Renal Development

Urine Production Supplements amniotic fluid Starts 10th weeks Problem results in oligohydramnios Kidney Migration Kidneys are formed in the pelvis and ascend to lumbar location Failure to ascend results in pelvic kidney There is progressive revascularization as kidneys ascend

Renal Development Tissue arises from intermediate mesoderm called nephrogenic cords Lateral to the aorta Divided into 3 stages: Pronephros Forms first Non-functional Mesonephros Forms second Functional weeks 6-10 Mesonephric ducts Connects the mesonephros to the cloaca Cloaca is later partitioned into bladder & urethra and rectum Ureteric buds Sproat distally from mesonephric ducts Induce formation of metanephros Metanephros Gives rise to final kidney and ureters The allantosis forms the urachus (after the lumen is obliterated) and ultimately the median umbilical ligament

Molecular Regulation Mesenchyme expresses GDNF, HGF & WT1 Stimulates branching of, and receptability to ureteric bud Ureteric bud in turn produces FGF2 & BMP7 which stimulate mesenchyme proliferation

Bladder and Urethra Development Develop from hindgut endoderm ( cloaca) Anterior cloaca forms the urogenital sinus, posterior forms the rectum Urogenital sinus is divided into three parts: Vesical portion Continuous with allantosis Develops into the bladder However, mesonephric ducts that develop into the ureters are incorporated into the bladder as the trigone Different embryological origins Smooth muscle develops from mesoderm Neck Develops into membranous urethra (females) or prostatic and membranous urethra (males) Definitive urogenital sinus Develops into vestible of the vagina (females) or penile urethra (males)

Embryology Page 1

Renal Congenital Anomalies

Horseshoe kidney Fusion of the lower lobes Benign Predisposition to nephrolithiasis Pelvic Kidney Failure of the kidneys to ascend Presentation Hydronephrosis & vesicoureteric reflux Can lead to pain and infection Potter's Sequence Due to a malformation of the ureteric bud Results in bilateral renal agenesis Fetus is unable to produce urine from swalled amniotic fluid, resulting in oligohydramnios Presentation Limb deformities Clubfoot, flipper hands and/or hyperextensible joints Facial deformities Sloping forehead, flattened nose, recessed chin and low floppy ears Pulmonary hypoplasia Results in death Other Cystic Diseases Simple cysts Cysts are filled with a clear fluid Benign Aquired cystic disease Associated with dialysis Histology shows calcium oxalate crystals Can lead to renal cell carcinoma

Kidney Cystic Disease Multicystic renal dysplasia Due to lack of induction of sacral intermediate mesoderm Cysts vary in size Abnormal structures and lobe formation Childhood polycystic kidney disease Mutation in PKHD1 gene that encodes fibrocystin Leads to enlarged, sponge-like kidneys Adult polycystic kidney disease Late onset autosomal dominant disease characterized by bilateral, multiple expanding cysts Cysts contain red/brown fluid Leads to renal failure Mutation of either: PKD1 gene that encodes polycystin-1 PKD2 gene that encodes polycystin-2 Mutations result in abnormal cilia Cyst formation Presentation HTN Polyuria & proteinuria Berry anuerysms Mitral valve prolapse Renal colic Hematuria Treatment HTN control Dialysis

Renal Medullary Cystic Disease Medullary sponge kidney Common Multiple cystic dilations in the medullary collecting ducts Nephronophthisis & adult-onset medullary cystic disease Medullary cysts located at the corticomedullary junction Histology Cortical & tubular atrophy Interstitial fibrosis Hyalinization Gross Small kidneys with granular, contracted surface Presentation Polyuria & polydypsia Tubular acidosis Liver fibrosis Ocular problems Motor abnormalities Retinal dystrophy

Embryology Page 2

Renal Anatomy
Posterior Abdominal Wall Lymphatics Lower limbs drain into the deep inguinal nodes, common iliac nodes and finally the lumbar nodes The gluteal region, perineum and posterior abdominal wall drain directly into the lumbar nodes Lumbar nodes drain into lumbar trunks and then the cisterna chyli The inferior surface of the diaphragm drains into the celiac nodes and then the intestinal trunk The GI tract drains directly into the intestinal trunk Intestinal trunk drains into the cisterna chyli Cisterna chyli drains into the thoracic duct Bladder Located in the retropubic space Lined by transitional epithelium Forming rugae Sphincters External urethral Innervated by the pudendal nerve Internal urethral Present in males only Vessels Superior bladder is supplied by the superior vesical arteries from the internal iliac Inferior/posterior bladder is supplied by the inferior vesical arteries in males, and the vaginal arteries in females Innervation (parasympathetic) Parasympathetics from S2-S4 innervate the detrusor muscle Innervation (sympathetic) Fibers from T11-L2 Afferents Travel with parasympathetics Micturition Spinal reflex with CNS modification 1. Stretch receptors are integrated in the spinal cord 2. Efferent outflow via parasympathetics causes contraction of detrusor muscle Modifications can be inhibitory (mid-brain) or facilitory Pontine Hypothalamus Cortex Relexation of pelvic floor muscles, perineal muscles and external urethral sphincter

Ureters Retroperitoneal "Water under the bridge" Ureters pass under arteries and vas deferens in males Ureters pass under uterine artery and round ligament in females

Kidney Right kidney is more palpable and sits lower than the left (T12-L4) External features PerInephric fat Fat In the renal sinus PerAnephric fat Fat Around the kidney Segments of the kidney correspond to segmental branches of the renal artery Function Maintainence of ECF osmolarity Regualtion of total body water (TBW) Excretion of metabolic waste Urea (protein metabolism) Uric acid (nucleic acid metabolism) Creatinine (muscle breakdown) Urobilinogen (heme/RBC metabolism) Hormones & drug excretion Metabolized by liver, removed by kidney Endocrine functions Gluconeogenesis

Anatomy Page 3

Kidney Structure I
Lumbar Plexus Moms In Illinois Get Lucky Frequently On Love Muscular branches Nerve to quadratus lumborum Root T12-L4 Nerve to psoas major Root L2-L4 Nerve to psoas minor Root L1-L2 Illiohypogastric nerve Innervates hypogastric and butt Root L1 Illioinguinal nerve Root L1 Anterior labial nerve (female) Innervates naterior labia majora Anterior scrotal nerve (male) Innervates anterior scrotum Genitofemoral nerve Root L1-L2 Genital branch Innervates cremaster muscle and scrotum (male) Femoral branch Innervates femoral triangle Lateral femoral cutaneous nerve Root L2-L3 Innervates lateral thigh Femoral nerve Root L2-L4 Inervates anterior thigh muscles Obturator nerve Root L2-L4 Innervates medial thigh muscles Lumbosacral trunk Root L4-L5 Joins sacral plexus

Nephron Functional unit of the kidney Composed of: Renal corpuscle Tubular system Types of nephrons Cortical Short thin descending limb and do NOT have a thin ascending limb Located almost entirely in the cortex Loop of Henle barely penetrates the medulla Juxtamedullary Glomerulus is located at the junction between the cortex and medulla Contain exceptionally long Loop of Henle Long thin descending and ascending limb

