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Mini Brenner
Mini Brenner
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Michael R. Clarkson
Ciara N. Magee
Barry M. Brenner
Chapter 1
History
The history should initially focus on causes of renal hypoper-
fusion and nephrotoxin exposure. A meticulous review of the
medical record should include a careful search for ischemic
and nephrotoxic insults. Common causes of volume depletion
such as vomiting, diarrhea, excessive sweating, burns, and
renal salt wasting (e.g., diabetic ketoacidosis) must be investi-
gated. Evidence of effective circulating volume depletion
should also be evaluated (e.g., congestive heart failure, cirrho-
sis). A history of recent trauma with or without overt blood
loss or muscle trauma should raise the possibility of ischemia,
myoglobin-induced tubular necrosis, or both. Fever, rash, and
joint pains are associated with lupus nephritis, vasculitides,
endocarditis, drug allergy, and infectious diseases causing
intrinsic acute kidney injury. A history of dyspnea or hemop-
tysis may be a sign of pulmonary vasculitis, but more typically
3
4
Differentiation of Acute from Chronic Kidney
Table 1-1
Disease
Factor Significance
I History Long-standing history suggests
chronic kidney disease
Approach to the Patient with Renal Disease
Aspirin
Nonselective cyclooxygenase inhibitors
Cyclooxygenase-2 inhibitors
Heavy metals and poisons
Mercury
Arsenic
Cadmium
Lead
Ethylene glycol
Calcineurin inhibitors
Cyclosporine
Tacrolimus
Reverse transcriptase inhibitors
Indinavir
Stavudine
Immunomodulatory agents
Interferon-a
Therapeutic immunoglobulins
Antidepressants and anticonvulsants
Celexa
Phenytoin
Carbamazepine
Physical Examination
The physical examination can provide many clues to the
underlying cause of and potential therapy for AKI.
Skin
Petechiae, purpura, and ecchymoses suggest inflammatory or
vascular causes of kidney failure. Cutaneous infarcts may
result from embolic phenomena; cutaneous vasculitis mani-
festing as palpable purpura occurs in patients with septic
shock, atheroembolic disease, systemic vasculitis, and infec-
tive endocarditis. Diffuse erythematous maculopapular rash
may be observed in cases of drug-induced allergic interstitial
nephritis or in systemic collagen vascular disease such as sys-
temic lupus erythematosus. Reduced skin turgor may corrobo-
rate the presence of volume depletion, but is less reliable in
the elderly.
Eye
The eyes are examined for uveitis (interstitial nephritis and
necrotizing vasculitis), ocular muscle paralysis (ethylene gly-
col poisoning and necrotizing vasculitis), signs of severe
hypertension, atheroembolic lesions, Roth spots (endocardi-
tis), and cytoid bodies (cotton-wool exudates seen in acute
lupus nephritis). Conjunctivitis can be a result of vasculitis
or drug toxicity or a manifestation of end-stage renal disease
(ESRD) (“red eyes of renal failure”), the latter due to conjunc-
tival calcium deposition.
Abdomen
Abdominal examination may reveal a palpable bladder (uri-
nary obstruction). Also, tenderness in the upper quadrants
can be associated with ureteral obstruction or renal infarction.
Ascites may be observed in fulminant hepatic failure, severe
nephrotic syndrome, and Budd-Chiari syndrome, all of which
are associated with AKI. An abdominal bruit evokes the diag-
nosis of severe atherosclerotic disease, which can engender
renal failure from renal artery stenosis, thrombosis of the aor-
torenal bifurcation, or atheroembolic renal disease. A flank
mass can be a sign of renal obstruction from tumor or retroper-
itoneal fibrosis. In addition, a tense distended abdomen in a
patient who has just undergone surgery raises the possibility
of abdominal compartment syndrome.
Extremities
Examination of the extremities for signs of edema, evidence of
tissue ischemia, muscle tenderness (e.g., rhabdomyolysis
causing myoglobinuric renal failure), and arthritis (e.g., sys-
temic lupus erythematosus, rheumatoid arthritis, infections)
may provide clues to the diagnosis of renal failure.
Neuropsychiatric Features
Neuropsychiatric abnormalities range from signs of uremic
encephalopathy (confusion, somnolence, stupor, coma, sei-
zures) to focal neurologic abnormalities in specific diseases
such as the vasculitides. Cranial nerve palsies can be seen
in patients with ethylene glycol poisoning or vasculitides.
Altered and changing mental status is common in thrombotic
microangiopathies and systemic atheroembolism.
Urinalysis 9
Blood Tests
Increases in blood urea nitrogen (BUN) and serum creatinine
(Cr) levels are hallmarks of renal failure. The normal BUN/Cr
ratio of 10:1 is usually maintained in cases of intrinsic AKI.
The ratio is usually elevated (>20:1) in prerenal conditions
and in some patients with obstructive uropathy. In patients
with significant upper gastrointestinal bleeding, the BUN/Cr
ratio may increase further as digested blood proteins are
absorbed and metabolized by the liver. BUN/Cr ratio may be
reduced in liver failure, malnutrition, and rhabdomyolysis.
The serum creatinine level begins to rise within 24 to 48 hours
in patients with AKI after renal ischemia, atheroembolization,
or radiocontrast exposure—three major diagnostic possibili-
ties in patients undergoing emergency cardiac or aortic angi-
ography and surgery. Creatinine levels typically peak at 7 to
10 days in ischemic ATN, with resolution within the next 7
to 14 days in the absence of further ischemic or nephrotoxic
insults. These rapid changes are in marked contrast to the
delayed elevation in serum creatinine levels (commencing at
7 to 10 days) that is characteristic of many tubule epithelial
cell toxins (e.g., aminoglycosides, cisplatin).
Additional diagnostic clues can be gleaned from routine
biochemical and hematologic tests. Hyperkalemia, hyperpho-
sphatemia, hypocalcemia, and increased concentrations of
serum uric acid and creatine kinase (CK3 isoenzyme) suggest
a diagnosis of rhabdomyolysis. A similar biochemical profile
seen in the setting of AKI subsequent to cancer chemotherapy,
but with higher levels of uric acid, a urine uric acid/creatinine
ratio greater than 1.0, and normal or marginally elevated crea-
tine kinase, is typical of acute urate nephropathy and tumor
lysis syndrome. Severe hypercalcemia of any cause can
induce AKI. Widening of the serum anion gap ([Naþ] – [HCO3]
þ [Cl]) and of the osmolal gap (measured serum osmolality
minus calculated osmolality) is a clue to the diagnosis of eth-
ylene glycol toxicity. Severe anemia in the absence of hemor-
rhage may reflect the presence of hemolysis, multiple
myeloma, or thrombotic microangiopathy. Other laboratory
findings suggestive of thrombotic microangiopathy include
thrombocytopenia, dysmorphic RBCs (schistocytes) on a
peripheral blood smear, a low circulating haptoglobin level,
and an increased circulating level of lactate dehydrogenase.
Systemic eosinophilia suggests allergic interstitial nephritis 11
but may also be a prominent feature in other diseases, such
as atheroembolic disease and polyarteritis nodosa, particu-
larly the Churg-Strauss variant. Depressed complement levels
and high titers of antiglomerular basement membrane antibo- CH 1
dies, antineutrophil cytoplasmic antibodies, antinuclear anti-
Urine Na Plasma Cr
FENa ¼ 100
Urine Cr Plasma Na
In prerenal azotemia, the FENa is usually less than 1%,
while in ATN it is usually greater than 1%; exceptions to this
may occur in patients with ATN due to severe burns, radio-
contrast nephropathy or underlying liver disease. The FENa
is typically less than 1% in patients with acute glomerulone-
phritis, because tubular function remains intact with
increased, rather than decreased, proximal tubular sodium
reabsorption. Also, FENa is most accurate for differentiating
prerenal from intrarenal AKI when determined in the patient
with hypotension and oliguria. Because of these limitations,
FENa alone should not be used in assessing the cause of AKI.
Urine/plasma osmolality ratio (U/P Osm) is another useful
test of tubular function in the setting of AKI. With intact tubu-
lar function, the urinary osmolality exceeds plasma osmolality
three- to fourfold, whereas when tubules are damaged and
concentrating capacity is impaired, urine is isosthenuric to
plasma. Therefore, a U/P Osm value of 1 or less is consistent
with ATN, and a value greater than 1 is consistent with a pre-
renal cause. Routine urinalysis is the best diagnostic test if
only small volumes of urine are available for analysis. Diagno-
sis of acute uric acid nephropathy can be substantiated by
urine uric acid/urine creatinine ratio greater than 1.
Fluid Challenge
When prerenal AKI due to significant intravascular volume
depletion is suspected, a fluid challenge with an intrave-
nous infusion of normal saline may be helpful and should
improve renal blood flow with correction of renal failure
and increased urine output. This maneuver usually consists
of an infusion of 1 to 2 L of normal saline administered over
2 to 4 hours, depending on repeated bedside clinical evalu-
ation of the volume status and clinical judgment. Close and
careful bedside monitoring of vital signs, physical findings,
and urine output is required. Failure of this maneuver to
improve the vital signs and urine output may indicate
intrarenal or postrenal causes of renal failure. Caution must
be exercised during fluid challenge because of the potential
for precipitating pulmonary edema in patients with conges-
tive heart failure or intrarenal failure, which do not respond
to volume expansion. Therefore, the patient should be care-
fully and repeatedly examined, and the rate of fluid chal-
lenge adjusted according to the discretion of the treating
physician.
