated with acyclovir, famcyclovir, or va ricella-zoster immune globulin. Immune globulin is rarely required at this time. Patients with the new onset of varicella infection following transplantation or with diffuse zoster should be treated with intravenous acyclovir, 10 mg/kg, thr ee times per day, or famcyclorir depending on renal function. Infection in the t ransplant recipient, particularly in those who are primarily infected, can resul t in encephalitis, disseminated intravascular coagulation, pneumonia, bowel invo lvement, pancreatitis, dermatitis, and hepatitis. The attack rate in nonimmune i ndividuals of household contacts with varicella infections is 80% to 90%. Theref ore, if individuals have not previously had varicella infections at the time of transplant evaluation, vaccination with a live attenuated strain could be consid ered. Recently this strategy has been used in children prior to renal transplant ation. Attack rates in vaccinated individuals may be up to 31%, but the disease that develops is much milder compared with those susceptible individuals not pre viously vaccinated. Should resistant strains of varicella develop, foscarnet has been effective. Foscarnet is associated with a renal decline in renal function. (Adapted from Friedman-Kien [31]; with permission.) FIGURE 10-54 (see Color Plate) Varicella-zoster virus (VZV) ZV infections usually result in typical vesicular eruptions without dermatomal localization. Reactivation infection of orsal root ganglion usually causes a dermatomally localized By the time of renal transplantation, over infection. Primary V of generalized onset the virus from the d vesicular eruption.

Post-transplant Infections 10.29 FIGURE 10-55 Adenovirus infection of the colon. Adenovirus infections normally c ause asymptomatic infections, coryza, or pharyngitis. Infection in the first dec ade of life usually protects individuals from future infection as long as the im mune system is intact; however, in transplant recipients, adenovirus types 11, 3 4, and 35 have been shown to cause interstitial pneumonia, conjunctivitis, hemor rhagic cystitis, hepatitic necrosis, interstitial nephritis and gastroenteritis, and disseminated disease. Adenovirus infection may be latent prior to transplan t and reactivate post-transplant, or a primary infection may be acquired. Adenovirus has been shown to infect the bladder, uroepithelial cells, renal tubu lar cells (distal greater than proximal), the endothelium of the glomeruli and p eritubular capillaries, and, occasionally, mesangial cells. The outcome of adeno virus infection is related to the type of immunosuppression and the recipient ag e. The death rate during active infection in renal transplantation may be as hig h as 18% but may be even higher in younger patients. The onset of disease after transplantation is usually within 6 months of the transplant. Clinically, the mo st frequent symptoms of an adenovirus infection involve difficult micturition, i ncluding gross hematuria, fever, and, occasionally, renal dysfunction. The diagn osis is suspected when bacterial cultures are negative but there is gross hematu ria. The urinary symptoms usually last 2 to 4 weeks. The diagnosis is made by ur ine culture or by electron microscopy or light microscopy, where adenoviruses ar e seen as intranuclear basophilic viral inclusions with a narrow halo between th e inclusions and the nuclear membrane. Treatment has been somewhat successful us ing ganciclovir. Interferon therapy is difficult because of the risk of acute re nal failure or rejection in transplant recipients. Furthermore, efficacy is ques tionable because of the virus' ability to inhibit the mode of action of interferon . Ribavirin has successfully cleared the virus in several immunosuppressed patie nts. The use of IVIG has not been associated with reliable results. In the futur e, cidofovir may also be used for the treatment of adenovirus infections, but re nal insufficiency and proteinuria may limit use. FIGURE 10-56 Central nervous sy stem infection in the transplant recipient. CNScentral nervous system; CSFcerebros pinal fluid; MTB mycobacterium tuberculosis. CENTRAL NERVOUS SYSTEM INFECTION IN THE TRANSPLANT RECIPIENT Incidence 5%; mortality up to 85% for CNS infections Acute to subacute L. monocy togenes Subacute to chronic Cryptococcus neoformans Mycobacterium tuberculosis C occidiodes immitis Focal brain infection Aspergillus L. monocytogenes T. gondii N. asteroides Candida albicans Cryptococcus Progressive dementia Polyomavirus, H SV, CMV, HIV Symptoms Headachemay be mild, may have little meningismus Fevermay be mild altered consciousness Cerebrospinal fluid Lymphocytic pleocytosis (viral/f ungal/MTB) Hypoglycorrhaia Neutrophilic pleocytosis (bacterial) Over three-fourt hs of central nervous system infection is accounted for by L. monocytogenes C. n eoformans A. fumigatus Timing Early Listeria Nocardia Toxoplasma Aspergillus Lat eas above and due to chronic enhanced immunosuppression plus Cryptococcus and tub erculosis Diagnosis Physical examination CT scan identifies hypodense ring-enhan cing lesions CSF examination Directed lesional aspirates

10.30 Transplantation as Treatment of End-Stage Renal Disease CAUSES OF HEADACHE IN THE TRANSPLANT RECIPIENT Medications OKT3 (aseptic meningitis) ATG IVIgG Cyclosporine Tacrolimus Antihype rtensives Calcium channel blockers ACE inhibitors Nitrates Hydralozine Minoxidil Hypertension Neck tension, muscle pulls, ligamental irritation Sinusitis Ocular a bnormalities Excessive vomiting Migraine headaches exacerbated by cyclosporine, tacrolimus, and calcium channel blockers Stroke Infection of the central nervous system WORK-UP OF AN UNEXPLAINED HEADACHE History Character, pattern, positional relationships Fever, duration of headache and fever Location of headache Visual, movement, sensory impairment Bowel or bl adder incontinence Trauma Medications old and new Time of medications and relati onships to headache Physical examination Eye Neurological Complete the rest of t he examination If no papilledema or focal neurological deficitlumbar puncture If papilledema or focal deficitCT first if no mass lesionlumbar puncture Cerebrospina l fluid is sent for Cell count and differential Protein Glucose Gram's stain Funga l stains Acid fast stain Fungal culture Mycobacterial cultures Bacterial culture s Cryptococcal antigen Save cerebrospinal fluid in addition for other tests incl uding Histoplasma capsulatum or Coccidiodes immitis antibody titers FIGURE 10-57 Causes of headache in the transplant recipient. ACEangiotensinconver ting enzyme; CNScentral nervous system; ATGantithymocyte globulin. FIGURE 10-58 Work-up of an unexplained headache. FIGURE 10-59 Epstein-Barr virus (EBV). EBV is associated with asymptomatic infec tion, mononucleosis, hepatitis, and, rarely, interstitial nephritis. In transpla nt recipients, posttransplant lymphoproliferative disorder (PTLD) is also associ ated with EBV. EBV promotes B-cell proliferation, if left unchecked by immunosup pressive agents targeting the T-cell system. This chest radiograph shows multipl e pulmonary nodules of PTLD. Symptoms vary from no symptoms to diffuse organ inv olvement causing dysfunction. Any area of the body may be involved, with frequen t sites being the gums, chest, abdomen, and central nervous system. PTLD occurs during the first posttransplant year in approximately 50% of those developing PT LD. It is seen in 1% to 2% of renal transplant recipients. Primary EBV infection following transplantation and antilymphocyte agent use is associated with an in creased risk. Increasing quantitative blood EBV DNA levels may predict the onset of PTLD.

Post-transplant Infections 10.31 Viral Meningitis VIRAL MENINGITIS Causal agents Enterovirus Coxsackie* ECHO* Poliovirus Adenovirus Mumps Arbovirus Herpes group Cytomegalovirus* Herpes simplex virus 1 and 2* HHV-6* HHV-8* Varice lla-zoster virus* Epstein-Barr virus* Coronavirus HIV Influenza A, B Lymphocytic choriomeningitis virus Parainfluenza virus Rabies virus Rhinoviruses Rotavirus Japanese encephalitis virus* Tick borne encephalitis virus PML (JC) virus (in de velopment)* BK virus (in development)* FIGURE 10-60 Viruses causing meningitis in transplant recipients. The presentati on is usually with fever and headache alone or in conjunction with headache may be the initial symptom. Nuchal rigidity is rare in the transplant patient. Cereb rospinal fluid samples should be saved for viral analysis and analysis should be requested if the diagnosis is not rapidly available from standard studies. * Cerebrospinal fluid polymerase chain reaction available to make the diagnosis but locations vary Increased in transplant patients Black Hairy Tongue FIGURE 10-61 (see Color Plate) Black hairy tongue is the result of hypertrophy o f filiform papillae of the tongue, often seen in transplant patients after antib iotic treatment. The origin is unknown but is associated with topical or systemi c antibiotics, poor oral hygiene, smoking, alcohol, and the use of mouthwashes. Most often there are no symptoms; however, nausea, gagging, taste alteration, or halitosis are reported by some patients. Treatment includes brushing with a sof t brush and, occasionally, topical vitamin B, salicylic acid, gentian violet, or surgical removal. This entity is not to be confused with hairy leukoplakia, whi ch is composed of white corrugated plaques on the lateral surface of the tongue. These lesions may be small and flat or extensive and hairy. Microscopic evaluat ion shows epithelial cells with herpetic viral inclusions, specifically EpsteinBarr virus. Treatment is oral acyclovir.

10.32 Transplantation as Treatment of End-Stage Renal Disease Tinea Versicolor FIGURE 10-62 (see Color Plate) Tinea versicolor (pityriasis versicolor) is a chr onic superficial fungal disease caused by Malassezia furfur, a yeast normally fo und on the skin. It is in yeast form in the unaffected skin areas and in the myc elial phase on affected skin. The disease usually is located on the upper trunk, neck, or upper arms. Symptoms may include scaling, erythema, and pruritis. It m ay appear as slightly scaly brown macules or whitish macules. Treatment options include oral or topical terbinafine (1% cream or gel), oral or topical ketoconaz ole, oral fluconazole, or topical treatments, such as ciclopiroxolamine, pirocto neolamine, zinc pyrithione, or sulfur-containing substances, such as selenium su lfide; the most common treatment is selenium. Patients are asked to wet themselv es in the shower, turn off the water, apply the selenium and let it sit for 10 m inutes, and then rinse. Also, oral fluconazole, 200 mg, once or repeated once a week later is a simple and effective treatment. Of note, oral terbinafine, 250 m g, daily for 12 weeks is associated with slightly decreased cyclosporine levels. Terbinafine is an allylamine that binds to a small subfraction of hepatic cytoc hrome P450 in a type I fashion. Side effects seen during terbinafine use include gastrointestinal distress in up to 5% of patients and skin rashes in 2% of pati ents. Kaposi's Sarcoma FIGURE 10-63 (see Color Plate) Kaposi's sarcoma of the lower leg in a male transpl ant recipient. Kaposi's sarcoma is a tumor, perhaps of lymphatic endothelial origi n, that presents as purple papules or plaques that advance to nodules of the ext remities, oral mucosa, or viscera. In transplant recipients it presents on avera ge by 21 months post-transplant, with the largest number (46%) within the first post-transplant year. It is seen most often in men (3:1) and in those of Arabic, black, Italian, Jewish, and Greek ancestry. It accounts for 5.7% of the maligna ncies reported to the Cincinnati Transplant Tumor Registry (nonmelanoma skin can cers and in situ carcinomas of the uterine cervix excluded). Transplant programs in Italy and Saudi Arabia have reported higher rates of post-transplant Kaposi's sarcoma. Visceral involvement is less common in the transplant recipient than in the AIDS patient, but it must be remembered that it may be seen in the liver, l ungs, gastrointestinal tract, and nodes. Mortality is increased with visceral in volvement (57% versus 23%). HHV-8 has been proposed as the causal agent of this tumor; however, not all investigators feel the evidence is conclusive. Of note, the occurrence in AIDS patients is decreased in those who receive foscarnet, cid ofovir, and ganciclovir, but not acyclovir. Treatment includes decreasing immuno suppression, local radiation, excision, interferon, or chemotherapy.

Post-transplant Infections 10.33 Mucormycosis Most of the spores, once in the tissue, are contained by the phagocytic response . If this fails, as it often does in patients with diabetes mellitus and those o therwise immunosuppressed, germination begins and hyphae develop. The hyphae, as shown in the micrograph, are large, nonseptate, rectangular, and branch at righ t angles. Infection begins with the invasion of blood vessels, which causes necr osis and dissemination of the infection. The most common site of involvement is the rhino-orbital-cerebral area, accounting for approximately 70% of cases; howe ver, pulmonary, cutaneous, gastrointestinal, and disseminated infection may be s een. The chest radiograph during pulmonary infections may show an infiltrate, no dule, cavitary lesion, or pleural effusion. Gastric involvement may range from c olonization of peptic ulcers to infiltrative disease with vascular invasion caus ing perforation. Although classic for mucormycosis, a black eschar of the skin, nasal mucosa, or palate is present in only about 20% of patients early in the co urse of the disease and cannot be relied on for assistance in early diagnosis. S urvival is dependent on early diagnosis. Diagnosis is by biopsy with classic his tologic findings and by culture of tissue. Treatment includes amphotericin B, su rgical removal of the lesion, packing of the sinus areas with amphotericin Bsoake d packs, and perhaps hyperbaric oxygen. Liposomal amphotericin B has also been e ffective. Treatment must include both surgery and amphotericin B. FIGURE 10-64 Mucormycosis is caused by fungi of the order Mucorales, including R hizopus, Absidia, and Mucor. Mucorales are ubiquitous saprophytes found in the s oil and on decaying organic material, including bread and fruit. Human infection is believed to be caused by the inhalation of spores that initially land on the oral and nasal mucosa. Direct inoculation into tissues, however, has been repor ted. Condyloma Acuminata A FIGURE 10-65 Condyloma acuminata (anogenital/venereal warts) are caused by infec tion with human papillomavirus 6 or 11. In transplant recipients they may become extremely extensive. Treatment has included fluorouracil, podophyllin, podophyl lotoxin, intralesional interferon, topical interferon, systemic interferon, and, more recently, imiquimod, which causes the induction of cytokines, especially B interferon alpha. Lesions have responded in 50% of nontransplant patients receiv ing the 5% cream. Invasive treatments have included surgical excision, cryothera py, electrocautery, and carbon dioxide laser. Recurrences are common. A, Condylo ma acuminata in a male transplant recipient. B, Condyloma acuminata in a female transplant recipient.

10.34 Transplantation as Treatment of End-Stage Renal Disease Verruca Vulgaris A B FIGURE 10-66 Verruca vulgaris (common warts) are caused by human papillomaviruse s 1, 2, 3, 4, 5, 8, 11, 16, and 18, as well as others, with the highest percenta ge by type 4. Warts are found most often on the fingers, arms, elbows, and knees and are much more numerous in the immunosuppressed patient. Treatment modalitie s have been the same as for condyloma acuminata, with the addition of topical ci dofovir and hyperthermia. Therapy should be planned based on the location, exten t, and size of the lesions. Not all lesions need treatment. Early dermatologic r eferral is needed for those lesions that appear to be advancing rapidly as certa in papilloma viruses (16, 18, 31, 51, 52, 56) have been associated with squamous cell carcinomas of the skin and cervix. A and B, Verruca vulgaris of the finger and knee. Note the large size and multiple warts. C, Verruca planae, flat warts at multiple locations of the hand, also often seen on the face. C

Post-transplant Infections 10.35 Molluscum Contagiosum FIGURE 10-67 Molluscum contagiosum is an infection of the skin caused by the mol luscum contagiosum virus, a member of the pox virus family. Molluscum does not g row in culture or infected laboratory animals. Manifestations are pearly, pink, dome-shaped, glistening, firm lesions; in immunosuppressed patients, however, th ey may be over 1 cm in diameter and multiple lesions may occur together. The inf ection usually lasts up to 2 months in immunocompetent patients, but a chronic, recalcitrant, and disfiguring infection may occur in immunosuppressed patients. The virus is contracted and spreads via close contact with an infected person, f omites, or via autoinoculation. The incubation period is 2 weeks to 6 months. Th e diagnosis is made visually or by direct examination of curettings from the cen ter of the lesion showing molluscum intracytoplasmic inclusion bodies. Treatment is started for the prevention of spreading, to relieve symptoms, and for cosmet ic reasons. Treatment includes cryotherapy, curettage, podophyllin, cantharidin, trichloroacetic acid, phenol, salicylic acid, strong iodine solutions, lactic a cid, tretinoin, silver nitrate, and interferon alpha topical or intralesional, a nd possibly oral cimetidine, with adhesive tape occlusion. None of the available treatments result in a rapid or definite clearance in the immunosuppressed pati ent. Treatment of the underlying retrovirus infection has been shown to help in AIDS patients, and perhaps reviewing the degree of immunosuppression in the tran splant patient will help. A, Molluscum contagiosum papule. Note pearly umbilical ed appearance. B, Histologic slide of molluscum showing a cross section of the p apule. C, Close-up view of the molluscum bodies. A C B

10.36 Transplantation as Treatment of End-Stage Renal Disease Intestinal Protozoa SIMILARITIES AMONG THE INTESTINAL SPORE-FORMING PROTOZOA History Identified as human pathogens in recent decades Once considered rare pat hogens; now known to commonly cause infections The AIDS epidemic increased aware ness and recognition Biology Protozoa Intracellular location in epithelial cells of the intestine Spore or oocyst form is shed in stool Pathogenesis of diarrhea Unknown; possible abnormalities of absorption, secretion, and motility Intense infection of small bowel associated with dense inflammatory infiltrate May be as sociated with villus blunting and crypt hyperplasia Nonulcerative and noninvasiv e* Gut function and morphology related to number of organisms Epidemiology Common in tropical regions and places with poor sanitation Transmission is through fec al-oral route, person-to-person contact, and water or food Endemic disease of chi ldren Common source of epidemics in institutions and communities May cause travele r's diarrhea *Septata intestinalis may invade the mucosa. Probably true for all; co nclusively shown only for cryptosporidia. Not proven for microsporidia. Clinical manifestations Asymptomatic infection Self-limited diarrhea, nausea, and abdomin al discomfort in healthy children and adults Prolonged (subacute) diarrhea in so me immunocompetent patients Chronic diarrhea in immunodeficient patients Diagnosi s Microscopic stool examination should be initial approach Detection of cysts or spores in stool requires expertise and proper stains Antibiotic treatment Not u sually indicated in healthy persons with acute infection Indicated for chronic i nfection in immunodeficient patients FIGURE 10-68 Cryptosporidia, Isospora, cyclospora, and microsporidia are intesti nal spore-forming protozoa that infect enterocytes predominately of the small in testine. Infection occurs by ingesting the spores (oocytes) by person-to-person contact or ingesting contaminated food or water, including city or swimming pool water [32]. Infections in immunocompetent individuals may be asymptomatic or se lf-limited and associated with mild to moderate diarrhea and, less frequently, n ausea, abdominal cramping, vomiting, and fever. In immunodeficient patients, especially those with T-cell impairment, the infect ions may cause severe persistent diarrhea. The most common infection among the i ntestinal protozoas is cryptosporidium. The general prevalence of cryptosporidia in stool specimens in Europe and North America is 1% to 3%, and in Asia and Afr ica is 5% to 10%. Antibodies to cryptosporidia, however, have been found in 32% to 58% of adults. (Adapted from Goodgame [33]; with permission.)

Post-transplant Infections 10.37 Histoplasmosis interstitial spaces, it becomes a yeast, multiplies intracellularly, and dissemi nates until cell-mediated immunity develops (2 to 10 weeks). Organisms that diss eminate concentrate in the reticuloendothelial system. Disseminated disease is m arked by fever, weight loss, weakness, fatigue, and mild respiratory symptoms. T here may also be organ-specific symptoms, including those of urinary tract obstr uction. Histoplasma may be found in the glomerular capillary macrophages or macr ophages within the interstitium and be associated with focal medullary necrosis or papillary necrosis. The most common symptom of infection is fever, and often there are skin lesions, as shown in this figure, but central nervous system invo lvement is rare in transplant patients, as are abnormal chest radiographs. When present, chest radiographic findings include diffuse, nodular, patchy, or miliar y infiltrates; hilar adenopathy is uncommon. Diagnosis is made by identification of the yeast on a smear, histopathologic detection of intracellular organisms i n viable pulmonary tissue, a fourfold rise in antibody titers (only seen in abou t 50% of immunosuppressed patients), culture of the blood or tissue, or a urine antigen assay. Identification of the organism causing culture growth of a white, fuzzy mold (Histoplasma, Blastomyces, Coccidioides) is now performed by DNA hyb ridization. The bone marrow may be the most reliable source for sampling and sta ining for organisms. Treatment is amphotericin B occasionally, with long-term or al intraconazole after completing amphotericin. Resolution of infection may be m onitored by following the Histoplasma urinary antigen. FIGURE 10-69 Histoplasmosis is caused by the thermal dimorphic fungus Histoplasm a capsulatum that exists in its mycelial phase in nature and in the yeast form i n the human body. It is found in the soil enriched with bird or bat droppings in the Ohio and Mississippi River Valleys and in Texas, Virginia, Delaware, and Ma ryland. Disease is caused by primary infection or by reactivation of latent infe ction. Primary infection is acquired by inhalation of infectious microconidia, b y direct inoculation into the skin, or via an infected allograft. Once the micro conidia is lodged in the alveolar and Cryptococcosis CNS, where patients present with headache, fever, mental confusion, seizures, pa pilledema, long tract signs, or, uncommonly, meningismus. The onset of infection is anywhere from 6 months to years following transplantation. The onset may be very insidious, with nausea and headache occurring for weeks to months before th e fever develops. Pulmonary involvement presents asymptomatically or with dyspne a and cough. The chest radiograph shows wide variability in that circumscribed p ulmonary nodules, alveolar infiltrates, interstitial infiltrates with or without effusions, and cavitation may be seen. Cutaneous disease may be the first sign of dissemination in up to 30% of cases. Diagnosis is made by the identification of the yeast in the cerebrospinal fluid (CSF) or pulmonary secretions, the detec tion of cryptococcal antigen in the CSF or blood, or culture. Amphotericin B is the most common agent used for treatment, with some also favoring the use of flu cytosine and perhaps azole therapy for maintenance to prevent relapse. Specific patients may be treated with fluconazole alone. Serial determinations of the ser um cryptococcal antigen, which is positive in over 95% of patients with cryptoco ccal meningitis, may help to follow and modify the course of therapy. Patients s hould be treated until the cryptococcal antigen is negative, and then for anothe r 2 to 4 weeks for added safety. FIGURE 10-70 Cutaneous cryptococcosis, multiple lesions on the arm. Cryptococcus neoformans is an encapsulated yeast that exists worldwide, predominately in the soil contaminated by bird and other animal droppings. Infection is through inha lation with dissemination to the central nervous system (CNS), skin, mucous memb

ranes, bone, bone marrow, and genitourinary tract. Infection has also occurred t hrough the renal allograft. The most common disease site is the

10.38 Transplantation as Treatment of End-Stage Renal Disease Herpes Simplex FIGURE 10-71 (see Color Plate) Primary oral herpes simplex, mucosal membrane sho wing vesicles and ulceration. FIGURE 10-72 (see Color Plate) Primary herpes simplex stomatitis. FIGURE 10-73 Cutaneous herpes simplexherpetic whitlow. This condition may be conf used with a bacterial infection.

Post-transplant Infections 10.39 Central Nervous System Infections CEREBROSPINAL FLUID FINDINGS BY TYPE OF MENINGITIS Type Viral Fungal Tuberculous Bacterial WBC Count (per mm) 5.500 40400 1001000 400100,000 Differential, % >50 lymphocytes >50 lymphocytes >80 lymphocytes >90 PMNs Protein Level, mg/dL 30150 40150 40150 (may exceed 400) 80500 Glucose level, mg/dL Normal to low Normal Normal to low <35 Stain used Gram's India ink and cryptococcal antigen Acid-fast Gram's FIGURE 10-74 Cerebrospinal fluid findings in patients with bacterial meningitis. (Adapted from Maxon and Jacobs [34]; with permission.) References 1. Rubin RH, Wolfson JS, Cosimi AB, et al.: Infection in the renal transplant re cipient. Am J Med 1981, 70:405411. 2. Rubin RH: Infectious disease complications of renal transplantation. Kidney Int 1993, 44:221236. 3. Stratta R: International Congress on Immunosuppression, Orlando, FL, 1998. 4. Isada CM, Kastan BL, Goldm an MD, et al.: Infectious Disease Handbook, edn. 2. Lexi Comp, Inc., 19971998. 5. Maguire GP, Wormser GP: Preventing infections in the immunocompromised: Part 2. Journal of Respiratory Diseases 1994, 15:408. 6. Lake KD: Management of drug in teractions with cyclosporine. Pharmacotherapy 1991, 11:110S118S. 7. Yee GC: Pharm acokinetic interactions between cyclosporine and other drugs. Transplant Proc 19 90, 22:12031207. 8. Drugs for tuberculosis [letter]. Med Lett Drugs Ther 1992, 24 :1012. 9. Fishman JA: Pneumocystis carinii and parasitic infections in transplant ation. Infect Dis Clin North Am 1995, 9:10051044. 10. Hadley S, Karchmer AW: Fung al infections in solid organ transplant recipients. Infect Dis Clin 1995, 19:104 51074. 11. Harnett JD, Zeldis JB, Parfrey PS, et al.: Hepatitis B disease in dial ysis and transplant patients: further epidemiologic and serologic studies. Trans plantation 1987, 44:369. 12. Pirson Y, Alexandre GPJ, van Ypersele de Strihou C: Long-term effect of HBs antigenemia on patient survival after renal transplanta tion. N Engl J Med 1977, 296:194196. 13. Hillis WD, Hillis A, Walker WG: Hepatiti s B surface antigenemia in renal transplant recipients: increased mortality risk . JAMA 1979, 242:329. 14. Touraine JL, Traeger J: Renal TX at the University of Lyon. Clin Transpl 1989, 5:229238. 15. Dhar JM, Al-Khader AA, Al-Sulaiman MH, AlHasani MK: The significance and implications of hepatitis B infection in renal t ransplant recipients. Transplant Proc 1991, 23:1785-1786. 16. Roy DM, Thomas PP, Dakshinamurthy KV, et al.: Long-term survival in living related donor renal all ograft recipients with hepatitis B infection. Transplantation 1994, 58:118119. 17 . Pfaff WW, Blanton JW: Hepatitis antigenemia and survival after renal transplan tation. Clin Transplant 1997, 11:476479. 18. Fornairon S, Pol S, Legendre C, et a l.: The longterm virologic and pathologic impact of renal transplantation on chr onic hepatitis B virus infection. Transplantation 1996, 62:297299. 19. Pouteil-No ble C, Tardy JC, Chossegros P, et al.: Co-infection by hepatitis B virus and hep atitis C virus in renal transplantation: morbidity and mortality in 1098 patient s. Nephrol Dial Transplant 1995, 10 (suppl 6):122124. 20. Knoll GA, Tankersley MR

, Lee JY, et al.: The impact of renal transplantation on survival in hepatitis Cp ositive end-stage renal disease patients. Am J Kidney Dis 1997, 29:608614. 21. Th ervet E, Pol S, Legendre C, et al.: Low-dose recombinant leukocyte interferon- t reatment of hepatitis Cpositive end-stage renal disease patients: a pilot study. Transplantation 1994, 58:625627. 22. Magnone M, Holley JL, Shapiro R, et al.: Int erferon- -induced acute renal allograft rejection. Transplantation 1995, 59:10681 070. 23. Rostaing L, Izopet J, Baron E, et al.: Treatment of chronic hepatitis C with recombinant interferon alpha in kidney transplant recipients. Transplantat ion 1995, 59:14261431. 24. Rostaing L, Modesto A, Baron E, et al.: Acute renal fa ilure in kidney transplant patients treated with interferon alpha 2b for chronic hepatitis C. Nephron 1996, 74:512516. 25. Yasumura T, Nakajima H, Hamashima T, e t al.: Long-term outcome of recombinant INF- treatment of chronic hepatitis C in kidney transplant recipients. Transplant Proc 1997, 29:784786. 26. Dussol B, Cha rrel R, De Lamballerie X, et al.: Prevalence of hepatitis G virus infection in K idney transplant recipients. Transplantation 1997, 64:537539. 27. Murthy BVR, Mue rhoff AS, Desai SM, et al: Impact of pretransplantation GB virus C infection on the outcome of renal transplantation. J Am Soc Nephrol 1997, 8:11641173. 28. Fabr izi F, Lunghi G, Bacchini G, et al.: Hepatitis G virus infection in chronic dial ysis patients and kidney transplant recipients. Nephrol Dial Transplant 1997, 12 :16451651.

10.40 Transplantation as Treatment of End-Stage Renal Disease 32. Lemon JM, McAnulty JM, Bawden-Smith J: Outbreak of cryptosporidiosis linked to an indoor swimming pool. Med J Aust 1996, 165:613616. 33. Goodgame RW: Underst anding intestinal spore-forming protozoa: cryptosporidia, microsporidia, isospor idia, and cyclospora. Ann Intern Med 1996, 124:429441. 34. Maxson S, Jacobs: Vira l meningitis: tips to rapidly diagnose treatable causes. Postgrad Med 1993, 93:1 53166. 29. Histopathological impacts of hepatitis virus infection in hemodialysis patie nts: Should liver biopsy be performed before renal transplantation? Artif Organs 1997, 21:355358. 30. Schwartz A, Offermann G, Keller F, et al.: The effect of cy closporine on the progression of human immunodeficiency virus type 1 infection t ransmitted by transplantation: data on four cases and review of the literature. Transplantation 1993, 55:99-103. 31. Friedman-Kien AE: Cutaneous manifestations. In Atlas of Infectious Diseases, vol 1 (edn 2): AIDS. Philadelphia: Current Med icine; 1997:5.15.18.32.

Immunosuppressive Therapy and Protocols Angelo M. de Mattos T he 1990s have seen major steps in the dissection of basic mechanisms of alloreco gnition, and renal graft survival has achieved unprecedented clinical results. T ransplantation has turned into a widespread modality of therapy for patients wit h chronic renal failure that benefits thousands worldwide. Combinations of immun osuppressive agents have proved to be an effective strategy to inhibit diverse p athways of the multifaceted immune system, allowing the reduction of both dosage and adverse effects of each individual drug. As understanding of the molecular basis of the immune response has expanded rapidly, so have the possibilities for designing therapeutic interventions that are more effective, more specific, and safer than are current treatment options. As we reach the end of the century, s everal different and innovative approaches will add to this fascinating and comp lex therapy. CHAPTER 11

11.2 Transplantation as Treatment of End-Stage Renal Disease FIGURE 11-1 Mechanism of action for cyclosporine (Csa) and tacrolimus (Tac). The common cytoplasmic target for cyclosporine and tacrolimus is calcineurin. After binding to cyclophillin (Cyp), cyclosporine interacts with calcineurin, inhibit ing its catalytic domain. Thus dephosphorylation of transcription factors is pre vented, as exemplified by the nuclear factor of activated T lymphocyte (NF-AT). Despite having a different ligand called FK-binding protein (FK-BP), tacrolimus inhibits calcineurin in a similar way. Because phosphorylated transcription fact ors cannot cross the nuclear membrane, the production of key factors for lymphoc yte activation and proliferation (ie, interleukin-2, tumor necrosis factor- , in terferon, c-myc, and others) is inhibited [1]. NF-ATcnuclear factor of activated T-lymphocytecytoplasmic form; Pphosphorus; Cacalcium. Ca Csa/Cyp Calcineurin Tac/FK-BP IL-2 X P NF-ATc NF-AT box DNA DNA RNA IL-2 IL-2 receptor p m-TOR PHAS-1 Rapa/FKBP eIF-4F PHAS-1 p G1 S G0 M G2 FIGURE 11-2 Proposed mechanism of action for rapamycin (rapa). Rapamycin binds t o FK-binding protein (FK-BP). However, the immunosuppressive properties of rapam ycin are not due to inhibition of calcineurin. Rapamycin blocks the activating s ignal delivered by growth factors (exemplified by the interleukin-2 [IL-2] recep tor) by blocking the translation of the coding of messenger RNA (mRNA) for key p roteins required for progression through the G1 phase of the cell cycle. In this model the mammalian target of rapamycin (m-TOR, also called FRAP or RAFT1), pho sphorylates the translational repressor PHAS-I. Arrest of the cell cycle results , and the proliferation of lymphocytes is thereby inhibited. The full understand ing of the mechanism(s) of action of rapamycin is the focus of intense research at this time [2]. elF-4translation initiation factor belonging to the Ets family; G(0,1, and 2)quiescent; Mmitosis; Ssynthesis.

Immunosuppressive Therapy and Protocols 11.3 Azathioprine PRPP TIMP HGPRT 6-MP 6-m-MP Allopurinol Thiouric acid IMP D IMP HGPRT Hypoxanthine + PRPP Mycophenolate, mizoribine HGPRT PRPP + Adenine AMP GMP Guanine + PRPP ATP GTP Energy, signaling Energy RNA, DNA Glycoproteins FIGURE 11-3 Mechanism of immunosuppression of azathioprine and mycophenolate mof etil (MMF). Azathioprine and MMF prevent lymphocyte proliferation by way of inhi bition of purine base synthesis, thus resulting in decreased production of the b uilding blocks of nucleic acids (ie, DNA and RNA). Azathioprine is metabolized t o 6-mercaptopurine (6-MP), which is further converted to 6-ionosine monophosphat e. This molecule inhibits key enzymes in the de novo pathway of purine synthesis (adenosine monophosphate [AMP] and guanosine monophosphate [GMP]). MMF is metab olized to mycophenolic acid, which is a noncompetitive inhibitor of the enzyme t hat converts inosine monophosphate (IMP) to GMP. The depletion of GMP may have e ffects other than inhibition of nucleic acid production. Some events of T-lympho cyte activation are independent of guanosine triphosphate (GTP), as is the assem bling of certain adhesion molecules. ATPadenosine triphosphate; HGPRThypoxanthineguanine phosphoribosyl transferase; IMPD inosine-monophosphate dehydrogenase; PRP Pphosphoribosyl pyrophosphate; 6-m-MP6-methyl-mercaptopurine; TIMP thioinosine mono phosphate. (Adapted from de Mattos and coworkers [3,4].) Csa or FK-506 Csa or FK-506 Steroid Csa or FK-506 Aza or MMF Csa or FK-506 Stero id Aza or MMF Antilymphocytic Csa or FK-506 Steroid Aza or MMF Antilymphocytic C sa or FK-506 Steroid Aza or MMF } } } } 1 month Monotherapy Dual therapy

Triple therapy FIGURE 11-4 Summary of strategies for combining immunosuppressive agents. Curren tly, monotherapy (usually cyclosporine [Csa]) is not used in the United States. Dual therapy (involving cyclosporine or tacrolimus) is used commonly in Europe. Most centers in the United States use triple or quadruple therapy (induction or sequential). Some centers continue the induction with the antilymphocytic biolog ic agent for a predetermined period (usually 1014 days), overlapping with the ini tiation of cyclosporine (or tacrolimus). Alternatively, the biologic agent is di scontinued and cyclosporine (or tacrolimus) begun as soon as the graft function reaches a determined threshold, resulting in no overlap of these two agents. In living donor transplants, azathioprine (Aza) is commonly begun a few days before surgery. [5]. FK-506 tacrolimus; MMFmycophenolate mofetil. Quadruple therapy (induction versus sequential) 1 week

11.4 Transplantation as Treatment of End-Stage Renal Disease FIGURE 11-5 Evolution of monoclonal antilymphocytic antibodies. Monoclonal antib odies are the result of complex genetic engineering techniques. A, Differences a mong murine, chimeric, and humanized antibodies. Attempts to reduce side effects, improve efficacy, and decrease xenosensitization are the main reasons for develo pment of these modifications on the murine molecule. B, The different monoclonal antibodies, their classification regarding the molecular structure, and their t argets. Muromonab OKT3 (Ortho Pharmaceutical, Raritan, NJ) is the only monoclona l antibody commercially available at this time [6]. CD3 monomorphic membrane co-r eceptor present in T-lymphocytes; IL-2Rinterleukin-2R; TCRT-cell receptor. A Murine Monoclonal antibody Muromonab OKT3 Anti-Tac SDZ-CHIB T10B9 BMA 031 WT 32 Anti-ICAM 1 33B3-1 Humanized-chimeric Type Murine Murine Murine/Human Murine Murine Murine Murine R at Humanized-grafted Target CD3 IL-2R (CD25) IL-2R (CD25) TCR TCR CD3 CD54 IL-2R (C D25) B FIGURE 11-6 Experimental model of the vasoconstrictive effect of cyclosporine. S ome of the acute nephrotoxicity of cyclosporine is due to the significant yet re versible vasoconstrictive effect of the drug. A, Scanning electron micrograph of glomerulus of a rat not exposed to cyclosporine. Arrow indicates glomerular cap illary loop. AAafferent artery. B, After 14 days of cyclosporine treatment, the e ntire length of an afferent arteriole shows narrowing (magnification 500). Arrow indicates afferent artery. (From English and coworkers [7]; with permission.) A B

Immunosuppressive Therapy and Protocols 11.5 AGENTS USED IN RENAL TRANSPLANTATION Drug Cyclosporine Sandimmune (Sandoz Pharmaceuticals, East Hanover, NJ) Neoral (Sando z Pharmaceuticals, East Hanover, NJ) Dosage Starting dose: 710 mg/kg/d in 2 divided doses Maintenance: based on blood levels Starting dose: 710 mg/kg/d in 2 divided doses Maintenance: based on blood levels IV Csa equals one third of oral Csa; IV cyclosporine is given by continuous infu sion over 24 h Starting and maintenance dose: 13 mg/kg/d; IV dose equals half of oral dose Decrease dose by half for 50% decrease in leukocyte count Hold dose fo r leukocyte count of <3000 Adverse reactions Nephrotoxicity, hypertension, gingival overgrowth, hirsutism, hepatotoxicity, ne urotoxicity, hypomagnesia, hyperkalemia Same Cost Gelcaps: $1.61/25 mg; $6.42/100 mg Liquid: $6.41/100 mg, orally Gelcaps: $1.44/2 5 mg; $5.77/100 mg Liquid: $6.38/100 mg, orally $113.32/100 mg, IV Azathioprine Imuran (Glaxo Wellcome, Research Triangle Park, NC) Azathioprine (R oxane Laboratories, Columbus, OH) Azathioprine sodium (injectable) (Bedford Labo ratories, Bedford, OH) OKT3 (Ortho Pharmaceutical, Raritan, NJ) Muromonab-cd3 Leukopenia, anemia, thrombocytopenia, hepatitis, pancreatitis, alopecia, skin ca ncer, aplastic anemia (rare) $1.29/50-mg tablet $101.18/100-mg vial, IV $1.16/50-mg tablet $81.60/100-mg vial , IV Antithymocyte globulin Atgam (Upjohn Co, Kalamazoo, MI) Prednisone (various manu facturers) Deltasone (Upjohn Co, Kalamazoo, MI) FK-506, tacrolimus Prograf (Fuji sawa USA, Inc, Deerfield, IL) Induction: 2 mg/d (low-dose) 5 mg/d (standard) Rejection treatment: 5 mg/d Hold (delay) dose for weight gain >3% or temperature >39C Increase dose based on CD3+ cell count and CD3 density (suggested) Discontinue if anti-OKT3 antibody titer > 1:1000 Starting dose: 1530 mg/kg/d Decrease (or hold) dose for leukocytes <3000 o r platelets <100,000 Starting dose: 500 to 1000-mg infusion for 35 d Maintenance: taper schedule (variable) Cytokine release syndrome: fever, chills, chest pain, dyspnea, wheezing, noncard iogenic pulmonary edema, nausea, vomiting, diarrhea, headache, aseptic meningiti s, seizures, skin rash $672.00/5-mg vial Mycophenolate mofetil CellCept (Roche Laboratories, Nutley, NJ) Daclizumab (Roch e Laboratories, Nutley, NJ) Simulect (Novartis Pharmaceuticals Inc., East Hanove r, NJ) Starting dose: 0.150.3 mg/kg/d in 2 divided doses Avoid IV (0.050.1 mg/kg/d as a c ontinuous infusion over 24 h) Maintenance: based on blood levels Starting dose: 23 g/d orally in 2 divided doses (IV preparation in clinical trials) Maintenance: based on GI and bone marrow toxicities 1 mg/kg/d every 2 wk for a total of 5 do

ses 20 mg/d, given on days 0 and 4 post transplant Leukopenia, thrombocytopenia, fever, chills, skin rash, back pain, headache, nau sea, vomiting, diarrhea, horse serum sickness Fat redistribution, increased appe tite, weight gain, hyperlipidemia, hypertension, peripheral edema, hyperglycemia , skin atrophy, poor healing, acne, night sweats, insomnia, mood changes, blurre d vision, cataracts glaucoma, osteoporosis Nephrotoxicity, hypertension, hepatot oxicity, pancreatitis, diabetes, seizures, headache, insomnia, tremor, paresthes ia $262.24/250-mg vial $0.02$0.05/5-mg tablet Methylprednisolone, IV $17.88$35.50/500-mg vial $2.39/1-mg caplet $11.97/5-mg caplet $222.00/5-mg ampule, IV Nausea, vomiting, diarrhea, leukopenia, anemia, thrombocytopenia $2.04/250-mg caplet $4.08/500-mg tablet $102.00/500-mg, IV $418.20/25 mg, IV $12 24.00/20mg, IV Reported same as placebo Reported same as placebo Cost to the pharmacist based on the average wholesale price listing in Red Book, 1997 [8]. CD3monomorphic membrane co-receptor present in T-lymphocytes; Csacyclos porine; GIgastrointestinal. Adapted from de Mattos and coworkers [3,4]. FIGURE 11-7 A summary of the immunosuppressive agents currently used in human re nal transplantation is given. Dosages and costs are subject to local variation.