Anatomy Page 4

Kidney Structure II
Renal Corpuscle Filters the plasma Renal corpuscle is composed of the glomerulus and Bowman's space/capsule Fluid moves from the glomerulus into Bowman's space Molecules >8nm will NOT cross Unless (+) charged Small proteins can cross, but not large ones (EX: albumin) Damage results in proteins crossing and proteinuria Organic molecules and proteins cross Fluid filtration The 1st fluid barrier is composed of endothelial fenestrations in the glomerulus capillaries Creates a leaky capillary 2nd fluid barrier is the glomerular basement membrane (GBM) Lipid bilayer with a gel-like mesh of glycoproteins Collagen IV Laminin (glycoprotein) Fibronectin/entactin Heparin sulfate (proteoglycan) Negative charge aids in protein filtration Blood proteins STAY in the blood 3rd fluid barrier are the podocytes Podocytes contain pedicels (foot projections) along the basement membrane Filtration occurs between the pedicels through filtration slits Tubular System Divided into functional units: Proximal convoluted tubule (PCT) Continuous with Bowman's capsule Surrounded by peritubular capillaries arising from the efferent arterioles Reabsorbs essential substances lost during filtration (EX: glucose) Actively secretes substances EX: hormones, drugs Loop of Henle Thin descending limb ends at hairpin turn, then forms; Thin ascending limb Found only in juxtaglomerular nephrons Concentrates the interstitium Pumps Na+, K+, and Cl- from the lumen into the cells via NKCC-2 transporter Pumps ions into the interstitium via Na/K ATPase and K & Cl channelgs Interstitium is also concentrated by urea Surrounded by capillaries called vasa recta Arise from efferent arterioles Function is water uptake Ascending thick limb Passes between the afferent & efferent arterioles Location of juxtaglomerular apparatus Distal convoluted tubule (DCT) Travels back through the medulla, absorbing water and urea Located distal to juxtaglomerular apparatus Surrounded by peritubular capillaries Contains principal and intercalated cells Forms collecting duct Collecting duct Final passage of urine towards the renal pelvis

Juxtaglomerular Apparatus Composed of macula densa cells, extraglomerular mesangial cells and juxtaglomerular cells Macula densa Specialized epithelial cells of the ascending thick limb Sensitive to Na and flow rate through the DCT Regulate GFR through paracrine action Juxtaglomerular cells (JG cells) Specialized myoepithelial cells in the afferent arteriole Act as baroreceptors (monitor BP) Maintain normal GFR (via BP control) through release of renin Extraglomerular mesangial cells Contractile cells with receptors for both AG II and natriuretic factor Further regulate GFR

Anatomy Page 5

Fluid Dynamics and GFR I

ECF, ICF & Total Body Water (TBW) Although the osmolarity of ICF and ECF is the same, the composition of each is very different ECF Plasma and interstitial fluid Main cation is Na+ Main anions are Cl- and HCO3 75% is interstial fluid, 25% is plasma ICF Main cations are Mg+ and K+ Main anions are proteins and PO4 60-40-20 rule 60% of total weight is water (TBW) 40% of total weight is ICF (2/3 of TBW) 20% of total weight is ECF (1/3 of TBW) As body fat percent increases, TBW decreases Infants and children have a higher TBW than adults due to loss proportion of fat Aging and females have more body fat and thus a decreased TBW Glomerular Filtration Rate (GFR) Represents renal clearance that is neither reabsorbed nor secreted Gold standard for GFR measurement is inulin although creatinine is more useful clinically GFR = Ucreatinine x V / Pcreatinine V is urine flow rate (mL/min) Normal GFR is 120 mL/min BUN is also used to estimate GFR Decreased GFR causes elevated BUN and creatinine in the blood Filtration depends on Hydraulic permeability Surface area Net filtration pressure Net filtration pressure Favors filtration over the entire capillary due to stronger hydrostatic pressure than oncotic pressure Net oncotic pressure Usually OPPOSES filtration Negligable in Bowman's space Increases along the capillary due to the same protein concentration but reduced water Altered oncotic pressure in the blood wil change GFR Net hydrostatic pressure Usually FAVORS filtration Opposes filtration within Bowman's space Increased pressure within Bowman's space (kidney stone) will decrease GFR Due to BP and arterioles Afferent and efferent arterioles can contract Combinations that reduce blood flow will reduce GFR and vice versa Afferent contraction reduces GFR Efferent contraction increases the pressure upstream, this increasing GFR Surface area Reduced surface area results in reduced GFR Contraction of mesangial cells in response to vasoactive paracrines Glomerular, GBM or podocyte damage Thickened GBM

GFR Autoregulation Goal of the kidney is to minimize changes and keep GFR steady Due to high pressure already within the glomerulus, it is extremely susceptible to pressure changes (HTN) which can cause damage Myogenic autoregulation (stretch) Increased pressure causes stretch of the afferent arteriole This leads to vasoconstriction of the afferent arteriole Maintains constant RBF Tubuloglomerular feedback As BP increases, filtrate increases Filtered Na+ is thus increased, resulting in increased Na+ in the DCT Increased Na+ is sensed by the macula densa Macula densa cells secrete paracrines, reducing BP in kidney

Physiology Page 6

Fluid Dynamics and GFR II

Other GFR Regulation Mechanisms Natriuretic peptide Increases GFR and water excretion Decreases Na+ reabsorption Via reduced ENaC phosphorylation Decreases renin secretion Produced in response to hypervolume, exercise and caloric restriction Sympathetic stimulation Activation of 1 receptors on renal arterioles (efferent > afferent) causes vasoconstriction Decreased RBF and GFR Prostaglandins/bradykinin PGE2 and PGI1 cause vasodilation of the afferent and efferent arterioles Increasing RBF and GFR NSAIDs inhibit PGE synthesis nd can interefere with these protective effects in the kidney AG II Vasoconstrictor of the efferent arteriole preferentially Can result in increased GFR if only the efferent arteriole is constricted, or decreased GFR if both arterioles are constricted Dopamine Dilates vessels and suppresses Na+ reabsorption in the proximal tubule by inhibiting Na/K ATPase Increased RBF and GFR Types of Transport Paracellular Substances travel through tight junctions between cells or cells themselves Passive diffusion Transcellular Substances or transported through the apical, cytoplasma and basolateral cell surfaces Uses channels and transporters

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Reabsorption & Secretion

Glucose Filtered freely and completely reabsorbed in the PCT Unless serum glucose is greater than 200 mg/dL Overwhelms the glucose transporters Glucose >350 mg/dL results in glucosuria Reabsorption Via SGLT-2 co-transporter Na+/glucose symporter Saturated at 200 mg/dL (splay) Secondary active transport maintains low Na+ gradient within the cell Na+ is pumped out at basolateral membrane Glucose is pumped into the interstitial fluid at the basolateral membrane by GLUT-2 Amino Acids and Proteins AAs are freely filtered and completely reabsorbed by secondary active transport and in the PCT Na+/AA co-transporter Proteins Peptides that cross are either degraded into AAs by luminar surface peptidases or reabsorbed via receptor-mediated endocytosis Related nitrogen metabolism Breakdown product of AA Excreted in several forms: Creatinine Breakdown product of creatine Directly reflects amount of muscle in the body Ammonium Uric acid Urea