Renal Angiography
A renal angiogram is helpful in patients with AKI due to vas-
cular disorders, including renal artery stenosis with AKI from
angiotensin-converting enzyme (ACE) inhibition, renal artery
emboli, and aortic atherosclerosis with acute aortorenal occlu-
sion, as well as in cases of systemic necrotizing vasculitides
such as polyarteritis nodosa and Takayasu arteritis. The use
of formal angiography is limited, however, by the risk of con-
trast nephrotoxicity.
Renal Biopsy
When clinical, biochemical, and noninvasive imaging studies
are insufficient for diagnosis and management of AKI, a renal
biopsy should be considered. Some studies show that biopsy
in the setting of AKI often has unexpected findings. Renal
biopsy is considered the “gold standard” for diagnostic accu-
racy in AKI, but in clinical practice, it is not often performed.
An exception is biopsy of a renal transplant, which is per-
formed relatively commonly in patients with AKI due to the
need to exclude transplant rejection. Patients presenting with
the clinical syndrome of rapidly progressive glomerulonephri-
tis (RPGN) should undergo renal biopsy promptly unless there
14 is an overt contraindication. This condition is considered a
medical emergency because effective kidney-preserving ther-
apy may be available and should be instituted as soon as
possible.
I
Approach to the Patient with Renal Disease
Physical Examination
The skin should be examined for excoriations due to uremic
pruritus, which are often seen on the back, torso, and lower
extremities. Vitiligo and periungual fibromas may be seen in
tuberous sclerosis. Neurofibromas may be a clue to renal disease
caused by underlying renal artery stenosis in patients with neu-
rofibromatosis. Hyperpigmented macules in the pretibial skin
are often observed in patients with cryoglobulinemic disease,
and livedo reticularis may be observed in those with atheroscle-
rotic ischemic nephropathy. A general sallow appearance
(urochromic pallor) of the skin is also a common finding in
patients with advanced CKD. Funduscopic examination may
demonstrate vascular findings, such as microaneurysms and
proliferative retinopathy characteristic of diabetic retinopathy.
Arteriolar narrowing, arteriovenous nicking, hemorrhage, and
exudates consistent with hypertension are also common. Less
common findings, which are more difficult to demonstrate on
routine examination, are anterior lenticonus and retinal flecks,
characteristic of Alport syndrome. Angioid streaks may be pres-
ent in patients with Fabry disease. Ocular palsy may be present
in patients with vasculitides (e.g., Wegener granulomatosis).
Diffuse conjunctivitis may indicate calcium-phosphorus depo-
sition in CKD with secondary hyperparathyroidism.
High-tone sensorineural hearing loss is overt in about 50%
of patients with Alport syndrome. Nasal and oropharyngeal
ulcers may be present in those with active lupus nephritis.
The presence of perforated nasal septum should raise the sus-
picion for Wegener granulomatosis or cocaine use. Examina-
tion for carotid or femoral bruit as a manifestation of
underlying atherosclerosis may also provide a clue to ische-
mic nephropathy as a cause of CKD.
Assessment of the cardiovascular and volume status is criti-
cal, because abnormal findings may require early and rapid
intervention before completion of the evaluation for CKD. Car-
diopulmonary examination for signs of volume overload is
essential for the evaluation and management of CKD, because
volume overload contributes to the development of hyperten-
sion, and many patients will have developed hypertensive
heart disease by the time of presentation (left ventricular
hypertrophy and heart failure). Cardiac murmurs may be pres-
ent in patients with endocarditis or atrial myxoma associated
with glomerulonephritis.
Abdominal examination should include a search for palpa- 17
ble kidneys, as observed in polycystic kidney disease and
tuberous sclerosis. A flank mass can be found in patients with
retroperitoneal fibrosis, lymphoma, or other tumors that can
obstruct the ureters. A palpable bladder or enlarged prostate CH 1
gland suggests chronic urinary outlet obstruction. Musculo-
Urinalysis
Urinalysis is not particularly useful for differentiating acute
from chronic kidney disease. Similar findings, such as
pyuria, hematuria, and proteinuria, can be seen in the two
disorders. The presence of oval fat bodies in the urine,
signifying high-grade proteinuria, implies a glomerular dis-
ease, as does the presence of dysmorphic red blood cells. Cal-
cium oxalate crystals may be seen in the urine of patients
with hereditary or secondary forms of oxalosis causing kid-
ney disease. The presence of calcium phosphate and sodium
urate crystals may signify previous stone disease as a cause
of CKD. Triple phosphate crystals may suggest recurrent uri-
nary tract infection and staghorn calculi causing CKD. As
discussed later, proteinuria is an important finding in any
patient with CKD.
Renal Biopsy
Renal biopsy is the most definitive method of differentiating
acute from chronic kidney disease. A biopsy is used to estab-
lish diagnosis, determine treatment regimen, collect prognos-
tic information, and track the clinical course of CKD,
especially in glomerulonephritis. Histologic findings of
chronicity include glomerulosclerosis, tubular atrophy, and
interstitial fibrosis. Interstitial fibrosis is the best indicator of
chronicity and best prognosticator of long-term outcome.
Renal biopsy is a low-risk procedure in stable patients with
CKD, including the elderly. Notwithstanding this, renal
biopsy ideally should be performed only when the findings
are likely to alter clinical management. Most physicians
would consider the biopsy of a small, shrunken kidney to be
ill-advised.
Laboratory Assessment of
Kidney Disease
DETECTION AND DIAGNOSIS OF KIDNEY
DISEASE
Because patients in early stages of chronic kidney disease
(CKD) often exhibit few signs or symptoms, tests for screening
and diagnosis are critical in nephrology. In clinical practice,
these tests are used to detect the presence of kidney disease,
ideally at an early enough stage that therapy may be instituted
to prevent associated morbidity and fatality; to establish a
specific diagnosis, thereby directing therapy; to monitor dis-
ease progression; and to ascertain response to treatment. Tests
that measure the glomerular filtration rate (GFR) best detect
abnormalities in kidney function, although they may be less
useful from a screening viewpoint, as patients with early
CKD may have normal or even increased GFR. Guidelines
developed by the National Kidney Foundation’s Kidney Dis-
ease Outcomes Quality Initiative (K/DOQI) define stages of
CKD largely based on GFR. Urinalysis may be useful in detect-
ing early abnormalities and may aid in the decision to perform
a kidney biopsy. Examination of the urine sediment may also
help to establish a diagnosis. No single test of the GFR is ide-
ally suited for every clinical application. Rather, the goal
should be to select the most accurate and precise test to
answer the question being addressed in the safest, most cost-
effective, and most convenient manner possible in the popula-
tion being studied.
Overview
GFR ¼ ðU V Þ=ðP T Þ
21
22 where U is the urine concentration of creatinine, V is the urine
volume, and P is the average plasma concentration of creati-
nine over the time (T) of the urine collection.
I Serum Creatinine
Approach to the Patient with Renal Disease
Creatinine Clearance
Measuring the creatinine clearance rate obviates some of the
problems of using serum creatinine concentration as a marker
of GFR. Creatinine clearance should not be affected by
differences in steady-state creatinine production due to differ- 23
ences in muscle mass that affect serum creatinine level. How-
ever, the reliability of creatinine clearance is greatly
diminished by variability in tubular secretion of creatinine
and by the inability of most patients to accurately collect CH 2
timed urine samples. Prolonged storage of the urine can also
MDRD Equation
Alb, serum albumin (g/dL); BUN, blood urea nitrogen (mg/dL); MDRD,
Modification of Diet in Renal Disease; PCr, plasma creatinine (mg/dL).
If the subject is black, multiply by 0.762. If the subject is female, multiply by 0.762.
To convert the CG formula to SI units, simply omit the multiplication factor 72
from the denominator. Online calculation of the MDRD equation is available at
http://nephron.com.
24 collections and timed creatinine clearances offered no more pre-
cision than the Cockcroft-Gault formula.
Based on the results of isotopically measured GFR determi-
nations from the Modification of Diet in Renal Disease (MDRD)
I Study, the investigators derived a formula for estimating GFR
using readily measurable clinical variables (see Table 2-1).
Approach to the Patient with Renal Disease
Plasma Urea
Urea is not an ideal marker of GFR, and the plasma urea con-
centration alone is a poor measure of GFR. With a molecular
weight of 60 Da, urea is freely filtered at the glomerulus. How-
ever, it can be readily reabsorbed, and the amount of tubular
reabsorption is variable. In states of actual or effective intravas-
cular volume depletion, urea reabsorption can be substantial.
Plasma urea, or blood urea nitrogen (BUN), concentration is
affected by a number of factors other than alterations in GFR.
Increased plasma levels caused by greater production are seen
with elevated dietary protein intake, gastrointestinal bleeding,
and tetracycline use. Reduced levels of plasma urea can be seen
in patients with alcohol abuse and chronic liver disease.