11.6 Transplantation as Treatment of End-Stage Renal Disease CLINICALLY RELEVANT DRUG INTERACTIONS WITH IMMUNOSUPPRESSIVE DRUGS Drug Cyclosporin A and tacrolimus Diltiazem Nicardipine Verapamil Erythromycin Clarit hromycin Ketoconazole Fluconazole Itraconazole Methylprednisolone (high dose onl y) Carbamazepine Phenobarbital Phenytoin Rifampin Aminoglycosides Amphotericin B Cimetidine Lovastatin Azathioprine Allopurinol Warfarin ACE inhibitors Mycophen olate mofetil Acyclovir-ganciclovir (high doses only) Antiacids Cholestyramine A CEangiotensin-converting enzyme. Adapted from de Mattos and coworkers [3,4]. Effect Increased blood levels Mechanism Decreased metabolism (inhibition of cytochrome P-450-IIIA 4) Increased blood levels Increased blood levels Decreased metabolism (inhibition of cytochrome P-450-IIIA 4) Decreased metabolis m (inhibition of cytochrome P-450-IIIA 4) Increased blood levels Decreased blood levels Unknown Increased metabolism (inhibition of cytochrome P-450-IIIA 4) Increased renal dysfunction Increased serum creatinine Decreased metabolism Incr eased bone marrow toxicity Decreased anticoagulation effect Increased bone marro w toxicity Increased levels of acyclovir-ganciclovir and mycophenolate mofetil D ecreased absorption Decreased absorption Additive nephrotoxicity Competition for tubular secretion Myositis, increased cr eatine phosphokinase, rhabdomyolysis Inhibiting xantine oxidase Increased prothr ombin synthesis or activity Not established Competition for tubular secretion Bi nding to mycophenolate mofetil Interferes with enterohepatic circulation FIGURE 11-8 Clinical relevant drug interactions with immunosuppressive agents. C lose monitoring of drug levels is required periodically with concomitant use of drugs with potential interaction. Drug level monitoring is clinically available for cyclosporin A and tacrolimus. Monitoring of non-immunos uppressive drug level is also important when used with potential interacting imm unosuppressive agents.

Immunosuppressive Therapy and Protocols 11.7 NEW IMMUNOSUPPRESSIVE AGENTS UNDERGOING CLINICAL TRIALS Agent Rapamycin Leflunomide Brequinar Deoxyspergualin SKF-105685 Mizoribine CTLA-4Ig Mechanism of action Inhibition of cytokine action (downstream of interleukin-2 receptor and other gr owth factors) Inhibition of cytokine action (expression of or signaling by way o f interleukin-2 receptor) Inhibition of DNA and RNA synthesis (pyrimidine pathwa y) Inhibition of DNA and RNA synthesis (pyrimidine pathway) Unknown (related to heat-shock proteins?) Unknown (stimulation of suppressor cells?) Inhibition of D NA and RNA synthesis (de novo purine pathway) Blockage of T-cell co-stimulatory pathway FIGURE 11-9 Proposed mechanisms of action of new immunosuppressive drugs current ly undergoing clinical or preclinical trials in organ transplantation [9]. Acknowledgments The author would like to thank Ali Olyaei, Pharm D., for his assistance with the preparation of this manuscript. References 1. Clipstone NA, Crabtree GR: Calcineurin is the key signaling enzyme in T lymph ocyte activation and the target of the immunosuppressive drug.Ann NY Acad Sci US A 1993, 696:2030. Brunn GJ, Hudson CC, Sekulic A, et al.: Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin.Science 1997 , 277:99101. de Mattos AM, Olyaei AJ, Bennet WM: Pharmacology of immunosuppressiv e medications used in renal diseases and transplantation.Am J Kid Dis 1996, 28:6 31637. de Mattos AM, Olyaei AJ, Bennet WM: Mechanism and risks of immunosuppressi ve therapy. In Immunologic Renal Disease. Edited by Neilson EG, Couser WG. Phila delphia: Lippincott-Raven; 1996:861885. 5. 6. Barry JM: Immunosuppressive drugs i n renal transplantation: a review of the regimens. Drug 1992, 44:554566. Powelson JA, Cosimi AB: Antilymphocyte globulin and monoclonal antibodies. In Kidney Tra nsplantation: Principles and Practice, edn 4. Edited by Morris PJ. Philadelphia: WB Saunders Co; 1994. English J, Evan A, Houghton DC, Bennett WM: Cyclosporinei nduced acute renal dysfunction in the rat.Transplantation 1987, 44:135141. Red Bo ok: Drug Topics. Montvale, NJ: Medical Economics Company, Inc., 1998. First MR: A n update on new immunosuppressive drugs undergoing preclinical and clinical tria ls: potential applications in organ transplantation.Am J Kid Dis1997, 29:303317. 2. 7. 3. 8. 9. 4.

Evaluation of Prospective Donors and Recipients Bertram L. Kasiske A ll patients should be considered for transplantation when it is determined that renal replacement therapy will someday be required. In some cases, the evaluatio n can be completed and the patient can receive transplantation before initiating chronic maintenance dialysis. Prospective candidates for transplantation must b e carefully screened for potentially fatal cancers and infections that are made worse by immunosuppression. Hepatic, pulmonary, cardiovascular, and gastrointest inal disorders all may increase the risks of surgery and chronic immunosuppressi on. Patients must be carefully screened for these disorders. In many cases, inte rvention before transplantation may help reduce the recipient's risks of transplan tation. Detailed guidelines have been established to evaluate prospective candid ates for transplantation [1]. Living donors offer the recipient optimal graft su rvival, reduced waiting time, and an opportunity for preemptive transplantation (ie, before initiating dialysis). The evaluation of prospective living donors mu st ensure that the donation is safe for both donor and recipient. However, the p rimary focus of this evaluation must always be on protecting the well-being of t he prospective donor. Both the short-term surgical risks and the long-term risks of having a single kidney must be carefully defined. The evaluation also must e nsure the donor has no disease that could be transmitted with the kidney. Guidel ines have been developed for the evaluation of living prospective donors [2]. Wh en no suitable living donors are available, the prospective recipient can be pla ced on the waiting list for a cadaveric kidney. Unfortunately, because the numbe r of patients needing cadaveric kidneys has grown much faster than has the numbe r of available kidneys, the median waiting time is now over 2 years. This shorta ge has led many transplantation centers to use cadaveric kidneys, which are asso ciated with reduced graft survival. In particular, graft survival is affected by the age of the kidney donor. Many centers are expanding the age limits of accep tability to reduce waiting times. A detailed discussion of the selection, retrie val, preservation, and allocation of cadaveric kidneys is beyond the scope of th is review. CHAPTER 12

12.2 Transplantation as Treatment of End-Stage Renal Disease Evaluation of Prospective Transplantation Recipients Initial evaluation of recipients Irreversible renal failure Currently on dialysis? Yes No Monitor rate GFR decline Dialysis likely in 6 months? Yes Prospective living donor? No No Yes FIGURE 12-1 Initiating the evaluation. Before transplantation it must be clearly established that renal failure in the patient is irreversible. When the prospec tive recipient is not already on chronic maintenance dialysis, however, preempti ve transplantation (ie, transplantation before initiating dialysis) should be co nsidered. Because the waiting time for a cadaveric kidney is generally long, pre emptive transplantation usually is possible only when a prospective living donor is available. In any case, the rate of decline in the glomerular filtration rat e (GFR) must be monitored closely in patients with progressive renal disease. Th e evaluation process should begin when it is anticipated that transplantation ma y be required within 6 months. (From Kasiske and coworkers. [1]; with permission .) Evaluate prospective living donor Evaluate potential recipient Cancer screening in recipients Screen for cancer Current or past evidence of cancer? No Yes FIGURE 12-2 Screening for cancer. An active malignancy is an absolute contraindi cation to transplantation. Effective screening measures for patients at risk inc lude chest radiograph, mammogram, PAP test, stool Hemoccult, digital rectal exam ination, and flexible sigmoidoscopy examination. Patients who have had a life-th reatening malignancy but are potentially cured may be candidates for transplanta tion when there has been an appropriate disease-free interval. This interval gen erally is at least 2 years, and longer in the case of some malignancies. (From K asiske and coworkers [1].) Appropriate disease-free interval? Proceed with evaluation

Evaluation of Prospective Donors and Recipients 12.3 Screening for infection in recipients Yes Appropriate treatment and disease-free interval 100 90 80 70 Graft survival, % Active infection? No HIV positive? No History of TB or positive PPD without adeq uate therapy? No Yes Discourage transplantation 60 50 40 30 20 CMV r/d n/n n/p p/n p/p n 4670 5970 7299 11,257 Yes Consider prophylactic treatment Assess risk for other infections 10 0 FIGURE 12-3 Screening for infection. An active potentially life-threatening infe ction is a contraindication to transplantation. Patients with human immunodefici ency virus (HIV) are usually not candidates for transplantation. Patients with a history of tuberculosis (TB) or a positive purified protein derivative (PPD) sk in test who have not been adequately treated should generally receive prophylact ic therapy. (From Kasiske and coworkers [1].) 0 1 2 3 4 5 Years after transplantation FIGURE 12-4 Assessing the risks of cytomegalovirus (CMV) infection after transpl antation. CMV is a major cause of morbidity and mortality after transplantation. The incidence and severity of CMV are associated with the serologic status of t he donor (d) and recipient (r), the risks generally being the following: recipie nt negativedonor negative less than recipient positivedonor negative less than rec ipient negative donor positive less than recipient positivedonor positive. As show n in these data from the United Network for Organ Sharing Scientific Registry, t he rate of graft survival tends to be less in recipients of kidneys from donors who test positive for CMV infection. The serologic status of both the donor and recipient is often used to determine which patients are candidates for prophylac tic or preemptive anti-CMV therapy after transplantation. (From Cecka [3]; with permission.)

Assessment for recurrent renal disease in recipients Renal disease with potentia l to recur? No Yes FIGURE 12-5 Assessing the risk of renal disease recurrence. Although the risk fo r recurrence of the underlying renal disease is rarely great enough to preclude transplantation, patients and physicians must be aware of this risk. In some cas es it may be prudent to delay transplantation until the underlying disease is qu iescent. (From Kasiske and coworkers [1].) Wait until quiescent Yes Risk acceptable? No Proceed with evaluation Avoid transplantation

12.4 100 90 80 Transplantation as Treatment of End-Stage Renal Disease FIGURE 12-6 The influence of underlying renal disease on graft survival. As show n in these data from the United Network for Organ Sharing Scientific Registry, 3 -year graft survival rates in groups of patients with different underlying cause s of renal failure vary substantially. The 3-year graft survival rates for recip ients with renal diseases that do not recur (eg, Alport's syndrome and polycystic kidney disease [PKD] were about 80%. Graft survival rates for patients with dise ases that may recur in the transplanted kidney varied from 60% to 83%. Of course , most of these differences in graft survival may be due to factors associated w ith the underlying cause of renal failure (eg, cardiovascular disease) and not d isease recurrence itself. Focal segmental glomerulosclerosis (FSGS), hemolytic u remic syndrome (HUS), Henoch-Schnlein purpura (HSP), and hereditary oxalosis can cause graft failure relatively soon after transplantation. Membranoproliferative glomerulonephritis (MPGN), scleroderma, IgA nephropathy, and diabetes generally cause graft failure only after several years. Numbers above bars indicate numbe r of patients who had that disease. (From Cecka [3]; with permission.) Cannot recur 411 3072 1058 Can recur in transplant organ 685 31 39 134 101 41 5421 70 3-year graft survival, % 60 50 40 30 20 10 0 Alport's syndrome PKD FSGS MPGN HUS IgA Scleroderma Oxalosis HSP Diabetes type II Evaluation for liver disease in recipients Symptoms or enzymes suggesting liver disease? No Discontinue Yes Consider cholecystectomy for gallstones Yes Toxic dr ug or alcohol No Consider biopsy and treatment Measure HBsAg and HCV antibody Ye s Elevated TIBC or ferritin No No Evaluation for viral hepatitis in recipients Positive HBeAg or HCV? Yes Antibody or HBeAg? No Elevated enzymes? No Elect Yes biopsy? No Severe disease on biopsy ? No No Moderate disease on biopsy? Yes Yes Consider avoiding transplantation No Yes Yes FIGURE 12-7 Evaluation of patients with signs and symptoms of liver disease. Pat ients with cholecystitis should be considered for cholecystectomy. For other pat ients with signs and symptoms of liver disease, potential hepatic toxins should be considered. The incidence of liver disease from iron deposition has declined with the diminishing use of blood transfusions in dialysis patients, but may be seen occasionally in patients with a high total iron binding capacity (TIBC) or

ferritin. All prospective candidates for transplantation must be screened for he patitis B and C by testing for the presence of hepatitis B surface antigen (HBsA g) and hepatitis C virus (HCV) antibodies. Both viruses can cause potentially fa tal liver disease after transplantation. Fortunately, the incidence of hepatitis B is declining among patients with renal disease, largely as a result of the us e of effective vaccination programs. (From Kasiske and coworkers [1]; with permi ssion.) Proceed with evaluation Acceptable risk? FIGURE 12-8 Viral hepatitis. Patients whose test results are positive for antibo dies or hepatitis e-antigen (HBeAg) are at high risk for succumbing to liver dis ease and most likely are not candidates for transplantation. A liver biopsy shou ld be considered for all patients with hepatitis C virus (HCV) antibodies or hep atitis B surface antigen. Patients with severe chronic active hepatitis or cirrh osis on biopsy generally are not candidates for renal transplantation unless sim ultaneous liver transplantation is being considered. Whether antiviral therapy b efore transplantation can increase the number of patients who are candidates for transplantation is unclear. (From Kasiske and coworkers [1]; with permission.)

Evaluation of Prospective Donors and Recipients 1.0 0.8 0.6 0.4 0.2 0 0 2 4 Years after transplantation 6 8 21 16 13 10 9 7 6 1 12.5 29 5 78 59 52 47 45 34 20 2 1.0 0.8 Patient survival, % 0.6 0.4 0.2 0 0 79 69 67 62 57 45 Graft survival, % 22 17 15 12 11 8 6 1 Relative risk: 1.27 (0.62, 2.60) Relative risk: 3.33 (1.40, 7.93) AntiHCV positive AntiHCV negative

AntiHCV positive AntiHCV negative 2 4 Years after transplantation 6 8 A B FIGURE 12-9 Effects of pretransplantation hepatitis C virus (HCV) serology resul ts on survival of the graft (A) and patient (B). Numbers above (antiHCV negative) and below (antiHCV positive) survival curves indicate the number of patients at risk during that time interval. The relative risk after transplantation associat ed with the patient testing positive for HCV antibodies before transplantation also is shown, along with 95% confidence intervals. Although no statistically significant effect of HCV on graft survival was seen, patient surv ival was significantly diminished among those who tested positive for HCV after transplantation. Not all investigators have confirmed these findings. (From Peri era and coworkers [4]; with permission.) Evaluation of effects of smoking in recipients Dyspnea on exertion or smoking hi story? No Currently smoking? No Yes Smoking cessation program Yes Past history o f IHD? No High risk for IHD? No Severe lung disease on function tests? No Evalua te for CHF Yes Wait until adequate resolution with therapy Yes Evaluation of IHD in recipients Active angina? No Yes Yes Yes Stress test positive? No Risk factor intervention Imaged coronary lesions severe? Yes Revascularization successful? No Reconsider transplantation candidacy No Yes Proceed with evaluation FIGURE 12-10 Lung disease. Few studies exist that address the effects of cigaret te smoking on outcome after renal transplantation. Because the risks of transpla ntation surgery no doubt are increased by cigarette smoking, candidates for tran splantation should be referred to smoking cessation programs. (From Kasiske and coworkers [1]; with permission.) FIGURE 12-11 Ischemic heart disease (IHD). The incidence of IHD is several fold higher in renal transplantation recipients compared with the general population. Patients with IHD before transplantation are at high risk to develop IHD events after transplantation. Therefore, angiography should be considered in candidate s for transplantation who have angina pectoris. Candidates with currently asympt omatic IHD and those at high risk for IHD should undergo a stress test. Patients with severe coronary artery disease on angiography must be considered for a rev ascularization procedure before transplantation. Aggressive management of risk f actors is appropriate for all patients, with or without IHD. (From Kasiske and c oworkers [1]; with permission.)

12.6 100 90 Free of cardiac events, % 80 70 60 50 40 30 20 10 0 0 3 Transplantation as Treatment of End-Stage Renal Disease (13) (9) (7) (10) Revascularized (4) Medically treated (2) 6 9 12 15 18 21 24 Follow-up, mo FIGURE 12-12 Effects of surgical versus medical management of coronary disease b efore renal transplantation in candidates who have insulin-dependent diabetes. I n this study, 26 patients with insulin-dependent diabetes who were found to have over 75% stenoses in one or more coronary arteries were randomly allocated to e ither medical management or a revascularization procedure before transplantation . Ten of the 13 patients who were managed medically and 2 of the 13 who had reva scularization performed had a cardiovascular disease end point within a median o f 8.4 months after transplantation (P < 0.01). These findings suggest that trans plantation candidates who have diabetes should be screened for silent coronary a rtery disease because revascularization decreases morbidity and mortality after transplantation. The numbers in parentheses indicate the number of patients bein g followed at that time. (From Manske and coworkers [5]; with permission.) Evaluation of CHF in recipients Signs and symptoms of CHF? No Proceed with evalu ation Yes Adequate response to medical management? No Reconsider transplant cand idacy Yes Exclude secondary causes FIGURE 12-13 Congestive heart failure (CHF). Myocardial performance has been sho wn to improve in some patients after renal transplantation. Thus, a low ejection fraction alone does not automatically exclude patients from transplantation. In contrast, patients with severe irreversible myocardial disease may not be good candidates for transplantation. Occasionally, patients may be candidates for sim ultaneous heart and kidney transplantation. (From Kasiske and coworkers [1]; wit h permission.) Evaluation of CVD in recipients History of stroke or TIA? No Carotid bruit? No H igh-risk ADPKD patient? No Yes Large intracranial aneurysm on imaging? No Yes Ri sk factor intervention Yes Yes Recent symptoms? No Consider carotid ultrasonogra phy Yes Refer to neurologist FIGURE 12-14 Cerebral vascular disease (CVD). Patients must not undergo surgery within 6 months of a stroke or transient ischemic attack (TIA). Asymptomatic pat

ients with a carotid bruit should be considered for carotid ultrasonography beca use patients with severe carotid disease may be candidates for prophylactic surg ery. Patients with autosomal dominant polycystic kidney disease (ADPKD) and eith er a previous episode or a positive family history of a ruptured intracranial an eurysm must be screened with computed tomography or magnetic resonance imaging. Patients found to have an aneurysm over 7 mm in diameter may benefit from prophy lactic surgery. (From Kasiske and coworkers [1]; with permission.) Consider prophylactic surgery Proceed with evaluation

Evaluation of Prospective Donors and Recipients 12.7 Evaluation of PVP in recipients PVD unresponsive to conservative management? No Yes Consider repair before or at transplantation Yes Consider invasive intervent ion FIGURE 12-15 Peripheral vascular disease (PVD). Peripheral vascular disease is c ommonly associated with coronary artery disease, cerebral vascular disease, or b oth. However, PVD itself may require intervention before transplantation to prev ent infection and sepsis after transplantation. In addition, some patients may h ave aortoiliac disease severe enough to require intervention before transplantat ion. Rarely, vascular disease is severe enough to make it difficult to find an a rtery suitable for the anastomosis of the allograft renal artery. (From Kasiske and coworkers [1]; with permission.) Aortoiliac vascular disease? No Proceed with evaluation Psychosocial evaluation of recipients Psychosocial evaluation Free of limiting cognitive impairment? Yes Recent alcohol or drug abuse? No No FIGURE 12-16 Psychosocial evaluation. Patients must be free of cognitive impairm ents and able to give informed consent. Most transplantation centers require pat ients with a history of alcohol or drug abuse to demonstrate a period of supervi sed abstinence, generally 6 months or more [6]. Similarly, patients with a past history of medication adherence poor enough to suspect that the immunosuppressiv e regimen will be compromised may need to delay transplantation until reasonable adherence can be demonstrated [6]. (From Kasiske and coworkers [1]; with permis sion.) Yes Yes Supervised abstinence? No Free of limiting No psychiatric illness? Yes History of limiting medication nonc ompliance? No Yes Refer until resolved Proceed with evaluation

12.8 Transplantation as Treatment of End-Stage Renal Disease Assessment of the medical risks to recipients BMI >35 kg/m2 No Yes Consider weight reduction program Yes Age >65? No Yes FIGURE 12-17 Assessing the medical risks of transplantation surgery. Obesity inc reases the risks of surgery, and a weight reduction program before transplantati on must be considered for very obese patients. Older age is a relative contraind ication to transplantation; however, it is difficult to precisely define an uppe r age limit for all patients. Rather, age and overall medical condition must be considered together. Hypertension should be controlled before transplantation. W hen control of hypertension is difficult, bilateral nephrectomy should be consid ered before transplantation. BMIbody mass index. (From Kasiske and coworkers [1]; with permission.) No further evaluation Additional risk acceptable? Yes Native kidney nephrectomy No Hypertension unresponsive to medical management? No Proceed with evaluation 100 90 80 70 60 50 40 30 20 10 0 0 * 100 * * * * * * * Graft survival, % 90 80 70 Survival, % * 3 Obese patients Nonobese patients Obese patient grafts Nonobese patient grafts 60 50 40 30 20 Age 05 618 1945 4660 >60 n 198 1144 14994 10933 3908 t1/2 15.1 8.7 9.4 9.9 8.0 6

9 12 Time, mo 15 18 21 24 FIGURE 12-18 Effects of obesity on patient and graft survival. In this case-cont rol study, 46 obese (body mass index > 30 kg/m2) recipients of cadaveric renal t ransplantation were compared with nonobese controls matched for the following af ter transplantation: age, gender, diabetes, panel reactive antibody status, graf t number, cardiovascular disease, date of transplantation, and immunosuppression . Survival of patients and grafts was significantly less among obese patients co mpared with controls (P < 0.01 and P < 0.05, respectively). The following occurr ed more often in obese versus nonobese patients: delayed graft function, postope rative complications, wound complications, and new-onset diabetes. (From Holley and coworkers [7]; with permission.) 10 0 0 1 2 3 4 5 Years after transplantation FIGURE 12-19 Effects of the recipient's age on renal allograft survival. Data from the United Network for Organ Sharing Scientific Registry indicate that recipien ts over the age of 60 have slightly less allograft survival compared with younge r recipients. t1/2graft survival half-life (in years) the first year after transp lantation. (From Cecka [3]; with permission.)

Evaluation of Prospective Donors and Recipients Evaluation of diabetes and hyperparathyroidism in recipients 12.9 100 84.7 Pancreas graft survival, % Difficult to control diabetes? No Yes Consider simultaneous kidney-pancreas transplantation 80 71.4 73.5 77.4 73.2 69.0 Simultaneous kidney transplantation (n=3336) 61.8 60 40 20 0 54.4 52.5 46.0 39.4 39.2 27.7 No previous kidney transplantation Symptomatic hyperparathyroidism or uncontrolled hypercalcemia? No Yes Consider parathyroidectomy 27.7 22.6 Previous kidney transplantation (n=273) Need for medication that may jeopardize recipient or graft? No Yes Discontinue or reduce risk 0.25 1.0 2.0 3.0 4.0 5.0

Years after transplantation Proceed with evaluation FIGURE 12-20 Diabetes and hyperparathyroidism. Patients with difficult to contro l diabetes may be candidates for simultaneous kidney-pancreas transplantation. H owever, patients with diabetes who have a living donor are generally better off undergoing transplantation with the living donor kidney alone. Patients with sym ptomatic hyperparathyroidism or uncontrolled hypercalcemia should be considered for parathyroidectomy before transplantation. Medications that interfere with th e metabolism of immunosuppressive agents such as cyclosporine should be substitu ted with appropriate alternatives, if possible, before transplantation. (From Ka siske and coworkers [1]; with permission.) FIGURE 12-21 Pancreas graft survival in recipients of pancreatic transplantation with simultaneous, no previous, and previous kidney transplantation. Survival r ates of pancreatic grafts are best when pancreatic and kidney transplantations a re performed at the same time. (Data from the United Network for Organ Sharing S cientific Registry [8].) Urologic evaluation in recipients Signs or symptoms of bladder dysfunction? Yes History of recurrent UTIs? Yes No Ultrasonography, cystoscopy, and/or retrograde pyelogram normal? No Indications for native kidney nephrectomy? Yes Yes Conside r native kidney nephrectomy Bladder insufficiency? No No Consider ureteral diver sion or intermittent self-catheterization Yes Proceed with evaluation No Yes No VCUG normal? FIGURE 12-22 Urologic evaluation of transplantation recipients. Patients without signs and symptoms of bladder dysfunction generally do not need additional urol ogic testing. However, patients with bladder dysfunction must be evaluated to en sure that the bladder is functional after transplantation and that potential sou rces of urinary tract infection (UTI) are eliminated. Such patients can be scree ned initially with voiding cystourethrography (VCUG). (From Kasiske and coworker s [1]; with permission.)

12.10 Transplantation as Treatment of End-Stage Renal Disease Evaluation of active colonic disease in recipients PUD and pancreatitis Signs or symptoms of active PUD? No Yes Endoscopic or radiographic confirmation? No Yes History of diverticulitis? Yes No Severe diverticular disease on barium enema? No Other active colonic disease? No Proceed with evaluation Yes Consider partial colectomy Yes Adequate response to medical management? Yes History of pancreatitis? No Yes No Consider pretransplantation surgical treatment Defer transplantation until quiescent Delay transplantation until evaluation and treatment FIGURE 12-23 Diverticulitis and inflammatory bowel disease. Patients with a hist ory of symptomatic diverticulitis must be evaluated for partial colectomy before transplantation. Inflammatory bowel disease generally should be quiescent at th e time of transplantation. (From Kasiske and coworkers [1]; with permission.) Proceed with evaluation FIGURE 12-24 Peptic ulcer disease (PUD) and pancreatitis. Patients with PUD or p ancreatitis must undergo evaluation and treatment before transplantation. Both c onditions may be exacerbated by corticosteroids used after transplantation. (Fro m Kasiske and coworkers [1]; with permission.) FIGURE 12-25 Immunologic evaluati on for living donor transplantation. Generally, transplantation donors and recip ients must have compatible blood groups. Tissue typing is also carried out, and the degree of human leukocyte antigen (HLA) matching may be taken into account i n selecting the best living donor when more than one donor is available. Just be fore transplantation, the recipient's serum is tested against donor cells to be ce rtain no preformed antibodies are present in the recipient that may cause a hype racute rejection. A positive crossmatch (X-match) generally precludes transplant ation from that donor. CDCcell-dependent cytotoxicity. (From Kasiske and coworker s [1]; with permission.) Evaluation of transplantation from a living donor Potential living donor? Yes Bl ood and tissue typing No Consider cadaveric donor ABO compatible? Yes T-cell CDC X-match negative? Yes No No

Assess likelihood of false-positive results HLA identical? Yes No Yes Presence of autoantibodies? No Transplantation Consider other donor Proceed with evaluation

Evaluation of Prospective Donors and Recipients Donor-specific transfusions in recipients Consider other donor Adjusted graft su rvival, % No Negative X-match, flow cytometry, or antiglobulin? Yes X-match nega tive? No Yes Transplantation 12.11 100 1y 5 y>1 y 84% First transplantation? Yes Consider DST No 90 80 70 60 P= 0.04 P= 0.02 76.4% 50 26,585 19,187 20,461 15,087 4172 3164 3303 2444 40 0 FIGURE 12-26 Donor-specific transfusion (DST). When the living donor is non human leukocyte antigen identical and it is the recipient's first transplantation, some centers use donor-specific blood transfusions before transplantation to enhance graft survival. Unfortunately, donor-specific transfusions may induce the forma tion of antibodies against the donor that will preclude the transplantation. Mos t centers have abandoned the use of random blood transfusions as part of the pre paration of recipients for cadaveric transplantation. X-match cross-match. (From Kasiske and coworkers [1]; with permission.) 0 1-5 6-10 >10 0 1-5 6-10 >10 Number of pretransplantation transfusions FIGURE 12-27 Effects of random blood transfusions on first cadaveric renal allog raft survival. Blood transfusions before transplantation had a small but statist ically significant beneficial effect on 1-year graft survival. However, a small reduction occurred in 5-year graft survival (among patients who survived at leas t 1 year with a functioning kidney) that was attributable to random donor blood transfusions before transplantation (From Gjertson [9]; with permission.) FIGURE 12-28 Immunologic evaluation for cadaveric transplantation. Donors and recipien ts must have compatible blood groups. Tissue typing is carried out, and the degr ee of matching is used in the allocation of cadaveric organs. Some data suggest

that the presence of human leukocyte antigen (HLA) mismatches that were also mis matched in a previous graft (especially at the DR locus) may lead to early graft loss. Thus, it may be wise to avoid these mismatches. When the percentage of pa nel reactive antibodies (PRA) is over 10%, tests may be carried out to determine whether some of the antibodies are autoreactive rather than alloreactive. Autor eactive antibodies may not increase the risk for graft loss as do alloreactive a ntibodies. The presence of high titers of alloreactive antibodies usually is due to previous pregnancies, transplantations, and blood transfusions. Determining antibody specificities may be useful in avoiding certain HLA antigens. In the hi ghly sensitized patient (PRA > 50%) it may be difficult to find a complement-dep endent cytotoxicity (CDC) cross-matched (X-match) negative donor. Avoiding blood transfusions may help the titer decrease over time. DTT1, 4-dithiothreitol (DTT) . (From Kasiske and coworkers [1]; with permission.) Immunologic evaluation for cadaveric transplantation No living donor No First transplantation? Yes PRA 11% Yes Waiting list No Review typing from previous grafts Autologous X-match positive? No Identify HLA specificities Yes Increasing PRA? N o No Final CDC X-match negative? Yes PRA after DTT or analogous cell adsorption Periodic antibody screening Yes Transplantation

12.12 Transplantation as Treatment of End-Stage Renal Disease Evaluation of Prospective Living Donors 100 90 80 Graft survival, % 70 60 50 40 30 20 10 0 0 HLA-identical sibling donor (n= 1984) Spousal donor (n= 368) Parental donor (n= 3368) Living unrelated donor (n=129) Cadaveric graft (n= 43,341) Cadaveric graft , urine flow 1st day, no dialysis (n=32,281) Cadaveric graft, no urine 1st day, dialysis required in 1st week (n= 11,060) 100 90 80 70 Graft survival, % P< 0.025 60 50 40 30 20 Graft: HLA-identical 1-haplotype Zero-haplotype n 2288 3082 808 t1/2 25.5 16.0 1 1.9 1 2 Years after transplantation 3 FIGURE 12-29 Effects of donor source on renal allograft survival. Data from the United Network for Organ Sharing Scientific Registry were used to compare 3-year graft survival rates between recipients of kidneys from different donor sources . The best graft survival was seen in recipients of human leukocyte antigen (HLA )identical sibling donors. Grafts from spouses and other living unrelated donors, however, survived just as well as did grafts from parental donors and better th an grafts from cadaveric donors. These data have encouraged centers to use emoti onally related donors to avoid the long waiting times for cadaveric kidneys. (Fr om Terasaki and coworkers [10]; with permission.) 10 0 0 1 2 3 4 5 Years after transplantation FIGURE 12-30 Effects of human leukocyte antigen (HLA) matching on living related graft survival. Graft survival is best for HLA-identical grafts from siblings a nd next best for one-haplotype mismatched grafts. Importantly, the half-life (t1 /2) of grafts that survived at least 1 year is proportional to the degree of mat ching. This information can be used along with other factors to select the most suitable among two or more living prospective donors. (From Cecka [3]; with perm ission.) FIGURE 12-31 Use of living donors. A suitable living donor is better th an a cadaveric donor because graft survival is better and preemptive transplanta tion is possible. The best donor usually is a family member. Psychosocial and bi ological factors must be taken into account when choosing among two or more livi ng prospective donors. Every effort must be made to ensure that the donation is truly voluntary. Caregivers should tell prospective donors that if they do not w ish to donate, then friends and relatives will be told the donor was not medicall y suitable. (From Kasiske and coworkers [2]; with permission.)