Organic Cations Most are freely filtered or actively secreted at the PCT Endogenous (hormones) and exogenous (drugs) substances Secretion (basolateral absorption) is via organic cation Urea transporters (OCT) Freely filtered Uniporter Secreted in the Loop of Henle via OCT Secretion (into the lumen) is via a H+-antiport 50% is reabsorbed by urea transporters in the collecting duct Urea is a waste product from the metabolism of AA Converted from ammonia by the liver Phosphate Can also be converted into glutamine by the liver Filtered load always exceeds transport max Glutamine is actively pumped into the PCT epithelial Slight increase in filtered load produces cells from the blood and the lumen of the PCT substantial phosphate loss Glutamine is then converted back into ammonium Reabsorbed via a Na/Pi transporter and bicarb Bicarb is symported back into the blood with Na+ Ammonium is antiported into the lumen via Na+ Chloride Paracellular diffusion Follows Na+ and water Cl-/HCO3- antiport on the basolateral membrane Cl- enters the cell, HCO3- is pumped into the interstium

Organic Anions Active secretion is via organic anion transporters (OAT) on the basolateral membrane (absorption into PCT epithelial cells) Responsible for majority of drug and metabolite secretion Urate Filtered freely Reabsorbed in the PCT Secreted in late PCT via OAT Transport insufficiency results in gout PAH (para-aminohippuric acid) 100% cleared in single pass Filtered freely and actively secreted Used to estimate renal plasma flow

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Nephron Physiology I
General Each segment of the nephron depends on the action of the basolateral Na/K ATPase to maintain low intracellular Na+ concentration For secondary active transport Proximal Tubule Major site of reabsorption Solutes and water are reabsorbed proportionally Tubular fluid is isosmotic Reabsorbs: ALL glucose and AA 60%-70% of filtered electrolytes (including Na+, 60%) and water 50% or filtered urea Na+ is reabsorbed via cotransport with other substances and countertransport with HCO3through the Na+/H+ antiporter Na+ is reabsorbed with Cl- in the distal PCT by lumen positive potential difference Ammonia is secreted to buffer the secreted H+ AG II acts on the proximal tubule to stimulate Na+ reabsorption ANP blocks Na+ reabsorption Limited gluconeogenesis Precursors are glutamine and lactose Contributes 20% of total glucose Significant role during fasting & acidotic states Early DCT Impermeable to water and urea But ADH susceptible AG II stimulates Na+ reabsorption ANP blocks Na+ reabsorption PTH increases Ca+ reabsorption

Loop of Henle Main purpose is to setup the hyperosmolarity of the medulla Thin descending limb Reabsorbs 20% of filtered water (water permeable) Thin ascending limb Impermeable to water and has no reabsorption Actively pumps ions into the interstitium Thick ascending limb Diluting segment of the tubular system Impermeable to water, but reabsorbs solutes (thus diluting the urine) Active transport of Na+ into the interstitium

Late DCT and Collecting Duct Principle cells Reabsorb Na+ and water secrete K+ via Na/K ATPase Intercalated cells Important for acid-base regulation Secrete H+ and reabsorb K+ and HCO3 Contain carbonic anhydrase Combine CO2 & H2O forming H+ & HCO3 H+ is secreted into the lumen via either Na+/H+ antiporter or H+-ATPase HCO3- enters the interstitium Aldosterone stimulates Na+ reabsorption and K+ secretion (principle cells) and H+ secretion (intercalated cells) ADH results in the insertion of aquaporins into the luminal membrane Water reabsorption is increased Collectign duct Urea passively diffuses into the interstitium Passes through the renal medulla and is impermeable to water But ADH susceptible Concentrates the urine during low fluid levels (with ADH) and dilutes urine during high fluid levels (lack of ADH)

Physiology Page 9

Nephron Physiology II
Setting Up the Hyperosmotic Renal Medullary Interstitium The osmolarity in the medulla can reach 1400 mOsM (normal interstitium is 300 mOsM) Due to extremely high concentration of solutes Major factors that contribute to medullary hyperosmolarity Active transport of Na+, K+ and Cl- out of the thick ascending limb of the loop of Henle Active transport of ion from the collecting ducts Passive diffusion of urea from the collecting ducts Water transport out of the medulla via the vasa recta and peritubular capillaries Setting up the medulla hyperosmotic gradient The most important cause is the active transport of Na+, K+ and Cl- into the interstitium in thethick ascending limb of the loop of Henle Capable of establishing a 200 mOsM difference between the lumen and interstitium Ascending limb is impermeable to water so gradient is NOT diluted Initial set-up starting with 300 mOsM of normal fluid 1. Active transport of ions into the interstitium in the thick ascending limb of loop of Henle i. Creates a 200 mOsM difference (200:lumen, 400:interstitium) 2. Tubular fluid in the descending limb of the loop of Henle equilibrates with interstitium i. As the descending limb of the loop of Henle is permeable to water, water flows out of the tubular fluid into the interstitium 1) Water is carried away from interstitium by vasa recta, preventing dilution of interstitium ii. Tubular fluid in the descending limb of loop of Henle is now 400 mOsM 3. Fluid from the descending limb enters the ascending limb of the loop of Henle i. Again, a concentration gradiant is established by the ion transporter in the thick ascending limb 1) Except now the starting point is 400 mOsM instead of 300 mOsM (result is 300:lumen, 500:interstitium) 4. Steps are repeated over and over establishing final concentration gradient

Physiology Page 10

Electrolyte Regulation I
K+ Regulation Na+ Regulation Control Na+ is the most abundant ion in the ECF and Chronic control is via the renal system thus is closely linked to the amount of water in Acute contol is the buffering capacity of intracellular stores ECF Storage (Acute control) Therefore Na+ osmolarity is controlled by 98% of K+ is stored intracellularly the intake and secretion of water (diluting Increased K+ release increases extracellular [K+] and increasing the osmolarity Caused by: respectively) Acidosis Excretion is primarily through the use of Reduces the activity of the Na/K ATPase ADH Intake is primarily through the thirst Less K+ is pumped into the cell; mechanism more remains outside Aldosterone increases Na+ reabsorption from Cell lysis the lumen in the distal tubule Exercise Increased ECF osmolarity As water moves OUT of the cells toward a hyperosmotic ECF, K+ follows EX: hyperglycemia Increased K+ uptake reduces extracellular [K+] Caused by: Insulin Aldosterone Release from the adrenal cortex is stimulated by increased plasma [K+] Alkalosis Increases the activity of the Na/K ATPase Decreased ECF osmolarity As water moves INTO the cell, K+ follows Catecholamines (Epi & NE) Increased cellular uptake counteracts K+ loss due to repeated action potentials during times of stress Chronic control (kidney regulation) Reabsorption Majority (65%) is reabsorbed in the proximal tubule via osmotic pull of water K+ follows water Remainder is absorbed in the thick ascending limb of the loop of Henle via NKCC-cotransporter Secretion/excretion Occurs in the DCT via principal cells Basolateral Na/K ATPase increases intracellular [K+] which then diffuses into the lumen Simulated by: Increased Na+ delivery to the distal nephron Increased tubular flow Increased plasma [K+] and aldosterone Increases the activity of the basolateral Na/K ATPase Aldosterone also increases luminal wall permeability