URINALYSIS
CH 2
Color
Specific Gravity
Urine pH
Urine pH is usually measured with a reagent test strip. Most
commonly, the double indicators methyl red and bromthymol
blue are used in the reagent strips to give a broad range of col-
ors at different pH values. In conjunction with other specific
28 urine and plasma measurements, urine pH is often invaluable
in diagnosing systemic acid-base disorders. By itself, however,
urine pH provides little useful diagnostic information. The
normal range for urine pH is 4.5 to 7.8. Very alkaline urine
I (pH > 7.0) is suggestive of infection with a urea-splitting
organism, such as Proteus mirabilis. Prolonged storage can
Approach to the Patient with Renal Disease
Glucose
Ketones
Protein
Normal Physiology
The upper limit of normal total urine protein excretion in
healthy adults is 150 to 200 mg/day. The upper limit of normal
albumin excretion is 30 mg/day. Most urinary protein consists
of Tamm-Horsfall protein, a glycoprotein that is formed on
the epithelial surface of the thick ascending limb of the loop
of Henle and early distal convoluted tubule. Immunoglobulin
A and urokinase are also secreted by the renal tubule and
appear in the urine in small amounts. Disruption of the glomer-
ular capillary wall barrier can lead to the filtration of a large
amount of high-molecular-weight plasma proteins that over-
whelm the limited capacity of tubular reabsorption and cause
protein to appear in the urine, resulting in glomerular protein-
uria. Tubular damage or dysfunction that inhibits the normal
resorptive capacity of the proximal tubule may result in tubular
proteinuria that generally consists of lower-molecular-weight
proteins. Increased production of normal or abnormal plasma
proteins can be filtered at the glomerulus, overwhelming the
resorptive capacity of the proximal tubule. Although increased
urine protein excretion can also result from increased tubular
production of protein, this is rarely the case.
I
Applications of Urine Protein Measurement
Approach to the Patient with Renal Disease
Formed Elements
Urine Microscopy Methods
A midstream, “clean-catch” specimen should be collected
when possible; the patient should be instructed to retract the
foreskin or labia. A high urine concentration and a low urine
34 pH help preserve formed elements. Thus, a first-void morning
specimen, which is most likely to be acidic and concentrated,
should be used whenever possible. Strenuous exercise and
bladder catheterization can cause hematuria, and urine speci-
I mens collected to detect hematuria should not be obtained
under these conditions. Urine should be examined as soon
Approach to the Patient with Renal Disease
Hematuria
Gross hematuria may first be detected as a change in urine
color. Microscopic hematuria can be identified by dipstick
methodology, microscopic examination, or both. Even when
the urine is red, or when a dipstick screening test result is pos-
itive, the sediment should be examined to determine whether
red blood cells are present. The presence of other pigments,
such as free hemoglobin and myoglobin, can masquerade as
hematuria. An occasional red blood cell can be seen in normal
individuals, but generally there are only one or two cells per
high-power field. The differential diagnosis of hematuria is
broad, but for practical purposes can be categorized as origi-
nating in either the upper or lower urinary tract. Red blood
cells originating in glomeruli have been reported to have a dis-
tinctive dysmorphic appearance that is most readily appre-
ciated with phase-contrast microscopy.
The differential diagnosis of hematuria is broad (Table 2-2).
Kidney vascular causes include arterial and venous thrombo-
sis, arteriovenous malformations, arteriovenous fistula, and
the nutcracker syndrome (compression of the left renal vein
between the aorta and superior mesenteric artery). Most
35
Table 2-2 Common Sources of Hematuria
Vascular Coagulation abnormalities
Excessive anticoagulation
Arterial emboli or thrombosis CH 2
Arteriovenous fistula
Nutcracker syndrome
Leukocyturia
More than one white cell per high-power field can be consid-
ered abnormal. The differential diagnosis of leukocyturia is
broad. The presence of proteinuria or casts suggests a glomer-
ular source. Most often, leukocytes in the urine are polymor-
phonuclear. However, it should not be assumed that all
urinary leukocytes are neutrophils. The presence of non-
neutrophil white blood cells in the urine, for example, eosino-
phils, can sometimes be an important diagnostic clue.
Although the true sensitivity and specificity of urinary eosino-
phils for detecting different clinical kidney diseases are
unclear, eosinophiluria has been associated with a variety of
other renal diseases (Table 2-3).
Urine Fat
In the absence of contamination, urinary lipids are almost
always pathologic. Lipids usually appear as free fat droplets
or oval fat bodies. They have a distinctive appearance but are
most readily seen under polarized light as doubly refractile
“Maltese crosses.” Urinary lipids are most commonly asso-
ciated with proteinuria and are particularly common in
patients with the nephrotic syndrome. Urine fat can also be
seen in bone marrow or fat embolization syndromes.
Casts
Casts are cylindrical bodies many times larger than leuko-
cytes and red blood cells. They form in distal tubules and
collecting ducts where Tamm-Horsfall glycoprotein precipi-
tates and entraps cells present in the urinary space. Dehydra-
tion and the resulting increased tubular fluid concentration
favor the formation of casts. An acid urine is also conducive
to cast formation. The differential diagnosis of cast formation
is aided by considering the type of cast found. Hyaline or
finely granular casts can be seen in normal individuals and
provide little useful diagnostic information. Cellular casts
are generally more helpful. Red blood cell casts are distinc-
tive and indicate glomerular disease. White blood cell casts
are most commonly associated with interstitial nephritis
but can also be seen in glomerulonephritis. Casts made up
of renal tubular epithelial cells are always indicative of tubu-
lar damage. Coarsely granular casts often result from the
degeneration of different cellular casts and their presence is
usually pathologic, although nonspecific. Waxy casts are also
nonspecific. They are believed to result from the degenera-
tion of cellular casts and, thus, can be seen in a variety of
kidney diseases. Pigmented casts usually derive their dis-
tinctive color from bilirubin or hemoglobin and are found
in hyperbilirubinemia or hemoglobinuria, respectively.
38 Crystals and Other Elements
A large variety of crystals can be seen in the urine sediment.
Most result from urine concentration, acidification, and
ex vivo cooling of the sample and have little pathologic signifi-
I cance. However, an experienced observer can gain useful infor-
mation about patients with microhematuria, nephrolithiasis, or
Approach to the Patient with Renal Disease
Microorganisms
The most common cause of bacteria in the urine is contamina-
tion, particularly in specimens that have been improperly col-
lected. The concomitant presence of leukocytes, however,
suggests infection. Fungal elements can also be seen, especially
in women. Like bacteria, fungi can be contaminants or patho-
gens. The most common protozoan seen in the urine is Tricho-
monas vaginalis. Urinary parasites are generally not seen in the
urine sediment. In Africa and the Middle East, however, Schis-
tosoma haematobium is common.
KIDNEY BIOPSY
Indications
At present, no specific clinical indications mandate the use of
kidney biopsy, and its utility must be considered in the context
of the patient’s needs, in terms of diagnosis, prognosis, and ther-
apy. Nonetheless, there are clinical settings in which kidney
biopsy is likely to be most useful. These include the following:
Nephrotic Syndrome
A renal biopsy is indicated for the investigation of all cases of
the nephrotic syndrome with two exceptions:
• Children with the idiopathic nephrotic syndrome, in which
minimal change glomerulopathy, which is sensitive to steroid
therapy, accounts for nearly 80% of cases in children. How-
ever, in children who do not respond to an appropriate course
of steroids, or who have frequent relapses over a year, a kid-
ney biopsy may be indicated.
• Diabetic patients in whom the history and urinalysis are 39
consistent with a diagnosis of diabetic nephropathy (diabe-
tes mellitus for longer than 10 years, inactive urinary sedi-
ment, normal renal ultrasound).
In patients with evidence of elevated levels of serum or urinary CH 2
light chains in association with proteinuria in the ranges seen
Non-nephrotic Proteinuria
The value of renal biopsy in the setting of lesser degrees of
proteinuria (<2 g) is less certain. Many of these patients will have
either focal segmental glomerulosclerosis or membranous
nephropathy. However, at this degree of proteinuria immunosup-
pressive treatment would not be contemplated and nonspecific
measures to reduce proteinuria (ACE inhibition) can be instituted
without reference to renal histologic findings. Indications to pro-
ceed to biopsy would include evidence of a fall in the GFR,
worsening proteinuria, or evidence of a systemic process (e.g.,
vasculitis, systemic lupus erythematosus, or multiple myeloma).
Isolated Hematuria
Patients with isolated hematuria should be closely evaluated
to exclude extrarenal causes of hematuria, such as uroepithe-
lial malignancy in patients with known risk factors or age
over 40 years. The differential diagnosis of isolated hema-
turia includes thin basement membrane disease and IgA
nephropathy. In the absence of proteinuria, most clinicians
forgo renal biopsy as the prognosis in this setting is typically
excellent.
40 Post-transplantation Biopsy
Biopsy of the transplanted kidney has been established as an
important diagnostic and therapeutic technique in the manage-
ment of patients in whom rejection of the kidney allograft is
I suspected. It has become particularly important in an era when
the differential diagnosis of decreased allograft function includes
Approach to the Patient with Renal Disease
Other Indications
There does not appear to be any indication for a kidney biopsy
in patients with chronic, end-stage renal failure, and biopsy
in this setting is probably associated with a higher risk of com-
plications. In patients with acute kidney injury, in whom no
obvious cause for rapid deterioration in kidney function can
be found, kidney biopsy may be indicated. Biopsy in this
setting appears valuable mostly for those few patients with
acute allergic interstitial nephritis, in whom a course of corti-
costeroids may be of benefit. Cholesterol embolic acute kidney
injury without the typical clinical presentation has been more
commonly observed in older patients with atherosclerotic
disease, posing a diagnostic challenge. Because some of these
patients may regain kidney function after prolonged intervals,
closer attention to kidney function during dialysis is appropri-
ate. However, a clear-cut case for the utility of a kidney biopsy
for diagnosis, prognosis, or therapy has not been made in
patients with acute kidney injury.
MODALITIES
Plain Film of the Abdomen
This study may also be known as a KUB, or radiograph of the
kidneys, ureter, and bladder. The examination itself yields
little significant information. Renal size and contour may be
estimated if the renal outlines can be seen, calcifications
may be visualized, and other abdominal findings may be
noted. If performed, it should only be considered a starting
point. Intravenous iodinated contrast material is usually nec-
essary for the opacification of the kidneys and urinary tract
on radiographic examinations.