Choice of living donor versus cadaveric transplantation Candidate for renal tran splantation Willing to accept living donor? No Yes Willing and available ABO-compatible living related donor? No Yes Evaluate for cadaveric transplantation No Cross-match negative? Yes No Willing and available ABO-compatible emotionally related donor? Yes Proceed with evaluation

Evaluation of Prospective Donors and Recipients Preliminary evaluation for a living donor Economic risk acceptable? No No Volunt arism reasonably certain? Yes Yes Financial incentive? No Preliminary medical ev aluation No No Yes Psychosocial evaluation 12.13 Risk assessment for living donor No Age and renal function acceptable? Yes Surgical risk acceptable? Yes Long-term r isk acceptable? Yes Yes Consider alternative donor Yes HIV, hepatitis, or pregnancy test positive? N o No Risk acceptable? Yes Proceed with evaluation No No Screening for diabetes n egative? Yes Yes CMV titer positive or history of tuberculosis? Consider alterna tive donor No Risk acceptable? Yes Risk of recurrent disease? No Yes Risk of diabetes? No Proceed with evaluation FIGURE 12-32 Preliminary evaluation of a living prospective donor. The prospecti ve donor must be made aware of the possible costs associated with donation, incl uding travel to and from the transplantation center and time away from work. The prospective donor must undergo a psychological evaluation to ensure the donatio n is voluntary. A preliminary medical evaluation should assess the risks of tran smitting infectious diseases with the kidney, eg, infection with human immunodef iciency virus (HIV) and cytomegalovirus (CMV). (From Kasiske and coworkers [2]; with permission.) FIGURE 12-33 Assessing risks. Older age may place the living prospective donor a t greater surgical risk and may be associated with reduced graft survival for th e recipient. The prospective donor must be informed of both the short-term surgi cal risks (very low in the absence of cardiovascular disease and other risk fact ors) and the long-term consequences of having only one kidney. With regard to lo ng-term risks, it should be considered whether there is a familial disease that the living donor may be at risk to acquire and whether having only one kidney wo uld alter the natural history of renal disease progression. These questions are often most pertinent for relatives of patients with diabetes. (From Kasiske and coworkers [2]; with permission.) FIGURE 12-34 Donor age restrictions used by tra nsplantation centers. Results of an American Society of Transplantation survey o f the United Network for Organ Sharing centers showed that many centers either u se no specific age exclusion criteria or have no policy. Among those that use an upper age limit, there appears to be a bell-shaped curve, with 65 years of age at the median. (From Bia and coworkers [11]; with permission.) 30 27 22 Transplantation centers, % 20 15 13 13 10 6 3

0 No age exclusion 55 60 65 70 7580 Exclude if age in years is greater than: No policy or do not know

12.14 100 90 80 Transplantation as Treatment of End-Stage Renal Disease Progressive effect (each 10 y) (0.3) (1.4) (2.5) 90 88 Static effect (20.2) (17.1) (14.0) -20 Transplantation centers, % 70 61 -15 -10 -5 Glomerular filtration rate, mL/min (52) 0 5 60 50 40 30 20 10 0 Mildly elevated FBS Normal FBS but abnormal GTT Mild type II diabetes < 50y Mild type II diabetes < 30y (0.3) 46 Progressive effect (each 10 y) (76) (101) 0 25 50 Proteinuria, mg/d Static effect (2.4) 75 100 (5.1) Progressive effect (each 10 y) (0) (1.1) (2.2) 0 1.0 2.0 3.0 4.0 Systolic blood pressure, mm Hg 5.0 FIGURE 12-35 Screening living prospective donors for diabetes. Results of the su rvey of the United Network for Organ Sharing centers showed that most centers ex clude patients with a mildly elevated fasting blood sugar (FBS) and patients wit h normal FBS but an abnormal glucose tolerance test (GTT). Most centers exclude donors with mild type II diabetes. (From Bia and coworkers [11]; with permission .)

FIGURE 12-36 Long-term risks of kidney donation. In a meta-analysis combining 48 studies of the long-term effects of reduced renal mass in humans, no evidence w as found of a progressive decline in renal function after a 50% reduction in ren al mass. Indeed, a small but statistically significant increase occurred over ti me in the glomerular filtration rate. A small increase in urine protein excretio n occurred; however, the rate of increase per decade was less than that generall y considered an abnormal amount of protein excretion, eg, 150 mg/d. A small incr ease in systolic blood pressure was noted; however, it was not enough to lead to an increase in the incidence of hypertension. Thus, it appears that the long-te rm risks of kidney donation are very small. Shown are multiple linear regression coefficients and 95% confidence intervals. Failure of the confidence interval t o include zero indicates P < 0.05. (From Kasiske and coworkers [12]; with permis sion.) FIGURE 12-37 Blood pressure (BP) criteria for excluding living prospectiv e donors. Results of the survey of the United Network for Organ Sharing centers showed that most exclude prospective donors who require antihypertensive medicat ion or whose BP is persistently elevated over 130/80 mm Hg. However, most center s do not exclude living prospective donors who occasionally have BP readings ove r 130/80 mm Hg or patients with so-called white coat hypertension. (From Bia and coworkers [11]; with permission.) 70 64 60 54 50 Transplantation centers, % 40 30 20 20 12 10 0 Controlled on one BP medication Persistently 130/90 mm Hg Occasionally 130/ 90 mm Hg 130/90 mm Hg in doctor's office only 9 No policy or do not know

Evaluation of Prospective Donors and Recipients Evaluation of prospective donors with proteinuria, hypertension, or kidney stone s Proteinuria or pyuria? Yes Evaluation indicates low risk? No Consider alternat ive donor Yes Yes Normal renal imaging and low risk for ADPKD? No Yes Relative w ith hereditary nephritis? Yes No No Relative with ADPKD? Yes Evaluation of donor risks in recipients with familial renal diseases No 12.15 Hypertension? No Blood pressure high normal? Yes No Yes Male with No hematuria? No Female with acceptable low risk? Yes Male with no hematuria? No Yes No Risk acceptable? History of kidney stones Yes Evaluate No Proceed with evaluation Yes No Yes Isolated hematuria Proceed with evaluation Consider alternative donor No Evaluation indicates low risk? No Risk acceptable? Yes FIGURE 12-38 Proteinuria, hypertension, or kidney stones in living prospective d onors. Prospective donors with pyuria must be evaluated for possible infection a nd other reversible abnormalities. Proteinuria is generally a contraindication t o donation. Hypertension also must be considered at least a relative contraindic ation to donation. Patients with a history of nephrolithiasis but no current or recent stones may be considered for donation after first undergoing urologic and metabolic evaluations for stones. (From Kasiske and coworkers [2]; with permiss ion.) FIGURE 12-39 Risks to the related donor when the recipient has familial renal di sease. Donors for relatives with autosomal dominant polycystic kidney disease (A DPKD) may be permitted to donate if over 25 years old and results on renal imagi ng are negative for cysts. Some younger persons may be permitted to donate if ge netic studies indicate that the risk for subsequent ADPKD is very low. Male rela tives of individuals with hereditary nephritis can be donors if they do not have hematuria. Male relatives with hematuria cannot be donors. Female relatives wit hout hematuria may donate; however, women of child-bearing age who might be carr iers must consider the possibility of someday donating a kidney to a child of th eir own with the disease. Female relatives with hematuria should not donate when

other evidence of renal disease exists; however, in the absence of such evidenc e the exact risk of donation is unknown. Occasionally, donors with isolated micr ohematuria (not hereditary) and a negative evaluation may be suitable donors. (F rom Kasiske and coworkers [2]; with permission.) FIGURE 12-40 Final steps in eva luating a living prospective donor. Renal artery angiography is performed to def ine the anatomy of the renal artery system and exclude other previously undetect ed abnormalities. Recent studies have shown that spiral computerized tomography can replace angiography without loss of sensitivity or specificity and with less risk and inconvenience to the prospective donor. (From Kasiske and coworkers [2 ]; with permission.) Final evaluation of prospective living donors Donor-specific transfusion? No Yes Consider alternative donor No Cross-match negative? Yes Angiography results acce ptable? No Yes Schedule transplantation surgery

12.16 Transplantation as Treatment of End-Stage Renal Disease Use of Marginal Cadaveric Donor Kidneys 100 90 80 70 Graft survival, % 60 50 40 30 20 10 0 0 1 2 3 4 5 Years after transplantation Age 618 1930 3145 4660 >60 n 6652 7354 7532 6476 1928 t1 /2 10.9 11.7 9.8 6.9 5.2 FIGURE 12-41 Donor age. When there are no suitable living donors, recipients are placed on the cadaveric waiting list. The transplantation center must always de cide whether a particular cadaveric kidney being offered for transplantation is suitable for the individual recipient. The shortage of organs and long waiting t imes have caused many centers to accept kidneys from older donors and kidneys th at may be damaged. Data from the United Network for Organ Sharing clearly demons trate the decreased graft survival rates of kidneys from older donors. As a comp romise, some advocate using kidneys from older donors for older recipients. In a ny case, so-called marginal kidneys should be offered to recipients with appropr iate informed consent. (From Cecka [3]; with permission.) References 1. Kasiske BL, Ramos EL, Gaston RS, et al.: The evaluation of renal transplant c andidates: clinical practice guidelines. J Am Soc Nephrol 1995, 6:134. Kasiske BL , Ravenscraft M, Ramos EL, et al.: The evaluation of living renal transplant don ors: clinical practice guidelines. J Am Soc Nephrol 1996, 7:22882313. Cecka JM: T he UNOS Scientific Renal Transplant Registry. In Clinical Transplants 1996. Edit ed by Cecka JM, Terasaki PI. Los Angeles: UCLA Tissue Typing Laboratory, 1997:114 . Periera BJG, Wright TL, Schmid CH, Levey AS: The impact of pretransplantation hepatitis C infection on the outcome of renal transplantation. Transplantation 1 995, 60:799805. Manske CL, Wang Y, Rector T, et al.: Coronary revascularisation i n insulin-dependent diabetic patients with chronic renal failure. Lancet 1992, 3 40:9981002. Ramos EL, Kasiske BL, Alexander SR, et al.: The evaluation of candida tes for renal transplantation: the current practice of U.S. transplant centers. Transplantation 1994, 57:490497. Holley JL, Shapiro R, Lopatin WB, et al.: Obesit y as a risk factor following cadaveric renal transplantation. Transplantation 19 90, 49:387389. 8. 1996 Annual Report of the U.S. Scientific Registry for Transpla nt Recipients and the Organ Procurement and Transplantation Network Transplant Da ta: 19881995. UNOS, Richmond, VA, and the Division of Transplantation, Bureau of Health Resources Development, Health Resources and Services Administration, U.S. Department of Health and Human Services; 1996. 9. Gjertson DW: A multi-factor a nalysis of kidney graft outcomes at one and five years posttransplantation: 1996 UNOS Update. In Clinical Transplants 1996. Edited by Cecka JM, Terasaki PI. Los Angeles: UCLA Tissue Typing Laboratory. 1997: 343360. 10. Terasaki PI, Checka M, Gjertson DW, Takemoto S: High survival rates of kidney transplants from spousal and living unrelated donors. N Engl J Med 1995, 333:333336. 11. Bia MJ, Ramos EL , Danovitch GM, et al.: Evaluation of living renal donors. the current practice of US transplant centers. Transplantation 1995, 60:322327. 12. Kasiske BL, Ma JZ, Louis TA, Swan SK: Long-term effects of reduced renal mass in humans. Kidney In t 1995, 48:814819. 2. 3. 4. 5. 6.

7.

Medical Complications of Renal Transplantation Robert S. Gaston W ith long-term function of allografts increasingly the norm, detection and manage ment of medical complications assume greater importance in the care of renal tra nsplantation recipients. At least two trends in transplantation seem likely to m ake medical surveillance even more crucial. First, better control of adverse imm unologic events early after transplantation has significantly reduced graft loss caused by rejection; the impact of later events (especially death with a functi oning organ and chronic rejection) on graft and patient survival is proportionat ely larger. Second, with successful transplantation now fairly routine, it is be ing offered to a broader spectrum of candidates, including increasingly older pa tients with multiple coexisting medical problems. Because more patients with imm unosuppression are now being cared for over increasingly longer periods of time, the impact of comorbid events on outcomes must be reduced. Medical complication s in the renal allograft recipient represent the often overlapping impact of sev eral variables. At the time of transplantation, significant comorbidity may alre ady be present and can be of immediate concern. Other problems may have originat ed in the milieu of chronic renal failure, such as hyperparathyroid bone disease or hypertension, but may evolve differently after transplantation. Finally, new complications may result from specific toxicities of pharmaceutical agents, ref lecting the overall impact of immunosuppression. In many cases, all of these ele ments contribute to overt clinical illness. For instance, cardiovascular disease is now the most common cause of death in renal allograft recipients [1]. Corona ry disease may have predated transplantation (indeed, coronary disease is a comm on cause of death among all patients with end-stage renal disease). After transp lantation, hypertension and hyperlipidemia, perhaps exacerbated by administratio n of cyclosporine and corticosteroids, result in accelerated atherosclerosis, fu rther potentiating preexisting cardiac problems. To intervene appropriately requ ires a comprehensive understanding of all the variables involved: any decision t o lessen the impact of one risk factor (eg, withdrawing steroids) may result in unintended consequences (eg, acute rejection). CHAPTER 13

13.2 Transplantation as Treatment of End-Stage Renal Disease the calcineurin-inhibitor (either cyclosporine or tacrolimus) [2]. Therapeutic c onsiderations in treating patients on either of the calcineurin inhibitors are r emarkably similar in terms of both adverse effects and drug interactions (Figs. 13-1 and 13-2) [35]. Common azathioprine toxicities include bone marrow suppressi on and alopecia. Because azathioprine is metabolized by xanthine oxidase, concom itant use with allopurinol is problematic. MMF causes less bone marrow suppressi on than does azathioprine and does not interact with allopurinol, facilitating t herapy of gout. However, gastrointestinal complaints (usually dose-related nause a, bloating, or diarrhea) are common. In addition, MMF may exacerbate the gastro intestinal toxicity of tacrolimus. Corticosteroid toxicities are well described; protocols designed to minimize corticosteroid exposure of transplantation recip ients remain the ideal pursued by many physicians who treat these patients. FIGURE 13-1 Despite differing structures, both cyclosporine and tacrolimus bind to intracellular receptors in T cells, forming a combination that then inhibits calcineurindependent pathways of cell activation. Although slight differences ex ist in sideeffect profiles between the two drugs, their overall impact is remark ably similar. In many cases, dose reduction may ameliorate the toxic effect; how ever, the benefit of dose reduction must be weighed against increasing the risk of acute rejection in each patient. CyAcyclosporine; FKtacrolimus. An obvious prerequisite to caring for transplant recipients is a thorough unders tanding of immunosuppressive therapies [2]. Although acute rejection can occur a t any time, the greatest risk is during the first 90 days after transplantation. Accordingly, immunosuppression is most intense during this time, and the chance s of suffering its consequences are great (eg, drug toxicities, infection, and s ome malignancies [lymphoma]). In general, tapering to a less arduous regimen ove r time is done, with resulting reduction in the risks of toxicity and infection. With long-term survival, however, the duration rather than the intensity of imm unosuppression becomes more critical and strongly influences the risks of other complications, including malignancies (skin), bone disease, and atherosclerosis. Current maintenance immunosuppressive therapy involves multidrug regimens (incl uding azathioprine or mycophenolate mofetil [MMF] and corticosteroids) built aro und a cornerstone, ADVERSE EFFECTS OF CYCLOSPORINE AND TACROLIMUS Renal Hypertension Gastrointestinal Metabolic Glucose intolerance (FK > CyA) Hyperkalemia Hyperlipidemia (CyA > FK) Hyperurice mia Hypomagnesemia Cosmetic Neurologic Hepatotoxicity (abnormal transaminase levels) Nephrotoxicity (azotemia) Nausea, vomiting, diarrhea (FK > CyA) Gingival hypertrophy Headache (CyA only, especially Paresthesias in combination with Seizures calcium antagonists) Tremor Hirsutism (CyA > FK) COMMON DRUG INTERACTIONS WITH CYTOKINE INHIBITORS Drugs that commonly increase blood levels of cyclosporine and tacrolimus Bromocr yptine Cimetidine Clarithromycin Clotrimazole Diltiazem Erythromycin Fluconazole

Itraconazole Ketoconazole Mefredil Methylprednisolone Nicardipine Verapamil Dru gs that commonly decrease blood levels of cyclosporine and tacrolimus Carbamazep ine Phenobarbital Phenytoin Rifampin FIGURE 13-2 Cyclosporine and tacrolimus are subject to remarkably similar intera ctions, owing in part to a common pathway of metabolic degradation, the cytochro me P-450 enzyme system. Although the drugs listed here predictably alter blood l evels of the calcineurin inhibitors, other interactions may also occur.

Medical Complications of Renal Transplantation 13.3 1.0 0.8 Risk month 0.6 0.4 0.2 0.0 0 2 4 6 8 10 Months posttransplant 12 FIGURE 13-3 Risk of acute rejection in cadaver kidney transplantation. This grap h, derived from the parametric analysis techniques of Blackstone and coworkers [ 6], depicts the risk of acute rejection over time. Using an immunosuppressive pr otocol including cyclosporine, mycophenolate mofetil, and prednisone, the risk o f acute rejection is greatest during the first 2 months after transplantation, d iminishing significantly afterward. Because the risk of rejection is greatest, i mmunosuppressive therapy is most intense during this period. Correspondingly, co mplications related to immunosuppressive therapy (including infections and speci fic drug toxicities) also are most likely during this time. 1.0 Incidence rate 0.8 0.6 0.4 0.2 0 5 7.5 10 12.5 15 17.5 20 Tacrolimus level ( whole blood), ng/mL 22.5 25 Rejection Toxicity FIGURE 13-4 Relationship between blood levels of tacrolimus, immunosuppressive e fficacy, and toxicity [7]. As tacrolimus levels diminish, particularly during th e early period after transplantation, the risk of toxicity is reduced accordingl y. However, the risk of acute rejection increases. Toxicity still can occur at v ery low drug levels, as can rejection at high levels. The relationship between t hese variables beyond the first 6 to 12 months after transplantation is not well established. A similar plot could be constructed for cyclosporine. (Adapted fro m Kershner and Fitzsimmons [7].) Complications of Immunosuppression Malignancy Kaposi's (6%) Other (36%) Lymphomas (24%) FIGURE 13-5 Types and distribution of malignancies among renal transplant recipi ents in the current era of cyclosporine use. In these patients the risk of malig nancy is increased approximately fourfold when compared with the general populat ion [8]. Malignancies likely to be encountered in the transplantation recipient differ from those most common in the general population [9,10]. Lymphomas and Ka posi's sarcoma may evolve as a consequence of viral infections. Women are at an in creased risk for cervical carcinoma, again related to infection (human papilloma virus). Surprisingly, the solid tumors most commonly seen in the general popula tion (eg, of the breast, lung, colon, and prostate) do not occur with significan tly greater frequency among transplant recipients. Nonetheless, long-term care o f these patients should involve standard screening for these malignancies at app ropriate intervals. (From Penn [9]; with permission.) Skin and lip (34%)

13.4 Transplantation as Treatment of End-Stage Renal Disease FIGURE 13-6 Primary basal cell carcinoma. Cutaneous carcinomas (primarily basal cell and squamous cell) comprise the greatest percentage of tumors in transplant recipients. They tend to be most problematic in fair-skinned persons whose life style includes significant sun exposure; the risk increases with duration of imm unosuppression. In immunocompetent patients the risks of these lesions usually a re limited; however, in transplant recipients these lesions can be very aggressi ve and metastasize locally or even systemically. The best management is aggressi ve prevention: exposure to ultraviolet radiation from the sun should be minimize d through diligent use of protective clothing, hats, and sunscreen. When suspici ous lesions develop, early recognition and removal are of utmost importance. FIGURE 13-7 Posttransplantation lymphoproliferative disease (PTLD): histologic a ppearance of a renal allograft infiltrated by a monoclonal proliferation of B ly mphocytes. Non-Hodgkin's lymphomas, of which PTLD is a variant, occur in 1% to 3% of transplant recipients and in many cases are linked to an infectious cause. PT LD can be of either polyclonal or monoclonal B-cell composition, with lymphocyte s driven to proliferate by infection with the Epstein-Barr virus [1113]. Developm ent of PTLD is strongly linked to the intensity of immunosuppression and may reg ress with its reduction. However, most often in the setting of splanchnic involv ement and monoclonal proliferation, as depicted, PTLD can follow a more aggressi ve unrelenting course despite withdrawal of immunosuppressive therapy. Hematologic Complications 200 Serum erythropoietin level, U/L 1st peak 2nd peak 150 100 50 25 0 0 10 20 30 40 50 60 Days after transplantation 70 80 FIGURE 13-8 The course of normal erythropoiesis after renal transplantation show ing mean serum erythropoietin levels of 31 recipients [14]. An initial burst of erythropoietin (EPO) secretion at the time of engraftment does not result in ery thropoiesis. As excellent graft function is achieved, a second burst of EPO secr etion is normally followed by effective production of erythrocytes. The hatched area is the range of serum erythropoietin levels in normal persons without anemia. An emia is a common complication. Many patients leave the dialysis population with diminished iron stores and are unable to respond to erythropoietin produced by t he successful allograft. Iron replacement therapy successfully restores erythrop oiesis in these patients. Another common cause of anemia after transplantation i s bone marrow suppression owing to drug therapy with azathioprine or mycophenola te mofetil (MMF), an effect that is usually dose-related [15,16]. Other drugs, n otably angiotensin-converting enzyme inhibitors and angiotensin receptor antagon ists, may also inhibit erythropoiesis [17]. Neutropenia also is a common complic

ation after transplantation. It can reflect dose-related bone marrow suppression owing to drug therapy with azathioprine or MMF or an idiosyncratic response to a number of drugs commonly used in this population (acyclovir, ganciclovir, sulf a-trimethoprim, H2 blockers). Alternatively, neutropenia can be a manifestation of systemic viral, fungal, or tubercular infections. The approach to the patient with neutropenia usually involves reducing the dose or discontinuing the potent ial offending agents, along with a careful search for infections. In some settin gs of refractory neutropenia, administration of filgrastim (granulocyte colonyst imulating factor, Neupogen) reduces the duration and severity of neutropenia. (Fr om Sun and coworkers [14]; with permission.)

Medical Complications of Renal Transplantation 62 60 58 56 54 52 50 48 46 44 42 40 PRE 1 2 3 4 5 6 9 Months on enalapril (mean 74.5 mo) 12 15 13.5 FIGURE 13-9 Posttransplant erythrocytosis (PTE). PTE (a hematocrit of >0.52) aff ects 5% to 10% of renal transplantrecipients, most commonly male recipients with excellent allograft function [17]. PTE usually occurs during the first year aft er transplantation. Although it may resolve spontaneously in some patients, PTE persists in many. It has been linked to an increased risk of thromboembolic even ts; however, our own experience is that such events are uncommon. Previous manag ement involved serial phlebotomy to maintain the hematocrit at 0.55 or less (das hed line). More recently, hematocrit levels have been found to normalize in almo st all affected patients with a small daily dose of angiotensin-converting enzym e inhibitor (ACEI) or angiotensin II receptor antagonist. The pathogenetic mecha nisms underlying PTE and its response to these therapies remain poorly understoo d; although elevated serum erythropoietin levels decrease with ACEI use, other p athways also appear to be involved. Cardiovascular Complications Death rate per 1000 patient years 8 7 6 5 4 3 2 1 0 Malignancy Cardiac Infectiou s Stroke Cause of death in patients with functioning transplants Diabetic Nondiabetic Hematocrit, % FIGURE 13-10 Causes of death in renal allograft recipients. Cardiovascular disea ses are the most common cause of death, largely reflecting the high prevalence o f coronary artery disease in this population [1]. The risks are particularly hig h among recipients who have diabetes, as many as 50% of whom, even if asymptomat ic, may have significant coronary disease at the time of transplantation evaluat ion [18]. Effective management of cardiac disease after transplantation mandates documentation of preexisting disease in patients at greatest risk [19]. DEMOGRAPHIC VARIABLES HIGHLY PREDICTIVE OF CORONARY DISEASE IN RENAL TRANSPLANTA TION CANDIDATES WITH INSULIN-DEPENDENT DIABETES MELLITUS Age > 45 y Electrocardiographic abnormality: nonspecific ST-T wave changes Histo ry of cigarette smoking Duration of diabetes > 25 y FIGURE 13-11 Demographic variables highly predictive of coronary disease in rena l transplantation candidates with insulin-dependent diabetes mellitus. Most tran splant centers screen potential candidates, particularly persons with diabetes, for coronary disease before transplan tation. In patients with diabetes who have end-stage renal disease with none of the demographic characteristics listed, the risk for coronary disease is low. Co nversely, in patients who are insulin-dependent and have any of these risk facto rs, the prevalence of coronary disease is sufficiently high to justify angiograp hy. A randomized study of medical therapy versus revascularization in transplant ation candidates who have insulin-dependent diabetes and coronary disease showed superior outcomes with prophylactic revascularization, even in the absence of o vert symptomatology [20]. (Adapted from Manske and coworkers [18].)

13.6 75 Transplantation as Treatment of End-Stage Renal Disease FIGURE 13-12 Hypercholesterolemia and hypertriglyceridemia. Hypercholesterolemia and hypertriglyceridemia are common after kidney transplantation. Approximately two thirds of transplant recipients have low density lipoprotein (LDL) or total cholesterol levels signifying increased cardiac risk; 29% have elevated triglyc eride levels 2 years after transplantation (Kasiske, Unpublished data). Not only is hyperlipidemia a clear risk factor for coronary disease (see Figs. 13-13 and 13-14), but it may also contribute to the progressive graft dysfunction associa ted with chronic rejection [21,22]. HDLhigh density lipoprotein. (From Bristol-My ers Squibb [23]; with permission.) 50 n=591 n=429 60 45 30 15 0 100 200 300 400 Cholesterol, mg/dL 75 n=588 74% 40 30 20 10 0 70 130 190 250 310 LDL, mg/dL 40 n=430 63% , 60 45 30 15 0 100 200 300 400 Triglycerides, mg/dL 29% 32 24 16 8 0 0 35 50 65 80 95 HDL, mg/dL 10% , RISK FACTORS FOR CORONARY MORBIDITY IN RENAL ALLOGRAFT RECIPIENTS Positive Age: Male 45 y Female 55 y or premature menopause Family history of premature co ronary heart disease Smoking Hypertension HDL cholesterol < 35 mg/dL Diabetes me llitus GUIDELINES FOR LIPID-LOWERING THERAPY Diet therapy Negative HDL cholesterol 60 mg/dL LDL cholesterol, mg/dL No CHD and <2 risk factors No CHD and 2 risk factors CHD Initiation 160 130 100 Goal <160 <130 100 Diet plus drug therapy LDL cholesterol, mg/dL No CHD and <2 risk factors No CHD and 2 risk factors CHD Initiation 190 160 130

Goal <160 <130 100 FIGURE 13-13 Risk factors for coronary morbidity in renal allograft recipients. In addition to elevated low density lipoprotein (LDL) cholesterol levels, risk f actors known to contribute to coronary morbidity often are present in renal allo graft recipients. About 40% of recipients are over 45 years old, and 23% have di abetes. Smoking, hypertension, and hyperlipidemia are among the risk factors mos t amenable to long-term modification. (For guidelines in instituting lipid-lower ing therapy see Figure 13-14 [24].) FIGURE 13-14 The indications for lipid-lowering therapy and its goals are based on the clinical history, risk factor profile (see Fig. 13-13), and low density l ipoprotein (LDL) cholesterol level in individual patients. CHDcoronary heat disea se. (From Grundy [24]; with permission.)

Medical Complications of Renal Transplantation 13.7 Prograf CyA Lipid level, mg/dL 250 p<0.001 229.8 193.9 P<0.05 198.6 165.4 FIGURE 13-15 Cyclosporine (CyA) and corticosteroid therapies clearly contribute to hyperlipidemia in renal allograft recipients. Although dose reduction can red uce lipid levels, it may also increase the risk of acute rejection. As depicted, early experience in a large multicenter trial indicates that tacrolimus may hav e a less adverse impact on lipid metabolism than does cyclosporine [25]. (From F ujisawa USA [26]; with permission.) 125 0 Cholesterol Triglycerides

THERAPEUTIC OPTIONS IN LIPID-LOWERING THERAPY HDL cholesterol Cholesterol LDL cholesterol Triglycerides Control groups Diet HMG CoA inhibitors Fibrates Fish oil Probucol Niacin 111 -2814 -569 -3812 2343 -6621 -4828 16 -2115 -516 -369 -49 -1522 -5925 -4918 -6924 -86 -13.512 1010 CAUSES OF HYPERTENSION AFTER TRANSPLANTATION Intrinsic Delayed graft function Acute rejection Chronic rejection Cyclosporine nephropath y, chronic Recurrent primary renal disease (glomerulonephritis, hemolytic uremic syndrome, and so on) Extrinsic Native kidneys Immunosuppression: Cyclosporine Tacrolimus Corticosteroids Transp lantation renal artery stenosis Hypercalcemia mg/dL changes 95% CI. FIGURE 13-16 A recent meta-analysis of published trials in renal transplant reci pients demonstrated these benefits of the various treatments. Pharmacologic ther apy should be instituted at low doses with cautious surveillance for potential a dverse effects, especially liver dysfunction or rhabdomyolysis. These adverse ev ents may occur more frequently in transplant recipients owing to the effect of c yclosporine on drug disposition. Levels of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors are substantially higher in patients receiving b oth drugs [27]. HDLhigh density lipoprotein; LDLlow density lipoprotein. (Adapted from Massy and coworkers [27]; with permission.) FIGURE 13-17 In the current era of immunosuppressive therapy, hypertension affec ts roughly two thirds of transplant recipients. Unlike hypertension in the gener al population, posttransplant hypertension often reflects the impact of readily

definable (and potentially treatable) factors on systemic blood pressure [2830]. These may be grouped conveniently into those originating within the allograft (i ntrinsic) and those originating elsewhere (extrinsic).

13.8 Transplantation as Treatment of End-Stage Renal Disease Diagnosis and treatment of hypertension in the renal transplant recipient Blood pressure 140/90 Stable GFR? Yes Optimal blood levels of cyclosporine or tac rolimus? Yes ECF volume status acceptable? Yes Administer antihypertensive agent (CA, ACEI, or other) Adequate response to therapy? Yes Acceptable side effect p rofile? Yes Continue antihypertensive therapy Reassess periodically Yes Adequate response to therapy? No Re-evaluate allograft function and drug therapy Conside r TRAS Evaluate allograft function No Reduce dose of cyclosporine or tacrolimus Consider salt restriction and/or diuretic No No Intervention fails to normalize BP Multidrug regimen: add agents of different cl asses as necessary No FIGURE 13-18 Hypertension in the renal transplant recipient. In these patients i t may be possible to approach diagnosis and therapy in a fairly standardized fas hion. In transplant recipients with blood pressure readings consistently over 14 0/90 mm Hg, intervention is warranted. The initial approach includes assessment of allograft function, extracellular fluid volume (ECF) status, and immunosuppre ssive dosing. If these variables are stable, it is reasonable to proceed with an tihypertensive therapy. Calcium antagonists (CA) are effective agents and may of fer the added benefit of attenuating cyclosporineinduced changes in renal hemody namics. Verapamil, diltiazem, nicardipine, and mibefradil increase blood levels of cyclosporine and tacrolimus and should be used with caution. Common problems with CAs that may limit their use include cost, refractory edema, and gingival h yperplasia. Angiotensin antagonists (ACEIs and receptor antagonists) are also ef fective; their use requires close monitoring of renal function, serum potassium levels, and hematocrit levels. Diuretics frequently are useful adjuncts to thera py in recipients owing to the salt retention that often accompanies cyclosporine use. Other antihypertensive medications offer no particular benefits or drawbac ks and can be employed as needed. The rationale of multidrug therapy is to emplo y agents that block hypertensive responses via interruption of differing pathoge netic pathways. As antihypertensive drugs are added, this consideration should r emain paramount [31,32]. GFRglomerular filtration rate; TRAStransplanted renal art ery stenosis. FIGURE 13-19 Transplant renal artery stenosis (TRAS). TRAS accounts for less tha n 5% of cases of hypertension after transplantation. Nonetheless, TRAS should al ways be considered in patients with refractory hypertension who develop renal in sufficiency after addition of an ACEI to the therapeutic regimen. Although nonin vasive studies (such as a renal scan with captopril) may be helpful in diagnosin g TRAS, angiography remains the gold standard for diagnosis. Revascularization o f the allograft by either surgical or angioplastic techniques may improve renal function and ameliorate hypertension [33,34].

Medical Complications of Renal Transplantation 13.9 Gastrointestinal Complications GASTROINTESTINAL TRACT COMPLICATIONS IN RENAL TRANSPLANTATION RECIPIENTS Nausea and vomiting 4 30 20 12 Drug Cyclosporine Tacrolimus MMF Azathioprine Diarrhea 3 32 31 Rare Other complications Hepatotoxicity, constipation Hepatotoxicity, constipation Constipation, dyspepsi a Hepatotoxicity, pancreatitis FIGURE 13-20 Complications affecting the gastrointestinal (GI) tract remain rela tively common in transplant recipients. Both tacrolimus and mycophenolate mofeti l (MMF) cause bloating, nausea, vomiting, and diarrhea in a dose-dependent manne r, particularly when used in combination [15,16,25]. Some authors have noted tha t this rather nonspecific GI toxicity occurs more commonly with Neoral than with Sandimmune (both from Sandoz Pharmaceuticals, East Hanover, NJ). A B FIGURE 13-21 (See Color Plate) Endoscopic image of candida esophagitis with diff use white exudate (panel A) and colitis induced by cytomegalovirus infection wit h submucosal hemorrhage, ulcers, and diffuse mucosal edema (panel B). The availa bility and common use of effective prophylaxis against acid-peptic disease (eg, H2 blockers, omeprazole, and antacids) have significantly reduced the frequency of upper gastrointestinal bleeding. However, infectious agents such as cytomegal ovirus and candida continue to be problematic, particularly in the setting of th e more intense immunosuppression afforded by drugs such as mycophenolate mofetil (MMF) and tacrolimus. FIGURE 13-22 Histologic image of chronic active hepatitis secondary to infection with the hepatitis C virus (HCV). Note the periportal distribution of the lymph ocytic infiltrate. Recent identification of HCV has caused intense reevaluation of the causes, frequency, and natural history of liver disease in renal allograf t recipients. As the percentage of patients with end-stage renal disease who are infected with the hepatitis B virus has diminished, HCV has become the most pro blematic cause of liver disease. In recipients with HCV antibodies, immunosuppre ssive therapy may potentiate liver injury from the virus and accelerate the cour se of time over which cirrhosis develops. Nonetheless, in patients who desire tr ansplantation and have wellpreserved liver function, little evidence exists of b etter longevity on dialysis. HCV can be transmitted easily from donor to recipie nt in solid organ transplantation. Because kidney transplantation is not a lifesaving procedure, most transplant centers choose not to use kidneys from donors who are infected with HCV. Previously, liver disease was thought to be a common cause of death in renal allograft recipients. As blood transfusions have become less common in the dialysis population and hepatitis B virus less prevalent, the risk of death owing to hepatic disease seems to have diminished. Unfortunately, therapies for HCV-related hepatitis (interferon- ) have proved to be of questio nable efficacy and may stimulate rejection of the renal allograft [3537].

13.10 Transplantation as Treatment of End-Stage Renal Disease Musculoskeletal and Metabolic Complications 0 Change in density, % 3 * Males Females Both genders 6 9 12 * * * * * 18 0 6 Months after transplantation FIGURE 13-23 Mean percentage changes in bone mineral density of the lumbar spine after transplantation. Substantial bone loss can occur quite early after transp lantation. Metabolic bone disease in this setting is usually multifactorial. Mos t often, patients who had end-stage renal disease before transplantation already have some degree of renal osteodystrophy, exacerbated in some cases by the impa ct of aluminum toxicity or 2-microglobulin amyloidosis. Patients with diabetes a re particularly at risk for low-turnover bone disease. Administration of cortico steroids and cyclosporine also contributes to bone loss. Although biochemical ev idence of secondary hyperparathyroidism usually resolves during the first year a fter transplantation, some patients may have persistent parathyroid-driven bone resorption, with or without hypercalcemia, and may require surgical parathyroide ctomy. Asterisk values significantly different from those at the time of transpla ntation. (From Julian and coworkers [38]; with permission.) FIGURE 13-24 Bone densitometry. Bone densitometry offers a noninvasive method to quantitate bone mass. Here, a renal transplant recipient demonstrates marked os teoporosis, with bone density greater than 2 standard deviations below age- and gender-matched controls. In recent years, new therapeutic options (including bis phosphonates, estrogens, and thiazides) have offered hope of preserving or even increasing bone mass [38,39]. BMDbone mass density. FIGURE 13-25 Magnetic resonance imaging of osteonecrosis. Osteonecrosis most com monly affects the femoral head but can affect any weightbearing bone. The most d ebilitating complication of renal transplantation, its incidence seems to be dec reasing (<10% of transplant recipients). This decrease reflects better managemen t of calcium and bone homeostasis during long-term dialysis and less intense ste roid use after transplantation. The pathogenesis of osteonecrosis remains poorly understood, and therapeutic options are limited (pain management while awaiting progression to the need for joint replacement). Magnetic resonance imaging is a sensitive diagnostic method, allowing detection of osteonecrosis at a very earl y stage [39]. FIGURE 13-26 Photograph of gouty inflammation of joints (tophus). Gout is the cl inical manifestation of hyperuricemia. After transplantation, cyclosporine can e xacerbate hyperuricemia, and severe gout can be problematic even in the presence of chronic immunosuppression. Management of gouty arthritis usually involves so me combination of colchicine and judicious use of short courses of nonsteroidal anti-inflammatory drugs. Concomitant administration of allopurinol and azathiopr ine can cause profound bone marrow suppression and is avoided by most physicians who treat transplant recipients. Because the metabolism of mycophenolate mofeti l (MMF) is not dependent on xanthine oxidase, use of allopurinol in patients tre ated with MMF is relatively safe [39,40].