Physiology Page 11

Kidney Endocrine Functions

Major Kidney Endocrine Function RBC production regulation/erythropoietin Synthesized in the kidneys in response to hypoxia Stimulates RBC proliferation and maturation Binds to proerythroblasts, accelerating their maturation Deficiency of EPO can result from chronic kidney disease, renal malignancy or an AE of chemotherapy Vitamin D synthesis Vitamin D is stored in the liver but is dependent on plasma Ca+ for its activation and action Decreased Ca+ stimulates PTH secretion from the parathyroid PTH activates 1- -hydroxylase in the kidney Converts vitamin D from inactive to active form Active vitamin D facilitates Ca+ and phosphate reabsorption in the kidney and small intestine Different than PTH alone (stimulates Ca+ reabsorption but inhibits PO4- reabsorption) Production of renin (RAAS) Produced and released by the juxtaglomerular cells Production of prostaglandins Required for vasodilation of the afferent arterioles Increases GFR and RBF Hormones Acting on the Kidney Atrial natriuretic peptide (ANP) Released by the atria in response to increased stretch Causes vasodilation of afferent arterioles, vasoconstriction of efferent arterioles, and decreases Na+ reabsorption in the DCT & CD Increases GFR (slightly) Increased natriuresis PTH Inhibition of PO4- reabsorption in the PCT Inhibits Na+/PO4- cotransport Stimulation of Ca+ reabsorption in the DCT Aldosterone Synthesized in the adrenal cortex Synthesized and excreted in response to changes in the ECF via RAAS and increased plasma [K+] Stimulates mineralocorticoid receptors (MRs) on principle cells Increases permeability of apical surface to Na+ and K+ Results in increased Na+ reabsorption and K+ excretion Stimulates H+secretion by intercalated cells ADH Released from the posterior pituitary in response to high serum osmolarity and diminished blood volume Also produced in response to AG II Determines whether the kidney produces dilute or concentrated urine Decreased plasma volume is sensed as decreased BP by baroreceptors Increased ADH secretion Increased water reabsorption Concentrated urine and increased total body water Increased plasma volume results in decreased fluid osmolality Osmoreceptors swell in the hypothalamus Inhibits firing to supraoptic nuclei Decreased ADH secretion Decreased water reabsorption Dilute urine and decreased total body water ADH acts on V2 receptors on the principal cells in the collecting duct Increases the insertion of aquaporins into the apical membrane Water moves out of the collecting duct into the interstitium High levels of ADH also act on V1 receptors on arterioles causing vasoconstriction Particularly important during hemorrhage to maintain BP

Physiology Page 12

RAAS
Renin-Angiotensin-Aldosterone System (RAAS) Regulates BP Renin is released in response to: Hypotension Results in decreased perfusion Perceived as decreased stretch by the JG cells Increased renal parasympathetic activity 1 stimulation 1 agonists (isoproterenol) stimulate renin secretion 1 antagonist (propranolol) inhibit renin secretion Decreased Na+ delivery to the kidneys Renin cleaves angiotensinogen to angiotensin I (AG I) Angiotensinogen is produced by the liver Angiotensin converting enzyme (ACE) converts AGI to AG II Located in the lung endothelium AG II has numerous effects: Direct vasoconstriction (fast response) Increases TPR Venous constriction increases venous return to the heart Increased BP Increased constriction of the efferent arterioles Increased GFR Aldosteron synthesis and release from the adrenal cortex (slow response) Aldosterone promotes Na+ reabsorption in the DCT & CD Decreased excretion of salt and water Increased ECF and blood volume Direct action on the kidney AG II stimulates Na/H exchange in the proximal tubule Increased reabsorption of Na+ and HCO3 ADH secretion from the posterior pituitary Increased water reabsorption Increased ECF volume and BP Increased sympathetic activity

Physiology Page 13

Acid-Base Homeostasis
Buffer Systems Ammonia buffer system Found in the kidney Creates a new bicarb and excretes a H+ Glutamine is metabolised to HCO3- and NH4+ HCO3- is pumped into the interstitium NH4+ is secreted via the Na+/NH4+ exchanger and excreted in the urine Ammonia (NH3) can also diffuse into the lumen and combine with H+ (pumped via an H+ ATPase) pH determines the amount of H+ secreted During acidosis, there is increased NH4+ secretion Phosphate buffer system Found in the kidney Creates a new bicarb and secretes a H+ Largely responsible for the low acidity and buffering of the urine Carbonic anhydrase creates H+ and HCO3 H+ is secreted and combines with HPO4forming H2PO4- which is then excreted in the urine HCO3- is pumped into the interstitium Bicarbonate buffer system Found in lung and kidney Bicarb and H+ are formed from CO2 and H2O via carbonic anhydrase Process is reversible Kidney: proximal and distal tubule cells Kidney Responsible for long-term changes in acid-base homeostasis Bicarb production Ammonia and the phosphate buffer system H+ secretion Most H+ is secreted in the form of either NH4+ & H2PO4 Direct H+ secretion occurs in intercalated cells via H+ ATPase HCO3- filtration and H+ secretion HCO3- is filtered freely, H+ is pumped into the lumen by various mechanisms H+ ATPase Na/H antiporter Via secondary active transport HCO3 and H+ combine in the lumen via carbonic anhydrase (CA) CO2 diffuses back into the cells and combines with water, again via carbonic anhydrase forming HCO3- and H+ H+ is pumped back into the lumen, HCO3- is pumped into the interstitium Net result is H+ remains in lumen, while HCO3- is reabsorbed Increased plasma pH Metabolic alkalosis Lower amount of available H+ for lumenal secretion Lower H+ in the lumen Decreased H+ for HCO3- to combine with via CA Increased HCO3- excretion Lowers plasma pH Metabolic acidosis Excess H+ results in increased H+ secretion Compete HCO3- reabsorption Increased H+ excretion Increased activity of phosphate and ammonia buffer systems Increased plasma pH HCO3- reabsorption Increased by CO2 and AG II Stimulation of the Na/H antiporter leads to an increased in bicarb reabsorption Increased ECF volume causes decreased HCO3reabsorption and dilutional acidosis Decreased ECF volume causes increased HCO3reabsorption and contraction alkalosis

Lungs Regulate short term changes in acid-base homeostasis via ventilation Ventilation is triggered by decreased pH Increases CO2 removal, thus lowering the plasma [H+] Raises the pH CO2 ventilation controls pH via the bicarbonate buffer system Metabolic acidosis (loss of HCO3-) increases the respiratory rate Decreases amount of CO2 (increased CO2 removal) Lowers plasma [H+] (raises pH) Metabolic alkalosis (increased HCO3-) decreases the respiratory rate Promotes CO2 retention Increases plasma [H+] (lowers pH)

Physiology Page 14

Electrolyte Disorders I
Hyperkalemia Etiology Addison's disease Cell lysis and increased K+ release Hemolysis Rhabdomyolysis Insulin deficiency DM Impaired K+ secretion Decreased urine flow Renal failure (acute or chronic) Renal tubular defects and acidosis DM Sickle cell Obstruction Transplant Clinical Tingling/parasthesia Arrhythmia Muscle weakness EKG abnormalities and arrhythmia Can lead to V. fib Wide QRS Peaked T wave Flat P wave Treatment Dialysis Reduce cardiac effects IV Ca+ stabalizes the myocardium Promote K+ movement into cells Insulin & glucose -Agonsist Albuterol and epi Increase K+ excretion Diuretics (NOT K+ sparing) Cation-exchange resins ( sodium polystyrene sulfonate) Bind K+ in the GI tract, increases excretion Inhibit K+ Hypomagnesemia Etiology Dietary deficiency with poor absorption Clinical A/N/V Lethargy Personality changes Hypocalcemia and hypokalemia Treatment Magnesium sulfate Hypokalemia Etiology Dehydration Increased K+ excretion V/D Enterocollitis Alkalosis Insulin Diuretics (loop or thiazide) Increased aldosterone levels Hypomagnesemia Clinical Neuromuscular Cramps, fatigue and muscle weakness Ileus Respiratory paralysis Cardiac Arrhythmia EKG abnormalities U waves Flat/inverted T waves ST segment depression Treatment IV K+ Magnesium correction Hypernatremia General clinical symptoms arise >160mEq and are neurologic Tremors and ataxia Irritability and confusion Seizures Coma and death Etiology Dehydration and water loss Hyperglycemia with diabetic ketoacidosis Central DI Nephrogenic DI Treatment Treat underlying cause IV NS or LR