Intravenous Urography
Ultrasound
Ultrasonography is the first-line examination in the azotemic
patient for assessing renal size and the presence or absence
of hydronephrosis and obstruction. It is used to assess the vas-
culature of native and transplanted kidneys, to guide renal
biopsy, and to characterize renal cysts or masses. Overall renal
echogenicity is generally compared with the liver on the right
and spleen on the left; normal kidneys are less echogenic by
comparison. The demonstration of increased echogenicity
suggests the presence of renal parenchymal disease, although
this finding is nonspecific and does not correlate with the
degree or severity of kidney injury. Renal size is easily
measured; the normal longitudinal dimension of the right
kidney is 11 cm 1 cm, the left being 11.5 cm 1 cm.
Computed Tomography
Computed tomography (CT) is now increasingly used in the
assessment of the genitourinary tract, and is often the first-line
examination to be performed in patients with ureteric colic,
44 renal stone disease, renal trauma, renal infection and abscess,
renal mass, and urothelial abnormalities. The kidney can be
scanned in the arterial, venous, nephrographic, and delay
phases, allowing for a more complete assessment. CT urogra-
I phy assesses the kidney as a whole (anatomic), the vascular
tree (function and perfusion), and the excretory (urothelial)
Approach to the Patient with Renal Disease
RENAL INFECTION
Imaging is rarely used or needed in the uncomplicated case
of acute pyelonephritis. It is reserved for the patient who is
not responding to conventional antibiotic treatment, patients
with an unclear diagnosis, those with coexisting stone disease
and possible obstruction, patients with diabetes and poor
50 antibiotic response, and immunocompromised patients. Imag-
ing is used to assist in confirming the diagnosis and determine
the extent of disease. It is also used in assessing complications
of acute pyelonephritis including renal abscess, emphysema-
I tous pyelonephritis, and perinephric abscess.
IVU findings in acute pyelonephritis include renal enlarge-
Approach to the Patient with Renal Disease
RENAL MASSES
Renal masses are quite common with simple renal cysts found
in more than 50% of patients over the age of 50. The vast
majority of renal masses are simple cysts, with solid renal
masses, such as renal cell carcinoma, in the minority.
Renal Cysts
Typically, renal cysts are asymptomatic, cortical in location,
and may be single or multiple. The cause is unknown. Intra-
cystic hemorrhage or infection can produce pain or fever.
52 Ultrasound is an excellent means of diagnosing a simple renal
cyst if all imaging criteria are met:
• The lesion is round or oval and must be anechoic (no inter-
nal echoes).
I • The cyst must be well circumscribed with a smooth wall.
• The image must be enhanced through transmission of the
Approach to the Patient with Renal Disease
Renal Cancer
INTERVENTIONAL NEPHROLOGY
Interventional nephrology is a rapidly expanding field in
which nephrologists have become actively involved in
performing a wide variety of procedures, including vascular
access procedures, as outlined in Table 3-1. A discussion of
the technical aspects of angioplasty, and other related proce-
dures (discussed in the following sections), is beyond the
scope of this text.
Thrombectomy of Grafts
Angioplasty of Fistulas
Cryoplasty Balloon
Cryotherapy with the cryoballoon is a novel therapy for
patients with intractable stenoses at the venous anastomosis
of AV grafts. This technique utilizes cold temperatures at the
balloon site to cause apoptosis of the intimal layer. There are
64 currently no published randomized studies comparing the
outcomes of graft stenosis treated with cryoplasty versus with
angioplasty alone.
I
CENTRAL VEIN STENOSIS
Approach to the Patient with Renal Disease
Control of Extracellular
Fluid Volume and the
Pathophysiology of
Edema Formation
CONTROL OF EXTRACELLULAR FLUID
VOLUME
71
72 • Sensors that detect changes in ECF volume relative to vas-
cular and interstitial capacitance.
• Effector mechanisms that ultimately modify the rate of Naþ
excretion by the kidney to meet the demands of volume
II homeostasis.
Adjustments in effector mechanisms occur in response to
Disturbances in Control of Body Fluid Volume and Composition
Volume Receptors
Volume detectors are located at several locations throughout
the body including cardiopulmonary and arterial baroreceptors,
as well as renal, central nervous system, and hepatic sensors.
Each compartment can be viewed as reflecting a unique charac-
teristic of overall circulatory function, such as cardiac filling,
cardiac output, renal perfusion, or fluid transudation into the
interstitial space. Sensors within each compartment monitor a
physical parameter (e.g., stretch, tension) that serves as an
index of circulatory function within that compartment. These
signals are then transduced via neural and hormonal signals
to the efferent limb of the integrated homeostatic response sys-
tem. In addition to its role as a major effector target responding
to signals indicating the need for adjustments in Naþ excretion,
the kidney participates in the afferent limb of volume homeo-
stasis. In the kidney, the volume sensors are found in the juxta-
glomerular apparatus of the afferent arteriole. Signals from this
site affect volume homeostasis primarily via modulation of
the renin-angiotensin-aldosterone system (RAAS) and intrare-
nal hemodynamics such that alteration in the ECF results in
adjustments in physical forces governing tubular Naþ handling.
In contrast, the effects of cardiopulmonary and neural receptors
are mediated primarily through the actions of natriuretic pep-
tides and the sympathetic nervous system.
Effector Mechanisms
The major renal effector mechanisms defending against
changes in volume status include the RAAS, sympathetic ner-
vous system, and natriuretic peptides and intrarenal factors
(tubuloglomerular feedback).
Renin-Angiotensin-Aldosterone System
The RAAS plays a major role in the regulation of ECF volume
homeostasis. Renin release from the kidney is enhanced in
situations that compromise extracellular volume homeostasis,
such as loss of blood volume, reduced ECF volume, “effec- 73
tive” circulating volume depletion (heart failure, cirrhosis),
diminished salt intake, and hypotension. Renin release accel-
erates the generation of angiotensin II (A-II), the principal effec-
tor of the RAAS, which has multiple actions: it raises the blood CH 4
pressure by arterial vasoconstriction; it promotes efferent arte-
Vasopressin
Release of arginine vasopressin (AVP) from the posterior pitu-
itary occurs in response to an increase in plasma osmolality
(via osmoreceptor stimulation) or decreased effective circulat-
ing volume and blood pressure (nonosmotic baroreceptor
stimulation). AVP enhances water permeability and reabsorp-
tion in the medullary collecting duct via aquaporin II chan-
nels, but also increases Naþ reabsorption mainly in the
cortical and outer medullary collecting ducts via activation
of the epithelial Naþ channel (ENaC). Vasopressin has potent
arteriolar vasoconstrictive effects, resulting in significant
increases in systemic vascular resistance. In terms of overall
volume homeostasis, the predominant influence of AVP in
response to perceived ECF depletion results indirectly from
water accumulation or blood pressure changes. The systemic
vasoconstrictor effects, which might reasonably be assumed
the predominant defense of blood pressure, are buffered by a
concomitant increase in baroreflex-mediated sympathoinhibi-
tion or by an increase in prostaglandin (PG) E2, which blunts
vasocontriction and has a direct vasodepressive action. None-
theless, at supraphysiologic concentrations of vasopressin,
such as occur when effective circulating volume is severely
compromised, it plays an important role in supporting arterial
blood pressure and maintaining adequate organ perfusion.
74 Prostaglandins
Within the kidney, PGs play an integral role in the regulation
of renal function including hemodynamic regulation, renin
secretion, growth response, and tubular transport mechan-
II isms. PGs are formed from the metabolization of arachidonic
acid by the two principal isomers of cyclooxygenase (COX-1
Disturbances in Control of Body Fluid Volume and Composition
Natriuretic Peptides
Atrial natriuretic peptide (ANP), an endogenous 28-amino-acid
residue peptide of cardiac origin, has been the most extensively
studied member of the NP family, which contains at least two
other members, brain natriuretic peptide and C-type natriuretic
peptide. ANP is released in response to atrial stretch as occurs
in the setting of volume overload. At the renal level, ANP
increases the GFR and the filtered load of Naþ via an elevation
of glomerular capillary hydrostatic pressure secondary to a
combination of efferent arteriolar vasoconstriction and afferent
arteriolar vasodilatation. ANP antagonizes reabsorption of Naþ
mediated by A-II and it directly inhibits Naþ reabsorption in
the inner medullary collecting duct and NaCl reabsorption in
the distal tubule via inhibition of the thiazide sensitive NaþCl
co-transporter.
Tubuloglomerular Feedback
Intrarenal physical factors, acting at the level of the coupling
of tubule reabsorption to glomerular filtration, are also
involved in regulating urinary Naþ excretion, responding to
afferent limb signals that indicate volume perturbation. The
mechanisms mediating tubuloglomerular feedback are beyond
the scope of this text but include changes in hydrostatic and
oncotic pressure within the peritubular capillaries, alterations 75
in flow-related proximal reabsorption of Naþ, and changes in
Naþ handling in the loop of Henle. The net result of these
changes is enhanced Naþ excretion in states of ECF volume
expansion and vice versa. CH 4
Renal Losses
The most common renal cause of ECF volume depletion is
Naþ wasting due to diuretic use. This is most frequently
observed with loop diuretic use and is more common in the
elderly, in whom the homeostatic responses to volume con-
traction are impaired. The combination of a loop diuretic
and the thiazide diuretic metolazone causes a brisk diuresis
that is frequently associated with volume depletion in clinical
practice, and should be undertaken with caution in the out-
patient setting. Other causes of renal Naþ wasting include
osmotic diuresis (hyperglycemia, mannitol administration,
postobstructive diuresis), primary renal salt wasting syn-
dromes (Bartter’s syndrome, medulary cystic kidney disease),
and secondary renal salt wasting syndromes (aldosterone
deficiency). Free water loss generally does not induce hypovo-
lemia unless the losses are severe (>10 L/day) and the patient
is denied free access to water, resulting in hypernatremic
hypovolemia.