Medical Complications of Renal Transplantation 13.11 INCIDENCE OF POST-TRANSPLANT DIABETES MELLITUS PTDM (defined as requiring insulin 30 d) Prograf * (n=151) % n Initial At 1 year At 18 mo 30 25 18 15.9 18.5 12.0 CyA (n=151) % n 8 5 0 4.0 3.3 3.3 P value >0.001 >0.001 *Patients without history of diabetes. FIGURE 13-27 Photograph of gingival hyperplasia. Gingival hyperplasia occurs in approximately 10% of transplant recipients treated with cyclosporine. Its severi ty reflects the interaction of effective dental hygiene, cyclosporine dose, and concomitant administration of calcium antagonists (particularly dihydropyridines ). This complication does not seem to occur with use of tacrolimus, and complete resolution of gingival hyperplasia has been noted with conversion from cyclospo rine-based therapy [25,41]. FIGURE 13-28 Post-transplantation diabetes mellitus (PTDM). PTDM complicates the course of treatment in 5% to 10% of patients on cyclosporinebased immunosuppres sive therapy. It is more common in blacks and in patients with a family history of glucose intolerance. PTDM often reflects the substantial steroid-related weig ht gain that sometimes occurs after transplantation. The severity of PTDM can be attenuated by weight loss and corticosteroid withdrawal, although the latter ma y not be advisable owing to the risk of rejection. In a multicenter trial, PTDM occurred with greater frequency among patients treated with tacrolimus, particul arly blacks. Although PTDM resolved over time in almost half of affected patient s (as doses of tacrolimus and corticosteroids were gradually reduced), PTDM rema ined more common in patients receiving tacrolimus [25,42,43]. CyAcyclosporine. (F rom Fujisawa USA [26]; with permission.) Acknowledgments The author thanks his colleagues at the University of Alabama at Birmingham for contributing many of the illustrations used in this chapter: Drs. Ralph Crowe, B ruce Julian, Catherine Listinsky, Brendan McGuire, Klaus Monckemuller and Collee n Shimazu. References 1. 2. United States Renal Data System: 1996 Annual Data Report. Bethesda, MD: Th e National Institutes of Health; 1996. Suthanthiran M, Morris RE, Strom TB: Immu nosuppressants: cellular and molecular mechanisms of action. Am J Kidney Dis 199 6, 28:159172. Venkataramanan R, Swaminathan A, Prasad T, et al.: Clinical pharmac okinetics of tacrolimus. Clin Pharmacokinet 1995, 29:404430. Borel JF, Baumann G, Chapman I, et al.: In vivo pharmacological effects of cyclosporin and some anal ogues. Adv Pharmacol 1996, 35:115246. Campana C, Regazzi MB, Buggia I, Molinaro M : Clinically significant drug interactions with cyclosporin. An update. Clin Pha rmacokinet 1996, 30:141179. 6. Blackstone EH, Naftel DC, Turner ME: The decompens ation of time varying hazard into phases, each incorporating a separate stream o f concomitant information. J Am Stat Assoc 1986, 81:615. 7. Kershner RP, Fitzsim mons WE: Relationship of FK506 whole blood concentrations and efficacy and toxic ity after liver and kidney transplantation. Transplantation 1996, 62:920926. 8. G aya SBM, Rees AJ, Lechler RI, et al.: Malignant disease in patients with long-te rm renal transplantations. Transplantation 1995, 59:17051709. 9. Penn I: Cancers in cyclosporine-treated versus azathioprine-treated patients. Transplantation Pr

oc 1996, 28:876878. 10. Penn I: Occurrence of cancers in immunosuppressed organ t ransplantation recipients. In Clinical Transplantations 1994. Edited by Terasaki PI, Cecka JM, Los Angeles: UCLA Tissue Typing Laboratory; 1995, 99109. 3. 4. 5.

13.12 Transplantation as Treatment of End-Stage Renal Disease 27. Massy ZA, Ma JZ, Louis TA, Kasiske BL: Lipid-lowering therapy in patients wi th renal disease. Kidney Int 1995, 48:188198. 28. Luke RG. Hypertension in renal transplantation recipients. Kidney Int 1987, 31:10241037. 29. Chapman JR, Marcen R, Arias M, et al.: Hypertension after renal transplantation. A comparison of cy closporine and conventional immunosuppression. Transplantation 1987, 43:860864. 3 0. Curtis JJ: Hypertension following kidney transplantation. Am J Kidney Dis 199 4, 23:471475. 31. Gaston RS, Curtis JJ: Hypertension in renal transplant recipien ts. In Therapy in Nephrology and Hypertension. Edited by Brady HR, Wilcox CS. Ph iladelphia: W.B. Saunders Co; 1999:440443. 32. Curtis JJ, Luke RG, Jones P: Hyper tension in cyclosporine-treated renal transplantation recipients is sodium-depen dent. Am J Med 1988, 85:134138. 33. Curtis JJ, Luke RG, Whelchel JD, et al.: Inhi bition of angiotensinconverting enzyme in renal transplantation recipients with hypertension. N Engl J Med 1983, 308:377381. 34. Hricik DE, Browning PJ, Kopelman R, et al.: Captopril-induced functional renal insufficiency in patients with bi lateral renal-artery stenoses or renal-artery stenosis in a solitary kidney. N E ngl J Med 1983, 308:373376. 35. Vosnides GG: Hepatitis C in renal transplantation . Kidney Int 1997, 52:843861. 36. Pereira BJG, Levey AS: Hepatitis C virus infect ion in dialysis and renal transplantation. Kidney Int 1997, 51:981999. 37. Knoll GA, Tankersley MR, Lee J, et al.: The impact of renal transplantation on surviva l in hepatitis C-positive ESRD patients. Am J Kidney Dis 1997, 29:608614. 38. Jul ian BA, Laskow DA, Dubovsky J, et al.: Rapid loss of vertebral mineral density a fter renal transplantation. N Engl J Med 1991, 325:544550. 39. Julian BA, Quarles LD, Niemann KMW: Musculoskeletal complications after renal transplantation: pat hogenesis and treatment. Am J Kidney Dis 1992, 19:99120. 40. Lin HY, Rocher LL, M cQuillan MA, et al.: Cyclosporine-induced hyperuricemia and gout. N Engl J Med 1 989, 321:287292. 41. Noble S, Markham A: Cyclosporin: a review of the pharmacokin etic properties, clinical efficacy and tolerability of a microlesion-based formu lation (Neoral). Drugs 1995, 50:924941. 42. Jindal RM: Posttransplantation diabet es mellitus: a review. Transplantation 1994, 58:12891298. 43. Hricik DE, Mayes JT , Schulak JA: Independent effects of cyclosporine and prednisone on posttranspla ntation hypercholesterolemia. Am J Kidney Dis 1991, 18:353358. 11. Randhawa PS, Jaffe R, Demetris AJ, et al.: Expression of Epstein-Barr virusen coded small RNA (by the EBER-1 gene) in liver specimens from transplantation rec ipients with post-transplantation lymphoproliferative disease. N Engl J Med 1992 , 327:17101714. 12. Cockfield SM, Preiksaitis JK, Jewell LD, Parfrey NA: Post-tra nsplantation lymphoproliferative disorder in renal allograft recipients. Transpl antation 1993, 56:8896. 13. Young L, Alfieri C, Hennessy K, et al.: Expression of Epstein-Barr virus transformation-associated genes in tissues of patients with EBV lymphoproliferative disease. N Engl J Med 1989, 321:10801085. 14. Sun CH, War d HJ, Wellington LP, et al.: Serum erythropoietin levels after renal transplanta tion. N Engl J Med 1989, 321:151157. 15. Tricontinental Mycophenolate Mofetil Ren al Transplantation Study Group: A blinded, randomized clinical trial of mycophen olate mofetil for the prevention of acute rejection in cadaveric renal transplan tation. Transplantation 1996, 61:10291037. 16. Sollinger HW, US Renal Transplanta tion Mycophenolate Mofetil Study Group: Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. Transplanta tion 1995, 60:225232. 17. Gaston RS, Julian BA, Curtis JJ: Posttransplantation er ythrocytosis: an enigma revisited. Am J Kidney Dis 1994, 24:111. 18. Manske CL, W ilson RF, Wang Y, Thomas W: Atherosclerotic vascular complications in diabetic t ransplantation candidates. Am J Kidney Dis 1997, 29:601607. 19. Manske CL, Thomas W, Wang Y, Wilson RF: Screening diabetic transplantation candidates for coronar y artery disease: identification of a low risk subgroup. Kidney Int 1993, 44:6176 21. 20. Manske C, Wang Y, Wilson RF, et al.: Coronary revascularization in insul in dependent diabetic patients with chronic renal failure. Lancet 1992, 340:99810 02. 21. Kasiske BL: Risk factors for accelerated atherosclerosis in renal transp lantation recipients. Am J Med 1988, 84:987992. 22. Massy ZA, Guijarro C, Wiederk

ehr MR, et al.: Chronic renal allograft rejection: immunologic and nonimmunologi c risk factors. Kidney Int 1996, 49:518524. 23. Bristol-Myers Squibb: Hyperlipide mia and atherosclerosis in organ transplantation: can we alter the natural histo ry? Princeton: BristolMyers Squibb. 24. Grundy SM for the National Cholesterol E ducation Program: Second report of the Expert Panel on Detection, Evaluation, an d Treatment of High Blood Cholesterol in Adults. Circulation 1994, 89:13291445. 2 5. Pirsch JD, Miller J, Deierhoi MH, et al.: A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. Tr ansplantation 1997, 63:977983. 26. Fujisawa USA, Inc.: Comparative trial of Progr af-based therapy vs. cyclosporine-based therapy after cadaveric renal transplanta tion. Deerfield, IL: Fujisawa USA, Inc.

Technical Aspects of Renal Transplantation John M. Barry R enal transplantation is the preferred treatment method of endstage renal disease (ESRD). It is more cost-effective than is maintenance dialysis [1] and usually provides the patient with a better quality of life [2]. Adjusted mortality risk ratios indicate a significant reduction in mortality for kidney transplantation recipients when compared with that for patients receiving dialysis and patients receiving dialysis who are on a waiting list for renal transplantation (Fig. 141) [3]. The indication for renal transplantation is irreversible renal failure t hat requires or will soon require long-term dialytic therapy. The evaluation of candidates for renal transplantation is discussed in Chapter 12. Generally accep ted contraindications are noncompliance, active malignancy, active infection, hi gh probability of operative mortality, and unsuitable anatomy for technical succ ess [4]. The technical aspects of kidney transplantation are discussed, primaril y through the illustrations of kidney preparation and of a living donor renal tr ansplantation. Kidneys from living donors require little preparation by the tran splantation team because most of the dissection has already been done during the nephrectomy. Further separation of the renal artery or arteries from the renal vein(s) will allow separation of the arterial and venous suture lines in the rec ipient and will prevent the technical inconvenience of side-by-side anastomoses. The right kidney from a living donor usually has a cuff of the inferior vena ca va attached to the renal vein. This provides the recipient team with maximum ren al vein length and a wide lumen for anastomosis. The renal arteries in a kidney graft from a living donor are not attached to aortic patches as they usually are in the cadaveric kidney. The technical aspects of livingdonor harvesting are no t illustrated here. CHAPTER 14

14.2 Transplantation as Treatment of End-Stage Renal Disease ADJUSTED MORTALITY RISK RATIOS FOR END-STAGE RENAL DISEASE BY TREATMENT MODALITY Treatment modality All patients on dialysis Patients on dialysis who are on a waiting list Cadaveri c kidney transplantation recipients Living-donor related kidney transplantation recipients TECHNICAL CONSIDERATIONS FOR RECIPIENTS OF KIDNEY TRANSPLANTATION Kidney graft Right or left Gross appearance and size Arterial anatomy Venous anatomy Ureteral anatomy Risk ratio 1.0 0.48 0.32 0.21 Recipient Abdominal wall anatomy Size Arterial anatomy Venous anatomy Urinary tract anatom y and function Gender Data from US Renal Data System [3]. FIGURE 14-1 The adjusted mortality risk ratio for patients on dialysis placed on the renal transplantation waiting list is greater than that for kidney transpla ntation recipients, suggesting transplantation itself results in a reduced morta lity risk for patients with end-stage renal disease who are treated [3]. FIGURE 14-2 A number of factors concerning the kidney graft and recipient determ ine the technique of renal transplantation in each recipient. Placement of the k idney graft in the contralateral iliac fossa is preferable because the renal pel vis becomes the most medial of the vital renal structures and thus readily avail able for future reconstruction if ureteral stenosis occurs. Areas of previous ab dominal surgery such as ileostomy, colostomy, renal transplantation, or a perito neal dialysis exit site are avoided, if possible. A kidney too large for the rec ipient's iliac fossa is usually placed in the right retroperitoneal space and reva scularized with the aorta or common iliac artery and interior vena cava or commo n iliac vein. Pelvic vascular disease and previous renal transplantation determi ne whether the aorta or internal iliac, external iliac, common iliac, native ren al or splenic artery will be selected for renal artery anastomosis. The use of b oth internal iliac arteries in serial renal transplantations in men is avoided t o prevent impotence [5]. The method of urinary tract reconstruction depends prim arily on the status of the recipient's bladder, continent reservoir, or incontinen t intestinal conduit. Cadaveric Kidney Graft FIGURE 14-3 Instrument setup for cadaveric kidney graft preparation. The towel p revents renal movement during dissection.

Technical Aspects of Renal Transplantation FIGURE 14-4 Preparation of a left cadaveric kidney graft. The kidney and its vit al structures are surrounded by other tissues. The cadaveric kidney graft can re quire an hour of preparation time because the specimen usually includes a portio n of the inferior vena cava, an aortic cuff, the adrenal gland, variable amounts of perinephric tissue, sometimes pieces of muscle, and occasionally damaged ren al vessels. 14.3 FIGURE 14-5 Renal vein dissection. The adrenal and gonadal veins have been isola ted. They will be divided between ligatures. FIGURE 14-6 Renal artery dissection. In this posterior view, the aortic patch an d main renal artery have been separated from the surrounding tissues. FIGURE 14-7 Left cadaver kidney graft after preparation. The adrenal gland and e xcess perinephric tissue have been removed. Fibrofatty tissue is left around the renal pelvis and ureter to ensure blood supply to the ureter. The aortic patch, renal vein, and ureter will be further modified to provide a best fit in the reci pient.

14.4 Transplantation as Treatment of End-Stage Renal Disease Preparation of Kidney Graft Vessels FIGURE 14-8 Venoplasties for right renal vein extension of a cadaveric kidney gr aft [68]. AC, Use being made of the inferior vena cava. D,Use being made of the ex ternal iliac vein of the cadaveric donor. A FIGURE 14-9 Preparation of the renal allograft with multiple renal arteries [9]. A and B, The use of aortic patches when the kidney is from a cadaveric donor is demonstrated. C and D, The possibil ities that exist when an aortic patch is not part of the specimen, such as when the kidney is from a living donor. E, The segmental renal artery also can be ana stomosed to the inferior epigastric artery using an endto-end technique. A B or C B D C E D The Kidney Transplantation Operation DIVISION OF OPERATING ROOM RESPONSIBILITIES FOR RECIPIENTS OF KIDNEY TRANSPLANTA TION Anesthesiologist Anesthetic induction Placement of central venous access line Administration of a ntibiotics Administration of immunosuppressants Administration of heparin Assura nce of conditions for diuresis Surgeon Patient position Bladder catheterization Initial skin preparation Incision and e xposure of operative site Renal revascularization Urinary tract reconstruction W ound closure FIGURE 14-10 After the induction of anesthesia, the anesthesia team places a dou ble- or triple-lumen central venous access catheter, usually via the internal ju gular vein. While that is taking place, the surgical team places a retention cat heter (usually 20F with a 5-mL balloon), fills the bladder to 30 cm H2 pressure or 250 mL (whichever occurs first), connects the catheter to a three-way system or clamped urinary drainage system, and places the clamp(s) within reach of the anesthesiologist for control during the operation. The preoperative antibiotic i s administered by the anesthesia team. The surgical team shaves both sides of th e patient's abdomen from just above the umbilicus to the distal edge of the mons p ubis. The skin is wiped with alcohol, and the nursing team completes the skin pr eparation. The skin over both iliac fossae is prepared in the event an unexpecte d vascular contraindication is detected on the chosen side. If immunosuppressant therapy has not been administered, the anesthesia team begins that protocol.

Technical Aspects of Renal Transplantation 14.5 Adult Recipient FIGURE 14-11 Surgeon's view of the right iliac fossa operative site. In this proce dure, a 40-year-old man will be receiving his brother's left kidney, which has a s ingle artery, single vein, and single ureter. The renal vessels will be anastomo sed to his right external iliac artery and vein, and urinary tract reconstructio n will be by extravesical ureteroneocystostomy [10,11]. The patient is positione d with the head slightly down, supine, and rotated toward the surgeon, who is st anding on the patient's left side. FIGURE 14-12 (see Color Plate) Exposure of the right iliac fossa. The contents o f the iliac fossa are exposed by incising the skin, subcutaneous tissues, anteri or rectus sheath, external and internal oblique muscles, and the transversalis m uscle and fascia. The inferior epigastric artery is divided between ligatures, t he spermatic cord is preserved (in women, the round ligament is divided between ligatures), and the rectus muscle and peritoneum are retracted medially. This ex poses the genitofemoral nerve (white umbilical tape), the external iliac vein (b lue tape), and the external and internal iliac arteries (red tapes). FIGURE 14-13 Determining best fit. The kidney graft is placed in the wound and the renal vessels stretched to the recipient vessels to determine the best sites fo r the arterial and venous anastomoses. FIGURE 14-14 Isolation of the arteriotomy site. Heparin (3050 U/kg) is administer ed intravenously, and vascular clamps are placed on the external iliac artery. T he distal clamp is applied first so that the arterial pressure will distend the targeted artery. The external iliac artery is incised longitudinally, the lumen is irrigated with heparinized saline, and fine monofilament vascular sutures are placed in four quadrants to receive the spatulated renal artery. When the recip ient artery has significant arteriosclerosis, an endarterectomy can be done or a 5- or 6-mm aortic punch can be used to create a smooth round arteriotomy.

14.6 Transplantation as Treatment of End-Stage Renal Disease FIGURE 14-15 Completed end-to-side renal arterytoexternal iliac artery anastomosis . Many surgeons perform the arterial anastomosis first because it is smaller tha n is the venous anastomosis. Thus, the kidney can be moved about more easily to expose the arterial anastomosis when it is not tethered by a previously complete d venous anastomosis. An ice-cold electrolyte solution is periodically dripped o nto the kidney graft to keep it cold during vascular reconstruction. FIGURE 14-16 Isolation of the right external iliac vein. The kidney is retracted medially, and a segment of the external iliac vein is isolated between Rumel to urniquets. The cephalad tourniquet is applied first so that increased venous pre ssure will dilate the vein. FIGURE 14-17 Renal vein anastomotic setup. The renal vein is anastomosed to the side of the external iliac vein with the same suture technique that was used for the arterial anastomosis. FIGURE 14-18 Completed venous and arterial anastomoses.

Technical Aspects of Renal Transplantation 14.7 FIGURE 14-19 Revascularized kidney transplantation. The usual clamp release sequ ence is as follows: proximal vein, distal artery, proximal artery, and distal ve in. Arterial spasm is treated by subadventitial injection of papaverine. FIGURE 14-20 Urinary tract reconstruction [1011]. Unstented parallel incision ext ravesical ureteroneocystostomy requires a bladder full of antibiotic solution, c learance of fat from the superolateral surface of the bladder, and placement of the ureter under the spermatic cord to prevent ureteral obstruction. Parallel in cisions are made 2 cm apart in the seromuscular layer of the bladder to expose t he bladder mucosa. FIGURE 14-21 Submucosal tunnel creation. A right-angle clamp is used to develop the tunnel and to pull the transplantation ureter through it. FIGURE 14-22 Bladder mucosa incision. After the ureter is spatulated on its vent ral surface, single-armed 5-0 absorbable sutures are placed in the heel and in eac h of the dog-ears of the ureter. A double-armed horizontal mattress suture of the same material is placed in the toe of the ureter so that the needles exit on the m ucosal side. The bladder is drained by unclamping the catheter tubing, and the b ladder mucosa is incised.

14.8 Transplantation as Treatment of End-Stage Renal Disease FIGURE 14-23 Partially completed ureteral anastomosis. The heel and dog-ears of the spatulated ureter have been sutured to the bladder mucosa. The horizontal mattre ss suture will be passed through the full thickness of the bladder wall and tied distal to the seromuscular incision. This will close the toe and anchor the urete r to the bladder. FIGURE 14-24 Completed ureteroneocystostomy. The distal seromuscular incision ha s been closed over the ureter, which now lies in a submucosal tunnel. FIGURE 14-25 Deep wound closure. A suction drain has been placed around the kidn ey graft deep in the wound, and the musculofascial interrupted sutures are ready to be tied. FIGURE 14-26 Completed wound closure. Scarpa's fascia has been closed over the mus culofascial sutures, and the skin has been closed with a 4-0 absorbable subcutic ular suture. This procedure accurately approximates the skin and eliminates subs equent staple or skin suture removal.

Technical Aspects of Renal Transplantation 14.9 DIURESIS ENHANCEMENT IN KIDNEY TRANSPLANTATION Living-donor kidney transplantation Maintain CVP 510 cm H2O Maintain MAP 60 mm Hg Maintain SBP 90 mm Hg Mannitol, 0.2 0 g/kg, IV over 1 h, start with first vascular anastomosis Furosemide, 0.20 mg/k g, IV during second half of second vascular anastomosis Cadaveric kidney transplantation Same Same Same Increase mannitol dose to 1 g/kg (maximum 50 g) IV Increase furos emide dose to 1 mg/kg IV Albumin, 1 g/kg (to 50 g), IV over 23 h Verapamil, 010 mg , into renal artery based on blood pressure and weight FIGURE 14-27 Artist's depiction of the completed kidney transplantation. CVPcentral venous pressure; IVintravenous; MAPmean arterial pressure; SBPsystemic bl ood pressure. Modified from Dawidson and Ar'Raja [12]. FIGURE 14-28 Maneuvers for diuresis enhancement [12]. Several intraoperative man euvers can be used to promote diuresis. Child Recipient FIGURE 14-29 Transplantation of a kidney from an adult into a small child. The t echnique is modified for transplantation of a large kidney into a small recipien t. The renal artery is anastomosed to the distal aorta or common iliac artery, a nd the shortened renal vein is anastomosed to the interior vena cava or common i liac vein.

14.10 Transplantation as Treatment of End-Stage Renal Disease Postoperative Care POSTOPERATIVE CARE DURING HOSPITALIZATION AFTER KIDNEY TRANSPLANTATION Remove on 5th postoperative day, administer dose of antibiotic Remove 612 wk post operatively in clinic Remove when 30 mL/24 h or in 3 wk if volume > 30 mL/24 h D iscontinue in 2448 h (check intraoperative culture results first) Patient-control led analgesia Living donor: fixed rate of 125200 mL/h of D5W in 0.45% normal sali ne Cadaveric donor: replace insensible loss with D5W, replace urine output mL fo r mL with 0.45% normal saline Immunosuppressants Protocol (covered in Chapter 11 ) Protocol (covered in Chapter 10) Infection prevention Peptic ulcer prevention Protocol (covered in Chapter 12) Foley catheter Ureteral stent, if used Suction drain(s) Antibiotics Pain control Intravenous fluids FIGURE 14-30 Postoperative clinical pathway. IVintravenous. Urologic Complications Evaluation of kidney transplantation hydronephrosis Hydronephrosis Radioisotope venogram + furosemide wash-out T1/2 < 1020 min T1/2 1020 min Percutaneous nephrostomy Nephrostogram T1/2 > 1020 min Percutaneous nephrostomy Nephrostogram FIGURE 14-31 Algorithm for evaluation of kidney transplantation hydronephrosis [ 9]. The generally accepted criterion for exclusion of upper urinary tract obstru ction is a washing out of half of the radioisotope from the renal pelvis in less than 10 minutes. Obstruction is considered to be present when this value is ove r 20 minutes. Percutaneous nephrostomy allows anatomic definition of the obstruc tion and temporary drainage of the hydronephrotic kidney. A generally accepted c riterion for the diagnosis of obstruction with the percutaneous pressure-flow Wh itaker test is fluid infusion into the pelvis at the rate of 10 mL/min, resultin g in a renal pelvic pressure over 20 cm H2O. Nephrostomy drainage plus serial serum creatinine levels No or Whitaker test Obstruction ? Yes No repair Repair

Technical Aspects of Renal Transplantation 14.11 CAUSES OF KIDNEY TRANSPLANTATION URETERAL OBSTRUCTION Cause Blood clot Edema Technical error Lymphocele Ischemia Periureteral fibrosis Stone Tumor FIGURE 14-32 Causes of renal transplantation ureteral obstruction. Hydronephrosi s owing to ureteral obstruction is one of the two most common urologic complicat ions for which invasive therapy is required, the other being perigraft fluid col lection. Early causes of ureteral obstruction are usually apparent within the fi rst few days after renal transplantation. Late causes become apparent weeks to y ears later. Late Early X X X X X X X X X Evaluation of treatment of perigraft fluid collection Perigraft fluid collection > 50 mL ? Hydronephrosis ? Decreased renal function ? Ipsilateral leg swelling ? Fever ? Pain ? "No" to all "Yes" to any Aspirate Serum Lymph Urine Blood Pus Repeat ultrasound No Significant recurrence ? Yes FIGURE 14-33 Algorithm for evaluation and treatment of perigraft fluid collectio n [9]. Perigraft fluid collection is one of the two most common urologic complic ations for which invasive therapy is required, the other being hydronephrosis ow ing to ureteral obstruction. Serum, urine, lymphatic fluid, blood, and pus can b e differentiated by creatinine and hematocrit determinations and by microscopic examination of the fluid. Urine has a high creatinine level, serum and lymphatic fluid have low creatinine levels, and blood has a relatively high hematocrit le vel. Lymphocytes are present in lymphatic fluid, and polymorphonuclear leukocyte s with or without organisms are present in pus. Open surgical drainage is usuall y necessary for fluid collections showing infection. Significant lymphoceles hav e been successfully treated with percutaneous sclerosis or by marsupialization i nto the peritoneal cavity by either a laparoscopic or open surgical technique. P ersistent urinary extravasation often requires open surgical repair. Significant bleeding requires exploration and control of bleeding. Restudy as necessary Serum

Lymph Urine Blood Repair Explore Drain

14.12 Transplantation as Treatment of End-Stage Renal Disease Results of Renal Transplantation US KIDNEY GRAFT SURVIVAL RATES FOR TRANSPLANTATIONS DONE FROM 1991 TO 1995 Donor Cadaver Living Number 36,417 13,771 1 y, % 84 92 5 y, % 60 75 10 y (projected), % 43 62 Data from Cecka [13]. FIGURE14-34 The 5-year patient survival rates for recipients of cadaveric and li vingdonor kidney transplantations were 81% and 90%, respectively [13]. Kidney tr ansplantation survival rates have steadily improved since the 1970s because of t he following: careful recipient selection and preparation, improvement in histoc ompatibility techniques and organ sharing, contributions from our colleagues in government and the judiciary, improvements in immunosuppressive therapy and infe ction control, careful monitoring of recipients, and refinement of surgical tech niques. What we accomplish today as a matter of routine was only imagined by a f ew just decades ago. References 1. United Network for Organ Sharing: The UNOS Statement of Principles and Object ives of Equitable Organ Allocation. UNOS Update 1994, 10:20. Evans RW, Manninea DL, Garrison LP, et al.: The quality of life of patients with end-stage renal di sease. N Engl J Med 1985, 312:553. US Renal Data System, USRDS 1997 Annual Data Report, National Institutes of Health, Bethesda, MD: National Institute of Diabe tes and Digestive and Kidney Diseases, 1997:7273. Nohr C: Non-AIDS immunosuppress ion. In Care of the Surgical Patient, Vol. 2. Edited by Wilmore DW, Brennan MF, Harken AH, et al. New York: Scientific American; 1989:118. Gittes RF, Waters WB: Sexual impotence: the overlooked complication of a second renal transplant. J Ur ol 1979, 121:719. Barry JM, Fuchs EF: Right renal vein extension in cadaver kidn ey transplantation. Arch Surg 1978, 113:300. Corry RJ, Kelly SE: Technique for l engthening the right renal vein of cadaver donor kidneys. Am J Surg 1978, 135:86 7. 8. Barry JM, Hefty TR, Sasaki T: Clam-shell technique for right renal vein ex tension in cadaver kidney transplantation. J Urol 1988, 140:1479. 9. Barry JM: R enal transplantation. In Campbell's Urology. Edited by Walsh PC, Retik AB, Vaughan ED, Wein AJ. Philadelphia: WB Saunders Co, 1997:505530. 10. Barry JM: Unstented extravesical ureteroneocystostomy in kidney transplantation. J Urol 1983, 129:91 8. 11. Gibbons WS, Barry JM, Hefty TR: Complications following unstented paralle l incision extravesical ureteroneocystostomy in 1000 kidney transplants. J Urol 1992, 148:38. 12. Dawidson IJA, Ar'Raja A: Perioperative fluid and drug therapy d uring cadaver kidney transplantation. In Clinical Transplants 1992. Edited by Te rasaki PI, Secka JM. Los Angeles: UCLA Tissue Typing Laboratory; 1993:267284. 13. Cecka JM: The UNOS Scientific Renal Transplant Registry. In Clinical Transplant s 1996. Edited by Terasaki PI, Cecka JM. Los Angeles: UCLA Tissue Typing Laborat ory; 1997:114.

2. 3. 4. 5. 6. 7.

Kidney-Pancreas Transplantation John D. Pirsch Jon S. Odorico Hans W. Sollinger I n the United States, diabetes mellitus is the third most common disease and four th leading cause of death from disease. Diabetes is the leading cause of blindne ss, the number one cause of amputations and impotence, and one of the most frequ ently occurring chronic childhood diseases. Diabetes is also the leading cause o f end-stage renal disease in the United States, with a prevalence rate of 31% co mpared with other renal diseases. Diabetes is also the most frequent indication for kidney transplantation, accounting for 22% of all transplantation operations . Increasingly, pancreas transplantation is being offered to patients who would benefit from kidney transplantation (called simultaneous pancreas-kidney transpl antation) or who have had a previously successful kidney transplantation (called sequential pancreas after kidney transplantation). Relatively few transplantati on centers are performing pancreas transplantation alone in patients with severe life-threatening complications of diabetes. Pancreas transplantation has been c riticized because of the increased morbidity associated with the procedure and l ack of controlled trials demonstrating significant benefit to the secondary comp lications of diabetes. However, many of these criticisms have been overcome with improvement in surgical techniques and pancreas transplantation preservation an d with more potent immunosuppressive regimens. The relative frequency of pancrea s transplantation, common surgical procedures, and outcomes of patients undergoi ng pancreas transplantation are discussed. CHAPTER 15

15.2 Urologic 2% Transplantation as Treatment of End-Stage Renal Disease Unknown 6% Unknown 6% Other 11% PCKD 5% Nephritis 8% GN 19% DM 31% PCKD 8% HTN 12% Other 18% GN 26% HTN 26% Diabetes 22% FIGURE 15-1 Disease prevalence resulting in end-stage renal disease (ESRD) from the United States Renal Data Service (1993 to 1995). In the continental United S tates at the end of 1995, 257,266 patients had ESRD. Diabetes mellitus (DM) acco unts for nearly one third of all patients newly diagnosed with ESRD who require kidney transplantation. GNglomerulonephritis; HTNhypertensive nephropathy; PCKDpoly cystic kidney disease. FIGURE 15-2 Kidney transplantations by diagnosis (October 1987 through December 1994). Approximately 10,000 patients receive kidney transplantations in a given year. Of the primary renal diseases requiring transplantation, diabetes accounte d for 22% of all kidney transplantations performed in the United States. GNglomer ulonephritis; HTNhypertensive nephropathy; PCKDpolycystic kidney disease. 1200 Total US NonUS n=9012 n=6640 n=2372 157 774 201 528 201 417 181 530 200 557 130 1027 167 842 115 1022 1000 800 600 218 146 213 249 400 85 50 112 51 111 112 147 170 200 32 66 6 9 78

11 8 79 19 20 80 30 24 81 36 38 0 Pre78 82 83 84 85 86 Year 87 88 89 90 91 92 93 94 95 96 FIGURE 15-3 Pancreas transplantations per year. The number of pancreas transplan tations performed per year in the United States has been increasing. In 1995 and 1996, over 1000 pancreas transplantations were performed in the United States. A smaller number were performed outside of the United States.

Kidney-Pancreas Transplantation 15.3 8000 7000 6000 Recipient number 5000 4000 3000 2000 1000 0 1988 1989 1990 1991 Y ear 1992 1993 1994 1995 INCLUSION CRITERIA FOR PANCREAS TRANSPLANTATION Type I diabetes mellitus Ability to undergo the procedure Emotional and psycholo gical stability Age less than 60 y Secondary complications of diabetes Financial resources FIGURE 15-4 Relative proportion of simultaneous pancreas-kidney (SPK) transplant ations versus cadaveric kidney transplantations in the United States. Despite an increasing number of SPK transplantations over the past 7 years, pancreas trans plantation is a less common procedure than is cadaveric kidney transplantation a lone. FIGURE 15-5 The inclusion criteria for pancreas transplantation are relatively f ew. Patients usually have type I diabetes mellitus and must have the physical st amina to undergo a major abdominal operation. The patient's age is important, with 60 years of age usually being the cutoff. In some transplantation centers, the cutoff age is 50 years. The patient should demonstrate emotional and psychologic al stability, and significant secondary complications of diabetes must be presen t. Because Medicare does not pay for pancreas transplantations, recipients must use either private insurance or personal funds. EXCLUSION CRITERIA FOR PANCREAS TRANSPLANTATION Significant cardiac disease Substance abuse Psychiatric illness History of nonco mpliance Extreme obesity Active infection or malignancy No secondary complicatio ns of diabetes 1000 SPK PTA PAK 800 Number of transplants 600 400 200 FIGURE 15-6 The exclusion criteria for pancreas transplantation include signific ant cardiac disease, substance abuse, psychiatric illness, and a history of nonc ompliance. Extreme obesity, active infection, and malignancy are relative contra indications to transplantation. Patients with few or very mild secondary complic ations of diabetes may be candidates for kidney transplantation alone. 0 1988 1989 1990 1991 1992 Year 1993 1994 1995 1996 FIGURE 15-7 Types of pancreas transplantation procedures and relative frequency per year (January 1988 through December 1996). Three different indications for p ancreas transplantation exist. Patients with type I insulin-dependent diabetes w ho require kidney transplantation may undergo a simultaneous pancreas-kidney (SP K) transplantation or receive a kidney transplantation followed by a pancreas tr ansplantation during a separate operation (called pancreas after kidney [PAK] tr ansplantation). Patients without significant renal disease may undergo pancreas transplantation alone (PTA). The relative proportion of the types of transplanta tions is shown. Most pancreas transplantations performed in the United States ar e of the SPK type, followed by PAK transplantations. Presently, few PTA transpla

ntations are performed.

15.4 Transplantation as Treatment of End-Stage Renal Disease Transplantation Operation or external iliac artery. The portal vein of the allograft is anastomosed to the common iliac vein or distal inferior vena cava. Likewise, on the left side the renal artery and vein are anastomosed to the common iliac artery and vein, respe ctively. To restore the continuity of the urinary tract, a standard ureteroneocy stostomy is constructed to the dome of the bladder. Because the pancreas has dua l endocrine and exocrine functions, it is necessary to perform another anastomos is to handle exocrine secretions. A variety of techniques to manage pancreatic e xocrine secretions have been proffered over the years with less than satisfactor y results. These include duct occlusion, open drainage into the peritoneal cavit y, and creation of a button of duodenum and anastomosing this or the pancreatic duct directly to the bladder. Currently, the most commonly performed technique i n the United States is drainage of pancreatic exocrine secretions into the bladd er (bladder drainage, BD), as depicted [1]. The BD technique involves fashioning a short segment of donor duodenum, which is transplanted along with the pancrea s. Then the donor duodenum is anastomosed to the dome of the recipient bladder i n a side-to-side manner. In this way exocrine secretions, including enzymes, pro enzymes, water, and sodium bicarbonate, are diverted into the urinary tract. Thi s technique is safe, reliable, and well tolerated; however, it is associated wit h a number of specific urinary tract complications. As a consequence of implanta tion into the iliac fossa, the pancreatic allograft is drained into the systemic venous circulation, as depicted. This results in systemic venous, rather than p ortal venous, insulin release and peripheral hyperinsulinemia. An alternative ap proach practiced by some surgeons is portal venous drainage. In this approach th e portal vein of the allograft is anastomosed to the superior mesenteric vein of the recipient in an end-to-side fashion. This technique establishes drainage of insulin into the portal venous blood flow, perhaps a more physiologic situation (procedure not shown). The results of the two techniques are largely comparable . Fortunately, patients have suffered no adverse effects of systemic venous drai nage and hyperinsulinemia. Solitary pancreaticoduodenal allografts are implanted into either iliac fossa, at whichever point the iliac vessels permit vascular a nastomoses. This procedure is done, usually and preferentially, on the right sid e. Otherwise, the operative sequence duplicates that of the combined procedure. FIGURE 15-8 Simultaneous pancreas-kidney allograft procedure. Most pancreas tran splantations performed in the United States are whole organ pancreaticoduodenal allografts from cadaveric donors transplanted simultaneously with the kidney fro m the same donor [1]. Because the pancreas from a patient with diabetes still su bserves digestive function, it is not removed. Therefore, the pancreaticoduodena l allograft is transplanted to an ectopic location, usually the right iliac foss a. Similarly, the kidney allograft is transplanted ectopically to the contralate ral iliac fossa. The reconstructed arterial supply to the pancreas, as shown in Figure 15-9, is anastomosed to the common

Kidney-Pancreas Transplantation 15.5 Ligated splenic A and V Splenic A Iliac Y graft Ligated CBD SMA Ligated SMA and SMV FIGURE 15-9 Preparation of the pancreaticoduodenal allograft and arterial recons truction. The donor pancreas, duodenum, and spleen are perfused in situ with col d University of Wisconsin solution and harvested en bloc with the liver. The pan creaticoduodenal graft is separated from the liver graft and prepared on the sur gical back table at 4oC. The spleen is first removed by ligating the splenic art ery and vein. The duodenal segment is shortened to approximately 10 cm, and the suture lines are reinforced. The common bile duct (CBD) and the superior mesente ric artery and vein (SMA and SMV) have been ligated previously in the donor. A v ariety of techniques exist to reconstruct the dual arterial blood supply to the pancreas. In our experience, the most favorable approach entails using an iliac artery bifurcation graft harvested from the same donor. As shown, the external i liac arterial limb of the graft is anastomosed to the SMA, and the hypogastric a rterial limb is anastomosed to the splenic artery. This technique is reliable an d associated with a very low thrombosis rate. The venous anastomosis (portal vei n to iliac vein or inferior vena cava) can be performed without tension by compl ete mobilization of both the donor portal vein and the recipient iliac vein. A v enous extension graft is rarely necessary and probably increases the risk of thr ombosis. FIGURE 15-10 Enteric drainage (ED) technique. An alternative approach to bladder drainage, ED is, perhaps, a more physiologic method of handling pancreatic exoc rine secretions. ED is the preferred method in Europe and is rapidly gaining pop ularity in the United States [1]. Most commonly, it is performed as depicted wit hout a Roux-en-Y anastomosis. The donor duodenal segment is anastomosed in a sid e-to-side fashion to the ileum or distal jejunum. Long-term graft survival, thro mbosis rates, and primary nonfunction rates are no different when comparing the two techniques [13]. Performed with expertise, both techniques should yield excel lent results. Several significant advantages of the ED technique over bladder dr ainage make ED our technique of choice.