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Electrolyte Disorders II
Hyponatremia General clinical symptoms are neurologic <120mEq? N/V Irritability and confusion Seizures <110mEq? Coma and death Treatment is generally hypertonic saline Different types based on the total volume of fluid in the body Hypovolemic hyponatremia Etiology GI losses Acute viral gastroenteritis Dehydration Renal salt wasting Acute renal failure Clinical Orthostasis Decreased skin turgor Hypotension 3rd spacing Treatment Rehydration with NS Euvolemic hyponatremia Etiology Hypothyroidism Cortisol deficiency Hypopituitarism SIADH Treatment Water restriction Loop diuretics Hypervolemic hyponatremia Etiology CHF Cirrhosis/liver failure Nephrotic syndrome Clinical Edema Treatment Salt and water restriction Loop diuretics

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Metabolic Acidosis/Alkalosis
General Lab changes in pH, paCO2 & HCO3- will be in the same direction Anion gap Na - (HCO3 + Cl) Normal is 10-12 Renal Tubular Acidosis Type I (distal) Aquired defect in the acidification of urine Etiology Sjogren's Lithium Sarcoidosis Obstruction Amphotericin B Type II (proximal) Aquired defect that results in renal loss of HCO3 Etiology Myeloma Renal transplant Type IV Abnormal ammonium excretion Associated with: DM Chronic kidney disease Glomerulosclerosis

Metabolic Acidosis Clinical Decreased pH, paCO2 and HCO3- (large) 1.2 paCO2 / 1 HCO3 Decreased HCO3- due to: Loss of HCO3 Increased H+ Types High anion gap metabolic acidosis MUDPILES (etiology): Methanolo Uremia Diabetic ketoacidosis Phenformin & Paraldehyde Isoniazid, Infection & Iron Lactic acidosis Ethylene glycol Salicylates Non/normal anion gap metabolic acidosis HARDUPS (etiology): Hyperalimentation Acetazolamide, Acid infusion & Addison's Renal tubular acidosis Diarrhea Ureteroenteric shunt Pancreatic fistula Spironolactone Treatment IV HCO3-

Metabolic Alkalosis Clinical Increased pH, paCO2 and HCO3- (large) 0.7 paCO2 / 1 HCO3 Etiology CLEVER PD Contraction (volume) Licorice & laxatives Endocrine Cushing's Hyperaldosteronism Vomiting Excessive alkali Milk-alkali syndrome Excessive ingestion of calcium and absorbable alkali Calcium carbonate or milk and sodium bicarbonate Refeeding alkalosis Refeeding with a carbohydrate rich diet after prolonged fasting Potassium reduction (hypokalemia) Diuretics Treatment IV NaCl, KCl and Mg Spironolactone is due to mineralocorticoid excess

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Respiratory Acidosis/Alkalosis
General pH & paCO2 will change in opposite directions 10 change in paCO2 / 0.08 change in pH Respiratory Alkalosis Occurs secondary to low plasma CO2 concentration Etiology Central Head trauma Stroke Anxiety, stress & hyperventilation Salicylates & sepsis Progesterone Pulmonary Pulmonary embolism Asthma Pneumonia Iatrogenic Increased RR on mechanical ventilation Types Acute 2 HCO3 / 10 paCO2 decrease Chronic 4 HCO3 / 10 paCO2 decrease

Respiratory Acidosis Occurs secondary to CO2 retention Etiology Inhibition of medullary respiratory center Drugs Opiates, sedatives and anesthetics CNS tumors & trauma CNS hypoxia Pickwickian syndrome Weakness of respiratory muscles Guillain-Barre syndrome Myasthenia gravis Toxins Botulinum Organophosphates Muscle relaxants Scoliosis, myopathy & muscular dystrophy Decreased CO2 exchange COPD ARDS Types Acute 1 HCO3 / 10 paCO2 increase Chronic 4 HCO3 / 10 paCO2 increase Treatment Patent airway -agonist Ventilator

Simplified Acid-Base Problem Analysis R = Respiratory; M = Metabolic Mnemonic --> Ravage Me MaRy

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Glomerulopathies
General Divided into two groups based their pathogenesis and clinical manifestions: Nephrotic syndrome Primarily a result of increased GBM permeability Diseases: Minimal change disease Focal segmental glomerulosclerosis (FSGS) Membranous glomerulopathy MPGN (can present as nephrotic or nephritic) Diabetic nephropathy Renal amyloidosis SLE Nephritic syndrome Direct inflammatory damage to the glomeruli Diseases: Acute proliferative glomerulonephritis Poststreptococcal/infectious Rapidly progressive glomerulonephritis (RPGN) RPGN, crescentic Anti-GBM disease & Goodpasture's MPGN IgA nephropathy (Berger's disease) Alport's syndrome & Thin basement membrane disease Classification Diffuse involves all glomeruli Focal does not Global involves the entire glomerulus Segmental involves only part of the glomerulus Histology Sclerosis Accumulation of collagenous matrix that contributes to capillary lumen obliteration and fibrous adhesions Hyalinosis Accumulation of eosinophilic dense material that also contributes to capillary lumen obliteration Basement membrane thickening Often due to deposition of immune complexes Hypercellularity Due to cellular proliferation, leukocyte infiltration and crescent formation Diagnosis of ALL glomerulopathies is dependent on RENAL BIOPSY Glomerular diseases can ultimately lead to chronic glomerulonephritis and renal failure Glomerulopathy Pathogenesis GBM thinning Alport syndrome Thin basement membrane disease Epithelial damage Diabetic nephropathy (DM) Minimal change disease FSGS Antigen-antibody complex deposition Circulating complex deposition in the kidney Often exhibit granular staining Diseases: SLE MPGN Renal amyloidosis RPGN (Type II) Proliferating glomerulonephritis Intrinsic complex deposition Anti-GBM antibodies Exhibit linear staining RPGN (Type I) Anti-GBM disease Goodpasture's Antibodies against fixed antigens Exhibit granular staining RPGN (Type III) Heymann nephritis Antibodies against Heymann antigen in the subepithelial basement membrane Antibodies against planted antigens Exhibits granular staining Membranous glomerulopathy