Gastrointestinal Losses
Gastrointestinal secretions exceed several liters per day of
electrolyte-rich fluid, the majority of which is reabsorbed. Vol-
ume depletion is commonly observed if significant amounts
of gastrointestinal secretions are either lost (vomiting, osmotic
diarrhea, nasogastric suction) or are increased (secretory
diarrhea) in the absence of adequate water and electrolyte
repletion.
Hemorrhage
Hemorrhage from any site can lead to life-threatening volume
depletion. Excluding traumatic blood loss, common causes
encountered in clinical practice include variceal hemorrhage
and bleeding from a peptic ulcer.
76 Sequestration
Sequestration of fluid into the third spaces, if severe, can
cause ECF volume depletion. Commonly encountered clinical
scenarios include intestinal obstruction, pancreatitis, crush
II injuries, peritonitis, and hip fractures.
Disturbances in Control of Body Fluid Volume and Composition
Body Weight
A rapid decline in body weight is a key finding in the evalua-
tion of the patient with volume contraction, particularly in the
elderly patient in whom other physical signs are often highly
unreliable. The change in body weight not only aids in the
diagnosis of volume depletion, but can also help guide therapy.
Serum Indices
Analysis of blood biochemistry is useful in the determination
of ECF volume status based on knowledge of the normal phys-
iologic response to volume contraction outlined earlier. Vol-
ume depletion leads to enhanced proximal tubule salt and
water retention, thereby increasing the passive reabsorption
of urea, leading to a rise in the normal blood urea nitrogen
(BUN) to creatinine ratio from the normal level of 10:1 to over
20:1. Factors that alter urea generation independent of renal
clearance (e.g., corticosteroid use) can affect the reliability of
this index. The nonosmotic release of vasopressin can trigger
a modest decrement in the serum Naþ concentration, while
hemoconcentration (high hematocrit) may result from plasma
volume contraction. Analysis of the acid-base status can fur-
ther elucidate the underlying cause of the volume-contracted
state. A hypochloremic metabolic alkalosis is characteristic
78 of volume depletion due to diuretic use, vomiting, or nasogas-
tric suctioning. In contrast, diarrhea can lead to heavy losses
of bicarbonate-rich fluids with secondary NaCl retention by
the kidney, giving rise to a hyperchloremic metabolic acidosis.
II
Urine Indices
Disturbances in Control of Body Fluid Volume and Composition
Thirst
Thirst is the body’s defense mechanism to increase water con-
sumption in response to a perceived water deficit. However,
the vast majority of fluid ingested is determined by influences
HYPERNATREMIA
Hypernatremia, defined as plasma Naþ level greater than
146 mEq/L, implies a deficiency of total body water relative
to total body sodium rather than total body Naþ overload.
When approaching a patient with either hypo- or hypernatre-
mia, it is important to understand the following key concept:
Total body Naþ stores are a major factor determining ECF
volume status; however, the measured serum Naþ reflects
only the concentration of sodium within the ECF. Analysis
of the serum Naþ without reference to the physical examina-
tion or other laboratory indices of volume status gives no
information regarding a patient’s ECF volume status.
The patient with hypernatremia may be hypovolemic, euvo-
lemic, or hypervolemic, and clinical determination of the vol-
ume status is attained by evaluating several factors including
the physical examination findings (e.g., blood pressure, skin
turgor), laboratory findings (e.g., BUN/creatinine ratio) and
hemodynamic parameters (e.g., central venous pressure).
Hypernatremia rarely develops in patients who have free
access to water because the hyperosmolar-induced thirst sensa-
tion triggers avid water ingestion that returns the serum osmolal-
ity to normal or near normal. When access to free water is
limited, such as may occur in critically ill patients, infants,
and patients with dementia, then either free water losses in
excess of Naþ losses (diarrhea, osmotic diuresis), free water
losses alone (diabetes insipidus), or augmented Naþ intake with-
out sufficient free water (hypertonic feeds, NaHCO3 administra-
tion) can lead to the development of hypernatremia. As Naþ is
the principal determinant of serum osmolality, hypernatremia is 91
associated with a rise in serum osmolality, which causes fluid to
exit brain cells, causing cell shrinkage and a variety of neurologic
sequelae. Depending on the speed of onset of the hypernatremia,
these sequelae include restlessness, anxiety, confusion, coma, CH 5
seizures, and most dramatically, central pontine myelinolysis
Hypovolemic Hypernatremia
Euvolemic Hypernatremia
Euvolemic hypernatremia implies a disorder of urinary con-
centration related to either the absence of AVP or a resistance
to the actions of AVP within the principal cells in the distal
tubule. The common causes of euvolemic hypernatremia are
discussed in the following sections.
92 Central Diabetes Insipidus
Central diabetes insipidus (CDI) is caused by inadequate secre-
tion of AVP from the posterior pituitary in response to osmotic
stimulation. In most cases, this is due to destruction of the neu-
II rohypophysis by a variety of acquired or congenital anatomic
lesions, which damage the neurohypophysis by either direct
Disturbances in Control of Body Fluid Volume and Composition
Osmoreceptor Dysfunction
The primary osmoreceptors that control AVP secretion and
thirst are located in the anterior hypothalamus. Lesions of this
region result in hyperosmolality through a combination of
impaired thirst and osmotically stimulated AVP secretion,
known as “adipsic hypernatremia” in recognition of the pro-
found thirst deficits found in most patients. All cases of
osmoreceptor dysfunction reported to date have been due to
variable degrees of osmoreceptor destruction caused by the
same types of lesions that can cause classic CDI, but in con-
trast, they are located, or extend, more anteriorly in the hypo-
thalamus. One lesion unique to this disorder is an anterior
communicating cerebral artery aneurysm, which is associated
with spontaneous or postsurgical infarction of the osmore-
ceptive region of the hypothalamus. Several patterns of
93
Table 5-2 Etiology of Hypotonic Polyuria
Central Diabetes Insipidus
Congenital (congenital malformations, autosomal dominant, AVP-
neurophysin gene mutations) CH 5
Drug/toxin-induced (ethanol, diphenylhydantoin, snake venom)
Hypervolemic Hypernatremia
Treatment of Hypernatremia
To reduce the risk of CNS damage from protracted exposure to
severe hyperosmolality, in most cases the plasma osmolality
should be lowered relatively rapidly within the first 24 hours,
to a range of 320 to 330 mOsm/kg H2O or by replacing approx-
imately 50% of the free water deficit (see later discussion). In
chronic hypernatremia and sustained hyperosmolality the
brain counteracts osmotic shrinkage by increasing the intra-
cellular content of solutes. However, once the brain has
adapted by increasing its solute content, rapid correction of
the hyperosmolality can trigger cerebral edema and neurologic
injury. Therefore, further correction to a normal plasma osmo-
lality should be extended over the next 24 to 72 hours to avoid
triggering cerebral edema. This slower correction is especially
important in children, where several studies have indicated
that limiting correction of hypernatremia to a maximal rate
of 0.5 mmol/L/hour prevents the occurrence of symptomatic
cerebral edema with seizures. In addition, the possibility of
associated thyroid or adrenal insufficiency should also be con-
sidered because patients with CDI caused by hypothalamic
masses may have associated anterior pituitary function defi-
ciency. Acute hypernatremia with associated neurologic signs
can be corrected over a shorter period (<24 hours).
96 Hypovolemic Hypernatremia
Restoration of the ECF volume is the primary therapeutic
maneuver in hypovolemic hyponatremia. This is accom-
plished with 0.9% NaCl, which is relatively hypotonic com-
II pared to the serum in the patient with hypernatremia. Once
euvolemia is established and ongoing losses (Naþ and water)
Disturbances in Control of Body Fluid Volume and Composition
Euvolemic Hypernatremia
The total body water deficit in a hypernatremic patient can be
estimated using the following formula:
during the initial therapy, and then at least daily until stabili-
zation or resolution of the DI. It is generally advisable to
ensure polyuria still exists before administration of
subsequent doses of desmopressin because postoperative DI
is often transient. The clinical management of acute traumatic
DI after injuries to the head is similar to that of postsurgical
DI, except that the possibility of anterior pituitary insuffi-
ciency must also be considered in such cases, and the patient
should be given stress doses of hydrocortisone (100 mg intra-
venously every 8 hours) until anterior pituitary function can
be definitively evaluated.
Osmoreceptor Dysfunction. The acute management of a
patient with osmoreceptor dysfunction involves the correction
of the underlying free water deficit. The long-term manage-
ment of osmoreceptor dysfunction syndromes requires a thor-
ough search for a potentially treatable cause (see Table 5-2), in
conjunction with the use of measures to prevent recurrence of
dehydration. The mainstay of management is education of the
patient and family about the importance of continuous regula-
tion of fluid intake in accordance with the hydration status.
This can be done most efficaciously by establishing a daily
schedule of water intake based on changes in body weight,
regardless of the patient’s thirst. If polyuria coexists, desmo-
pressin should be given as for any patient with DI.
Gestational Diabetes Insipidus. The treatment of choice is
desmopressin, because it is not degraded by oxytocinase/vaso-
pressinase and appears to be safe for both mother and child,
with minimal stimulation of the uterine oxytocin receptors.