15.6 Transplantation as Treatment of End-Stage Renal Disease COMPARISON OF BLADDER DRAINAGE VERSUS ENTERIC DRAINAGE TECHNIQUES Bladder drainage (BD) Advantages Ability to monitor urinary amylase levels as an indicator of rejectio n [6] ?Decreased risk of perioperative intra-abdominal infections Enteric drainage (ED) Advantages No need for enteric conversion in up to 25% of patients who have urol ogic complications Less metabolic acidosis and chronic dehydration [3] Shorter l ength of hospital stay secondary to less dehydration Early removal of urinary ca theter and fewer UTIs Ability to perform portal venous drainage, if desired Disa dvantages ?Increased risks of perioperative peripancreatic infections Difficult to diagnose pancreatic enzyme leaks Disadvantages Risks of developing urologic complications in up to 25% of patient s, including urethritis, urethral disruption, and hematuria Risk of recurrent UT Is greater for BD than for ED [3] Prolonged urinary catheter drainage needed to decompress bladder anastomosis for healing Frequent postoperative admissions for dehydration and metabolic acidosis and need for bicarbonate replacement UTIsurin ary tract infections. FIGURE 15-11 Early attempts using enteric drainage (ED) techniques resulted in p rohibitively high rates of intra-abdominal abscesses, wound infections, and myco tic aneurysms threatening both graft and patient. Thereafter, bladder drainage ( BD) via a duodenocystostomy evolved in the United States as the safest and most frequently performed exocrine drainage procedure. It has been suggested that BD affords the ability to monitor urinary amylase levels as an indicator of rejecti on, which may be useful in the setting of a solitary pancreas transplant. Howeve r, in recipients of simultaneous pancreas-kidney (SPK) transplant in whom kidney function serves as a marker of rejection monitoring of urinary amylase levels i s not necessary to achieve excellent long-term graft survival. As experience gre w with BD, however, it was found that up to 25% of patients with BD developed a significant urologic or metabolic complication requiring surgical conversion of exocrine secretions to ED [4,5]. Renewed interest in primary ED has resulted. Se veral recent retrospective studies have compared BD pancreas transplants to ED transpl ants. These studies have demonstrated equivalent short-term graft survival rates without increased risks of infectious complications and pancreatic enzyme leaks [13]. ED is associated with fewer urinary tract infections (UTIs) and no hematur ia. Patients who have ED experience less dehydration and metabolic acidosis and, as a result, a reduced need for fluid resuscitation and bicarbonate supplementa tion [3]. Finally, in patients who have ED the Foley catheter can be removed wit hin several days, whereas patients who have BD require prolonged drainage (up to 14 days) to permit healing of the duodenocystostomy. Consequently, with ED, pat ients are able to leave the hospital sooner. ED has proved to be more physiologi c and results in less morbidity compared with BD. Therefore, ED is rapidly gaini ng popularity as the method of choice for handling graft exocrine secretions in pancreas transplantation.

Kidney-Pancreas Transplantation 15.7 Immunosuppression and Monitoring IMMUNOSUPPRESSIVE PROTOCOLS SPK ATGAM (20 mg/kg/d for 10 d) MMF (3 g/d) Neoral (8 mg/kg/d) Prednisone (500 mg int raoperatively; 250 mg on postoperative days 1 and 2; 30 mg/d thereafter) PAK and PTA ATGAM (20 mg/kg/d for 10 d) or OKT3 (510 mg/d for 10 d) MMF (2 g/d) FK506 (8 mg/d ) Prednisone (500 mg intraoperatively; 250 mg on postoperative days 1 and 2; 30 mg/d thereafter) ATGAMantithymocyte globulin, polyclonal serum; FK506 tacrolimus, Prograf (Fujisawa USA, Inc., Deerfield, IL); MMFmycophenolate mofetil, RS-61443, CellCept (Roche L aboratories, Nutley, NJ); OKT3muromonab, murine antihuman CD3 monoclonal antibody ; PAKpancreas after kidney transplantation; PTApancreas transplantation alone; SPKs imultaneous pancreas-kidney transplantation. FIGURE 15-12 Because the best treatment of rejection is prevention, the most eff icacious regimen of immunosuppressive drugs should be used first. Quadruple-drug immunosuppressive regimens, including the use of antithymocyte globulin (ATGAM) or OKT3, have been accepted as standard at most pancreas transplant centers. Re cent data from the United Network for Organ Sharing and several smaller retrospe ctive comparative trials provide evidence that antiT-cell antibody induction ther apy may lessen the severity and delay the onset of rejection and may improve sho rt-term graft survival in recipients of simultaneous pancreas-kidney (SPK) trans plants [1,7,8]. This is the current practice. The development of newer more spec ific immunosuppressive agents, however, recently has changed the face of modern immunosuppression in solid organ transplantation and raises the possibility of s uccessful pancreas transplantation without induction therapy. Mycophenolate mofe til (MMF) has recently replaced azathioprine (AZA) as maintenance immunosuppress ive therapy in kidney transplantation alone, SPK, and pancreas transplantation a lone. MMF is a potent noncompetitive reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). IMPDH is an essential enzyme in the de novo purine synthetic pathway upon which lymphocyte DNA synthes is and proliferation are strictly dependent. Compared with AZA, MMF has no assoc iation with pancreatitis and has less association with leukopenia. Moreover, whe reas AZA is not useful in treating ongoing rejection, MMF can salvage refractory acute renal allograft rejection in up to half of patients. By virtue of this me chanism of action, MMF provides more effective and specific immunosuppression wi th less risk compared with AZA. Similarly, Neoral, a microemulsified formulation of cyclosporine (CsA) has replaced standard CsA therapy with Sandimmune (both d rugs from Sandoz Pharmaceuticals, East Hanover, NJ). Because of gastroparesis an d autonomic dysfunction, patients with diabetes exhibit unpredictable absorption of CsA. The new formulation of CsA has an increased rate and extent of drug abs orption with lower inter- and intra-individual pharmacokinetic variability than does Sandimmune, particularly in patients with diabetes. Improved bioavailabilit y and more reliable pharmacokinetics may translate into fewer rejection episodes and improved graft survival. Experience with tacrolimus (FK506) in pancreas tra nsplantation for induction, maintenance, and rescue therapy has demonstrated tha t it is safe, well tolerated, and has a low risk of glucose intolerance. Moreove r, particularly for solitary pancreas transplants, strikingly improved short-ter m graft survival results have been reported [9,10]. The mechanism of action of F K506 as a calcineurin inhibitor is similar to that of CsA. FK506 has a better si de-effect profile compared with CsA, causing less hirsutism, less hyperlipidemia , but somewhat more neurotoxicity. Unlike CsA, FK506 can rescue patients with re

fractory rejection and treat ongoing rejection. One caveat when using FK506 in c ombination with MMF is the risk of overimmunosuppression. Several studies have h ighlighted the fact that FK506 may increase blood levels of the active metabolit e of MMF, mycophenolic acid, in a clinically relevant manner [11]. By reducing t he incidence of rejection, these modern immunosuppressants have resulted in impr oved short- and long-term graft survival. Fewer rejection episodes will likely t ranslate into an overall reduction in the glucocorticoid dosage being given in t he perioperative period. This reduction may favorably impact short-term infectio us complications and long-term steroid-related adverse side effects.

15.8 Transplantation as Treatment of End-Stage Renal Disease FIGURE 15-13 (see Color Plate) Pancreas transplantation biopsy. Pancreas allogra ft biopsy is the gold standard for evaluating pancreas allograft dysfunction and for diagnosing acute rejection. In a pancreas transplantation recipient, indica tions for the need of a biopsy to rule out rejection include elevated amylase or lipase levels, unexplained fever, and glucose intolerance. In patients with sim ultaneous pancreas-kidney (SPK) transplantation, pancreas rejection most commonl y (about 90%) occurs simultaneously with kidney rejection. As a result, a diagno sis of rejection relies almost entirely on serum creatinine, 2-microglobulin, an d renal allograft biopsy. However, in the setting of sequential pancreas after k idney transplantation or pancreas transplantation alone (PTA) in which isolated pancreas rejection occurs, predicting rejection with a serologic or urinary mark er is more difficult. To date, no marker has been identified that can predict re jection accurately enough to warrant treatment without first performing a biopsy . Thus, the ability to perform pancreas allograft biopsy is essential in the pos toperative care of recipients of PTA. In addition to a biopsy, radiologic evalua tion of the allograft with ultrasonography (to evaluate vascular flow) and compu ted tomography (CT) scan (to rule out pancreatic enzyme leaks and fluid collecti ons) are complementary studies that deserve consideration for all episodes of al lograft dysfunction. Percutaneous core biopsies of the pancreas allograft with r ealtime ultrasonography or CT guidance have been shown to be safe and reliable [ 1214]. A and B, After the gland is assessed for vascular patency an appropriate p ortion of the pancreas is identified that is free of major vessels and overlying viscera (usually the body or tail). C, A 20-gauge automated biopsy needle is ad vanced into the pancreas graft under real-time ultrasonography, and a biopsy is obtained. In pancreaticoduodenal grafts with bladder drainage (BD) a cytoscopic transduodenal biopsy offers the opportunity to obtain biopsy specimens from both the pancreas and duodenum. Success rates for obtaining tissue for pathologic re view in both techniques are 85% to 95%. Firm adherence of the pancreas to surrou nding structures and use of real-time ultrasonography reduce the risks of compli cations related to biopsy. Overall, complications occur in 5% to 10% of patients , which can include bleeding, pancreatic duct leak, hematuria (in BD pancreas tr ansplants), and asymptomatic transient hyperamylasemia. Rarely does a complicati on require a repeat operation or result in graft loss. A B C

Kidney-Pancreas Transplantation 15.9 Management of Complications approach that balances aggressive immunosuppression against risks of infection. A diagnosis of rejection is dependent on biopsy of either the kidney or pancreas allograft in recipients of SPK transplantation or of the pancreas allograft in pancreas transplantation alone. Because of the double-edged sword of aggressive antirejection treatment, an episode of graft dysfunction should not be treated w ithout biopsy-proven histopathologic evidence of immunologic graft injury. Rulin g out infectious and anatomic causes of graft dysfunction with appropriate radio logic studies is equally important. Drachenberg and coworkers [15] and Nakhleh a nd Sutherland [16] have defined histologic criteria for grading pancreas allogra ft rejection that are practical from the standpoint of being able to prognostica te outcome and response to therapy. Serial histologic studies of pancreas reject ion (as in this case) have shown that lymphocytic infiltrates initially involve the exocrine portion of the gland and that islet cell tissue becomes involved la ter [12]. As a result, exocrine dysfunction is frequently the first clinical sig n of rejection (manifested by either elevated serum amylase or decreased urinary amylase levels). Consequently, early rejections without evidence of islet cell involvement usually can be treated successfully. On the contrary, the success of antirejection treatment is far less successful when initiated after the develop ment of hyperglycemia [17]. A, Normal pancreas allograft core biopsy demonstrati ng an acinar lobule and preserved individual islet of Langerhans without inflamm atory infiltrate (magnification 200). B, Needle core biopsy demonstrating glandu lar architecture with fibrous septae interdigitating between acinar lobules. An infiltrate is present that can be described as mononuclear, predominantly lympho cytic, perivascular, and septal. Endothelialitis is seen in a medium-sized vein at the upper central edge of the biopsy specimen. These features are consistent with mild acute cellular rejection (magnification 200). C, Needle core biopsy de monstrating intense septal inflammation with activated lymphocytes. Early acinar inflammation is present in the right upper lobule. Eosinophils also are present in the dense septal infiltrate. These findings also are consistent with mild ac ute cellular rejection (magnification 200). Moderate rejection is characterized by significant acinar inflammation and arteritis. Severe rejection is suggested when, in addition to the features listed above, confluent acinar necrosis with e xtensive acinar inflammation and ductal epithelial necrosis are present. Feature s indicating a poor prognosis include arteritis, confluent acinar necrosis, isle t inflammation and necrosis, ductal epithelial necrosis, and fibrosis. Mild acut e rejection usually is reversible with bolus corticosteroid therapy. In contrast to renal allograft rejections, however, most mild pancreas allograft rejections are somewhat recalcitrant to bolus steroid immunotherapy. Steroids may worsen p otentially compromised glycemic control, thus complicating treatment. Therefore, significant rejection of the pancreas allograft may be best treated with antibo dy therapy, although a randomized control trial comparing the two treatment opti ons has not been carried out. FK506 is commonly employed as rescue therapy in pa ncreas transplant episode recipients who are experiencing a significant acute re jection episode while on cyclosporine or Neoral (Sandoz Pharmaceuticals, East Ha nover, NJ). Irreversible allograft rejection was a frequent occurrence several y ears ago. Today, it is unusual, occurring in less than 5% of patients. A B C FIGURE 15-14 Pancreas allograft rejection. Rejection occurs with greater frequen cy after pancreas and simultaneous pancreas-kidney (SPK) transplantation than af ter kidney transplantation alone, predictably in 75% to 85% of patients. This di

fference requires a strategically different

15.10 Transplantation as Treatment of End-Stage Renal Disease FIGURE 15-15 Indications for enteric conversion (EC). A set of complications uni que to pancreas transplantation arise as a consequence of urinary diversion of g raft exocrine secretions. The development of one of these complications is the m ost frequent cause for re-admission to the hospital after pancreas transplantati on with BD. These include the following: persistent gross hematuria, recurrent o r chronic urinary tract infections (UTIs), urethritis, urethral stricture or dis ruption, urinary or pancreatic enzyme leak, graft (reflux) pancreatitis, and exc essive bicarbonate loss and acidosis [18]. Surgical conversion to ED is indicate d when these complications are incapacitating or refractory to conservative ther apy. Except for leaks and pancreatitis, these complications are largely avoided in ED pancreas grafts. Hematuria in the immediate postoperative period is usuall y mild and self-limited, occasionally requiring irrigation, cytoscopic fulgurati on, or both. Hematuria occurring late after transplantation (ie, months to years ) may be caused by UTIs, suture granulomas, bladder stones, or ulceration of the duodenal segment. In total, hematuria occurs in 17% of patients. Conversion to ED is indicated when hematuria persists despite appropriate therapy and is requi red in up to a third of patients who present with late or chronic hematuria. Pan creatic enzyme or urinary leaks also can occur in the early postoperative period or as late as several years after transplantation. Early leaks usually occur at the bladder-duodenum suture line, whereas late leaks occur most commonly at the lateral duodenal staple line or at the location of a duodenal ulcer. The cause is unclear. Whereas some early leaks may be technically related, late leaks are more likely a result of rejection, cytomegalovirus infection, ischemia, or a com bination of all these. Patients usually present with sudden-onset lower abdomina l pain, fever, leukocytosis, increased serum amylase and slightly increased crea tinine. Diagnosis is confirmed by cystogram (see Fig. 15-17). Fortunately this c omplication is unusual, occurring in 10% to 15% of patients. The most common inf ectious complication after pancreas transplantation is UTI, occurring in 63% of pancreas transplant recipients with BD. These recipients may be more predisposed to UTIs than are kidney transplant recipients because of the additive effect of several factors. These factors include alkalinization of the urine secondary to bicarbonate exocrine secretion, presence of a diabetic neurogenic bladder with incomplete emptying, mucosal injury at the bladder anastomosis, and prolonged ca theter drainage. Occasionally, a cause for therapyresistant or recurrent infecti ons is found on cystoscopy and study of the upper tracts also is indicated. When no source is found, EC is indicated. If persistent, urethritis may result in ur ethral stricture, disruption, or both. Although its exact cause is unclear, uret hritis is most likely caused by the digestive action of pancreatic enzymes on th e urothelium. Urethritis usually is manifested as perineal pain and discomfort d uring urination and seems to occur almost exclusively in males. Initially, conse rvative treatment with Foley catheter drainage for several weeks is recommended. When perforation occurs, it usually is in the membranous portion of the urethra and presents with perineal and testicular swelling. To avoid complications of u rethral stricture and disruption, early enteric conversion is recommended when u rethritis fails to respond to an initial short course of conservative treatment. Fortunately, these complications are unusual, occurring in only 5% of simultane ous pancreas-kidney (SPK) transplantation recipients. Early postoperative hypera mylasemia, thought to be caused by preservation injury, is not uncommon and, for tunately, usually is asymptomatic and improves rapidly. Persistent or marked ele vations of amylase indicate possible technical errors, including ductal ligation or leak. Graft pancreatitis (sometimes referred to as reflux pancreatitis) pres ents in a manner similar to that of a leak. Graft pancreatitis is further define d by absence of a leak on radiologic study; evidence of gland edema on CT scan, without evidence of abscess or fluid collections; and; most important, resolutio n of symptoms within 48 hours of Foley catheter drainage. Treatment with Foley c atheter drainage for several days is usually successful. When an infection is fo und in the patient's urine at this time, appropriate parenteral antibiotics may be

beneficial. Metabolic acidosis is present postoperatively in about 80% of patie nts after pancreas transplantation with BD and usually is due to excessive urina ry loss of bicarbonate-containing exocrine fluids. Because urinary bicarbonate l oss is accompanied by an obligate loss of fluid, low serum levels are associated with dehydration. Oral fluid replacement should be instituted to maintain a ser um bicarbonate level of at least 20 to 25 mg/dL, and dehydration is treated appr opriately. Fortunately, this problem usually stabilizes over time and infrequent ly requires conversion from bladder to enteric drainage. Indications for enteric conversion Metabolic acidosis 2% Reflux pancreatitis Rec urrent 3% urinary Hematuria 19% tract infections 11% Urethritis 23% Leak 42%

Kidney-Pancreas Transplantation 1.0 0.9 0.8 Fraction of patients converted 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 Kaplan-Meier rate = 28% 15.11 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 1 2 Time to EC Percent 3 4 5 Years 6 7 8 Duodenum Side to side duodenoenterostomy A 7 8 Years 9 10 11 12 13 14 15 B Bladder FIGURE 15-16 Incidence and procedure in enteric conversion (EC). A, Surgical con version of pancreatic exocrine secretions from bladder drainage to enteric drain age is necessary in many patients. Whereas half of patients receive EC within th e first postoperative year, a significant percentage must undergo EC up to 5 yea rs after transplantation. B, EC involves taking down the duodenocystostomy, repa iring the bladder, and performing a simple side-to-side duodenoenterostomy. In o ur experience of performing 95 ECs over a 14-year period in 480 simultaneous pancreas-kidney (SPK) transplant recipients, only one graft was lost within 3 months of EC [5]. No differences were found in patient, kidney, o r pancreas graft survival when comparing SPK transplant recipients who underwent EC with those who did not. The frequency of urologic complications and need for EC have prompted a changing trend toward performing primary enteric drainage; h owever, neither of these problems appears to impact negatively on graft survival . FIGURE 15-17 Pancreatic enzyme and urinary leaks. A leak of urine, activated pan creatic enzymes, or both, is one of the most devastating and life-threatening in fectious complications after pancreas transplantation. Patients exhibit sudden-o nset lower abdominal pain, fever, leukocytosis, increased serum amylase levels, and increased serum creatinine levels. Diagnosis is confirmed by cystogram. When no leak is identified, voiding cystourethrography (VCUG) with gastrograffin (pa nel A) or a VCUG using technetium (Tc99m) in normal saline is performed (panels

BE). (Continued on next page) A

15.12 Transplantation as Treatment of End-Stage Renal Disease B C D FIGURE 15-17 (Continued) In our opinion, a Tc99m-VCUG is the most sensitive test , because extravasation may occur only during the high-pressure phase of voiding [19]. B, This gastrograffin-VCUG demonstrates duodenal segment and anastomosis in the region of the dome of the bladder in an oblique anteroposterior projectio n. A leak of contrast is identified at the lateral duodenal segment staple line. B and C, Normal Tc99mVCUG scintigraphy is shown. Radioactive tracer is seen wit hin the confines of the intact urinary tract, refluxing into the duodenal segmen t (large black arrow) and renal transplantation collecting system (small black a rrow). D and E, Tc99m-VCUG demonstrates spill of radioactive tracer outside of t he bladder and duodenal segment (large white arrowhead). Later, radioactive trac er is also present in the pelvis and between loops of bowel throughout the perit oneal cavity (small white arrowheads). For small leaks that are contained early, treatment consists of bladder decompression with a urinary catheter for 2 to 3 weeks. Large leaks and those that recur after conservative therapy require explo ration, repair of the involved suture line, and enteric conversion. E Careful inspection of the duodenal segment is essential, and biopsy of the duode nal mucosa to search for rejection or cytomegalovirus pathology may be revealing in determining the cause. In most cases, however, the exact cause remains enigm atic despite careful investigation. In some cases, simultaneous diversion of the fecal stream with a Roux-en-Y anastomosis or proximal ileotransverse colostomy is advocated. Rarely is a urinary leak secondary to disruption of the ureteroneo cystostomy. Enzyme leaks are more difficult to diagnose in enterically drained p ancreata. A diagnosis in this setting relies on contrast-enhanced computed tomog raphy (CT) scan, which usually demonstrates peripancreatic fluid collections. Wh en drained percutaneously, these fluid collections reveal infection with enteric organisms and an elevated fluid amylase level. Surgical treatment of leaks in E D pancreata requires an individualized approach that usually involves repair, dr ainage, and diversion of the fecal stream. An expeditious diagnosis, depending o n a high index of suspicion, and aggressive surgical intervention are essential to manage these life-threatening complications.

Kidney-Pancreas Transplantation 15.13 FIGURE 15-18 Urethral disruption. When left untreated, urethritis usually progre sses to urethral disruption. Retrograde urethrography in a recipient of a simult aneous pancreas-kidney transplant with bladder drainage demonstrates perforation of the membranous urethra with extensive extravasation of contrast. Immediate t reatment is placement of a suprapubic cystostomy or, if possible, a Foley cathet er. Enteric conversion follows, which is 100% successful. Sequelae of this proce ss include stricture and bladder outlet obstruction. SPK patient survival by era 100 90 80 70 60 50 40 0 6 12 % Years 8789 9091 9293 9497 n Txs 532 908 1125 2387 1 Yr surv. 90% 91% 92% 94% US cadaveric pancreas transplantations 10/1/19877/31/1997 FIGURE 15-19 Patient and graft survival rates for simultaneous pancreas-kidney ( SPK) transplantations in the United States. The survival rates have improved ove r the past 10 years. The current 1-year patient survival rate for SPK is 94% (pa nel A), with an 89% kidney graft survival rate (panel B) and 82% pancreas graft survival rate (panel C). The differences over time are highly significant betwee n all eras. P = 0.002 A 18 24 30 36 42 Months posttransplantation 48 54 60 SPK pancreas graft function by era 100 80 60 % 40 20 0 0 6 12 Years 8789 9091 9293 9497 n Txs 532 908 1125 2387 1 Yr surv. 74% 75% 79% 82% US cadaveric pancreas transplantations 10/1/19877/31/1997 P = 0.0001 B 18 24 30 36 42 Months posttransplantation 48 54 60 SPK kidney graft function by era 100 90 80 70 60 50 40 0 6 12 % Years 8789 9091 9293 9497 n Txs 532 908 1125 2387 1 Yr surv. 86% 84% 86% 89% US cadaveric pancreas transplantations 10/1/19877/31/1997

P = 0.004 C 18 24 30 36 42 Months posttransplantation 48 54 60

15.14 Transplantation as Treatment of End-Stage Renal Disease PAK patient survival by era PTA graft function by era 100 80 60 Years 8789 9091 9293 9497 n Txs 77 76 84 209 1 Yr surv. 90% 96% 90% 95% 100 90 80 70 60 50 40 0 % US cadaveric pancreas transplantations 10/1/877/31/97 US cadaveric pancreas transplantations 10/1/877/31/97 Years 8789 9091 9293 9497 n Txs 46 49 72 92 1 Yr surv. 46% 51% 56% 74% % 40 20 P = NS 0 60 0 6 12 P 0.0001 6 12 A 18 24 30 36 42 Months posttransplantation 48 54 A 18 24 30 36 42 Months posttransplantation 48 54 60 PAK graft function by era 100 80 60 % 40 20 0 0 6 12 P 0.008 PTA patient survival by era 100 90 80 70 60 50 40 60 0 6 12 % Years 8789 9091 9293 9497 n Txs 46 49 72 92 1 Yr surv. 93% 90% 90% 93% US cadaveric pancreas transplantations 10/1/877/31/97 Years 8789 9091 9293 9497 n Txs 1 Yr surv. 77 56% 76 51% 84 52% 209 70% US cadaveric pancreas transplantations 10/1/877/31/97 P = NS B

18 24 30 36 42 Months posttransplantation 48 54 B 18 24 30 36 42 Months posttransplantation 48 54 60 FIGURE 15-20 Patient (panel A) and graft (panel B) survival rates for sequential pancreas after kidney (PAK) transplantations. For patients with PAK, the surviv al rate is similar to simultaneous pancreas-kidney transplantations but graft su rvival has been poorer until very recently. The 1-year PAK graft survival rate h as improved from 52% to nearly 70%. NSnot significant. FIGURE 15-21 Graft (panel A) and patient (panel B) survival rates for pancreas t ransplantation alone (PTA). A much smaller number of PTAs have been performed in the United States compared with sequential pancreas after kidney (PAK) transpla ntations and simultaneous pancreas-kidney (SPK) transplantations. The patient su rvival rate for PTA is similar to those of SPK and PAK transplantation; however, the PTA graft survival rate has been closer to that of the PAK rate until the m ost recent transplantation era. Advancements in immunosuppressive therapy have i mproved the 1-year graft survival rate of PTA transplantations from 56% to 74%. NSnot significant. FIGURE 15-22 Multiple studies have been performed on the effec ts of pancreas transplantation on the secondary complications of diabetes. Unfor tunately, most of these studies were performed with small numbers of patients an d were not randomized controlled studies. There are four major benefits of pancr eas transplantation for the secondary complications of diabetes: 1) Normoglycemi a has been demonstrated for an extended period of time as long as the pancreas i s functioning; 2) nephropathy has been shown to improve; 3) pancreas transplanta tion appears to prevent recurrent diabetic nephropathy in the transplanted kidne y; and 4) quality of life. Complete freedom from insulin injections, appears to be the major benefit of pancreas transplantation. Unfortunately, pancreas transp lantation does not appear to reverse established diabetic nephropathy in patient s with their own kidneys, and established retinopathy and vascular disease do no t appear to improve. EFFECTS OF PANCREAS TRANSPLANTATION ALONE ON SECONDARY COMPLICATIONS OF DIABETES Maintenance of normoglycemia Neuropathy Prevention of recurrent nephropathy Qual ity of life Retinopathy Vascular disease Beneficial Stabilization and improvemen t Beneficial Major None Minimal

Kidney-Pancreas Transplantation 16 14 12 10 8 6 4 Before transplantation 124 mo 266 mo After transplantation 15.15 Hemoglobin A1, % of total hemoglobin FIGURE 15-23 Glycosylated hemoglobin before and after pancreas transplantation. All patients have an abnormal hemoglobin A1 value before pancreas transplantatio n. Most patients, however, maintain a normal hemoglobin A1C after successful pan creas transplantation. (From Morel and coworkers [20]; with permission). 0.5 1.0 Motor index 1.5 2.0 2.5 Percent eyes with stable retinopathy grade 100 * 75 50 25 0 Pancreas transplant Control 0 12 24 36 48 60 Time following pancreas transplanta tion, mo 72 A 0.5 1.0 1.5 2.0 2.5 0 12 24 42 * FIGURE 15-25 Effects of pancreas transplantation on diabetic retinopathy. Retino pathy does not appear to improve after pancreas transplantation. A similar rate of deterioration was observed in both patients who had successful pancreas trans plantation compared with patients with diabetes who had kidney transplantation a lone. (From Ramsay and coworkers [22]; with permission). Sensory index B 0.5 1.0 1.5 2.0 2.5 0 12 24 42 Kidney pancreas Control Autonomic index 0

12 C 24 Months 42 FIGURE 15-24 Effects of pancreas transplantation on diabetic neuropathy. Careful studies of motor index (panel A), sensory index (panel B), and autonomic index (panel C) show a general trend of improvement over 42 months in patients who rec eived pancreas transplantation compared with patients in the control group. In p atients with pancreas transplantation, 70% had improved results on motor nerve t ests, nearly 60% on sensory tests, and 45% on autonomic tests. In patients in th e control group, only 30% had improved results on motor and sensory tests, 12% h ad improved autonomic tests, and nearly 50% had deterioration of neurologic func tion. (From Kennedy and coworkers [21]; with permission).

15.16 5 4 3 2 1 0 Transplantation as Treatment of End-Stage Renal Disease FIGURE 15-26 Effects of pancreas transplantation on recurrent diabetic nephropat hy. Pancreas transplantation appears to prevent the subsequent development of di abetic nephropathy in renal allografts [23]. Both mean glomerular volume (panel A) and mesangial volume (panel B) were significantly lower in patients with succ essful pancreas transplantation compared with recipients with diabetes who had u nsuccessful pancreas transplantation. 2p = 0.02 0.5 0.4 Mesangium volume 0.3 0.2 0.1 0.0 2p = 0.004 Glomerular volume A Kidney alone Kidney/ pancreas B Kidney alone Kidney/ pancreas 0.7 0.6 Mesangial fractional volume 0.5 0.4 0.3 0.2 0 Baseline 5 y Pancreas tran splant recipients Baseline 5 y Comparison group Mean glomerular volume, 106 m3 3.5 Total mesangium per glomerulus, 106 m3 Baseline 5 y Pancreas transplant recip ients Baseline 5 y Comparison group 3.0 2.5 2.0 1.5 1.0 0 1.8 1.5 1.2 0.9 0.6 0.3 0 Baseline 5 y Pancreas transplant recipients Baseline 5 y Comparison group A B C FIGURE 15-27 Effects of pancreas transplantation on established diabetic nephrop athy. Although there appears to be a benefit in the prevention of diabetic nephr opathy, there does not appear to be a benefit in patients who undergo pancreas t ransplantation in reversing established diabetic glomerular lesions. In this stu dy, mesangial fractional volume increased (panel A) and mean glomerular volume decre ased (panel B) in pancreas transplantation recipients but no significant change in total mesangial volume (panel C) occurred over a 5-year follow-up. (From Fior etto and coworkers [24]; with permission). FIGURE 15-28 (see Color Plates) Effec ts of pancreas transplantation on microvascular disease. The benefits of pancrea s transplantation on vascular disease have been variable. A, In this study, ther mography demonstrated a clear-cut improvement in diabetic microvascular disease after successful pancreas transplantation [25]. B, However, no evidence exists t

hat successful pancreas transplantation results in the regression of established macrovascular disease. A B

Kidney-Pancreas Transplantation 15.17 References 1. Gruessner A, Sutherland DER: Pancreas transplantation in the United States (U S) and Non-US as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR). In Clinical Transplants 1996 . Edited by Cecka JM, Terasaki PI. Los Angeles: UCLA Tissue Typing Laboratory; 1 996:4767. 2. Kuo PC, Johnson LB, Schweitzer EJ, Bartlett ST: Simultaneous pancrea s/ kidney transplantation: a comparison of enteric and bladder drainage of exocr ine pancreatic secretions. Transplantation 1997, 63:238243. 3. Odorico JS, Becker YI, Van der Werf WJ, et al.: Advances in pancreas transplantation: the Universi ty of Wisconsin experience. In Clinical Transplants 1997. Edited by Terasaki PI, Cecka JM. Los Angeles: UCLA Tissue Typing Laboratory; 1998:157166. 4. Sollinger HW, Messing EM, Eckhoff DE, et al.: Urological complications in 210 consecutive simultaneous pancreas-kidney transplants with bladder drainage. Ann Surg 1993, 2 18:561570. 5. Van der Werf WJ, Odorico JS, D'Alessandro AM, et al.: Enteric convers ion of bladder drained pancreas allografts: experience in 95 patients. Transplan tation Proc 1998, 30:441442. 6. Prieto M, Sutherland DER, Fernandez-Cruz L, et al .: Experimental and clinical experience with urine amylase monitoring for early diagnosis of rejection in pancreas transplantation. Transplantation 1987, 43:7379 . 7. Brayman KL, Egidi MF, Naji A, et al.: Is induction therapy necessary for su ccessful simultaneous pancreas and kidney transplantation in the cyclosporine er a? Transplantation Proc 1994, 26:25252527. 8. Wadstrom J, Brekke B, Wramner L, et al.: Triple versus quadruple induction immunosuppression in pancreas transplant ation. Transplantation Proc 1995, 27:13171318. 9. Bartlett ST, Schweitzer EJ, Joh nson LB, et al.: Equivalent success of simultaneous pancreas kidney and solitary pancreas transplantation. A prospective trial of tacrolimus immunosuppression w ith percutaneous biopsy. Ann Surg 1996, 224:440449. 10. Gruessner RW, Burke GW, S tratta R, et al.: A multicenter analysis of the first experience with FK506 for induction and rescue therapy after pancreas transplantation. Transplantation 199 6, 61:261273. 11. Zucker K, Rosen A, Tsaroucha A, et al.: Augmentation of mycophe nolate mofetil pharmacokinetics in renal transplant patients receiving Prograf an d CellCeptin combination therapy. Transplantation Proc 1997, 29:334336. 12. Allen RDM, Wilson TG, Grierson JM, et al.: Percutaneous biopsy of bladder-drained panc reas transplants. Transplantation 1991, 51:12131216. 13. Gaber AO, Gaber LW, Shok ouh-Amiri MH, Hathaway D: Percutaneous biopsy of pancreas transplants. Transplan tation 1992, 54:548550. 14. Bernardino M, Fernandez M, Neylan J, et al.: Pancreat ic transplants: CT-guided biopsy. Radiology 1990, 177:709711. 15. Drachenberg CB, Papadimitriou JC, Klassen DK, et al.: Evaluation of pancreas transplant needle biopsy. Transplantation 1997, 63:15791586. 16. Nakhleh RE, Sutherland DER: Pancre as rejection: significance of histopathologic findings with implication for clas sification of rejection. Am J Surg Pathol 1992, 16:10981107. 17. Stratta RJ, Tayl or RJ, Weide LG, et al.: A prospective randomized trial of OKT3 vs. ATGAM induct ion therapy in pancreas transplant recipients. Transplantation Proc 1996, 28:9279 28. 18. Sollinger HW, Odorico JS, Knechtle SJ, et al.: Experience with 500 simul taneous pancreas-kidney transplants. Ann Surg 1998, 228: 284296. 19. Rayhill SC, Odorico JS, Heisey DM, et al.: A comparison of the sensitivities of contrast and isotope voiding cystourethrograms for the detection of pancreas transplant blad der leaks. Transplantation Proc 1995, 27:31433144. 20. Morel P, Goetz FC, MoudryMunns K, et al.: Long-term glucose control in patients with pancreatic transplan ts. Ann Intern Med 1991, 115:694699. 21. Kennedy WR, Navarro X, Goetz FC, et al.: Effects of pancreatic transplantation on diabetic neuropathy. N Engl J Med 1990 , 322:10311037. 22. Ramsay RC, Goetz FC, Sutherland DER, et al.: Progression of d iabetic retinopathy after pancreas transplantation for insulin-dependent diabete s mellitus. N Engl J Med 1988, 318:208214. 23. Bilous RW, Mauer SM, Sutherland DE R, et al.: The effects of pancreas transplantation on the glomerular structure o f renal allografts in patients with insulin-dependent diabetes. N Engl J Med 198 9, 321:8085. 24. Fioretto P, Mauer SM, Bilous RW, et al.: Effects of pancreas tra

nsplantation on glomerular structure in insulin-dependent diabetic patients with their own kidneys. Lancet 1993, 342:11931196. 25. Abendroth D, Landgraf R, Illne r W-D, Land W: Evidence for reversibility of diabetic microangiopathy following pancreas transplantation. Transplantation Proc 1989, 21:28502851.