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Nephrotic Syndrome I
General Increased GBM permeability leads to a variety of clinical symptoms: Vitamin D deficiency Massive proteinuria Hypoalbuminemia Due to protein loss Albumin is the main mediator of serum oncotic pressure Edema Due to decreased serum oncotic pressure Fluid is lost to the interstitial space Decreased intravascular volume activates the RAAS, sympathetic system, ADH release and decreased release of ANP All these changes lead to increased Na+ and water retention, contributing to further edema Hyperlipidemia/lipiduria Due to increased production of serum lipoproteins by the liver in an attempt to maintain oncotic pressure Hypercoagulability Secondary to loss of anticoagulant factors through the glomeruli Increased risk of infection Due to loss of immunoglobulins through the glomeruli Particularly staphylococcal and pneumococcal Types Primary Affects the kidney ONLY Minimal change disease Membranous glomerulopathy FSGS MPGN Secondary Systemic diseases that also affect the kidney SLE DM Amyloidosis Minimal Change Disease Leading cause of nephrotic syndrome in children Frequently follows respiratory infection or immunizations Selective proteinuria (mostly albumin lost) Histology Glomeruli appear normal under light microscope Electron microscopy reveals effacement (loss) of visceral epithelial foot processes Lead to increased permeability Treatment Prednisone Alkylating agents Cyclophosphamide & Chlorambucil Membranous Glomerulopathy Leading cause of nephrotic syndrome in adults More common in men Histology Diffuse GBM thickening due to subepithelial deposits IgG and C3 deposits Associated with: Autoimmune disease Thyroiditis, SLE & RA Drugs Penicillamine, gold, NSAIDs & Captopril Malignancy Infection Hepatitis B & C Syphilis Schistosomiasis, malaria & leprosy Treatment Steroids are ineffective Transplant

Membranous Glomerulopathy "Spikes" of methenamine silver stain demonstrate increased GBM synthesis between subepithelial deposits. Diffuse thickening of the capillary wall is also visible.

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Nephrotic Syndrome II
FSGS Considered to be a more severe form of minimal change disease (similar effacement of foot processes) but with: Non-selective proteinuria Higher incidence of hematuria & HTN Reduced GFR Poor corticosteroid response Frequently progresses to chronic kidney disease & renal insufficiency Pathogenesis Epithelial damage leads to hypertrophy of affected glomeruli Causes hemodynamic changes such as HTN Ultimately leads to sclerosis and hypercellularity Histology Focal hyalinosis and segmental sclerosis Foam cells and microcyst formation Collapsing glomerulus Types Idiopathic HIV-associated FSGS More severe Higher incidence of collapsing glomeruli Dilation & fibrosis of tubule segments Treatment Oral glucocorticoids (20%-40% effective) Cyclophosphamide & cyclosporine

FSGS

MPGN Tram-track appearance of GBM

Membranoproliferative Glomerulonephritis (MPGN) Histology Thickened GBM Glomerular cell proliferation Leukocyte infiltration Crescents "Tram-track" GBM appearance due to deposits that separate the GBM (mostly Type II MPGN) Types Type I (idiopathic/secondary) More common in adults MPGN is secondary to immune complex deposition (Type III hypersensitivity) IgG and C3 deposit location is subendothelial Activation of alternative and classical complement pathway Associated with hepatitis B & C, SLE, HIV, schistosomiasis, malignancy and 1antitrypsin deficiency Type II (Dense deposit disease) MPGN is secondary to dense intramembrane immune complex deposition Associated with C3 nephritic factor (C3NeF) Binds C3 decreasing serum levels Deposits are C3 (no IgG) Can present as either nephrotic OR nephritic Treatment No effective therapy

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Nephritic Syndrome I
General Pathology is a result of glomerulus inflammation Clinical Hematuria & RBC casts Secondary to destruction of glomerular capillaries Oliguria Secondary to inflammatory cell infiltration and immune complex deposition Causes obstruction of the capilary lumen, decreasing GFR and leading to: Oliguria (<400 mL urine output/day) Azotemia (increased BUN and creatinine in the blood) due to inefficient filtering Proteinuria HTN Secondary to edema and increased fluid retention due to decreased GFR Diagnosis Renal biopsy Acute Proliferative Glomerulonephritis (Postreptococcal/Infectious) Frequently follows infection with GABHS Can also be associated with: Staph and pneumococcal Parasitic Malaria & toxoplasmosis Viral Hepatitis B & C, mumps, HIV, varicella and mononucleosis Appears 2-3 weeks following skin infection and 10 days following pharyngeal infection Most common in children 2-6 Y.O. Pathogenesis Secondary to immune complex deposition with resulting complement activation and inflammation Histology Hypercellularity and enlarged glomeruli IgG and C3 deposits (granular) Diagnosis "Smoky brown" urine (hematuria) with RBC casts Treatment Diuretics control HTN Penicillin Rapidly Progressive (Cresentic) Glomerulonephritis (RPGN) Not a disease per se, but a malignant form of nephritic syndrome Rapid loss of renal function (GFR) Severe oliguria Other nephritic symptoms Gross Kidneys are enlarged and pale with petechial hemorrhages Histology Sclerosis Crescents Proliferating parietal cells within Bowman's space Fibrin (due to fibrinogen escape into Bowman's space) accumulates between crescents Monocytes and macrophages in Bowman's space Crescents can lead to glomerular necrosis Types Type I (Anti-GBM antibody disease) Associated with Goodpasture's Linear deposits of IgG and C3 along the GBM Antigen is -chain of collagen IV Labs are ANCA-negative Treatment Plasmapheresis Cyclophosphamide Prednisone Treat until anti-GBM antibody is undetectable Type II (Immune complex deposition) Associated with: Henoch-Schonlein Purpura IgA nephropathy Cryoglobulinemia IgGs that reversibly precipitate in the cold Derm lesions include raised palpable purpura and acral purpura SLE Postreptococcal GN Granular deposits Labs are ANCA-negative Type III (Pauci-immune) Associated with: Polyarteritis nodosa Wegener's Microscopic polyangiitis Absence of deposits on the GBM Labs are ANCA-positive Treatment High dose corticosteroids & underlying cause

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Nephritic Syndrome II
IgA Nephropathy (Berger's Disease) Similar to Henoch-Schonlein Purpura, but without systemic manifestations (renal only) Common in children & young adults Most common form of glomerulonephritis worldwide Clinical Gross hematuira 24-48 hours post URI, UTI and GI infection Histology IgA deposits in the mesangium leads to glomerular injury and nephritic symptoms Also shows C3 deposits Treatment Spontaneously resolves only to recur every few months or during other infections 20%-50% of cases progress to ESRD within 20 years
RPGN Crescent masses and leukocytes within Bowman's space Alport's Syndrome & Thin Basement Membrane Disease Both are hereditary defects associated with type IV collagen Alport's syndrome X-linked mutation in 5 chain of type IV collagen Thin basement membrane disease Mutation in 3 or 4 chain of type IV collagen Clinical More pronounced in men (due to X-linkage) Nephritic symptoms Deafness Cataracts and lens dislocation Histology Foam cells GBM thinning Produces "basket-weave" appearance Ultimately progresses to ESRD Treatment Dialysis Transplant

Chronic Glomerulonephritis Progressive, end-stage glomerulonephritis Clinical Nephritic syndromes Loss of appetite & vomiting Anemia Weakness Gross Thin cortex Increased peripelvic fat Histology Glomeruli obliteration Arterial & arteriolar sclerosis Tubule atrophy Interstitial fibrosis Leukocyte infiltration Treatment Dialysis

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Renal Calculi & Amino Acid Disorders