During delivery, oral intake and desmopressin can be
continued, but parenteral fluid should be administered with
caution, as patients are susceptible to the development of
98 water intoxication and hyponatremia because of an inability
to excrete a free water load. Levels of oxytocinase/vasopressi-
nase decrease in plasma within several days, and depending
on the etiology, the disorder may disappear completely, or
II become asymptomatic.
Nephrogenic Diabetes Insipidus. By definition, patients
Disturbances in Control of Body Fluid Volume and Composition
Hypervolemic Hypernatremia
The principal therapeutic intervention in hypervolemic hyper-
natremia is induction of a natriuresis with a loop diuretic such
as furosemide. Patients with end-stage renal disease (ESRD)
may require hemodialysis. Care must be taken to avoid overly
rapid rates of correction, as may occur when furosemide and
hypotonic fluids are administered simultaneously.
HYPO-OSMOLAR DISORDERS
Hyponatremia (plasma [Naþ] < 130 mEq/L) is among the most
common electrolyte disorders encountered in clinical medi-
cine. As reviewed in the introduction to this chapter, changes
in plasma Naþ are usually associated with comparable
changes in plasma osmolality. When the “measured” osmolal- 99
ity exceeds the calculated osmolality by more than 10 mOsm/kg
H2O, an osmolar gap is said to be present. This occurs in two cir-
cumstances: (1) with a decrease in the water content of serum,
and (2) on addition of a solute other than urea or glucose to CH 5
the serum. A decrease in the water content of serum is usually
Etiology of Hyponatremia
CH 5
Hyponatremia with Extracellular Fluid Volume
Hepatic Failure
Patients with advanced cirrhosis and ascites frequently pres-
ent with hyponatremia consequent to their inability to excrete
a water load. This process results from a decrement in effec-
tive arterial volume (splanchnic venous pooling, decreased
plasma oncotic pressure due to hypoalbuminemia, peripheral
vasodilatation) leading to avid Naþ and water retention, again
thought to be via baroreceptor-mediated AVP release.
Nephrotic Syndrome
The incidence of hyponatremia in the nephrotic syndrome is
lower than in either congestive heart failure or cirrhosis, most
likely consequent to the higher blood pressure, higher glomer-
ular filtration rate (GFR), and more modest impairment in Naþ
and water excretion than in the other groups of patients. As
lipids are frequently elevated, a direct measurement of plasma
osmolality should be performed.
Renal Failure
Hyponatremia with edema can occur with either acute or
chronic renal failure owing to an inability to excrete an
ingested water load, often combined with an increased sensa-
tion of thirst.
Hyponatremia with Normal Extracellular Fluid 103
Volume
Glucocorticoid Deficiency
There is considerable evidence of an important role for gluco-
corticoids in the abnormal water excretion of adrenal insuffi-
ciency. The water excretory defect of anterior pituitary
insufficiency, and particularly corticotropin deficiency, is
associated with elevated AVP levels and corrected by physio-
logic doses of glucocorticoids. Prolonged glucocorticoid defi-
ciency has been associated with an AVP-independent
intrarenal process, leading to impaired water excretion, prob-
ably via alteration in renal hemodynamics.
Hypothyroidism
Hypothyroidism is associated with impaired free water excre-
tion and development of hyponatremia, reversible by treatment
with thyroid hormones. Both decreased delivery of filtrate to
the diluting segment and persistent secretion of AVP, alone or
in combination, have been proposed as mechanisms responsi-
ble for the defect. Experimental evidence suggests hyposensi-
tivity to AVP, as urine osmolality has been shown to be
relatively low for the circulating levels of the hormone.
Postoperative Hyponatremia
The incidence of hospital-acquired hyponatremia is high in
postoperative patients (4%). The majority of affected patients
appear clinically euvolemic and have detectable circulating
levels of AVP. Although this occurs primarily as a consequence
of administration of hypotonic fluids, a decrease in serum Naþ
can occur in this high AVP state, even when isotonic fluids are
given. The presence of hyponatremia is a marker for poor out-
come, however, because it reflects the severity of the underly-
ing disease, rather than the hyponatremia per se. A subgroup
of postoperative patients—nearly exclusively premenstrual
females—can develop catastrophic neurologic events, fre-
quently accompanied by seizures and hypoxia.
Strenuous Exercise 105
There is increasing recognition that strenuous exercise, such as
military training, marathons, or triathlons, can cause frequently
symptomatic hyponatremia. A recent prospective study of mar-
athon runners revealed that weight gain related to excessive CH 5
fluid intake was the strongest predictor of hyponatremia, fol-
Pharmacologic Agents
Chlorpropamide. The incidence of hyponatremia may be as
high as 7%, but severe hyponatremia (<130 mEq/L) occurs in
2% of patients so treated. The drug exerts its action primarily
by potentiating the renal action of AVP.
Carbamazepine. Carbamazepine possesses antidiuretic pro-
perties. The incidence of hyponatremia in carbamazepine-
treated patients is approximately 5%. The hyponatremia is
mediated by enhanced AVP release, enhanced sensitivity to the
action of AVP, and decreased sensitivity of the vasopressin
response to osmotic stimulation.
Psychotropic Drugs. A large number of psychotropic drugs
have been associated with hyponatremia, and they are fre-
quently implicated in the explanation of water intoxication
in psychotic patients. The elderly appear to be particularly
susceptible, with an incidence as high as 22% to 28%. The
tendency for these drugs to cause hyponatremia is thought to
be further compounded by their anticholinergic effect, which
stimulates water intake via drying of the mucous membranes.
The role of these drugs in impaired water excretion has not, in
most cases, been dissociated from the underlying psychiatric
disorder, and it may be that the pharmacologic agents are
not primarily responsible. Recently, an increasing number of
cases of amphetamine (Ecstasy)-related hyponatremia have
been described.
Antineoplastic Drugs. Vincristine exerts a direct neurotoxic
effect on the hypothalamic microtubule system, which then
alters normal osmoreceptor control of AVP release. The mech-
anism of the diluting defect due to cyclophosphamide admin-
istration is not fully understood, although may act via
potentiation of AVP, as the absolute levels of AVP are not
increased. The importance of anticipating potentially severe
hyponatremia in cyclophosphamide-treated patients who are
vigorously hydrated to avert urologic complications cannot
be overstated.
Narcotics. Opioid agonists have been reported to have
widely variable effects on AVP release. Agonists of m-receptors
have been shown to have antidiuretic properties, whereas
△-receptor agonists have the opposite effect.
106 Symptoms
Treatment
Hypovolemic Hyponatremia
Isotonic NaCl (0.9%) should be administered to patients with
hypovolemic hyponatremia. Importantly, if isotonic saline is
administered to patients with SIADH with a Uosm greater than
300 mOsm/L, worsening hyponatremia will result. This
occurs as the patient with SIADH is in Naþ balance. All of
the administered Naþ will therefore be excreted in a hyper-
tonic urine with the retention of free H2O.
Normovolemic Hyponatremia
If the patient is asymptomatic, the cornerstone of treatment is
water restriction. A guide to the degree of restriction required
can be estimated from the assessment of the urinary concen-
tration of Naþ and Kþ (see the following table). Because the
level of urine concentration is more or less fixed in many
patients with SIADH, any fluid intake above insensible losses
plus electrolyte-free water excretion (which can be a negative
figure) will cause the serum Naþ to fall. Therefore, the follow-
ing guide to therapy has been proposed:
108 (UNaþ þ UKþ)/Serum Naþ Water Restriction
>1 <500 mL/day
1 750 mL/day
Hypervolemic Hyponatremia
Fluid restriction with or without loop diuretic therapy is the
treatment of choice for patients with hypervolemic hyponatre-
mia. Dialysis may be required to normalize the serum Naþ in
patients with advanced CKD or ESRD.
Symptomatic Hyponatremia
If the patient is symptomatic, then rapid correction can be
achieved in the euvolemic patient by administration of hyper-
tonic saline (3% NaCl), which contains 513 mEq of Naþ/L.
The rate of administration required to increase the serum
Naþ concentration to 120 mEq/L, at a rate not to exceed
1 mEq/L/hour, can be derived from the earlier formula. For
example, a 70-kg man with a serum Naþ of 110 mEq/L would
require the following:
POLYURIA
There are two definitions of polyuria. The second illustrates
the importance of analyzing data on the basis of the prevailing
stimulus and knowledge of the expected renal response to an
abnormal plasma sodium (PNa):
• Nonphysiologic definition: In adults consuming a typical West-
ern diet, polyuria is present when the urine volume is very
noticeable or inconvenient—typically greater than 3 L/day.
• Physiologic definition: The urine volume is compared with
values expected for the same provocative stimulus. Hence,
polyuria is present when the urine volume is relatively
higher than expected. Under this definition, polyuria can
be present when the urine volume is much less than
3 L/day in one setting and not present when the urine vol-
ume is 4 L/day in another setting.