Transplantation in Children Jeanne A. Mowry R enal transplantation in children has been considered the treatment of choice for end-stage renal disease for many years [1]. Successful transplantation allows f or improved physical, social, and psychological rehabilitation, enabling a child to have a quality of life that usually is not attainable with dialysis. Improve ments in technology in pediatric transplantation have been significant in the 19 90s; however, owing to the inherent potential risks and benefits, the optimal ti ming for transplantation needs to be individualized to the child. Currently, dia lysis and transplantation need to be viewed as complementary parts of each child's lifelong treatment plan. Renal transplantation in children carries with it spec ial issues and problems that vary somewhat from those in adult transplantation. Because children are constantly growing and developing, technical, metabolic, im munologic, and psychological factors exist that are unique to children and must be considered. The current status of pediatric renal transplantation is reviewed , summarizing immunosuppressive regimens, outcomes, and complications. Because o f the low incidence of end-stage renal disease in children, much of the informat ion available about current practices and trends regarding pediatric renal trans plantation has been collected by national registries. To supplement the United S tates Renal Data Source, the North American Pediatric Renal Transplant Cooperati ve Study (NAPRTCS) was initiated in 1987 in an effort to capture information to improve the care of pediatric renal allograft recipients. Current NAPRTCS data i nclude information collected voluntarily from 123 centers on 3066 children who r eceived renal transplantation on or after January 1, 1987 [2]. This registry has been helpful in providing a mechanism through which the clinical course of a la rge number of children can be evaluated. CHAPTER 16

16.2 Transplantation as Treatment of End-Stage Renal Disease End-Stage Renal Disease Frequency 30 Rate per million population per year 25 20 15 10 5 0 04 59 1014 1519 Age, y Total 019 10 11 7 4 6 4 12 10 Male Female 24 21 FIGURE 16-1 The incidence of pediatric end-stage renal disease per million popul ation by age and gender and adjusted for race is depicted, as reported by the Un ited States Renal Data Source. This graph shows the average rate per year, 1993 to 1995. (From United States Renal Data System [3]; with permission.) Etiology DISEASES CAUSING END-STAGE RENAL DISEASE Disease category Urologic malformations Renal dysplasia Other congenital causes Focal segmental g lomerulosclerosis Other glomerulonephritides and immunologic diseases Hypertensi ve nephropathy Diabetic nephropathy All other causes Children <18 years, %* 26 17 15 11 14 0 0.1 17 Adults 2064 years, % , 4 0.3 5 2 17 22 40 10 FIGURE 16-2 Different diseases causing end-stage renal disease in children and a dults. The leading causes of chronic renal failure in young children are inherit ed disorders or congenital abnormalities of the urinary tract, especially obstru ctive uropathy and reflux nephropathy. Focal segmental glomerulosclerosis and ot her glomerular disorders are seen more often in older children. Almost no childr en develop end-stage renal disease as a result of diabetic nephropathy and hyper tension, the leading causes of end-stage renal disease in adults. (From Harmon [ 4]; with permission.) *Data from North American Pediatric Renal Transplant Cooperative Study. Data from United States Renal Data Source. 50 Each age group, % 40 30 20 10 0 17 37 44 Age group 04 (n = 715) Age group 519 (n = 4052) 21 13 13 5 6 5 15 11 13 FIGURE 16-3 Data from the United States Renal Data Source of the incident pediat ric cases by disease group and age group (04 vs 519 years), as a percentage of tot al pediatric end-stage renal disease within each age group. The numbers on top o f the bars indicate the percentage within each age group over 5 years, 1991 to 1 995. (From Harmon [4]; with permission.) GlomeruloCystic, Interstitial Hypertension Collagen Other and nephritis heredita ry, nephritis and and vascular unknown and pyelonephritis disease diseases conge nital diseases

Transplantation in Children 16.3 FIGURE 16-4 Voiding cystourethrogram in a child with posterior urethral valves s howing gross dilation of the posterior urethra with an abrupt change in caliber at the level of the external sphincter. Obstructive uropathy is reported to be t he cause of end-stage renal disease in 16.5% of pediatric transplantation recipi ents (the primary cause along with aplastic, hypoplastic, and dysplastic kidneys ) in the North American Pediatric Renal Transplant Cooperative Study 1995 Annual Report. (Courtesy of Philip Silberberg, MD.) FIGURE 16-5 Voiding cystourethrogram in grade 5 reflux nephropathy showing gross dilation of the collecting system and blunting of the fornices. Renal parenchym al scarring and destruction usually occur before the age of 5 years but may occu r in older age groups. Intrarenal reflux extends the vesicoureteric reflux into the collecting tubules and nephrons, allowing urinary access to the renal parenc hyma that can lead to renal scarring. (Courtesy of Philip Silberberg, MD.) FIGURE 16-6 Plain radiograph of a child with prune-belly syndrome showing a mark edly protuberant abdomen. This syndrome, also referred to as Eagle-Barrett syndr ome or triad syndrome, occurs almost exclusively in males. The three classic phy sical findings are the deficiency of the abdominal wall musculature, urinary tra ct anomalies characterized by an extremely dilated urinary tract, and bilateral intraabdominal testes. A wide spectrum in the severity of abnormalities is seen, with most children having some degree of renal dysplasia, along with bladder an d ureteric dysplasias (partial or complex lack of smooth muscle). (Courtesy of P hilip Silberberg, MD.) Transplantation Rates Rate of pediatric renal transplantations per 100 dialysis patient-years 50 43 Living related donor Cadaveric donor 33 31 22 24 27 26 40 30 20 10 0 04 59 28 16 28 FIGURE 16-7 Data from the United States Renal Data Source showing the 1995 rates of pediatric renal transplantations per 100 dialysis patientyears by recipient age. The rate of kidney transplantation varies inversely with recipient age grou p. Emphasis is placed on living related donors in the pediatric group with end-s tage renal disease. (From United States Renal Data System [3]; with permission.) 11 5 1014 1519 Recipient age Total 019 2044 (adult)

16.4 Transplantation as Treatment of End-Stage Renal Disease FIGURE 16-8 The national renal transplantation waiting list as of September 30, 1997. (From United Network for Organ Sharing Bulletin [6]; with permission.) NUMBER OF PATIENTS ON TRANSPLANTATION WAITING LIST Age groups, y 05 610 1117 1849 5064 65+ Total Number, % 78 0.21 124 0.33 421 1.13 20,971 56.07 12,784 34.18 3026 8.09 37,404 Renal Allograft Outcome 100 Graft survival, % Graft survival, % 80 60 40 20 0 0 10 20 30 40 Follow-up, m o 50 60 Living donor Cadaveric donor 100 80 60 40 20 0 0 Living donors 100 Graft survival, % 80 60 40 20 60 0 0 Cadaveric donors Primary First repeat Primary First repeat A 12 24 36 48 Time posttransplantation, mo B 12 24 36 48 60 Time posttransplantation, mo FIGURE 16-9 The estimated graft survival probabilities by allograft source from the 1995 North American Pediatric Renal Transplant Cooperative Study Annual Repo rt. The overall median follow-up for patients with functioning grafts is 29 mont hs. The estimated graft survival probabilities have improved by approximately 1 percentage point for cadaveric donor grafts compared with the data in the 1994 r eport. For living related donor grafts the estimated graft survival probabilitie s are similar to those in the previous report at 1 and 2 years, and 1 percentage point higher at 4 years. (From Warady and coworkers [5]; with permission.) FIGURE 16-10 Graft loss in young infants and children often caused by irreversib le acute rejection episodes. Rejection is, perhaps, a result of heightened immun e response in this age group [7]. Despite an improvement in graft survival in ch ildren over the past 5 years, the half-life of renal grafts in pediatric patient s remains around 10 years [8]. This half-life means that many of these children will need a second transplantation in their lifetime. Depicted are the North Ame rican Pediatric Renal Transplant Cooperative Study data stratifying the analysis of the percentage of graft survival by donor source. A, Graft survival rates fo r living donor transplantations, primary and first repeat. B, Survival rates for cadaveric donor source transplantations. Graft survival rates for repeat transp lantations did not correlate with early or late failure of the primary graft. (F rom Tejani and Sullivan [9]; with permission.)

Transplantation in Children 16.5 Factors Affecting Outcome Donor Age and Source Living donors 110 100 90 Calculated clearance, mL/min per 1.73m2 80 70 60 50 Cadaveric donors 0 1 years 25 years 612 years >12 years FIGURE 16-11 Data from the North American Pediatric Renal Transplant Cooperative Study for pediatric kidney allograft function, measured as calculated creatinin e clearance values for both cadaveric and living donors. Regardless of the donor source, younger recipients begin with higher calculated creatinine clearance va lues with a more rapid decline in function. Older recipients have more stable ca lculated creatinine clearance values with less of a decline in function. 110 100 90 80 70 60 50 6 12 18 24 30 36 42 48 54 60 Follow-up, mo 0.0 RISK FACTORS ASSOCIATED WITH GRAFT FAILURE 0.2 In (relative risk) 0.4 0.6 0.8 1.0 0 10 20 30 40 Cadaveric donor age, y 50 Cadaveric donor Recipient age (<2 y) Donor age (<6 y) Previous transplantation ATG, ALG, OKT3 ea rly administration (none) More than 5 lifetime transfusions No DR matches Annual cohort (1992 vs 1987) Relative risk increase 2.03 1.47 1.36 1.36 1.37 1.23 1.29 P 0.001 0.001 0.004 0.001 0.001 0.01 0.04 Living related donor Recipient age <2 y Black race More than 5 previous transfusions 1.4 1.9 1.7 0.08 <0.001 <0.001 FIGURE 16-12 The relationship between cadaveric donor age and the logarithm of t he relative risk of graft loss from all causes for pediatric recipients of cadav er-donor renal transplantations. The perfect donor is 21 years of age. The risk of graft loss is higher when the grafts used are from either younger or older dono rs. An equivalent risk of graft loss exists from donors who are 6 and 55 years o f age. (From Harmon [10]; with permission.) FIGURE 16-13 Risk factors associated with graft failure in a proportional hazard s model for recipients of donor grafts. ATGantithrombocytic globulin; ALGantilymph ocytic globulin. (From Warady and coworkers [5]; with permission.)

16.6 Transplantation as Treatment of End-Stage Renal Disease Recipient Age 1.0 0.9 Relative risk 0.8 0.7 0.6 0.5 0.4 0 2 4 6 8 10 12 14 16 18 Recipient age , y FIGURE 16-14 Relationship between recipient age and the relative risk of graft l oss for children who receive cadaveric donor transplantation. A strong inverse r elationship exists between the risk of graft loss and recipient age, particularl y in the group under 2 years of age. (From Harmon [10]; with permission.) Human Leukocyte Antigen Matching 100 90 Graft survival, % 80 70 60 50 0 0.5 1 1.5 Time, y 2 2.5 No A, no B, no DR No A, no B, DR match A and B match, no DR A and B and DR match FIGURE 16-15 Results of 4 years of experience monitoring outcomes by the North A merican Pediatric Renal Transplant Cooperative Study. These results suggest a st atistically significant beneficial effect of donor-related matching (P 0.05) whe n analyzing this allele with other effects unique to pediatric patients with reg ard to age. This figure displays the subgroup with a match at both the A and the B locus, or at neither, and compares that with the effect of adding a donor-rel ated (DR) antigen on the percentage of renal allografts surviving after transpla ntation. Owing to the relatively short follow-up, small sample size (1558 patien ts), and nonimmunologic factors pertinent to pediatric transplantation, it is di fficult to determine separate time-varying effects of class I versus class II ma tching. However, it does seem clear that no antigen matching has a worse prognos is at 1 year (72% graft survival) versus 1 or more antigen matching at each locu s (1-year 81% survival, 2-year 69% survival). (From McEnery and Stablein [11]; w ith permission.) Preparation for Transplantation Preemptive versus Previous Dialysis 100 90 Graft survival, % Graft survival, % 80 70 60 50 40 30 0 Preemptive Prior dialysis Living donor 100 90 80 70 60 50 40 30 0 Cadaveric donor Preemptive Prior dialysis A 10 20 30 40 50 Time posttransplantation, mo B 10 20 30 40 50 Time posttransplantation, mo FIGURE 16-16 Percentage of graft survival of initial living (panel A) and cadave ric donor (panel B) grafts in recipients with and without (preemptive) dialysis, indicating better survival rates in those who did not receive dialysis previous ly. The survival probabilities in the preemptive group are significantly better until adjustments are made for recipient age (01 years vs others) and number of p revious transplantations (>5 vs 05) in a proportional hazards model. (From Fine a nd coworkers [12]; with permission.)

Transplantation in Children 16.7 Vaccinations Hepatitis B (Hep B) Hep B-1 Hep B-2 Diptheria tetanus pertussis (DPT) H. influen zae type b (Hib) Polio Measles-mumpsrubella (M-M-R) Varicella (Var) Birth 1 2 4 6 Age, mo 12 DTaP or DTP Hib Polio DTaP or DTP Hib Polio DTaP or DTP Hib Hib Pol io M-M-R Var 15 18 4-6 Polio M-M-R or M-M-R Var 11-12 Age, y 14-16 Hep B-3 DTaP or DTP DTaP or DTP Hep B Td FIGURE 16-17 Infection remains a major cause of morbidity and mortality in pedia tric transplantation recipients. Many infections can be successfully prevented b y immunization. The recommended US immunization schedule for children (JanuaryDec ember 1997) before transplantation is outlined. Diphtheria-tetanus-pertussis vac cine, Haemophilus influenza type b vaccine, inactivated poliovirus vaccine, and hepatitis B immunizations can be given after transplantation but their efficacy may be suboptimal. The live attenuated vaccines, oral polio vaccine (OPV), measl es-mumps-rubella (M-M-R) vaccine, and varicella virus vaccine, usually are recom mended to be given only after immunosuppressive therapy has been discontinued fo r 3 months. Influenza A vaccines also should be administered yearly in the fall to pediatric transplantation recipients. The advent of the varicella virus vacci ne may decrease the chances of pediatric transplantation recipients developing s evere chickenpox and the incidence of zoster [13]. A recent survey by the North American Pediatric Renal Transplant Cooperative Study found that almost 90% of c enters recommend the use of influenza vaccine, whereas only 60% of centers recom mend pneumococcal vaccine for children with renal disease. Between 5% and 12% of centers recommend live viral vaccines, including OPV, M-M-R vaccine, and varicella virus vaccine, for immunosuppressed patients after renal transplantation. (From Furth and cowo rkers [14]; with permission.) Vaccines are listed under the routinely recommende d ages. Bars indicate the range of acceptable ages for vaccination. Shaded bars indicate catch-up vaccination: at 11 to 12 years of age, hepatitis B vaccine sho uld be administered to children not previously vaccinated, and varicella virus v accine should be administered to children not previously vaccinated who lack a r eliable history of having had chickenpox. This schedule indicates the recommende d age for routine administration of currently licensed childhood vaccines. Some combination vaccines are available and may be used whenever administration of al l components of the vaccine is indicated. Providers should consult the manufactu rers' package inserts for detailed recommendations. Approved by the Advisory Commi ttee on Immunization Practices (ACIP), American Academy of Pediatrics (AAP), and American Academy of Family Physicians (AAFP). (See Red Book [13] for more infor mation.)

16.8 Transplantation as Treatment of End-Stage Renal Disease Immunosuppression IMMUNOSUPPRESSIVE THERAPY AND FUNCTIONING GRAFTS Month 6 (n = 2999) Treated, % MMD* Prednisone Living donor Cadaveric donor Cyclosporine Living donor Cadaveric dono r Azathioprine Living donor Cadaveric donor 96 96 97 93 90 95 88 87 89 0.28 0.27 0.29 6.81 6.94 6.73 1.69 1.69 1.69 Month 12 (n = 2606) Treated, % MMD* 95 94 97 92 90 94 88 86 90 0.22 0.21 0.22 6.15 6.26 6.06 1.67 1.67 1.66 Month 24 (n = 1915) Treated, % MMD* 95 94 96 90 87 93 88 87 90 0.19 0.18 0.19 5.49 5.37 5.58 1.66 1.69 1.62 Month 36 (n = 1358) Treated, % MMD* 95 95 95 89 86 92 88 87 89 0.17 0.17 0.17 4.99 4.88 5.08 1.64 1.67 1.58 Month 48 (n = 890) Treated, % MMD* 95 96 94 88 85 90 89 89 87 0.16 0.16 0.16 4.69 4.28 4.89 1.68 1.73 1.64 Month 60 (n = 543) Treated, % MMD* 96 97 95 87 81 92 88 86 90 0.15 0.15 0.16 4.52 4.29 4.65 1.64 1.76 1.57 *MMDmedian daily doses, in mg/kg. FIGURE 16-18 Data from the North American Pediatric Renal Transplant Cooperative Study on immunosuppressive therapy and functioning grafts at selected times. Th e median daily dose of prednisone decreased from 0.28 mg/kg at 6 months to 0.17 mg/kg at 36 months, and then to 0.15 mg/kg at 5 years after transplantation. Alt ernate-day prednisone was prescribed to 9% of recipients at 6 months, 17% at 12 months, 24% at 24 months, and 27% at 48 months after transplantation. The daily dose of azathioprine did not c hange over time. The mean dose of cyclosporine has increased over the years in t he most recent reported study: the mean 1-year dosages after transplantation wer e 6.5, 7.0, 7.7, and 8.0 mg/kg/d for transplantations occurring in 1987, 1989, 1 991, and 1993, respectively. (From Warady and coworkers [5]; with permission.) Cyclosporine 20 18 Mean ( upper 95% CI) 16 14 12 10 8 6 4 2 0 1 6 12 18 24 30 Time posttranspl antation, mo 36 42 48 Cadaveric donor Recipient age, y 01 25 612 >12 A FIGURE 16-19 Data from the North American Pediatric Renal Transplant Cooperative Study of the maintenance dose of cyclosporine by donor source, recipient age, a nd time after transplantation. The dosage for the first month for 0- to 1-year-old cadaveric donor graft recipients (panel A) is 15.0 mg/kg/d, which is similar to the 14.4 mg/kg/d the living related donor graft recipients (panel B) receive. (Continued on next page)

Transplantation in Children 20 18 16 Mean (+upper 95% CI) 14 12 10 8 6 4 2 0 1 6 12 18 24 30 Time posttransp lantation, mo 36 42 48 Living related donor Recipient age, y 01 25 612 >12 16.9 B FIGURE 16-19 (Continued) By 4 years after transplantation the mean doses of all age groups are similar (mean and upper 95% CIs). (From Tejani and Sullivan [15]; with permission.) FIGURE 16-20 Data from the North American Pediatric Renal Tra nsplant Cooperative Study on late first rejection rates by quartiles of maintena nce cyclosporine dose at 1 year. The first acute rejection occurred over 1 year after transplantation. Patients not receiving cyclosporine (human leukocyte anti genidentical or those receiving tacrolimus [FK-506]) form a small group. The diff erence between the rejection rates for the other four groups are not statistical ly significant. The lowest rate of late first rejection, however, is observed in those patients receiving dosages of cyclosporine over 8.6 mg/kg/d. CsA cyclospor ine; SDstandard deviation. (From Tejani and Sullivan [15]; with permission.) LATE FIRST REJECTION RATES Mean year-1 CsA dosage, mg/kg/d CsA dosage, mg/kg/d* 0 >0 and 4.0 >4.0 and 5.9 >5.9 and 8.6 >8.6 N 80 185 186 188 184 Number of rejections Rejecting, % 9 41 44 46 29 11.3 22.2 23.7 24.5 15.8 Rejection (SD) 0.0 2.9(0.8) 4.9(0.6) 6.9(0.8) 11.7(2.7) Nonrejection (SD) 0.0 3.1(0.7) 5.0(0.6) 7.3 (0.8) 12.6(4.1) *Chi-squared test of percentage rejecting among four nonzero dose groups (P = 0. 163).

16.10 Transplantation as Treatment of End-Stage Renal Disease Tacrolimus COMPARISON OF TACROLIMUS AND CYCLOSPORINE Major advantages of tacrolimus Steroid sparing Less hypertension Rescue of cyclo sporine-resistant rejections Minor advantages of tacrolimus Better graft surviva l Less hirsutism Less gingival hypertrophy Less neurologic dysfunction Less meta bolic acidosis Less hyperlipidemia Major disadvantages of tacrolimus Increased v iral infections Cytomegalovirus Epstein-Barr virus Increased lymphoproliferative disease Minor disadvantages of tacrolimus Increased acute rejection? More diabe togenic? Hyperkalemia? Hypomagnesemia? Similarities of tacrolimus and cyclospori ne Nephrotoxicity FIGURE 16-21 The experience at Children's Hospital of Pittsburgh using tacrolimus has been that 14% of 43 pediatric patients managed with tacrolimus for a mean pe riod of 25 months developed posttransplantation lymphoproliferative disease (PTL D). This occurrence is very high compared with PTLD reported by the North Americ an Pediatric Renal Transplant Cooperative Study in only six of 1550 (0.39% or 0. 10%/y) children managed with various cyclosporine regimens [16]. Epstein-Barr vi rus (EBV) has a primary role in the development of PTLD, and an even higher rate of EBVrelated PTLD has been reported in children receiving tacrolimus for liver transplantation or rescue [17,18]. Children seem to have a greater predispositi on to PTLD than do adults. Therefore, children need closer monitoring for this d isorder when being managed with tacrolimus. The major advantages of tacrolimus o ver cyclosporine are a reduced severity of hypertension and an improved cosmetic appearance that, in turn, may improve patient compliance with medications. (Fro m Ellis [19]; with permission.) Mycophenolate Mofetil 50 Acute rejection episode, % 40 30 20 10 0 Living donor Cadaveric Mycophenolate donor mofetil 26% 19% 48% FIGURE 16-22 Initial studies at the University of California, Los Angeles Medica l Center (UCLA), using mycophenolate mofetil along with cyclosporine and prednis one, instead of azathioprine. In 37 pediatric renal transplantation recipients, an overall incidence of first acute rejection of just 19% was found (only 13% we re clinically significant). This is a decrease compared with the historical inci dence at UCLA (19871994) of acute rejection episodes in living related and cadave ric donor transplantations, which is 26% and 48%, respectively. The researchers saw a moderate increase in the incidence of infection after transplantation (mos tly caused by cyclomegalovirus) and gastrointestinal side effects. (From Ettenge r and coworkers [20]; with permission.) Azathioprine

Transplantation in Children 16.11 Growth in End-Stage Renal Disease Transplantation versus Dialysis 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 0 2 4 Kidney transplantation (n = 724) Average follow-up for calculating ESRD growth r ate = 10.4 mo US general population Dialysis (n = 578) P< 0.01 6 8 10 Age, y 12 14 16 Average age, 12.7 y 18 FIGURE 16-23 Chronic renal insufficiency and end-stage renal disease (ESRD) resu lting in physical growth and sexual development well below the potential for age and gender [21]. One of the benefits of transplantation in children has been to improve the growth rate; however, this may not occur in all patients [16,22,23] . Depicted is the overall comparison between adjusted annualized growth rates by age for prevalent pediatric transplantation and dialysis patients (1990 USRDS d ata) [24] and the US general population (19761980 data from the National Center f or Health Statistics) [25]. Shown are the results of a linear regression analysi s of growth rates for 578 patients on dialysis and 724 transplantation recipient s. Growth rates were adjusted to reflect the average characteristics of patients with ESRD at each age with regard to gender, race, ethnicity, baseline height, and duration of ESRD. At almost all ages, growth rates were higher for transplan tation recipients compared with patients on dialysis; however, the degree of adv antage declined with age. No pubertal growth spurt was seen in either treatment group. Although growth rates in adolescents between 15 and 18 years of age were higher than expected for both the dialysis and transplantation groups, the avera ge height achieved at the end of the study was still lower than expected. (From Turenne and coworkers [26]; with permission.) Growth rate, cm/y 1.0 Height Z 0.5 0 0 12 18 24 30 36 42 48 54 60 Follow-up, mo Sample sizes for h eight Z at follow-up months: Age group, y 6 24 48 0 1 years 155 99 48 25 years 441 312 160 612 years 1023 716 374 1317 years 1112 625 235 FIGURE 16-24 Data from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) on the mean change from baseline in standardized height scores in patients with graft function. The height standard deviation score (SDS), or Z score, is the current accepted measurement used to evaluate accelerated growth. The Z score is an attempt to standardize the height deficit of children with re nal failure to the height of healthy children. A positive change in Z score (+ Z ), for example, indicates a reduction in height deficit (ie, an acceleration of growth). At transplantation the mean height deficit (Z score or SDS) for all pat ients was -2.16 standard deviations (SD) below the appropriate age- and gender-a djusted levels. Recipients under 6 years of age at the time of transplantation s howed acceleration in linear growth after transplantation at 4 years' follow-up. C

hildren 6 years of age or older at time of transplantation showed no improvement in height deficit at 4 years' follow-up. Z score patient's height - height at 50% fo r age and standard deviation of height for age. (From Warady and coworkers [5]; with permission.)

16.12 Transplantation as Treatment of End-Stage Renal Disease Alternate-Day Corticosteroids Daily Alternate day * Significant difference between daily and alternate day gro up * * * * 0.8 Change in height SDS 0.6 0.4 0.2 0 0.2 * 12 24 36 48 Time posttransplantation, mo 60 FIGURE 16-25 Corticosteroids are an integral part of pediatric renal transplanta tion immunosuppressive protocols. In addition to hypertension and hyperlipidemia , one of the main adverse effects of daily steroid dosing in children is growth retardation. A review of North American Pediatric Renal Transplant Cooperative S tudy data, looking at the change in the height standard deviation score (SDS) fr om 30 days after transplantation to 12 to 60 months after transplantation analyz ed the difference between the 1477 children treated continuously on a daily or a lternate-day steroid regimen. The mean change in SDS was significantly greater f or the alternate-day group at each 12-month interval (P < 0.05). Of note is the fact that at 12 months, those children on alternate-day steroids had a mean seru m creatinine of 1.06 0.04 mg/dL as compared with 1.28 0.02 mg/dL for those on da ily steroids (P < 0.001). Alternate-day therapy also was more common in children without a rejection episode in the first 12 months after transplantation, recip ients of living donor grafts, white recipients, and children 2 to 12 years of ag e at the time of transplantation. (From Jabs and coworkers [27]; with permission .) FIGURE 16-26 Data from the North American Pediatric Renal Transplant Cooperat ive Study (NAPRTCS) evaluating the effects of alternate-day steroids on graft su rvival. Patients receiving alternate-day steroids at 12 months were compared wit h those receiving daily steroids. The NAPRTCS found that the survival of living donor (panel A) and cadaveric (panel B) grafts subsequent to 12 months did not d iffer between the steroid treatment groups. Because a number of factors contribu te to graft survival and the patients were not randomly delegated to steroid tre atment groups, a proportional hazards regression model for graft survival after 12 months also was developed. Again, the use of alternate-day steroids had no ad verse effect on graft survival for recipients of either living or cadaveric dono r grafts. (From Jabs and coworkers [27]; with permission.) 100 90 Graft survival, % 80 70 60 50 10 20 30 Living donor 100 90 Graft survival, % 80 70 60 50 Cadaveric donor Daily Alternate day Daily Alternate day A 40 50 Time, mo

60 10 20 30 B 40 50 Time, mo 60

Transplantation in Children 16.13 Recombinant Human Growth Hormone After Transplantation HEIGHT VELOCITY AND HEIGHT STANDARD DEVIATION SCORES Change in height velocity, cm/y Pubertal status Prepubertal Entering puberty Pubertal Change in height SDS Control +0.1 0.3 (n = 30) 0.1 0.4 (n = 11) +0.1 0.5 (n = 18) Control 0.3 1.6 (n = 30) 0.6 1.8 (n = 11) 0.7 2.1 (n = 18) Treated 3.7 1.6* (n = 28) 4.9 3* (n = 9) 4.3 2.2* (n = 29) Treated +0.6 0.3* (n = 28) +0.6 0.6* (n = 9) +0.7 0.5* (n = 29) *P < 0.0001 compared with control groups. FIGURE 16-27 Because growth often remains poor despite a functioning renal graft , a large multicenter controlled study was initiated to evaluate the effectivene ss of recombinant human growth hormone in stimulating growth in children with a kidney allograft. In all three groups a significantly different growth velocity and change in height SDS occurred during the first year of treatment with growth hormone (P < 0.0001) compared with a co ntrol group. Preliminary data from the second year of treatment also show a cont inued improvement in growth velocity compared with baseline; however, not of the magnitude seen during the first year. The mean glomerular filtration rate did n ot change significantly in the group receiving growth hormone. Acute rejection e pisodes were noted more frequently during treatment with growth hormone, especia lly for patients with a history of more than one episode. However, other factors , such as noncompliance with immunosuppressive medications, were not analyzed an d cannot be excluded. Values are expressed as mean standard deviation. SDSstandar d deviation score. (From Broyer [28]; with permission.) FIGURE 16-28 A Finnish s tudy investigating the possible association between growth hormone treatment and acceleration of chronic rejection and late allograft dysfunction in prepubertal children. The most common histologic findings between the eight growth hormone t reated and eight nontreated renal transplantation recipients are scored and comp ared (matched for age, donor age, human leukocyte antigen, immunosuppression, an d renal function) 36 months after transplantation. Improvement in growth was cle ar during administration of growth hormone, without a negative influence on allo graft survival. No significant difference in the amount of lymphocyte infiltrati on of the allografts between patients and the control group was seen. No acute r ejection episodes occurred in the recipients treated with growth hormone but one occurred in the control group. SDstandard deviation. (From Laine and coworkers [ 29]; with permission.) Mean semiquantitative score (06) 0 Interstitium Focal inflammation (lymphocytes) Diffuse inflammation Focal fibrosis Diffuse fibrosis Glomeruli Mesangial cell pr oliferation Mesangial matrix increase Arterioles Endothelial swelling Endothelia l proliferation Intimal proliferation Proximal tubules Dilation Atrophy Casts 1 2 3 4 5 6 Mean score Growth hormone Nontreated treated (SD) (SD) 1.6(1.7) 1.1(1.9) 2.6(1.8) 1.7(1.7) 1.3(1.5) 1.7(1.4) 0.3(0.8) 0.6(1.0) 1.6(1.6) 1.0(0.8) 2.1(0.7) 1.1(1.2

) 1.4(0.8) 0.9(0.9) 2.1(0.4) 0.7(1.0) 1.4(0.8) 2.7(1.0) 0.6(1.1) 0.3(0.8) 0.9(1. 1) 1.1(1.2) 0.7(0.8) 0.4(0.5) Growth hormone treated recipients Nontreated recipients P < 0.05 between groups

16.14 Transplantation as Treatment of End-Stage Renal Disease FIGURE 16-29 Analysis of the safety and efficacy of growth hormone in pediatric renal transplantation recipients. Overall, a catch-up in growth was reported in each study, with changes in height standard deviation score from 0.2 to 1.0. The se results were not as favorable as those reported when growth hormone was used in patients with chronic renal failure, perhaps owing to the use of corticostero ids after transplantation. In three studies, renal function was significantly de creased after administration of growth hormone. Twelve acute rejection episodes and four graft losses occurred; however, a causal relationship is unclear [30]. A controlled trial using growth hormone after transplantation is currently under way by the North American Pediatric Renal Transplant Cooperative Study to help e stablish the efficacy and safety of growth hormone in pediatric transplantation recipients. Calculated clearance according to the Schwartz formula, except for T onshoff (inulin clearance) [31]. (From Tonshoff [31]; with permission.) SAFETY AND EFFICACY OF GROWTH HORMONE TREATMENT Glomerular filtration rate, mL/min/1.73 m2* Reference Bartosh et al. Benfield et al. Fine et al. Ingulli and Tejani Tonshoff et al. Va n Dop et al. Van Es et al. Prepubertal Pubertal Serum creatinine, mg/dL Before 1.4 + 0.1 Patients, n 5 11 13 17 10 9 17 Before 51 + 6.8 75 + 20 67 + 27 59 (23 - 118) 71 (25 - 150) 67 (29 - 152) After 58 + 29 60 + 18 63 + 25 49 (19 - 102)* After 1.6 + 0.6 1.5 1.6* 1.6 + 0.6 72 (4.4 - 172) 83 (24 - 121) 2.1 + 0.9* 19 *P value significant. Median values. Complications after Transplantation Acute Rejection DIAGNOSIS OF ACUTE REJECTION Clinical picture Fever, weight gain, enlargement and tenderness of graft, hypert ension, reduced urinary output, decreased renal function, reduced urinary sodium excretion, and increased proteinuria Cyclosporine trough blood level When these levels are higher than expected, cyclosporine nephrotoxicity is suspected; howe ver, this does not rule out rejectionvery low levels, in the presence of elevated serum creatinine, suggest acute rejection, perhaps as a result of noncompliance Radionuclide renal studies Provide information about blood flow and the excreti on index, and aid in excluding extravasation and obstruction Renal sonography wi

th Doppler ultrasonography Provides information about kidney size, renal blood f low, corticomedullary differentiation, pyramid shape, and the collecting system; establishes the diagnosis of obstruction, extravasation, and renal artery steno sis Renal arteriogram Establishes the diagnosis of major renal vessel stenosis o r occlusion Magnetic resonance imaging Establishes the diagnosis of obstruction, renal vessel stenosis, or occlusion; aids in evaluating the corticomedullary ju nction and pyramid shape Fine-needle aspiration biopsy Identifies inflammatory c ells in the graft, tubular damage, cyclosporine toxicity, and cytomegalovirus in fection; aids in differentiating rejection, acute tubular necrosis, cytomegalovi rus infection, and cyclosporine nephrotoxicity Renal biopsy Remains the gold sta ndard for determining rejection and cyclosporine nephrotoxicity FIGURE 16-30 When impaired graft function occurs in pediatric renal transplantat ion recipients, rejection is the most common cause. A number of other conditions exist that also can result in an increase in serum creatinine and blood urea ni trogen, a decrease in urine output, or both, which must be differentiated from r ejection. In small children with large allografts, the most sensitive indication of rejection is hypertension. It is important to remember that in small childre n, a small increase in serum creatinine can reflect a significant decrease in th e glomerular filtration rate. Several methods to establish the cause of renal al lograft dysfunction are described; however, the diagnostic gold standard is the allograft core biopsy. Biopsy can easily be performed percutaneously in most chi ldren and should not be postponed once other variables have been eliminated and rejection is likely. (From Yadin and coworkers [32]; with permission.)

Transplantation in Children 100 80 Rejection, % 60 40 20 0 0 12 24 36 Follow-up, mo 48 60 Living donor Cadaveric donor 16.15 FIGURE 16-31 Data from the 1995 North American Pediatric Renal Transplant Cooper ative Study showing that the cumulative risk for first rejection is similar for living donor (LD) and cadaveric donor (CD) recipients in the first few weeks aft er transplantation. After the first month, however, the cumulative risk for a fi rst rejection is higher for recipients of a CD graft. By the end of the 48th mon th, 56% of LD recipients and 71% of CD recipients have had at least one rejectio n episode. Rejections were completely reversed (return to baseline creatinine) i n 53% of LD graft recipients, partially reversed (improved graft function but no return to baseline creatinine) in 40%, and resulted in graft failure or death i n 4% of cases. In CD, rejection episodes were completely reversed in 49%, partia lly reversed in 45%, and resulted in graft failure or death in 6%. (From Warady and coworkers [5]; with permission.) Chronic Rejection PREDICTORS OF GRAFT FAILURE FROM CHRONIC REJECTION Relative risk increase Acute rejection 2 acute rejections Late (>365 d) initial acute rejection Cadaveri c donor source Black recipient 3.1 4.3 2.3 1.6 1.6 P value <0.001 <0.001 <0.001 0.001 0.003 FIGURE 16-32 Multivariate analysis of data from the North American Pediatric Ren al Transplant Cooperative Study evaluating predictors of graft failure from chro nic rejection. A proportional hazards analysis of time to chronic rejection fail ure, eliminating other failures, is used to evaluate predictors of graft failure from chronic rejection. A 3.1fold increased risk of failure from chronic reject ion was seen after a single rejection episode. A second rejection increased the risk to over 13 times that of children who did not experience rejection. (From T ejani and coworkers [33]; with permission.) CAUSES OF GRAFT FAILURE Index graft failures Cause Primary nonfunction Vascular thrombosis Miscellaneous technical Hyperacute rejec tion, <24 h Accelerated rejection, 27 d Acute rejection Chronic rejection Renal a rtery stenosis Infection/discontinued medication Cyclosporine toxicity De novo k idney disease Patient discontinued medication Malignancy Recurrence of original disease Death Other *Four patients have had three graft failures. Second graft failures* n = 104 (%) 2(1.9) 20(19.2) 2(1.9) 2(1.9) 5(4.8) 16(15.4) 28(26.9) 0(0.0) 2(1.9) 0(0.0) 2(1. 9) 1(1.0) 1(1.0) 10(9.6) 9(8.7) 4(3.8) Total graft failures n = 985 (%) 30(3.0) 127(12.9) 18(1.8) 11(1.1) 31(3.1) 183(18.6) 267(27.1) 10(1.0) 19(1.9) 9( 0.9) 6(0.6) 19(1.9) 10(1.0) 67(6.8) 107(10.9) 71(7.2) n = 881 (%) 28(3.2) 107(12.2) 16(1.8) 9(1.0) 26(3.0) 167(19.0) 239(27.1) 10(1.1) 17(1.9) 9(1 .0) 4(0.5) 18(2.0) 9(1.0) 56(6.5) 98(9.0) 67(7.6) FIGURE 16-33 Data from the North American Pediatric Renal Transplant Cooperative Study showing causes of graft failure. Chronic rejection has become the most co mmon cause of graft failure (27.1%). Acute rejection causes up to 18.6% of graft

failures. Recurrence of primary disease (focal segmental glomerulosclerosis) ac counts for 6.8% of all failures. Vascular thrombosis continues to cause a signif icant number of graft failures (12.9%). (From Warady and coworkers [5]; with per mission.)