Renal Calculi Clinical Severe, colicky flank pain that radiates to the groin Hematuria, hydronephrosis and infection Types Calcium oxalate/Calcium phosphate Most common Etiology Hypercalcemia/hypercalciuria Hyperparathyroidism Bone disease, multiple myeloma & mets Sarcoidosis Milk-alkali syndrome Primary oxaluria type I Stones are radiopaque Struvite (ammonium magnesium phosphate) Due to excessively alkaline urine from UTI caused by urease (+) bacteria Proteus vulgaris or staphylococci Common in women Bacteria convert urea to ammonia, which then precipitates as a stone Stone are radiopaque Uric acid Associated with gout (hyperurecemia) or diseases that cause rapid cell turnover Leukemia & myeloproliferative disease More likely to form in acidic urine Stones of radiolucent Treatment Alkalinize the urine Carbonic anhydrase inhibitors (acetazolamide) Cystine Caused by patients with genetic defects in metabolism of cystine Cystinuria More likely to form in acidic urine Stones are radiolucent Treatment Alter CYS solubility, reduce CYS intake or increase CYS excretion (IV fluids) Diagnosis Abdominal X-ray Treatment Increased fluid intake Pain management Extracorporeal shockwave lithotripsy (ESWL) Surgery (nephrolithotomy) AA Metabolism Disorders Phenylketonuria (PKU) Defect in phenylalanine hydroxylase PAH gene Results in PHE buildup in the blood PHE is converted to phenylpyruvate Causes neurologic sequelae such as retardation Diagnosis is the presence of phenylpyruvate in the urine Treatment Detected at birth PHE restricted diet Alcaptouria Defect in tyrosine pathway Homogenisate oxidase HGD gene Can lead to arthritis and kidney & prostate stones Diagnosis is dark urine (oxidized) Primary oxaluria type I A transaminase defect in alanine-glyoxylate aminotransferase results in the inability to convert glyoxylate to glycine AGXT gene Results in buildup of glyoxylate, which spontaneously oxidizes to oxalate Oxalate crystalizes with Ca++ forming radiopaque Ca-oxalate stones Maple syrup urine disease Defect in -keto acid dehydrogenaseresults in the inability to decarboxylate branched chain AA Such as (I Love Vermont): Isoleucine Leucine Valine BCKD, DBT & DLD genes Urine smells like "burnt sugar" Results in neurological complications

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Amino Acid Disorders II

AA Transport Disorders Hartnup disease Error in neutral AA transporter located in the PCT & intestine results in numerous Pellegra-like symptoms: Failure-to-thrive & diarrhea Photosensitivity & dermatitis Ataxia, tremor, dementia, psych problems, retardation, psych problems, etc. Cystinuria Errors in basic AA transporters (cysteine) result in dimer formation and cystine stones Homocystinuria Autosomal recessive deficiency of cystathionine Bsynthase Clinical Marafanoid habitus Increased incidence of seizures Lens dislocation (DOWNWARD) Increased urinary excretion of homocystine Treatment Dietary restriction of MET

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Tubulointerstitial Disease
Urinary Casts General Tubulointerstitial Disease Usually an indication of tubular pathology Clinical Cells within the cast reveal an intrarenal source Casts Absence of cells (hyaline casts) are seen Absence of glomerular injury Tubular defects in normal individuals Can also indicate pyelonephritis Metabolic acidosis Casts are composed of a protein matrix of Inability to concentrate urine Polyuria/nocturia Tamm-Horsfall mucoprotein Epithelial cell casts Electrolyte disorders Findings Etiology Desquamated tubular cells in a Diffuse cortical necrosis Renal papillary necrosis protein matrix Etiology UTI & pyelonephritis ATN Drug Induced Tubulointerstitial nephritis Ethylene glycol toxicity Heavy metals Heavy metal poisoning Obstruction Acute transplant rejection Neoplasms RBC casts Ischemia Etiology Ischemia results in cortical and tubular infarction Glomerulonephritis Due to high metabolic rate of tubular cells, IgA nephropathy large amounts of oxygen are required Poststeptococcal DIC, microscopic polyangiitis, TTP & HUS glomerulonephritis Goodpasture's Malignant HTN Vasculitis Diffuse Cortical Necrosis Renal ishemia Due to infarction of the cortices of the kidney, secondary to WBC casts ischemia Findings Can progress to ARF Casts indicate inflammation in renal Etiology interstitium, tubules and glomeruli DIC, microscopic polyangiitis, sepsis, Obstetric WBCs in urine indicate acute cystitis complications, TTP & HUS Etiology Clinical Pyelonephritis Signs and symptoms of the systemic cause Interstitial nephritis Azotemia Lupus Proteinuria, hematuria, RBC casts Granular casts Granular casts Derived from renal tubular cells Etiology Renal Papillary Necrosis Severe renal disease Result of ischemic infarct of the renal papillae Nephrotic syndrome Associated with: Fatty casts DM, acute pyelonephritis, chronic phenacetin use Fat droplets in a hyaline matrix Clinical Often exhibit maltese-cross configuration Polyuria Etiology Rust-colored urine Nephrotic syndrome ARF Lloyd's sign Diagnosis Casts, hematuria and necrotic renal papillae X-ray may show nephrocalcinosis Treat underlying disease

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Urinary Tract Infections (UTI)

General UTI Etiology Outpatient E.coli Staphylococcus saprophyticus Sexually active young females Inpatient E.coli Children Children with recurrent UTIs should be evaluated for vesicoureteral reflux (VUR) Clinical Dysuria, frequency & urgency Suprapubic pain & painful urination Hematuria Confusion (elderly) Progressive symptoms F/N/V Lloyd's sign Positive flank pain (costovertebral angle/CVA tenderness) Diagnosis Clean catch or suprapubic tap (Gold Std) Urine culture Identifies specific bacteria Urine microscopy Pyuria (PMNs) & bacteriuria Urine dipstick Nitrites Leukocyte esterase Hematuria Voiding cystourethrogram Cystourethroscopy History Pathogenesis Bacterial virulence Altered host defence Elderly women have increased vaginal pH (menopause) Inefficient voiding Pregnancy Diabetics Increased glucose in the urine Treatment Appropriate antibiotic therapy No treatment is required for asymptomatic bacteriuria except: Preschool or pregnant General Pyelonephritis Infection of the upper urinary tract, including the kidneys Route of infection is either hematological or ascending UTI UTI is the most common Etiology Bacterial E.coli Klebsiella Staphylococcus saprophyticus & epidermis Proteus Viral Mostly in the immunocompromised CMV Adenovirus Polyomavirus Pathogenesis UTI leads to tract obstruction & urine stasis, eventually leading to VUR and intrarenal reflux VUR Can be due to genetic causes, such as a short ureter Treatment would be surgery Typically affects the tubules, interstitium and renal pelvis Types (similar clinical manifestations) Acute Clinical WBC casts Lloyd's sign F/N/V & malaise UTI symptoms Histology Interstitial suppurative inflammation Tubular necrosis Pyelonephritic scars Cortical surface of the kidney shows fibrous depressions Complications Papillary necrosis Perinephric abscess Treatment Appropriate antibiotics Chronic Histology Tubular atrophy, hypertrophy and/or dilation Gross Course, irregular renal scarring Located corticomedullarly overlying dilated, blunted & deformed calyces Flattened papillae

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Drug Induced Tubulointerstitial Nephritis