For example, when the PNa is in the high-normal range, vaso-
pressin is released to conserve water and excrete the maximal
Uosm possible. A typical osmole excretion rate is 600
to 900 mOsm/day in an adult and the maximum Uosm is approx-
imately 1200 mOsm/kg H2O. Therefore, in this setting
the expected minimum urine volume would be 0.5 L/day (600
1200). Now, if this patient had an impaired renal concentrat-
ing ability (e.g., a maximum Uosm of 600 mOsm/kg H2O), then
the patient’s minimum urine volume would be 1 L/day
when vasopressin acts (i.e., 600 600). In this latter circum-
stance, the 1 L/day urine output is twice the expected minimum
value, indicating polyuria due to an impaired renal concentrat-
ing ability. This example illustrates the error of using data gath-
ered in one population (subjects consuming their usual diet) to
define a condition such as polyuria in a population with a much
lower osmole excretion rate (subjects consuming a low-protein
and low-salt diet). In contrast, in a patient with a 24-hour Uosm
of 80 mOsm/kg H2O and a PNa of 131 mmol/L, a urine output of
4 L should not be considered polyuric. The urine volume is
inappropriately low because most adults can lower the Uosm
110 to close to 50 mOsm/kg H2O when vasopressin is maximally
suppressed, as should occur in the setting of hyponatremia.
The basis for this patient’s diminished diluting capacity could
be a very low level, but not absence, of vasopressin due to nono-
II smotic stimulation of hormone release (see previous discussion).
Disturbances in Control of Body Fluid Volume and Composition
PRIMARY POLYDIPSIA
Excessive fluid intake also causes hypotonic polyuria and, by
definition, polydipsia. Many different names have been used
to describe patients with excessive fluid intake, but primary
polydipsia remains the best descriptor because it does not pre- 111
sume any single cause for the increased fluid intake. Primary
polydipsia is often due to a severe mental illness, in which
case it is called psychogenic polydipsia. However, primary
polydipsia can also be caused by an abnormality in the osmo- CH 5
regulatory control of thirst, in which case it has been termed
Disorders of Acid-Base
Balance
The diagnosis and management of acid-base disorders in
acutely ill patients requires an accurate and timely assessment
of the underlying acid-base disturbance. Appropriate interpre-
tation requires simultaneous measurement of serum electro-
lytes and arterial blood gases, in addition to a clinical
appreciation of the predictable physiologic adaptations and
compensatory responses that occur with specific acid-base
disorders.
The acid-base status of the body is tightly controlled so as to
maintain the pH within a normal range of 7.35 to 7.45. This is
achieved through (a) chemical buffering both in the extra- and
intracellular fluid, and (b) regulatory mechanisms controlled
by the renal and respiratory systems. Primary changes in
serum concentrations of fixed acid or base, as reflected by
the serum HCO3 concentration, lead to either metabolic aci-
dosis or alkalosis, whereas primary changes in the partial
pressure of arterial carbon dioxide (PaCO2) lead to either respi-
ratory acidosis or alkalosis. The presence of an acid-base dis-
order is often consequent to, or complicated by, serious
illness, and the frequently complex presentation of these dis-
orders requires a systematic approach to both diagnosis and
management.
112
Step 2: Define the Major Acid-Base Disorder 113
Table 6-1 Acid-Base Abnormalities and Appropriate Compensatory Responses for Simple Disorders
First-Degree
Acid-Base Effect Expected Range of Limits of
Disorders Primary Defect on pH Compensatory Response Compensation Compensation
Respiratory Alveolar # " Renal HCO3 reabsorption Acute [HCO3] ¼ 38 mEq/L
acidosis hypoventilation (HCO3 ") D[HCO3]¼ þ1 mEq/L for
(" PCO2) each " DPCO2 of 10 mm Hg
Chronic [HCO3] ¼ 45 mEq/L
D[HCO3]¼ þ4 mEq/L for
each " DPCO2 of 10 mm Hg
Respiratory Alveolar " # Renal HCO3 reabsorption Acute [HCO3] ¼ 18 mEq/L
alkalosis hyperventilation (HCO3 #) D[HCO3] ¼ 2 mEq/L for
(# PCO2) each # DPCO2 of 10 mm Hg
Chronic [HCO3] ¼ 15 mEq/L
D[HCO3] ¼ 5 mEq/L for
each # DPCO2 of 10 mm Hg
Metabolic Loss of HCO3 or # Alveolar hyperventilation to " PCO2 ¼ 1.5[HCO3] þ 8 2 PCO2 ¼ 15 mm Hg
acidosis gain of Hþ pulmonary PCO2 excretion PCO2 ¼ last 2 digits of pH
(# HCO3) (# PCO2) 100
PCO2 ¼ 15 þ [HCO3]
Metabolic Gain of HCO3 or " Alveolar hypoventilation to # PCO2 ¼ þ 0.6 mm Hg for PCO2 ¼ 55 mm Hg
alkalosis loss of Hþ pulmonary CO2 excretion D[HCO3] of 1 mEq/L
(" HCO3) (" PCO2) PCO2 ¼ 15 þ [HCO3]
HCO3 7.6 7.5
pH = 0.1 + log 7.4
.03 pCO2
pCO2
50 pH = 7.62 – log
HCO3
24 pCO2 METABOLIC
H2 (mEq/L) = ALKALOSIS 7.3
HCO3
40 pH = 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 Chronic
H2 = 100 79 63 50 40 32 25 20 15
HCO3 mEq/L 1 pH = 80% LH2 H2 = (7.8 – pH) = 100 7.2
RESP ACIDOSIS
30
RESP ALKALOSIS Acute
NORMAL
20 Acute
20 30 40 50 60 70 80 90
pCO2 mm Hg
Figure 6-1. Acid-base (or Flenley) nomogram.
115
116 pH or serum HCO3. If it is assumed that the serum albumin is
within the normal range, for each mEq/L change in the AG
(DAG), there should be an approximately equal and opposite
change in the serum HCO3 (DHCO3) concentration. If the
II DAG is greater than DHCO3 this suggests the presence of a
metabolic acidosis with a superimposed metabolic alkalosis
Distrurbances in Control of Body Fluid Volume and Composition
METABOLIC DISORDERS
Metabolic Acidosis
Metabolic acidosis is characterized by a decrease in both the
blood pH and the serum HCO3 concentration, and may be
accompanied by a compensatory respiratory alkalosis,
depending on the acuity of the condition (see Fig. 6-1 and
Table 6-1). It develops as the result of a marked increase in
serum acid concentration, due either to an absolute increase
via increased endogenous production of acid (such as lactic
acid or ketoacids), or progressive accumulation of endogenous
acids due to impaired excretion (renal failure) or due to a rel-
ative increase secondary to loss of HCO3 stores (either renal
or gastrointestinal).
The Anion Gap 117
The AG is invaluable in the initial assessment and characteriza-
tion of the metabolic acidosis and should always be calculated:
½Ku =½Kp
TTKG ¼
Uosm =Posm
RESPIRATORY DISORDERS
Respiratory Acidosis
Respiratory acidosis occurs consequent to severe pulmonary
disease, respiratory muscle fatigue, or depressed ventilatory
control (Table 6-7). The increase in PaCO2 caused by reduced
alveolar ventilation is the primary abnormality leading to
acidemia. In acute respiratory acidosis, there is an immediate
compensatory elevation (due to cellular buffering mechan-
isms) in HCO3 which increases by 1 mEq/L for every
10 mm Hg increase in PaCO2. In chronic respiratory acidosis
(>24 hours), renal adaptation is achieved and the HCO3
increases by 4 mEq/L for every 10 mm Hg increase in PaCO2
129
Causes of Respiratory Acid-Base
Table 6-7
Disorders
Alkalosis
CNS Stimulation CH 6
Pain
Bronchitis
Adult respiratory distress syndrome
Barotrauma
Mechanical Ventilation
Hypoventilation
Permissive hypercapnia
Neuromuscular
Poliomyelitis
Kyphoscoliosis
Myasthenia gravis
Muscular dystrophies
Multiple sclerosis
Miscellaneous
Obesity
Hypoventilation
COPD, chronic obstructive pulmonary disease.
The need for the two equations is due to the increasing vol-
ume of distribution of HCO3 as acidemia worsens. Serum
electrolytes should be monitored hourly during the course of
therapy to facilitate timely modification of treatment, with
particular regard to the serum Kþ, which may decline precipi-
tously as the pH increases.
Treatment of Hyperkalemia
Treat accordingly Yes Evidence of increased History, physical examination Evidence of Yes Treat accordingly
and re-evaluate potassium load and basic laboratory tests transcellular shift and re-evaluate
No No
Low aldosterone
Drugs Other causes
• Amiloride • Tubulointerstitial diseases
• Spironolactone • Urinary tract obstruction Renin
• Triamterene • PHA type I
• Trimethoprim • PHA type II
• Pentamidine • Sickle cell disease High Low
• Eplerenone • Renal transplant
• Calcineurin inhibitors • SLE • Primary adrenal insufficiency • Diabetes mellitus
• Isolated aldosterone deficiency • Acute GN
• Heparin/LMW heparin • Tubulointerstitial diseases
• ACE-I/ARB • PHA type II
• Ketoconazole • NSAIDs
• β-Blockers
Figure 7-2. The diagnostic approach to hyperkalemia. ACE-I, angiotensin-converting enzyme inhibitor; acute GN, acute
glomerulonephritis; ARB, angiotensin II receptor blocker; CCD, cortical collecting duct; ECG, electrocardiogram; ECV,
effective circulatory volume; GFR, glomerular filtration rate; LMW heparin, low-molecular-weight heparin; PHA,
pseudohypoaldosteronism; SLE, systemic lupus erythematosus; TTKG, transtubular potassium gradient. (From Mount DB,
Zandi-Nejad K: Disorders of potassium balance. In Brenner & Rector’s The Kidney, 8th ed. Philadelphia, WB Saunders,
2005, pp 547–588.)