16.16 Transplantation as Treatment of End-Stage Renal Disease Vascular Thrombosis 100 All thrombosis, % 80 60 40 20 0 Living donor Cadaveric donor n = 38 n = 100 Day after transplantation Day > 15 Day 614 Day 35 Day 2 Day 1 Day 0 FIGURE 16-34 Data from the North American Pediatric Renal Transplant Cooperative Study showing vascular thrombosis is the third most common cause of graft failu re in pediatric transplantation recipients. The incidence varies between centers and has been reported to be as high as 20% in children under 2 years of age [34 ]. This figure depicts the timing of thrombotic graft failure by donor source. M ost of the thromboses occurred soon after transplantation. (From Singh and cowor kers [35]; with permission.) UNIVARIATE ANALYSIS OF RISK FACTORS Living donor, n All Recipient age 01 y 25 y 612 y >12 y Donor age 05 y 510 y >10 y Cold ischemia time <24 h >24 h Day 0/1 Antilymphocyte therapy No Yes Day 0/1 cyclosporine therapy No Yes Previous transplantation No Yes Native nephrectomy No Yes Previous dialys is No Yes Persistent ATN with >7 d of function No Yes *P < 0.01, test for trend. P = 0.01, test for trend. 38/2060 6/172 12/341 5/732 15/783 % 1.8 3.5* 3.4 0.7 1.9 Cadaveric donor, n 100/2334 7/78 19/343 36/827 38/1086 32/386 11/245 54/1667 44/1363 51/909 % 4.3 9.0 5.5 4.4 3.5 8.3* 4.5 3.2 3.2* 5.6 FIGURE 16-35 Recent univariate analysis of risk factors by the North American Pe diatric Renal Transplant Cooperative Study. Although the mechanisms that lead to thrombosis are unclear, numerous factors have been implicated, whether they be by direct or indirect means. In cadaveric donor kidney recipients, children less than 2 years of age had a significantly higher rate of thrombosis, as did child ren who received kidneys from donors who were under 5 years of age. Recipients o f cadaveric donor kidneys with prolonged cold ischemia time had a higher rate of thrombosis than did those with a cold ischemia time under 24 hours. ATNacute tub ular necrosis. (From Singh and coworkers [35]; with permission.) 28/1187 10/873 29/1115 9/945 30/1886 8/174 26/1440 12/617 11/680 27/1380 2.4 1.2 2.6* 1.0 1.6* 4.6 1.8 1.9 1.6 2.0 61/990 39/1344 66/1682 34/652 66/1723 34/611 82/1790 18/540 13/319 87/2015 6.2* 2.9 3.9 5.2 3.8 5.6 4.6 3.3 4.1 4.3 10/1929 3/79 0.5* 3.8 22/1844 13/365 1.2* 3.6

Transplantation in Children 16.17 Hypertension EVALUATING HYPERTENSION Months after transplantation Pretransplantation Patients, n Significant hypertension, % Severe hypertension, % 230 11 23 1 264 14 26 6 262 16 13 12 261 16 10 24 257 9 9 FIGURE 16-36 Data from the North American Pediatric Renal Transplant Cooperative Study evaluating hypertension. Hypertension is common in children after renal t ransplantation. The definition of hypertension used was taken from the Report of the Second Task Force on Blood Pressure Control in Children [15]. The percentag e of children exceeding age-adjusted blood pressure standards decreased consider ably over the 2-year period. (From Baluarte and coworkers [36]; with permission. ) CYCLOSPORINE DOSAGES IN RECIPIENTS WITH AND WITHOUT HYPERTENSION 1 mo Degree of hypertension Normotensive Significant Severe 2y n 213 22 22 FIGURE 16-37 North American Pediatric Renal Transplant Cooperative Study evaluat ing cyclosporine dosages in recipients with and without hypertension. CsAcyclospo rine. (From Baluarte and coworkers [36]; with permission.) n 161 36 69 CsA dosage, mg/kg 8.2 9.4 10.0 P = 0.11 CsA dosage, mg/kg 3.9 4.8 4.7 P = 0.23 Recurrent Disease GRAFT FAILURE FROM RECURRENT DISEASE Disease FSGS MPGN type I MPGN type II SLE HSP HUS Classical Atypical Recurrence rate, % 2530 70 100 540 5585 1220 25 Clinical severity High Mild Low Low Low to mild Moderate High

Those with recurrence whose graft failed, % 4050 1230 1020 5 520 010 4050 FIGURE 16-38 Recurrence rates and graft failure from recurrent disease. Some pri mary renal diseases may recur in the allograft, making the underlying disease an important consideration when evaluating a child for renal transplantation. Foca l segmental glomerular sclerosis and atypical hemolytic uremic syndrome recur in roughly 25% of cases. These diseases are severe clinically and lead to the high est percentage of graft failures, ie, 40% to 50%. In contrast, membranoprolifera tive glomerulonephritis type II recurs in all cases; however, it is not very sev ere clinically and leads to graft failure in only 10% to 20% of patients. FSGSfoc al segmental glomerulosclerosis; HSP Henoch-Schnlein purpura; HUShemolytic-uremic s yndrome; MPGNmembranoproliferative glomerulonephritis; SLE systemic lupus erythema tosus. (From Fine and Ettenger [37]; with permission.)

16.18 Transplantation as Treatment of End-Stage Renal Disease Other Causes of Renal Allograft Loss 100 90 Graft survival, % 80 70 60 50 40 30 0 Congenital and structural Glomerulonephritis Focal segmental glomerulosclerosis Congenital nephrotic syndrome 100 90 Graft survival, % 80 70 60 50 40 50 30 0 Hemolytic uremic syndrome Renal infarction Cystinosis Familial nephritis A 10 20 30 Months 40 B 10 20 30 Months 40 50 FIGURE 16-39 Data from the North American Pediatric Renal Transplant Cooperative Study showing that those patients receiving living donor kidneys who have conge nital nephrotic syndrome (CNS), focal segmental glomerulosclerosis (FSG) (panel A) or hemolytic uremic syndrome (HUS) (panel B) had the lowest 2-year graft surv ival rates. These rates range from 74.3% to 80.6%. In patients with focal segmen tal glomerular sclerosis, graft failure was attributed to disease recurrence in 13 of 39 (33%) patients who received kidneys from living related donors. B, The patients with familial nephritis or cystinosis had the highest graft survival ra tes (88.9% and 92.9%, respectively). (From Kashton and coworkers [38]; with perm ission.) FIGURE 16-40 Data from the North American Pediatric Renal Transplant Co operative Study for cadaveric donor renal allografts showing that the lowest gra ft survival rates occurred in children with focal segmental glomerular sclerosis or congenital nephrotic syndrome (panel A), or hemolytic uremic syndrome (panel B). These rates range from 40% to 58.9%. In patients with focal segmental glome rular sclerosis, graft failure was attributed to disease recurrence in 14 of 81 (17%) patients who received cadaveric donor kidneys. A, The highest graft surviv al rate correlated with the diagnosis of congenital and structural disease and g lomerulonephritis (72.2% and 73.5%, respectively). (From Kashton and coworkers [ 38]; with permission.) 100 90 Graft survival, % Graft survival, % 80 70 60 50 40 30 0 Congenital and structural Glomerulonephritis Focal segmental glomerulosclerosis Congenital nephrotic syndrome 100 90 80 70 60 50 40 30 10 20 30 Months 40 50 0 Hemolytic uremic syndrome Renal infarction Cystinosis Familial nephritis A B

10 20 30 Months 40 50 Mortality in Recipients 15 1-year Kaplan-Meier death rates, % 10 Dialysis FIGURE 16-41 Data from the United States Renal Data Source on pediatric patient 1-year death rates by age group and treatment mortality. Survival follow-up bega n on day 91 after onset of endstage renal disease for patients on dialysis incid ent in 1994, and from the date of transplantation for patients receiving transpl antations in 1994 [3]. CD Txcadaveric donor transplant; LRD Txliving related donor transplant. (From United States Renal Data System [3]; with permission.) 5 CD Tx LRD Tx 0 04 59 1014 Age groups 1519

Transplantation in Children 30 Total deaths = 290 Percentages add to 100 24 25 16.19 Deaths, % 20 13 12 6 4 7 4 6 10 FIGURE 16-42 Data from the United States Renal Data Source regarding distributio n of causes of death in children aged 0 to 19, 1993 to 1995. (From United States Renal Data System [3]; with permission.) 0 Cardiac Acute arrest myocardial infarction Other cardiac causes Cardiovascular disease Infection Malignancy Hemorrhage Other known causes Unknown causes CAUSES OF DEATH BY AGE GROUP Recipient age 01 Cause of death All causes Viral infection Bacterial infection Other infections Malignancy Cardi opulmonary Hemorrhage Recurrence of original disease Dialysis-related complicati ons Other Unknown 25 n (%) 33(100.0) 1(3.0) 6(18.1) 5(15.2) 2(6.1) 7(21.2) 4(12.1) 1(3.0) 0(0.0) 5(15.2) 2( 6.1) 612 n (%) 33(100.0) 6(18.2) 5(15.2) 3(9.1) 2(6.1) 10(30.3) 3(9.1) 0(0.0) 0(0.0) 3(9.1) 1(3 .0) 1317 n (%) 43(100.0) 8(18.6) 6(14.0) 3(7.0) 4(9.3) 6(14.0) 6(14.0) 1(2.3) 3(7.0) 5(11.6) 1( 2.3) FIGURE 16-43 Data from the North American Pediatric Renal Transplant Cooperative Study on causes of death by age group. This study revealed a high rate of attri tion among pediatric transplantation recipients under the age of 5 years. It is unclear whether this high rate is due to a higher rate of infection. (From Tejan i and coworkers [39]; with permission.) n (%) 27(100.0) 5(18.5) 3(11.1) 4(14.8) 1(3.7) 5(18.5) 3(11.1) 1(3.7) 1(3.7) 4(14.8) 0 (0.0) 100 95 Patient survival, % 90 85 80 75 70 0 12 24 36 48 Follow-up, mo 60 Living donor Cadaveric donor FIGURE 16-44 Data from the 1995 North American Pediatric Renal Transplant Cooper ative Study showing a total of 214 deaths. Infection was the leading cause of de ath, occurring in 74 patients. This graph depicts the survival distribution esti mates by donor source. Infants aged under 2 years at the time of transplantation have a mortality rate of 14%. This rate is significantly higher (P < 0.001) tha n in other age groups, with a mortality rate between 4.7% and 8.0%. (From Warady and coworkers [5]; with permission.) Numbers at risk at: Baseline 12 24 36 48 Living donor 1800 1393 1033 815 535 Cad

averic donor 1873 1362 1080 774 536

16.20 30 Cumulative mortality, % 25 20 15 10 5 0 0 Transplantation as Treatment of End-Stage Renal Disease FIGURE 16-45 Data from the North American Pediatric Renal Transplant Cooperative Study of patient mortality by recipient age. A significant difference (P < 0.00 1) in 1-year mortality rates by age groups occurred: 13.6% (21 of 154) for 0- to 1-year-old recipients; 8.0% (33 of 413) for 2- to 5-year-old recipients; 3.6% ( 33 of 926) for 6- to 12-year-old recipients; and 4.5% (43 of 964) for 13- to 17year-old recipients. Mortality also is increased for recipients of kidneys from young cadaveric donors. A dramatic increase in cumulative mortality is seen, wit h increasing concordance between young donor and recipient ages. (From Tejani an d coworkers [39]; with permission.) Recipient age 01 (n = 154) 25 (n = 413) 612 (n = 926) 1317 (n = 964) 10 20 30 40 Time posttransplantation, mo 30 Cumulative mortality, % 25 20 15 10 5 0 0 Acute tubular necrosis No (n = 2140) Yes (n = 310) FIGURE 16-46 The effect of acute tubular necrosis (ATN) on patient survival. The development of ATN leads to a significantly higher (P = 0.0001) mortality rate of 13.2% (risk ratio of 3.1) for the 310 patients reported on in the registry. A 25% mortality rate and 6.4 risk ratio were noted for the 188 patients who devel oped graft failure within 30 days after transplantation (P < 0.001). (From Tejan i and coworkers [39]; with permission.) 10 20 30 40 Time posttransplantation, mo References 1. Ettenger RB: Renal transplantation. In Renal Disease in Children. Edited by B arakat AY. New York: Springer-Verlag; 1990:371384. 2. Warady BA, Hebert D, Sulliv an EK, et al.: Renal transplantation, chronic dialysis and chronic renal insuffi ciency in children and adolescents: 1995 Annual Report of the North American Ped iatric Renal Transplant Cooperative Study. Pediatr Nephrol 1997, 11:4964. 3. Unit ed States Renal Data System: USRDS 1997 Annual Data Report. Am J Kidney Dis 30:S 128144. 4. Harmon WE: Treatment of children with chronic renal failure. Kidney In t 1995, 47:951961. 5. Warady BA, Hebert D, Sullivan EK, et al.: Renal transplanta tion, chronic dialysis and chronic renal insufficiency in children and adolescen ts: 1995 Annual Report of the North American Pediatric Renal Transplant Cooperat ive Study. Pediatr Nephrol 1997, 11:4964. 6. UNOS Bull 1997, 2(10), October. 7. T ejani A, Stablein D, Alexander S, et al.: Analysis of rejection outcomes and imp lications. Transplantation 1995, 59:502. 8. Stablein DM, Tejani A: Five-year pat ient and graft survival in North American children. Kidney Int 1995, 44:516. 9. Tejani A, Sullivan EK: Factors that impact on the outcome of second renal transp lants in children. Transplantation 1996, 62:606611. 10. Harmon WE: Treatment of c hildren with chronic renal failure. Kidney Int 1995, 47:951961. 11. McEnery P, St ablein DM: Does human lymphocyte antigen matching improve the outcome in pediatr ic renal transplants? J Am Soc Nephrol 1992, 2:S234S237. 12. Fine RN, Tejani A, S ullivan EK: Pre-emptive renal transplantation in children: report of the North A merican Pediatric Renal Transplant Cooperative Study. Clin Transplantation 1994, 8:474478. 13. Red Book: Report of the Committee on Infectious Diseases, edn 24. Edited by Georges Peter. Elk Grove: American Academy of Pediatrics; 1997:1819. 14 . Furth SL, Neu AM, Sullivan EK, et al.: Immunization practices in children with renal disease: a report of the North American Pediatric Renal Transplant Cooper ative Study. Pediatr Nephrol 1997, 11:443446. 15. Tejani A, Sullivan EK: Higher m aintenance cyclosporine dose decreased the risk of graft failure in North Americ an children: a report of the North American Pediatric Renal Transplant Study. J

Am Soc Nephrol 1996, 7:550555. 16. McEnery PT, Stablein DM, Arbus G, Tejani A: Re nal transplantation in children: a report of the North American Pediatric Renal Transplant Cooperative Study. N Engl J Med 1992, 326:17271732. 17. Tzakis AG, Rey es J, Todo S, et al.: Two-year experience with FK-506 in pediatric patients. Tra nsplant Proc 1993, 25:619621. 18. Reding R, Wallemacq PE, Lamy ME, et al. Convers ion from cyclosporine to FK-506 for salvage of immunocompromised pediatric liver allografts. Transplant 1994, 57:93100.

Transplantation in Children 19. Ellis D. Clinical use of tacrolimus (FK-506) in infants and children with re nal transplants. Pediatr Nephrol 1995, 9:487494. 20. Ettenger R, Cohen A, Nast C, et al.: Mycophenolate mofetil as maintenance immunosuppression in pediatric ren al transplantation. Transplant Proc 1997, 29:340341. 21. Rees L, Rigden SPA, Ward GM: Chronic renal failure and growth. Arch Dis Child 1989, 64:573577. 22. Tejani A, Fine R, Alexander S, et al.: Factors predictive of sustained growth in child ren after renal transplantation: The North American Pediatric Renal Transplant C ooperative Study. J Pediatr 1993, 122:397402. 23. Harmon WE, Jabs K: Factors affe cting growth after renal transplantation. J Am Soc Nephrol 1992, 2:S295S303. 24. United States Renal Data System: USRDS 1995 Annual Data Report. Bethesda, MD, Th e National Institutes of Health, The National Institute of Diabetes and Digestiv e and Kidney Diseases, 1995. Am J Kidney Dis 1995, 26:S1S186. 25. Najjar MF, Rowl and M: Anthropometric reference data and the prevalence of overweight. Vital Hea lth Stat 1987, 11:1073. 26. Turenne MN, Port FK, Strawderman RL, et al.: Growth rates in pediatric dialysis patients and renal transplant recipients. Am J Kidne y Dis 1997, 30:193203. 27. Jabs K, Sullivan EK, Avner ED, Harmon WE: Alternate da y steroid dosing improves growth without adversely affecting graft survival or l ong-term graft function. Transplantation 1996, 61:3136. 28. Broyer M: Results and side-effects of treating children with growth hormone after kidney transplantat ion: a preliminary report. Acta Paediatr Suppl 1996, 417:7679. 29. Laine J, Kroge rus L, Sarna S, et al.: Recombinant human growth hormone treatment: its effect o n renal allograft function and histology. Transplantation 1996, 61:898903. 16.21 30. Ingulli E, Tejani A: An analytical review of growth hormone studies in child ren after renal transplantation. Pediatr Nephrol 1995, 9:S61S65. 31. Tonshoff B: Efficacy and safety of growth hormone treatment in short children with renal all ografts: 3-year experience. Kidney Int 44:199207. 32. Yadin O, Grimm PC, Ettenger RB: Renal transplantation in children. Pediatr Ann 1991, 20:662667. 33. Tejani A , Cortes C, Stablein D: Clinical correlates of chronic rejection in pediatric re nal Transplantation: a report of the North American Pediatric Renal Transplant C ooperative Study. Transplantation 1996, 61:10541058. 34. Palleschi J, Novick AC, Braun WE: Vascular complications of renal transplantation. Urology 1990, 16:61. 35. Singh A, Stablein D, Tejani A: Risk factors for vascular thrombosis in pedia tric renal transplantation. Transplantation 1997, 63:12631267. 36. Baluarte HJ, G ruskin AB, Ingelfinger JR, et al.: Analysis of hypertension in children post-ren al transplantation: a report of the North American Pediatric Renal Transplant Co operative Study (NAPTRCS). Pediatr Nephrol 1994, 8:570573. 37. Fine RN, Ettenger R: Renal transplantation in children. Kidney Transplantation: Principles and Pra ctice, edn 4. Edited by Morris PJ. Philadelphia: WB Saunders Company; 1994:418. 38. Kashton CE, McEnery PT, Tejani A, Stablein DM: Renal allograft survival acco rding to primary diagnosis: a report of the North American Pediatric Renal Trans plant Cooperative Study. Pediatr Nephrol 1995, 9:679684. 39. Tejani A, Sullivan E K, Alexander S, et al.: Post-transplant deaths and factors that influence the mo rtality rate in North American children. Transplantation 1994, 57:547553.

Recurrent Disease in the Transplanted Kidney Jeremy B. Levy M any patients receiving renal allografts become identified simply as recipients o f kidney transplantation. All subsequent events involving changes in renal funct ion are attributed to the process and natural history of transplantation itself: acute and chronic rejection, immunosuppressive drug nephrotoxicity, graft vascu lature thrombosis or stenosis, ischemia, infection, and lymphoproliferative diso rders. However, it is important to remember the nature of the underlying disease that caused the initial renal failure, even if the disease occurred many years previously. Recurrence of the primary disease often causes pathologic changes wi thin the allograft; clinical manifestations such as proteinuria and hematuria; a nd less commonly, renal failure. Thus, focal segmental glomerulosclerosis (FSGS) frequently causes recurrent proteinuria after transplantation, which may begin as early as minutes after the graft is vascularized [1]. All patients with diabe tes develop recurrent basement membrane and mesangial pathology within their all ografts [2], and recurrent oxalate deposition can cause rapid renal allograft fa ilure in patients with oxalosis [3]. Identifying patients at particular risk of primary disease recurrence allows consideration of therapeutic maneuvers that ma y minimize the incidence of recurrence. Living-related transplantation poses add itional dilemmas. For many nephritides good evidence exists for an increased inc idence of recurrent primary disease in related as opposed to cadaveric grafts. D ata from the Eurotransplant Registry suggests a fourfold increased incidence of recurrence of glomerulonephritis, causing graft loss in grafts from living relat ed donors (16.7% vs 4%) [4]. Finally, the recurrence of glomerulonephritis after transplantation, in particular, can cause specific diagnostic problems. It may be caused by recurrent disease, development of de novo glomerulonephritis in the transplanted organ, or transplanted glomerulonephritis from a donor with unreco gnized disease. Glomerulonephritis after transplantation must be distinguished f rom chronic rejection causing glomerulopathy and cyclosporine-induced glomerulot oxicity. Each of the following diseases can present diagnostic dilemmas and caus e graft failure: CHAPTER 17

17.2 Transplantation as Treatment of End-Stage Renal Disease disease, which also may be true for the glomerulonephritides. Some evidence exis ts that in the glomerulonephritides there is a reduced incidence of recurrence w ith the use of cyclosporine. Confirmed recurrence of all the glomerulonephritide s causes graft loss in 4% of adults and 7% of children receiving allografts [4,5 ]. Although few data exist on the treatment of most forms of recurrent nephritis , plasma exchange or immunoadsorption are proving beneficial at reducing nephrot ic range proteinuria in recurrent FSGS [6,7], and recurrent renal oxalate deposi tion often can be abrogated after transplantation in patients with primary hyper oxaluria [8,9]. FIGURE 17-1 Many diseases can recur in transplanted kidneys, although fewer caus e graft failure. Those disorders that can cause loss of allografts include oxalo sis (primary hyperoxaluria) and some glomerulonephritides, particularly mesangio capillary glomerulonephritis (MCGN), focal segmental glomerulosclerosis, and som etimes hemolytic uremic syndrome. Diabetes recurs almost universally in isolated renal grafts but rarely causes graft failure. Histologic recurrence of diabetic vascular pathology and glomerular pathology is much more infrequent in patients receiving combined pancreas and kidney transplantations [10,11]. Hepatitis C vi rus is now recognized as a cause of a number of problems after transplantation, including an increased risk of recurrent and de novo glomerulonephritis (MCGN an d membranous) and allograft glomerulopathy [12]. recurrence of FSGS, mesangial immunoglobulin A disease, hemolytic uremic syndrom e, mesangiocapillary glomerulonephritis, and antiglomerular basement membrane dis ease. Overall, three groups of diseases recur in patients with transplantations: metabolic disorders, especially primary hyperoxaluria and diabetes; systemic di seases, including systemic lupus erythematosus, sickle cell disease, systemic sc lerosis, hepatitis C virusassociated nephropathies and systemic vasculitis; and a variety of glomerulonephritides. For immunemediated systemic diseases the stand ard transplantation immunosuppressive regimens often prevent recurrence of prima ry DISEASES THAT RECUR AFTER KIDNEY TRANSPLANTATION Metabolic Diabetes mellitus Oxalosis Amyloidosis Fabry's disease Systemic Systemic lupus erythematosus Systemic vasculitis Sickle cell disease Hepatitis C virus associated nephropathy Systemic sclerosis Glomerulonephritis Immunoglobulin A nephropathy Focal segmental glomerulosclerosis Henoch-Schonlein purpura Membranous nephropathy MCGN Hemolytic uremic syndrome Antiglomerular bas ement membrane disease DIFFERENTIAL DIAGNOSIS OF RECURRENT DISEASE AFTER KIDNEY TRANSPLANTATION De novo glomerulonephritis Transplanted glomerulonephritis Chronic rejection Acu te allograft glomerulopathy Chronic allograft glomerulopathy Cyclosporine toxici ty Acute rejection Allograft ischemia Cytomegalovirus infection FIGURE 17-2 Acute cellular rejection and cyclosporine toxicity usually can be di stinguished easily from recurrent glomerular disease. Recurrent hemolytic uremic syndrome, however, can cause a microangiopathy similar to cyclosporine toxicity , with erythrocyte fragments visible both in blood films and within glomerular c apillary loops. The major diagnostic difficulty lies with chronic rejection, esp ecially in the form of transplantation glomerulopathy, and de novo or transplant ed glomerulonephritis. Chronic transplantation glomerulopathy occurs in 4% of re nal allografts and usually is associated with proteinuria of more than 1 g/d, be

ginning a few months after transplantation. Chronic glomerulopathy shares some f eatures with both recurrent mesangiocapillary glomerulonephritis type I and hemo lytic uremic syndrome: glomerular capillary wall thickening, mesangial expansion , and double contour patterns of the capillary walls with mesangial cell interpo sition [13]. Thus, a definitive diagnosis of recurrent nephritis may require his tologic characterization of the underlying primary renal disease and a graft bio psy before transplantation.

Recurrent Disease in the Transplanted Kidney 17.3 FIGURE 17-3 Biopsy showing rejection (panel A) and membranous changes (panel B) in a woman 8 months after transplantation. The patient initially had idiopathic membranous nephropathy that progressed to end-stage renal failure over 5 years. She subsequently received a cadaveric allograft but developed proteinuria and re nal dysfunction after 8 months. The biopsy shows recurrent membranous disease, w ith thickened glomerular capillary loops (and spikes on a silver stain), and fea tures of acute interstitial rejection, with a pronounced cellular infiltrate and tubulitis. Additional sections also showed evidence of chronic cyclosporine tox icity. In many patients, transplantation biopsies have features of several patho logic processes. Recurrent nephritis can be overlooked in a biopsy showing evide nce of chronic rejection, cyclosporine toxicity, or both. A B FIGURE 17-4 Confirming a diagnosis of recurrent disease requires a renal biopsy. Features that favor recurrence include an active urine sediment with erythrocyt es and erythrocyte casts, heavy proteinuria, and normal cyclosporine levels. Ser ologic testing for antiglomerular basement membrane antibody is important in pati ents with Alport's or Goodpasture's syndrome, and blood film examination for patient s with previous hemolytic uremic syndrome. Immunofluorescence and electron micro scopic studies are rarely performed routinely on transplantation biopsies but ca n be vital in making a diagnosis of recurrent nephritis. INVESTIGATING RECURRENT DISEASE AFTER KIDNEY TRANSPLANTATION Renal biopsy with immunofluorescence and electron microscopy Cyclosporin A level Urine microscopy and culture 24-h urine protein Renal ultrasonography Antiglomer ular basement membrane autoantibody and antineutrophil cytoplasm antibody Cytome galovirus serology and viral antigen detection Hepatitis C virus serology and RN A detection

17.4 Transplantation as Treatment of End-Stage Renal Disease RECURRENT DISEASES AFTER KIDNEY TRANSPLANTATION Recurrent diseases that commonly cause graft failure Primary hyperoxaluria type I Focal segmental glomerulosclerosis Hemolytic uremic syndrome Henoch-Schonlein purpura Mesangiocapillary GN type I (and less commonl y, type II) Immunoglobulin A disease? Histologic recurrence only, graft failure uncommon Diabetes mellitus Immunoglobulin A disease Henoch-Schonlein purpura Membranous G N Mesangiocapillary GN type II Antiglomerular basement membrane disease Systemic vasculitis (antineutrophil cytoplasm antibodyassociated) Fabry's disease Histologic recurrence rare Systemic lupus erythematosus Systemic vasculitis Idiopathic rapidly progressive GN Membranous GN FIGURE 17-5 The prevalence and incidence of recurrent disease after transplantat ion is difficult to ascertain. Certainly, system lupus erythematosus and idiopat hic rapidly progressive glomerulonephritis rarely recur in grafts, whereas in so me groups of patients recurrence of focal segmental glomerulosclerosis is univer sal [4]. There is much debate as to the frequency of recurrence of immunoglobuli n A disease and whether there is any association of recurrence with graft dysfun ction [14,15]. Recurrence of an underlying primary renal disease may cause changes wit hin the allograft and predispose patients to acute rejection and graft failure, eg, upregulation of human leukocyte antigens in parenchymal tissue. Proteinuria and dyslipidemia also can lead to changes in the expression of cell surface prot eins critical for antigen presentation and immune regulation. HISTOLOGIC AND CLINICAL RECURRENCE OF RENAL DISEASE AFTER KIDNEY TRANSPLANTATION Disease Diabetes mellitus Primary hyperoxaluria Focal segmental glomerulosclerosis Immun oglobulin A nephropathy Henoch-Schonlein purpura Mesangiocapillary glomeruloneph ritis type I Mesangiocapillary glomerulonephritis type II Membranous nephropathy Antiglomerular basement membrane disease Systemic lupus erythematosus Hemolytic uremic syndrome Vasculitis Amyloidosis

Histologic recurrence rate, % 50100 40100 1015 without risk factors 50100 with risk factors 2575 3075 970 3040 357 1 045 116 2033 Clinical recurrence rate, % 10, after 10 years 32100 50 140 145 50100 1020 50 25 Rare 1050 040 2060 FIGURE 17-6 Accurate data for recurrence rates are difficult to obtain, especial ly because transplantation biopsies often are not performed routinely after tran splantation without a specific indication. Thus, some recurrence rates may be ov errepresented in failing grafts, with asymptomatic recurrence being undetected. Many recurrent diseases do not cause urinary abnormalities or symptoms. Diseases that are slowly progressive also may be underrepresented in studies with only a short follow-up time (eg, immunoglobulin A disease).

Recurrent Disease in the Transplanted Kidney 100 Graft survival, % 80 60 40 20 0 0 5 10 15 20 25 Patients with glomerulonephritis Patients without glomerulonephritis 17.5 100 Graft survival, % 80 60 40 20 0 0 5 Grafted since 1983, y 10 Grafted before 1983, y Patients with glomerulonephritis Patients without glomerulonephritis A B FIGURE 17-7 Actuarial cadaveric survival curves in patients with or without glom erulonephritis (GN) as the primary disease. A Significantly worse renal graft su rvival in patients receiving grafts before 1983 if their underlying disease was GN, rather than any other disease (P < 0.015; diabetes excluded). B, Since the i ntroduction of cyclosporine (in transplantations after 1983), graft survival curves are the sam e for patients with or without GN. For patients receiving a living related graft , however, GN still carries an excess risk of recurrent disease causing graft fa ilure [4]. (Adapted from from Michielsen [16].) RECURRENCE OF ORIGINAL GLOMERULONEPHRITIS CAUSING GRAFT FAILURE Living related donor (LRD) kidney transplantations Years after transplantation 01 12 23 34 45 Total Cadaveric kidney transplantations All cadaveric transplantation failures from re current GN, % 0.2 0.5 0.3 0.25 0.3 1.3 All LRD transplantation failures from recurrent GN, % 1.9 0.7 1.5 0 0.8 4.4 LRD graft failures from recurrent GN, % 25 9 33 0 14 16.7 Cadaveric graft failures from recurrent GN, % 1.5 8.7 5.8 4.8 6.6 4 FIGURE 17-8 Several studies have reported an increased incidence of recurrent gl omerulonephritis (GN) after renal transplantation in grafts from living related donors. In one study with histologic data available on both donors and recipient s, GN recurred in 8.7% of 149 cadaveric grafts compared with 25.8% of 124 living donor grafts [16,17]. The data shown here are from the Eurotransplant Registry. These data demonstrate a substantial excess of recurrent GN causing graft failu re in living donor grafts compared with cadaveric grafts from the same centers over the same time period [4]. Up to one third of all the graft failures in grafts f rom living related donors were due to recurrent disease compared with less than 1 in 10 graft failures in cadaveric transplantations. No difference in recurrenc e rates was seen in any of the first 5 years after transplantation. GNglomerulone phritis. (Adapted from Kotanko and coworkers [4].)

17.6 45 40 35 Recurrence, % 30 25 20 15 10 5 0 0 Transplantation as Treatment of End-Stage Renal Disease 40 35 Graft loss from recurrence, % 30 25 20 15 10 5 0 0 5 10 Time of follow-up, y 15 20 P<0.01 Nephx No Nephx P<0.02 Nephx No Nephx 5 10 Time of follow-up, y 15 20 A B FIGURE 17-9 Bilateral pretransplantation native nephrectomy has been advocated t o reduce the likelihood of recurrence of nephritis in renal transplantations. Th e data shown here indicate that of 364 transplantations in patients with a diagn osis of primary glomerulonephritis, an increased recurrence rate exists in those 61 patients with bilateral pretransplantation nephrectomies compared with the 3 03 patients without nephrectomy (24.6% vs 12.2%; P < 0.02) [18]. Overall, 14% of patients ha ving transplantation developed recurrent glomerulonephritis (panel A), and 52% o f grafts in these patients failed (panel B). Thus, pretransplantation nephrectom y has no place in preventing recurrent nephritis. (From Odorico and coworkers [1 8].) CAUSE OF GRAFT LOSS IN RENAL GRAFT RECIPIENTS WITH DIABETES DURING THE FIRST AND SECOND DECADES First decade, % (No. of patients) 56 (104) 16 14 2 24 31 (62) 0 (0) 8 (14) 5 (9) Cause Deaths with functioning grafts: Cardiovascular disease Sepsis Malignancy Other R ejection Recurrent diabetic nephropathy Technical Other Second decade, % (No. of patients) 76 (19) 40 4 16 16 16(4) 8 (2) 0 (0) 0 (0) Hyaline vasculopathy almost universal Glomerular capillary basement membrane thi ckening Mesangial Transplant expansion, microalbuminuria 18% of patients have severe mesangial expansion (Kimmelsteil-Wilson nodules) 0 2 3 Years 4

13 FIGURE 17-10 Recurrence of diabetes in renal allografts is a common histologic f inding but a rare cause of graft loss. The most frequent cause of death in the s econd decade after transplantation was cardiovascular disease, and the most comm on cause of graft loss was the death of a patient with a functioning graft. Only 2 of 100 patients surviving more than 10 years suffered graft loss from recurre nt diabetic nephropathy, occurring at 12.6 and 13.6 years after transplantation [2]. The incidence of vascular complications and the need for amputations, howev er, are substantially increased in patients with diabetes receiving transplantat ions. In most centers, overall graft survival rates are lower for recipients wit h diabetes than for those without diabetes. (Adapted from Najarian and coworkers [2].) FIGURE 17-11 Diabetic changes in renal allografts transplanted into patients wit h diabetes. Diabetic changes (especially glomerular capillary wall thickening an d hyaline vasculopathy) probably occur in all these recipients [2,10]. Diabetic changes occur slowly, however, and rarely are severe enough to cause graft dysfu nction. The serum creatinine at 10 years in 95 patients from Minnesota with rena l allografts functioning for more than 10 years was 1.5 0.1 mg/dL (mean standard error of the mean) and in 10 patients with allograft function for 15 or more yea rs was 1.6 0.3 mg/dL [2]. Classic nodular glomerulosclerosis is much rarer. Recur rence of diabetic nephropathy can be prevented by simultaneous pancreatic and re nal transplantation. At 2 years, most patients receiving a combined pancreatic a nd kidney graft have no histologic changes on renal biopsy and normal basement m embrane thickness on electron microscopy of glomerular tissue [10,11]. Intensive insulin treatment with good glycemic control after transplantation also prevent s the development of recurrent glomerular and arteriolar lesions.