Acute Drug Induced Etiologic agents Rifampin Diuretics Allopurinol Cimetidine Methicillin Pathogenesis Drug acts as a hapten Resulting immunologic response targets tubular cells and basement membranes Typically 15 days post-drug administration Histology Interstitial edema Lymphocytic infiltration Giant-cell granulomas Tubulointerstitial symptoms Clinical Rash Fever Eosinophiluria ARF Treatment Discontinue offending drug Analgesic Nephropathy Etiologic agents Phenacetin APAP Caffeine Codeine Aspirin Pathogenesis Generation of oxidative metabolites from the drugs results in cortical interstitial nephritis and renal papillary necrosis Clinical Depressed cortical areas overlying papillary necrosis UTI Tubular acidosis Treatment Drug withdrawl

NSAID Associated Tubulointerstitial Nephritis NSAID use results in decreased prostaglandin synthesis and tubular damage due to ishemia Associated with: ARF Acute hypersensitivity

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Renal Failure
Acute Renal Failure (ARF) Characterized by an abrupt onset decrease in renal function (GFR) <24 hours Condition is reversible Clinical Azotemia Oliguria/anuria Uremic syndrome Hyperkalemia Metabolic acidosis Type Pre-renal Problem with the BODY Hypovolemia Sepsis Shock CHF Renal Problem with the BEAN Nephritic or nephrotic Tubulointerstitial Post-renal Problem with the BLADDER Obstruction Treatment Maintain fluid and electrolyte balance Avoid nephrotoxic medications Treat cause Dialysis Chronic Renal Failure Characterized by a substantial decrease in renal function over a long period Etiology Renal artery stenosis DM & SLE HTN Amyloidosis Chronic glomerulonephritis Tubulointerstitial nephritis Adult polycystic kidney disease Renal cancer Chronic urinary tract obstruction Stages 1. Diminished renal reserve i. GFR is 50% of normal ii. Asymptomatic 2. Renal insufficiency i. GFR is 20%-50% normal ii. Clinical 1) Azotemia 2) Anemia 3) HTN 4) Polyuria/nocturia 3. Chronic renal failure i. GFR is <25% normal ii. Regulation failure of volume & solutes iii. Clinical 1) Uremia 2) Muddy-brown casts 3) Confusion 4) JVD iv. Treatment 1) Dialysis 2) Transplant 3) Symptomatic 4. End-stage renal disease (ESRD) i. GFR <5% normal ii. Clinical 1) Decreased albumin and Ca++ 2) Elevated K+, phosphate and uric acid 3) Pulmonary congestion and CHF 4) Pericarditis 5) Increased infections 6) Bone defects iii. Treatment 1) Dialysis 2) Furosemide

Consequences of Renal Failure Uremic syndrome Occurs as BUN rises Lethargy, seizures, myoclonus, asterixis & pericardial friction rub Failure of urea excretion results in gut bacterial conversion to ammonia (hyperammonemia) Hyperkalemia Failure to excrete dietary K+ Metabolic acidosis Na+ and water retention Anemia Failure of EPO production HTN Fanconi's syndrome Glucose, AA, phosphate and bicarb are passed into the urine

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Renal Cell Carcinoma (RCC)

General Most common primary tumor of the kidney Arises from tubular epithelium Common in males, 60-70 Y.O. Epidemiology Tobacco Obesity Heavy metal exposure HTN Petroleum products Gross Yellow, often located near the poles Invades the renal vein and IVC with mets to lung (50%), bones (33%) and regional nodes Clinical Hematuria Palpable mass CVA pain Fever Types Clear cell carcinoma Papillary renal cell carcinoma Chromophobe renal carcinoma Bellini duct carcinoma Treatment Nephrectomy Clear Cell Carcinoma Most common RCC Originates from the proximal tubular epithelium Histology Bizarre nuclei with clear or granular cytoplasm Gross Necrosis Yellow-gray due to lipid presence Associated with a defect of the VHL tumor suppressor gene on Chr 3p

Papillary Renal Cell Carcinoma Originates from the DCT Histology Papillary growth pattern Interstitial foam cells Psammoma bodies Rings of calcium Gross Hemorrhagic and cystic Associated with a defect in the MET gene on Chr 7

Chromophobe Renal Carcinoma Originates from the intercalated cells of the CD Histology Darkly staining with a perinuclear halo Characterized by loss of an entire chromosome

Bellini Duct Carcinoma Originates from medullary CD Histology "Hobnail" pattern Nests of malignant cells in fibrotic stroma

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Other Renal Associated Cancers and Miscellaneous Renal Disease

Bladder Cancer Affect men more than women 50-70 Y.O. Cancer of transitional cells (urothelium) of the bladder (90%) SCC is associated and only occurs with schistosomiasis Epidemiology Smoking Radiation -naphthylamine Cyclophosphamide Clinical Painless hematuria Urinary frequency Hydronephrosis Gross Papillary, red and elevated Frequently mets to the liver, lungs and bone Treatment Surgical resection Cystectomy with radiation & chemotherapy Gitelman's and Bartter's Syndrome Both are the result of defective Na+ reabsorption Gitelman's Defective Na+ reabsorption in the distal tubule Identical presentation as loop diuretic overdose Bartter's Defective Na+ reabsorption in the thick ascending limb of the loop of Henle Identical presentation as thiazide diuretic overdose Clinical (Gitelman's) Presents in adulthood Cramps Polyuria/nocturia Fatigue Hypotension Mg++ wasting Clinical (Bartter's) Presents early Ca++ wasting Polyuria/polydipsia Growth & mental retardation Treatment NSAIDs Mg++ replacement K+ supplementation Aldactone ACEIs

Wilms' Tumor Most common primary tumor of the kidney in early childhood (2-5 Y.O.) Due to loss of WT1 tumor suppressor gene on Chr 11 Clinical Large, palpable abdominal mass Can lead to intestinal obstruction Abdominal pain Fever Hematuria Diagnosis Abdominal ultrasound Gross Tan-gray with hemorrhage and necrosis Treatment Nephrectomy with chemotherapy Associated with: WAGR complex Wilms' tumor Aniridia GU malformation Retardation Denys-Drash syndrome Gonadal dysgenesis and renal abnormalities Beckwith-Wiedemann Syndrome

Beckwith-Wiedmann Syndrome Organomegaly or hemihypertrophy Macroglossia Neonatal hypoglycemia Abdominal wall defects Increased risk of embryonal tumors (Wilms') Treatment Treatment for neonatal hypoglycemia May cause permanent brain damage if unrecognized

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Renal Disease Treatments

Dialysis Indications Unresponsive to conservative treatment Hyperkalemia Encephalopathy Pericarditis/pleuritis Severe metabolic acidosis Complications Renal Calcium oxalate deposition Aquired cystic disease Vascular Smooth muscle cell accumulation Arterial intimal thickening Dialysis related amyloidosis Hypotension Sepsis Leukopenia Peritoneal Peritonitis Obesity Hyperglycemia Hyperlipidemia Transplant Indicated when unresponsive to conservative treatment and dialysis complications Absolute contraindications Active infection Malignancy HIV Hepatitis b surface antigen Vascular disease Active glomerulonephritis Relative contraindications 70+ Y.O. Psychiatric disease Hepatitis C with cirrhosis Or chronic hepatitis Dialysis/treatment non-compliance Primary renal disease

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