Recurrent Disease in the Transplanted Kidney 17.7 Alanine: glyoxylate aminotransferase (AGT) Glyoxylate Cofactor: pyridoxine Lacta te dehydrogenase L-a-hdrox acid oxidase Glycolate oxidase Glyoxylate reductase G lycine Oxalate Glycolate FIGURE 17-12 Primary hyperoxaluria type I in renal failure. Primary hyperoxaluri a type I is an autosomal recessive inborn error of metabolism resulting from a d eficiency (or occasionally incorrect subcellular localization) of hepatic peroxi somal alanineglyoxylate aminotransferase [8]. Patients excrete excess oxalate as a result of the increased glyoxylate pool. In many patients, renal disease is ma nifested by chronic renal failure. Once the glomerular filtration rate has decre ased below 25 mL/min the combination of oxalate overproduction and reduced urina ry excretion leads to systemic oxalosis, with calcium oxalate deposition in many tissues. Renal transplantation alone has yielded poor results in the past, with 1-year graft survival rates of only 26% [3]. Combined hepatorenal transplantati on simultaneously replaces renal function and corrects the underlying metabolic defect. The 1-year liver graft survival rate is 88%, with patient survival of 80 % at 5 years. Of 24 renal grafts from the European experience of hepatorenal tra nsplantation, 17 were still functioning at 3 months to 2 years after transplanta tion [19]. FIGURE 17-13 Histologic slide of a patient who received an isolated renal allogr aft for primary hyperoxaluria type I in which oxylate crystals are seen clearly within the tubules and interstitium. The major hazards for the renal graft after transplantation include early acute nephrocalcinosis caused by rapid mobilizati on of the systemic oxalate deposits. Acute tubular obstruction by calcium oxalat e crystals also can occur. Late nephrocalcinosis leads to progressive loss of re nal function over several years. Rejection episodes are less common in patients receiving combined liver and kidney grafts than in those receiving kidney transp lantation alone [3,19]. Acute rejection with renal dysfunction, however, causes additional episodes of acute calcium oxalate deposition in the kidney. Recurrent oxalosis can be seen as early as 3 months after transplantation. PATIENT MANAGEMENT IN RENAL OR HEPATORENAL TRANSPLANTATIONS FOR PRIMARY HYPEROXA LURIA Aggressive preoperative dialysis (and possibly continued postoperatively) Mainte nance of high urine output Low oxalate, low ascorbic acid, diet low in vitamin D Phosphate supplements Magnesium glycerophosphate High-dose pyridoxine (500 mg/d ) Thiazide diuretics FIGURE 17-14 Daily hemodialysis for at least 1 week before transplantation deple tes the systemic oxalate pool to some extent. Some centers continue aggressive h emodialysis after transplantation, regardless of the renal function of the trans planted organ. In patients receiving combined hepatorenal grafts, dietary measur es to reduce oxalate production are not as important as they are in patients rec eiving isolated kidney grafts. In these patients, excess production of oxalate f rom glyoxylate still occurs. Magnesium and phosphate supplements are powerful in hibitors of calcium oxalate crystallization and should be used in all recipients , whereas thiazide diuretics may reduce urinary calcium excretion. Pyridoxine is a cofactor for alanine glyoxylate aminotransferase and can increase the activity of the enzyme in some patients. Pyridoxine has no role in combined hepatorenal transplantation. For most patients the ideal option is probably a combined trans plantation when their glomerular filtration rate decreases below 25 mL/min [8,9]

17.8 Transplantation as Treatment of End-Stage Renal Disease AMYLOIDOGENIC AND RELATED DISEASES CAUSING RENAL FAILURE Disease Nonhereditary Systemic amyloidosis associated with chronic inflammatory disorder s (especially rheumatoid arthritis) Systemic amyloidosis associated with immune dyscrasia: multiple myeloma, monoclonal gammopathy, occult immune dyscrasia, lym phoma Hereditary Familial Mediterranean fever Ostertag-type (autosomal dominant, early hypertension, and renal impairment) Muckle-Wells syndrome (deafness, neph ropathy, urticaria, and limb pain) Hereditary renal amyloidosis Familial nephrop athic systemic amyloidosis Light chain deposition disease Fibril protein Amyloid A AL Precursor protein Serum amyloid A Monoclonal immunoglobulin light chain Serum amyloid A Not known Not known Fibrinogen Apolipoprotein A Immunoglobulin light chains Amyloid A Not known Not known Fibrinogen Apolipoprotein A AL or immunoglobulin l ight chains FIGURE 17-15 The most common cause of amyloidosis leading to renal failure is rh eumatoid arthritis [20]. However, increasing numbers of patients with myeloma an d AL amyloid, or primary amyloidosis, are now receiving peripheral blood stem ce ll transplantations or bone marrow allografts. Thus, these patients are survivin g long enough to consider renal transplantation. Over 60 patients with renal fai lure resulting from systemic amyloid A (AA) amyloidosis have been reported to ha ve received renal allografts. Graft survival in these patients is the same as th at of a matched population. Histologic recurrence of renal amyloid has been reported in 20% to 33% of these grafts with in 2 years of transplantation [20,21]. Patient survival is reduced, owing to inf ections and vascular complications, to 68% at 1 year and 51% at 2 years. Recurre nce is characterized by proteinuria 11 months to 3 years after transplantation. Recurrent light chain deposition disease is found in half of patients receiving allografts, with graft loss in one third despite plasmapheresis and chemotherapy [4]. Heavy proteinuria is seen at the onset of recurrence. ALprimary amyloidosis . FIGURE 17-16 Microradioangiography comparing the vasculature of the kidney in a patient with no disease (panel A) and a patient with homozygous sickle cell di sease (panel B) [22]. Despite the frequency of renal damage in sickle cell disea se, only 4% of patients progress to end-stage renal disease, and little experien ce exists with renal transplantation. Three patients have been reported with rec urrent sickle cell nephropathy. In one case, a patient developed renal dysfuncti on 3.5 years after transplantation; a biopsy showed glomerular sclerosis, tubula r atrophy, and interstitial fibrosis, without features of rejection. A second st udy reported recurrent sickle cell nephropathy leading to graft failure in two o f eight patients receiving transplantation [23]. Concentration defects were obse rved within 12 months of grafting. Patients also suffered an increased incidence of sickle cell crises after renal transplantation, possibly associated with the increase in hematocrit. A B

Recurrent Disease in the Transplanted Kidney 17.9 FEATURES OF RECURRENT SYSTEMIC LUPUS ERYTHEMATOSUS Rash Arthralgia Proteinuria (usually nonnephrotic) Increasing anti-DNA antibody titers Increasing antinuclear antibody titers Decreasing complement levels (C3 a nd C4) RELAPSE RATE IN ANTINEUTROPHIL CYTOPLASM ANTIBODYASSOCIATED SYSTEMIC VASCULITIS Relapse rate on dialysis, relapses/patient/y 0.088 0.24 0.3 Series Hammersmith Hospital 19741997 [26] Habitz and coworkers 19801995 [26] Schmitt and coworkers 19821993 [26] Patients, n 59 18 18 Relapse rate after transplantation, relapses/patient/y 0.018 0.06 0.1 FIGURE 17-17 Nephritis caused by systemic lupus erythematosus (SLE) rarely recur s in transplantations. SLE accounts for approximately 1% of all patients receivi ng allografts, and less than 1% of these will develop recurrent renal disease. T ime to recurrence has been reported as 1.5 to 9 years after transplantation [24, 25]. Cyclosporine therapy does not prevent recurrence. It is reasonable to ensur e that serologic test results for SLE are minimally abnormal before transplantat ion and certainly that patients have no evidence of active extrarenal disease. P atients with lupus anticoagulant and anticardiolipin antibodies are at risk of t hromboembolic events, including renal graft vein or artery thrombosis. These pat ients may require anticoagulation therapy, or platelet inhibition with aspirin. FIGURE 17-18 Recurrence of Wegener's granulomatosis or microscopic polyangiitis ha s been reported after transplantation, with overall renal and extrarenal recurre nce rates of up to 29% and renal recurrences alone of up to 16% [27]. Graft loss has been reported in up to 40% of patients with renal recurrence. In the most r ecent data from the Hammersmith Hospital, however, renal recurrences were rare, with only 0.018 relapses per patient per year after transplantation [26]. These patients have often been on long courses of immunosuppressive therapy before rec eiving a graft. Extrarenal recurrence of Wegener's granulomatosis can involve the ureter, causing stenosis and obstructive nephropathy. Serial monitoring of antin eutrophil cytoplasmic antibodies after transplantation is important in all patie nts with vasculitis because changes in titer may predict disease relapse [28,29] . (Adapted from Allen and coworkers [26].) RENAL COMPLICATIONS OF HEPATITIS C VIRUS AFTER KIDNEY TRANSPLANTATION Clinical: Proteinuria Nephrotic syndrome Microscopic hematuria Histologic and la boratory findings Mesangiocapillary glomerulonephritis with or without cryoglobu linemia, hypocomplementemia, rheumatoid factors Membranous nephropathy: normal c omplement, no cryoglobulinemia or rheumatoid factor Acute and chronic transplant ation glomerulopathy FIGURE 17-19 Recurrence of both mesangiocapillary glomerulonephritis (MCGN) and, less frequently, membranous nephropathy is well described after transplantation . Nineteen cases of de novo or recurrent MCGN after transplantation have been de scribed in patients with hepatitis C virus (HCV) [12]. Almost all had nephrosis and exhibited symptoms 2 to 120 months after transplantation. Eight patients had demonstrable cryoglobulin, nine had hypocomplementemia, and most had normal liv

er function test results. Membranous GN is the most common de novo GN reported i n allografts, and it is possible that HCV infection may be associated with its d evelopment [12]. Twenty patients with recurrent or de novo membranous GN and HCV viremia have been reported. In one study, 8% of patients with membranous GN had HCV antibodies and RNA compared with less than 1% of patients with other forms of GN (excluding MCGN) [30]. Prognosis in these patients was poor, with persiste nt heavy proteinuria and declining renal function.

17.10 Transplantation as Treatment of End-Stage Renal Disease FIGURE 17-20 Focal segmental glomerulosclerosis accounts for 7% to 10% of patien ts requiring renal replacement therapy. The overall recurrence rate is approxima tely 20% to 30% [1,4,31]. These numbers, however, may be an underestimate becaus e of biopsy sampling errors. Patients at high risk for recurrence can be identif ied, particularly children with rapid evolution of their original disease and me sangial expansion on biopsy [1,32]. Recurrence manifests with proteinuria (often 1040 g/d), developing hours to weeks after transplantation. In children the mean time to recurrence is 14 days. Recurrence is not benign and leads to graft loss in up to half of patients. Patients at highest risk for recurrence should not r eceive grafts from living related donors. RISK FACTORS FOR RECURRENT FOCAL SEGMENTAL GLOMERULOSCLEROSIS AFTER TRANSPLANTAT ION Risk factor Age <5 y Age < 15 y with progression to end-stage renal disease within 3 y First graft lost from focal segmental glomerulosclerosis Adults without risk factors Recurrence rate, % 50 80100 7585 1015 Graft loss occurs in half of all patients with recurrent focal segmental glomeru losclerosis and nephrotic syndrome. A. RECURRENT FOCAL SEGMENTAL GLOMERULOSCLEROSIS AND ACUTE RENAL FAILURE AFTER TR ANSPLANTATION Patients with recurrence, n Acute renal failure (23) No acute renal failure (50) 16 10 Patients with no recurrence, n 7 40 B. ACUTE REJECTION EPISODES AMONG ACUTE RENAL FAILURE CASES Patients with recurrence Acute renal failure >1 acute rejection episode No rejection 16 0 FIGURE 17-21 Patients with recurrent focal segmental glomerulosclerosis are at s ubstantially increased risk of developing both acute renal failure (panel A) aft er transplantation and acute rejection episodes (panel B). In one study, 23 of 2 6 patients with recurrence developed one or more episodes of rejection, compared with only 11 of 40 patients without recurrence [31]. Although the mechanism for the increased rate of acute dysfunction and rejection is unclear, proteinuria a nd dyslipidemia may alter the expression of cell surface immunoregulatory molecu les and major histocompatibility complex antigens. (Adapted from Kim and coworke rs [31].) No acute renal failure 7 3 Patients with no recurrence, no acute renal failure 11 29

Recurrent Disease in the Transplanted Kidney 6 Serum creatinine, mg/dL 10 8 6 4 2 0 55 155 Day after transplantation 1 3 2 3 Urinary protein excretion, g/d 4 Serum creatinine, mg/dL 10 8 6 4 2 0 60 110 160 210 260 6 4 2 5 5 2 Urinary protein excretion, g/d 10 8 Serum creatinine, mg/dL 10 8 6 4 2 0 500 520 540 560 580 4 17.11 12 10 8 6 4 2 A B Day after transplantation C Day after transplantation 3 Serum creatinine, mg/dL 10 8 6 4 2 0 400 500 600 3 2 1 Urinary protein excreti on, g/d 5 4 D Day after transplantation FIGURE 17-22 Serum creatinine concentrations and urinary protein excretion in fo ur patients (AD) with recurrent nephrotic syndrome after transplantation treated by protein adsorption. Each bar indicates one cycle of treatment and the numbers above the bars indicate the sessions of treatment in that cycle. A number of st udies have demonstrated that both plasma exchange and protein adsorption (using protein A sepharose), can decrease urinary protein excretion in recurrent focal segmental glomerulosclerosis [6,7,33]. Four examples are shown here. In this stu dy, protein excretion decreased by 82% but returned to pretreatment levels withi n 2 months in seven of eight patients. More intensive treatment regimens have le d to longer remissions [7]. The nature of the circulating factor responsible for protein leakage is unknown. There are case reports of children with recurrent f ocal segmental glomerulosclerosis responding to high-dose intravenous cyclospori ne with remission of nephrotic syndrome. However, cyclosporine does not prevent recurrence when used as part of the initial immunosuppressive regimen. (Adapted from Dantal and coworkers [6].) FIGURE 17-23 Segmental glomerular scars in a fun ctioning graft is a common finding. The interpretation of the biopsy requires kn owledge of the previous histology in the native kidneys and the clinical course after transplantation. Immunohistology and electron microscopy can be particular ly helpful in this setting. Recurrent focal segmental glomerulosclerosis is the most common cause of early massive proteinuria. Both rejection and cyclosporine therapy, however, can cause segmental scars indistinguishable from those of foca l segmental glomerulosclerosis. Recurrent or de novo immunoglobulin A disease in an allograft also can cause segmental glomerular scarring, but with mesangial h ypercellularity, immunoglobulin A detectable by immunostaining, and paramesangia l deposits on electron microscopy. DIFFERENTIAL DIAGNOSIS OF SEGMENTAL GLOMERULAR SCARS ON TRANSPLANTATION BIOPSY Diagnosis Recurrent FSGS Rejection Cyclosporine-related De novo FSGS Other glomerulonephri tides Features Recurrent heavy proteinuria within 3 mo Original disease caused renal failure in <3 y Insidious onset of proteinuria Features of chronic rejection on biopsy, es

pecially vascular sclerosis and glomerulopathy Previous thrombotic microangiopat hy affecting glomeruli Original disease not FSGS Chronic rejection excluded Char acteristic immunohistology and electron microscopy, especially in immunoglobulin A disease FSGSfocal segmental glomerulosclerosis. Urinary protein excretion, g/d

17.12 Transplantation as Treatment of End-Stage Renal Disease RECURRENT IMMUNOGLOBULIN A DISEASE Features Histologic recurrence, 25%75% Clinical recurrence, 1%40% Time to recurrence, 2 mo to 4 y Clinical presentation: asymptomatic, low-grade proteinuria, microscopic h ematuria Susceptibility: human leukocyte antigen B35, DR4; immunoglobulin A rheu matoid factors Graft loss, <10% FIGURE 17-24 Up to 75% of patients with immunoglobulin A (IgA) disease develop h istologic recurrence within their grafts, which usually presents with microscopi c hematuria and proteinuria [4,14,15]. Many patients, however, only will have re currence noted on a routine biopsy after transplantation. Most studies suggest t hat the risk of graft loss resulting from recurrent disease is low (<10%) [4]. H owever, longterm follow-up in some studies has suggested an increasing rate of g raft loss with time, approaching 20% at 46 months [14,15]. Conversely, one study has documented 100% graft survival at 2 years in patients with IgA disease who had IgA antihuman leukocyte antigen (HLA) antibodies [34]. The mechanism is uncle ar. The association of IgA disease and the HLA alleles B35 and DR4 may explain t he increased risk of recurrence in grafts from living related donors because fam ily members are more likely to share HLA genes. FIGURE 17-25 Histologic slide of a biopsy from a patient with recurrent immunogl obulin A (IgA) nephropathy. This patient developed proteinuria 9 months after re ceiving a cadaveric allograft. The biopsy shows features of recurrent IgA diseas e with mesangial expansion and a glomerular tuft adhesion to Bowman's capsule. Imm unohistology confirmed deposition of IgA in the mesangium. At the earliest stage s of recurrence, mesangial IgA and complement C3 are detectable by 3 months afte r transplantation, with electron-dense deposits in the paramesangium but normal appearance on light microscopy. In patients with progressive renal dysfunction, crescents often are found in the glomerulus. RECURRENT HENOCH-SCHONLEIN PURPURA Features Risk of recurrence, 30%75% Clinical recurrence, up to 45% Time to recurrence, imm ediately to 20 mo Clinical presentation: often asymptomatic; hematuria, proteinu ria, arthralgia, purpuric rash, melena Susceptibility: rapid development of rena l failure in native kidneys, age >14 y Graft loss: up to 20%, increased in graft s from living related donors FIGURE 17-26 Most studies have shown that histologic recurrence of HenochSchonle in purpura (HSP) is common but rarely causes graft loss. Grafts from living rela ted donors have a substantially increased risk of failure as a result of recurre nt HSP. Patients can develop both renal and extrarenal manifestations of HSP, es pecially arthralgia. Rapid evolution of the original disease and older age at pr esentation (>14 y) seem to be risk factors for clinical recurrence. Cyclosporine does not prevent recurrence. It has been arbitrarily suggested that transplanta tion should be avoided for 12 months after resolution of the purpura; however, i ndividual cases of recurrent disease have been reported despite delays of over 3 years between resolution of purpura and grafting.

Recurrent Disease in the Transplanted Kidney 17.13 MESANGIOCAPILLARY GLOMERULONEPHRITIS Feature Histologic recurrence Clinical recurrence Time to recurrence Clinical presentati on Type I 9%70% 30%40% 2 wk to 7 y (median, 1.5 y) Rarely asymptomatic; proteinuria, nephrot ic syndrome, microscopic hematuria Grafts from living related donor Type II 50%100% 10%20% 1 mo to 7 y (usually <1 y) Frequently asymptomatic nonnephrotic pro teinuria, microscopic hematuria Male, rapidly progressive course of initial dise ase, nephrotic syndrome after transplantation Risk factors FIGURE 17-27 Both mesangiocapillary glomerulonephritis (MCGN) type I (mesangial and subendothelial deposits) and type II (dense deposit disease) commonly recur after transplantation. Silent recurrence is found more often in type II disease, whereas recurrence of type I MCGN frequently causes nephrotic syndrome and graf t failure [35]. An increased risk of recurrence of type I MCGN occurs in grafts from living related donors. Type II disease recurs more often in male patients w ho progressed rapidly to end-stage renal failure before transplantation. The ons et of nephrotic syndrome in type II disease usually heralds graft failure. No es tablished treatment for recurrent disease exists, although anecdotally aspirin p lus dipyridamole and cyclophosphamide have been used with some success in recurr ent type I MCGN. Plasma exchange has been reported to improve the histologic cha nges and induce a clinical remission in one patient with recurrence of type II M CGN [36]. Mononuclear cell nucleus Capillary lumen Interpositioned mesangial cell Podocytes FIGURE 17-28 Electron micrographs of mesangiocapillary glomerulonephritis (MCGN) type I (A) and type II (B). The histologic features of recurrence are the same as for the primary disease. In type II MCGN the ribbonlike band of electron-dens e material within the glomerular basement membrane has been observed as early as 3 weeks after transplantation. Initially, the recurrence is focal but subsequen tly progresses to involve most of the capillary walls. Failing grafts frequently have segmental glomerular necrosis and extracapillary crescents. Making the dia gnosis is not difficult when electron microscopy has been performed on the trans plantation biopsy. In MCGN type I, electron-dense deposits first appear in the m esangium and subsequently in a subendothelial position. Mesangial cell interposi tion frequently is visible on electron microscopy, and on light microscopy the c apillary walls appear thickened and show a double contour. The differential diag nosis is MCGN caused by acute or chronic transplantation glomerulopathy. Global changes, immune deposits, and increased mesangial cells, however, are rare in ch ronic transplantation glomerulopathy. Endocapillary proliferation and macrophage s within capillary loops are important features of acute transplantation glomeru lopathy, which usually are absent in recurrent MCGN [13]. A

Endothelial cell Subendothelial deposits Basement membrane Endothelial cell Basement membrane Podocyte foot processes Cell nucleus Capillary lumen B Continuous band of electron-dense material in basement membrane

17.14 Transplantation as Treatment of End-Stage Renal Disease FEATURES OF RECURRENT AND DE NOVO MEMBRANOUS NEPHROPATHY AFTER TRANSPLANTATION Features Incidence Clinical presentation Time of onset Histology Risk factors for graft f ailure Incidence of graft failure De novo membranous 2%5% Often asymptomatic; proteinuria, nephrotic syndrome develops slowly 4 mo to 6 y (mean 22 mo) Identical to native membranous nephropathy, often shows feature s of chronic rejection None specific Increased over controls; may be as high as 50% but most patients also have chronic rejection Recurrent membranous 3%57% Proteinuria, nephrotic syndrome develops rapidly 1 wk to 2 y (mean 10 mo) I dentical to native membranous nephropathy, often shows features of chronic rejec tion Male gender, aggressive clinical course 50%60%, but some studies have shown no increased graft failure rate compared with other nephritides FIGURE 17-29 Recurrence of membranous nephropathy in transplantations is variabl e, with studies reporting incidences from 3% to 57% [4,37]. The major differenti al diagnosis is de novo membranous nephropathy in patients with a different unde rlying renal pathology. De novo allograft membranous glomerulonephritis reported in 2% to 5% of transplantations is often asymptomatic and usually associated wi th chronic rejection [38]. In contrast, recurrent disease frequently causes nephrotic syndrome, devel oping within the first 2 years after transplantation. Data on the incidence of g raft failure attributable to membranous disease are confusing. Cyclosporine ther apy has made no difference in the incidence of the two entities, and hepatitis C virus infection may be associated with membranous disease after transplantation . FIGURE 17-30 Histologic slide of a biopsy showing extensive spike formation alon g the glomerular basement membrane. This woman had recurrent membranous disease 8 months after transplantation. She developed nephrotic range proteinuria and su bsequent renal dysfunction. Both recurrent and de novo membranous glomerulonephr itis are indistinguishable from idiopathic membranous nephropathy. The initial l esions are generally stage I or II, although the deposits subsequently become di ffuse and intramembranous. FIGURE 17-31 (see Color Plate) Histologic slide showing deposition of antiglomeru lar basement membrane (GBM) antibody along the GBM, which is seen in over half o f patients with Goodpasture's syndrome who receive an allograft while circulating antibodies are still detectable [39]. In most of these cases no histologic abnor malities are seen within the glomerulus, however, and patients remain asymptomat ic with normal renal function. Approximately 25% of patients with antibody depos ition will develop features of crescentic and rapidly progressive glomerulonephr itis and subsequently suffer graft loss. Delaying transplantation for at least 6 months after antibodies have become undetectable reduces the recurrence rate to only 5% to 15%.

Recurrent Disease in the Transplanted Kidney 100 17.15 DIFFERENTIAL DIAGNOSIS OF LINEAR DEPOSITION OF IMMUNOGLOBULIN ALONG THE GLOMERUL AR BASEMENT MEMBRANE IN TRANSPLANTATION BIOPSY Immunosuppression alone Antibody titer, % 50 With plasma exchange + immunosuppression No treatment Recurrent antiglomerular basement membrane disease Antiglomerular basement membran e disease in patients with Alport's syndrome Chronic transplant glomerulopathy Dia betes mellitus Myeloma Recurrent mesangiocapillary glomerulonephritis type I (ra rely fibrillary nephritis, and normal cadaveric grafts after initial perfusion) 15 0 0 3 6 9 Time, mo 12 FIGURE 17-32 Without treatment, circulating antiglomerular basement membrane auto antibodies become undetectable within 6 to 18 months of disease onset [40,41]. T reatment of the primary disease with plasma exchange, cyclophosphamide, and ster oids leads to rapid loss of circulating antibodies. Patients who need transplant ation while circulating antibodies are still detectable should be treated with p lasma exchange before and after transplantation to minimize circulating antibody levels and with cyclophosphamide therapy for 2 months. A similar approach shoul d be used in patients with clinical recurrence. Patients who have linear immunog lobulin deposition in the absence of focal necrosis, crescents, or renal dysfunc tion do not require treatment. FIGURE 17-33 Linear immunoglobulin G (IgG) is found in 1% to 4% of routine renal allograft biopsies from patients with neither antiglomerular basement membrane ( GBM) disease nor Alport's syndrome. Linear antibody deposition in anti-GBM disease is diffuse and global and, in practice, is rarely confused with the nonspecific antibody deposition seen in other conditions. In chronic transplantation glomer ulopathy the antibody deposition is focal and segmental, and focal necrosis and cellular crescents are extremely rare. The finding of linear antibody deposits o n a transplantation biopsy should lead to testing for circulating anti-GBM antib odies. Early graft loss or dysfunction, along with linear IgG staining, may be t he first indication that a patient with an unidentified cause for end-stage rena l disease has Alport's syndrome. FIGURE 17-34 Mutations have been identified in ab out half of patients with Alport's syndrome and are found in the genes for the 3, 4, or 5 chains of type IV collagen, which are the major constituents of the glom erular basement membrane. After transplantation, approximately 15% of patients d evelop linear deposition of immunoglobulin G (IgG) along the glomerular basement membrane (GBM), and circulating anti-GBM antibodies specific for the 3 or 5 cha ins of type IV collagen [4244]. It is unclear why only some patients develop anti bodies. Clinical disease, however, is rare. Only 20% of patients with antibody d eposition develop urinary abnormalities from 1 month to 2 years after grafting. Those patients who do develop proteinuria or hematuria usually lose their grafts . In some cases, treatment with cyclophosphamide did not prevent graft loss. MUTATIONS IN GLOMERULAR BASEMENT MEMBRANE COLLAGEN GENES Chromosome Collagen 13 2 X X 1 and 2 chains of type IV 3 and 4 chains of type IV 5 chain of type IV

6 chain of type IV Diseases caused by mutations Autosomal recessive or dominant Alport's syndrome Classic X-linked Alport's syndrome Diffuse leiomyomatosis

17.16 Transplantation as Treatment of End-Stage Renal Disease FIGURE 17-35 The microangiopathic hemolysis of recurrent hemolytic uremic syndro me (HUS) is identical to the original disease, with extensive erythrocyte fragme ntation and thrombocytopenia. The incidence of HUS recurrence is difficult to as sess. At one extreme, five of 11 children suffered graft loss because of recurre nt disease. However, most series have reported substantially lower recurrence ra tes: no recurrences in 16 adults and children, one of 34 grafts in 28 children, and two probable recurrences of 24 grafts in 20 children [4,45,46]. Graft loss o ccurs in 10% to 50% of patients with recurrence. HUS has been diagnosed 1 day to 15 months after transplantation (usually in less than 2 months), and the incide nce of recurrence is increased in patients receiving grafts less than 3 months a fter their initial disease. Treatment of recurrent disease is plasma exchange fo r plasma or cryosupernatant, or plasma infusions, and dose reduction of cyclospo rine. Recurrence may be prevented by aspirin and dipyridamole. FIGURE 17-36 Bloo d film abnormalities, microangiopathic hemolytic anemia, thrombocytopenia, and a cute renal failure occur in accelerated hypertension and acute vascular rejectio n. A renal biopsy usually distinguishes acute vascular rejection, and malignant hypertension should be obvious clinically. The microangiopathy of cyclosporine c an be difficult to differentiate from hemolytic uremic syndrome; however, glomer ular pathology usually is less marked and vascular changes more obvious with cyc losporine toxicity. De novo hemolytic uremic syndrome also has been reported in patients treated with tacrolimus (FK-506) [27]. DIFFERENTIAL DIAGNOSIS OF RECURRENT HEMOLYTIC UREMIC SYNDROME Thrombotic microangiopathy associated with cyclosporine Acute vascular rejection Accelerated phase hypertension Tacrolimus- (FK-506) associated thrombotic micro angiopathy OTHER CONDITIONS THAT RECUR IN RENAL ALLOGRAFTS Disease Systemic sclerosis Fabry's disease Immunotactoid glomerulopathy Mixed essential cr yoglobulinemia Cystinosis Recurrence rate 20% Rare recurrence of ceramide in the graft 50% 50% 0% Outcome Usually graft failure Poor Nephrotic syndrome Poor Good Comments Differentiation from acute and chronic vascular rejection can be difficult Renal transplantation does not halt the progress of Fabry's disease because the new kid ney is not an adequate source of -galactosidase; patients have frequent systemic complications Nephrosis reported between 21 and 60 mo Recurrence associated wit h extrarenal features including arthralgias and purpura Cystinosis does not recu r; however, the allograft can become infiltrated by macrophages containing cyste ine, with no pathologic or clinical effect FIGURE 17-37 A number of other conditions have been reported to recur in allogra fts. Very few patients with systemic sclerosis have received transplantation, an d the incidence of acute renal failure caused by systemic sclerosis has declined with the widespread use of angiotensinconverting enzyme (ACE) inhibitors. About 20% of patients with a malignant course of scleroderma receiving a transplantat ion develop recurrence, which usually causes graft loss. The value of ACE inhibitors after t ransplantation is unknown. Two of four patients with immunotactoid glomerulopath y developed recurrent disease heralded by massive proteinuria. Transplantation i

n Fabry's disease rarely leads to graft-related problems; however, patients die fr om systemic complications of ceramide deposition.

Recurrent Disease in the Transplanted Kidney 17.17 MANAGEMENT OF RECURRENT DISEASE AFTER KIDNEY TRANSPLANTATION Disease Focal segmental glomerulosclerosis Treatment of recurrence Plasma exchange, immunoadsorption, steroids, angiotensin-converting enzyme inhib itors, nonsteroidal anti-inflammatory drugs With crescents: plasma exchange, cyt otoxics ?Steroids Aspirin, dipyridamole ?Plasma exchange ?Cytotoxics and steroid s Plasma exchange, cyclophosphamide Plasma exchange, plasma infusion Cyclophosph amide and steroids Glycemic control Aggressive perioperative dialysis, hydration , low oxalate diet, low ascorbic acid diet, phosphate supplements, magnesium gly cerophosphate, pyridoxine Immunoglobulin A nephropathy Henoch-Schonlein purpura Mesangiocapillary glomerul onephritis type I Mesangiocapillary glomerulonephritis type II Membranous nephro pathy Antiglomerular basement membrane disease Hemolytic uremic syndrome Antineut rophil cytoplasm antibodyassociated vasculitis Diabetes Oxalosis FIGURE 17-38 No controlled data exist on the management of recurrent disease aft er transplantation. For patients with primary hyperoxaluria, measures to prevent further deposition of oxalate have proved successful in controlling recurrent r enal oxalosis [9]. In diabetes mellitus, the pathophysiology of recurrent nephro pathy undoubtedly reflects the same insults as those causing the initial renal f ailure, and good evidence exists that glycemic control can slow the development of end-organ damage. Plasma exchange and immunoadsorption are promising therapie s for patients with nephrosis who have recurrent focal segmental glomerulosclero sis; however, these therapies do not provide sustained remission [6,7]. In all t hese cases, establishing a diagnosis of recurrent disease is critical in identif ying a possible treatment modality. WHEN TO AVOID USING LIVING RELATED DONORS IN KIDNEY TRANSPLANTATION Focal segmental glomerulosclerosis with risk factors for early recurrence Henoch -Schonlein purpura Mesangiocapillary glomerulonephritis type I Mesangiocapillary glomerulonephritis type II with risk factors (familial immunoglobulin A nephrop athy and hemolytic uremic syndrome) FIGURE 17-39 In these diseases, rapid recurrence leading to graft failure is fre quent enough to warrant extreme caution in using living related donors. Even exc luding these conditions, the overall rate of recurrence of glomerulonephritis is substantially increased in living related donors, and patients should be made a ware of this risk [4]. For familial diseases, the risk of recurrence is even hig her (eg, some families with immunoglobulin A disease and hemolytic uremic syndro me). Finally, recurrent glomerulonephritis has been reported in up to 30% of ren al isografts, with disease onset between 2 weeks and 16 years after grafting. References 1. Tejani A, Stablein DH: Recurrence of focal segmental glomerulonephritis postt ransplantation: a special report of the North American Pediatric Renal Transplan t Cooperative Study. J Am Soc Nephrol 1992, 2(suppl):258263. 2. Najarian JS, Kauf man DB, Fryd DS, et al.: Long term survival following kidney transplantation in 100 type I diabetic patients. Transplantation 1989, 47:106113. 3. Broyer M, Brunn er FP, Brynger H, et al.: Kidney transplantation in primary oxalosis: data from the EDTA registry. Nephrol Dial Transplant 1990, 5:332336. 4. Kotanko P, Pusey CD , Levy JB: Recurrent glomerulonephritis following renal transplantation. Transpl antation 1997, 63:10451052. 5. Cameron JS: Recurrent primary disease following re nal transplantation. In Advanced Renal Medicine. Edited by Raine AEG. Oxford: Ox

ford University Press; 1992:435448. 6. Dantal J, Bigot E, Bogers W, et al.: Effec t of plasma protein adsorption on protein excretion in kidney-transplant recipie nts with recurrent nephrotic syndrome. N Engl J Med 1994, 330:714. 7. Artero ML, Sharma R, Savin VJ, et al.: Plasmapheresis reduces proteinuria and serum capacit y to injure glomeruli in patients with recurrent focal glomerulosclerosis. Am J Kidney Dis 1994, 23:574581. 8. Watts RWE: Primary hyperoxaluria type 1. Q J Med 1 994, 87:593599. 9. Allen AR, Thompson EM, Williams G, et al.: Selective renal tra nsplantation in primary hyperoxaluria type 1. Am J Kidney Dis 1996, 27:891895. 10 . Bilous RW, Mauer SM, Sutherland DE, et al.: The effects of pancreas transplant ation on the glomerular structure of renal allografts in patients with insulin-d ependent diabetes. N Engl J Med 1989, 321:8085. 11. Remuzzi G, Ruggenenti P, Maue r SM: Pancreas and kidney/pancreas transplants: experimental medicine or real im provement? Lancet 1994, 343:2731. 12. Morales JM, Campistol JM, Andres A, et al.: Glomerular diseases in patients with hepatitis C virus infection after renal tr ansplantation. Curr Opinion Nephrol Hypertens 1997, 6:511515. 13. Porter KA: Rena l transplantation. In Pathology of the Kidney. Edited by Heptinstall RH. Boston: Little, Brown; 1992:17991934.

17.18 Transplantation as Treatment of End-Stage Renal Disease 31. Kim EM, Striegel J, Kim Y, et al.: Recurrence of steroid resistant nephrotic syndrome in kidney transplants is associated with increased acute renal failure and acute rejection. Kidney Int 1994, 45:14401445. 32. Senggutuvan P, Cameron JS , Hartley RB, et al.: Recurrence of focal segmental glomerulosclerosis in transp lanted kidneys: analysis of incidence and risk factors in 59 allografts. Pediatr Nephrol 1990, 4:218. 33. Savin VJ, Sharma R, Sharma M, et al.: Circulating facto r associated with increased glomerular permeability to albumin in recurrent foca l glomerulosclerosis. N Engl J Med 1996, 334:878883. 34. Mathew TH: Recurrence of disease following renal transplantation. Am J Kidney Dis 1988, 12:8596. 35. Glic klich D, Matas AJ, Sablay LB, et al.: Recurrent membranoproliferative glomerulon ephritis type I in successive renal transplants. Am J Nephrol 1987, 7:143149. 36. Oberkircher OR, Enama M, West JC, et al.: Regression of recurrent membranoproli ferative glomerulonephritis type II in a transplanted kidney after plasmapheresi s. Transplant Proc 1988, 20:418423. 37. Couchoud C, Pouteil-Noble C, Colon S, et al.: Recurrence of membranous nephropathy after renal transplantation. Transplan tation 1995, 59:12751279. 38. Schwarz A, Krause PH, Offermann G, et al.: Impact o f de novo membranous glomerulonephritis on the clinical course after kidney tran splantation. Transplantation 1994, 58:650654. 39. Levy JB, Pusey CD: Anti-GBM ant ibody mediated disease. In Nephrology. Edited by Wilkinson R, Jamison R. London: Chapman & Hall; 1997:599615. 40. Peters DK, Rees AJ, Lockwood CM, et al.: Treatm ent and prognosis in antibasement membrane antibody mediated nephritis. Transpla nt Proc 1982, 14:51321. 41. Simpson IJ, Doak PB, Williams LC, et al.: Plasma exch ange in Goodpasture's syndrome. Am J Nephrol 1982, 2:301311. 42. Turner AN, Rees AJ : Goodpasture's disease and Alport's syndromes. Ann Rev Med 1996, 47:377386. 43. Kall uri R, van den Heuvel LP, Smeets HJ, et al.: A COL4A3 gene mutation and post-tra nsplant anti- 3(IV) collagen alloantibodies in Alport syndrome. Kidney Int 1995, 47:11991204. 44. Ding J, Zhou J, Tryggvason K, et al.: COL4A5 deletions in three patients with Alport syndrome and posttransplant antiglomerular basement membra ne nephritis. J Am Soc Nephrol 1994, 5:161168. 45. Gagnadoux MF, Habib R, Broyer M: Outcome of renal transplantation in 34 cases of childhood hemolytic uremic sy ndrome and the role of cyclosporine. Transplant Proc 1994, 26:269270. 46. Agarwal A, Mauer SM, Matas AJ, et al.: Recurrent hemolytic uremic syndrome in an adult renal allograft recipient: current concepts and management. J Am Soc Nephrol 199 5, 6:11601169. 14. Odum J, Peh CA, Clarkson AR, et al.: Recurrent mesangial IgA nephritis follo wing renal transplantation. Nephrol Dial Transplant 1994, 9:309312. 15. Ohmacht C , Kliem V, Burg M, et al.: Recurrent IgA nephropathy after renal transplantation : a significant contributor to graft loss. Transplantation 1997. 16. Michielsen P: Recurrence of the original disease. Does this influence renal graft failure? Kidney Int 1995, 48(suppl 52):7984. 17. O' eara Y, Green A, Carmody M, et al.: Recu rrent glomerulonephritis in renal transplants: fourteen years' experience. Nephrol Dial Transplant 1989, 4:730734. 18. Odorico JS, Knechtle SJ, Rayhill SC, et al.: The influence of native nephrectomy on the incidence of recurrent disease follo wing renal transplantation for primary glomerulonephritis. Transplantation 1996, 61:228234. 19. Watts RWE, Danpure CJ, De Pauw L, et al.: Combined liver-kidney a nd isolated liver transplantation in primary hyperoxaluria type 1. Nephrol Dial Transplant 1991, 6:502511. 20. Pasternack A, Ahonen J, Kuhlback B: Renal transpla ntation in 45 patients with amyloidosis. Transplantation 1986, 42:598601. 21. Liv neh A, Zemer D, Siegal B, et al.: Colchicine prevents kidney transplant amyloido sis in familial Mediterranean fever. Nephron 1992, 60:418422. 22. Statius van Eps LW: Nature of concentrating defect in sickle cell nephropathy. Lancet 1970, i:4 50454. 24. Montgomery R, Zibari G, Hill GS, et al.: Renal transplantation in pati ents with sickle cell nephropathy. Transplantation 1994, 58:618620. 24. Goss JA, Cole BR, Jendrisak MD: Renal transplantation for systemic lupus erythematosus an d recurrent lupus nephritis: a single center experience and review of the litera ture. Transplantation 1991, 52:805810. 25. Lochhead KM, Pirsch JD, D'Alessandro AM,

et al.: Risk factors for renal allograft loss in patients with systemic lupus e rythematosus. Kidney Int 1996, 49:512517. 26. Allen AR, Pusey CD, Gaskin G: ANCA associated vasculitis: outcome and relapse on renal replacement therapy. J Am So c Nephrol 1997, 8:81A. 27. Dantal J, Giral M, Hoormant M, et al.: Glomerulonephr itis recurrences after transplantation. Curr Opin Nephrol Hypertens 1995, 4:14615 2. 28. Jayne DR, Gaskin G, Pusey CD, et al.: ANCA and predicting relapse in syst emic vasculitis. Q J Med 1995, 88:127133. 29. De'Oliviera J, Gaskin G, Pusey CD, et al.: Relationship between disease activity and anti-neutrophil cytoplasmic anti body concentration in long-term management of systemic vasculitis. Am J Kidney D is 1995, 25:380. 30. Takishita Y, Ishikawa S, Okada K: Two cases of membranous g lomerulonephritis associated with hepatitis C virus. Nippon Jinzo Gakkai Shi 199 4, 36:12031207.