159
160
Table 7-3 Acute Management of Severe Hyperkalemia
Stabilize myocardium with calcium salts
Calcium gluconate 10% 10 mL as IV bolus
II Shift potassium into cells
Intravenous glucose (50 mL of 50%) with 5–10 IU of insulin
Disturbances in Control of Body Fluid Volume and Composition
and
10–20 mg nebulized albuterol over 10 min (2–4 mL of 5 mg/mL
albuterol solution)
or
Subcutaneous terbutaline injection (7 mg/kg)
Potassium removal with dialysis (in patients with ESRD, or when
conservative measures are unsuccessful in the non-ESRD
population)
ESRD, end-stage renal disease.
From Putcha N, Allon M: Management of hyperkalemia in dialysis patients. Semin
Dial 20:431–439, 2007.
Removal of Potassium
Diuretics. Diuretics have a relatively modest effect on uri-
nary Kþ excretion in patients with chronic kidney disease.
However, they are useful in correcting chronic hyperkalemia
in patients with the syndrome of hyporeninemic hypoaldos-
teronism and selective renal Kþ secretory problems (e.g.,
post-transplantation or trimethoprim administration). In
patients with impaired renal function, the following are
recommended:
• Oral diuretics with the highest bioavailability and the least
renal metabolism (e.g., torsemide, bumetanide) to minimize
the chance of accumulation and toxicity
• Intravenous agents (short-term) with the least hepatic
metabolism (e.g., furosemide rather than bumetanide)
• Combination loop-thiazide therapy, although this may acti-
vate tubuloglomerular feedback and decrease GFR
• Use of the maximal effective “ceiling” dose
Mineralocorticoids. Fludrocortisone may be useful in treat-
ing chronic hyperkalemia in patients with hypoaldosteronism
with or without hyporeninism, those with SLE, kidney trans-
plant recipients on cyclosporine, and as a preventive agent
in ESRD patients on hemodialysis with interdialytic hyperka-
lemia, although the available data are limited. Mineralocorti-
coids are thought to lower potassium by two mechanisms:
(1) augmentation of colonic potassium excretion, and (2) stim-
ulation of Naþ/Kþ-ATPase on the cell membrane to enhance
extrarenal potassium excretion. The recommended dose is 0.1 163
to 0.3 mg/day. In patients with ESRD on hemodialysis, this
regimen reduces serum Kþ by up to 0.5 to 0.7 mmol/L. Close
monitoring of blood pressure and weight after initiation of
these medications is prudent, especially in patients without CH 7
ESRD.
Disorders of Calcium,
Magnesium, and Phosphate
Balance
DISORDERS OF CALCIUM METABOLISM
The extracellular calcium concentration is tightly maintained,
reflecting the actions of multiple hormones (parathyroid hor-
mone [PTH], calcitonin, and vitamin D) on bone, intestine,
kidney, and parathyroid tissue. This homeostatic system is
modulated by dietary and environmental factors (including
vitamins, hormones, medications, and mobility). The normal
total extracellular calcium concentration is 9 to 10.5 mg/dL
(2.25–2.65 mmol/L) of which approximately 50% is bound to
serum proteins, the remainder existing as free ionized calcium
(pathophysiologically relevant fraction). Alterations in the
serum pH can alter the fraction of ionized calcium: alkalosis
promotes the binding of serum free Ca2þ to albumin; the con-
verse is true in the setting of acidosis. Although an alteration
in ionized calcium is usually reflected by altered total cal-
cium, this may not be the case if the serum protein concentra-
tions are abnormal. A useful rule is to add 0.8 mg/dL for every
1-mg depression in serum albumin below 4 mg/dL to “correct”
for hypoalbuminemia.
Hypercalcemia
Signs and Symptoms
The clinical manifestations of hypercalcemia reflect both the
degree of hypercalcemia and rate of increase. Neuromuscular
sequelae are common, and include altered mental status,
depression, fatigue, and muscle weakness. Frequent gastroin-
testinal complications include constipation, nausea, and
vomiting; peptic ulcer disease is rare, pancreatitis exceedingly
so. Hypercalcemia causes polyuria and polydipsia; significant
hypercalcemia can lead to severe dehydration. Nephrolithiasis
and nephrocalcinosis are seen in 15% to 20% of cases of pri-
mary hyperparathyroidism (HPT). Hypercalcemia causes a
shortened QT interval on electrocardiograms due to an
increased rate of cardiac repolarization. Heart block and other
166
arrhythmias also may be observed. Even mild hypercalcemia 167
may be of clinical significance, as some studies have sug-
gested an increased cardiovascular risk from relatively mild,
although prolonged, elevation in serum calcium.
CH 8
Diagnosis
Management of Hypercalcemia
The treatment of mild chronic hypercalcemia should be
directed at the underlying cause. However, immediate therapy
is required for patients with acute severe hypercalcemia
(>14 mg/dL/3.5 mmol/L). Volume depletion is almost univer-
sal in severe hypercalcemia. Volume repletion and induction
of saline diuresis prompt a calciuresis and are central to suc-
cessful therapy. Patients should be initially administered 200
to 300 mL/hour of 0.9% NaCl; tapering thereafter to 100 to
200 mL/hour at the clinical discretion of the treating physician.
Once volume is replete, loop diuretics may be administered to
augment the urinary calcium losses. Care should be taken not
to use loop diuretics prior to volume expansion as this may trig-
ger prerenal acute kidney injury (AKI). The patient’s volume
status must be closely monitored during the administration of
large amounts of saline and diuretic, particularly in
hospitalized patients with cardiac or pulmonary disease.
Bisphosphonates such as pamidronate (30–90 mg IV over
2 hours) and zoledronate (4 mg IV over 15 minutes) are highly
172 effective at lowering the serum calcium; a single dose may
control the serum calcium for several weeks. They act via
inhibition of osteoclast function in areas of high bone turnover
and appear to be particularly efficacious in patients with
II malignancy. Calcitonin, an effective inhibitor of osteoclast
bone resorption, is of limited use as sole therapy for hypercal-
Disturbances in Control of Body Fluid Volume and Composition
Hypocalcemia
The clinical manifestations of hypocalcemia vary greatly and,
when present, are predominantly neurologic and neuromus-
cular. The most common clinical manifestations are muscle
cramps and numbness in the digits. Severe hypocalcemia
can cause laryngeal spasm, carpopedal spasm, bronchospasm,
seizures, and even respiratory arrest. Mental changes include
irritability, depression, and decreased cognitive capacity. Bed-
side signs of hypocalcemia include ipsilateral facial muscle
twitching in response to tapping the facial nerve (Chvostek
sign) and carpal spasm induced by brachial artery occlusion
(Trousseau sign). Electrocardiographic (ECG) changes include
prolongation of the QT interval. Long-standing hypocalcemia
may result in dry skin, coarse hair, alopecia, and brittle nails.
Teeth may be absent or hypoplastic. Calcification of the basal
ganglia and cerebral cortex may be detected by computed
tomography (CT) in chronic hypocalcemia.
Although the total calcium concentration generally reflects
the physiologically relevant ionized fraction, hypoalbumine-
mia affects the total calcium measurement, without affecting
the ionized level. Pseudohypocalcemia may also occur due
to interference with colorimetric calcium assays by some gad-
olinium-based contrast agents commonly used in magnetic
resonance imaging. The most common causes of hypocalce-
mia in the nonacute setting are hypoparathyroidism, hypo-
magnesemia, renal failure, and vitamin D deficiencies.
Acquired Hypoparathyroidism 173
Surgical hypoparathyroidism is the most common cause of
acquired hypoparathyroidism. It is observed after total thy-
roidectomy, radical neck dissection, and repeated operations
for parathyroid adenoma. Hypoparathyroidism may result CH 8
from inadvertent removal of the parathyroid glands or vascu-
Magnesium-Related Disorders
Both hypomagnesemia and hypermagnesemia are associated
with hypocalcemia. Mg2þ is an extracellular CaR agonist and
infusion of Mg or hypermagnesemia inhibits PTH secretion.
Chronic severe hypomagnesemia results in hypocalcemia,
via intracellular Mg2þ depletion and its effect on PTH gland
function. Hypomagnesemia also alters end-organ responsive-
ness to PTH. Typically, these patients have low or inappropri-
ately normal PTH levels for the degree of hypocalcemia
observed. The appropriate therapy is Mg2þ repletion; in the
absence of adequate Mg repletion, the hypocalcemia is resis-
tant to PTH or to vitamin D therapy. Hypoparathyroidism
can also occur acutely due to hypermagnesemia (e.g., high
doses of magnesium sulfate used in the obstetric setting),
likely via CaR-mediated inhibition of PTH secretion.
Autoimmune Disease
Type I polyglandular autoimmune syndrome, also referred to
as APECED (autoimmune polyendocrinopathy, candidiasis,
ectodermal dystrophy syndrome), is a recessive disorder. Its
cardinal features are childhood onset of hypoparathyroidism
in association with adrenal insufficiency and mucocutaneous
candidiasis. The gene for APECED has been localized to chro-
mosome 21q, and is termed AIRE (autoimmune regulator).
Autoantibodies against parathyroid tissue have been reported
in a significant percentage of cases of hypoparathyroidism, but
the causative role of these antibodies is unclear. CaR has been
identified as a possible autoantigen in some cases of autoimmune
hypoparathyroidism (either isolated or polyglandular).
Medications
Bisphosphonates, mithramycin, and calcitonin, all of which
inhibit bone resorption, may depress serum calcium to subnor-
mal levels. Administration of citrated blood during massive
transfusion can cause hypocalcemia. Similarly, significant
hypocalcemia may occur after plasmapheresis.
Foscarnet (trisodium phosphoformate) can cause hypocalcemia
through the chelation of extracellular calcium ions; normal total
calcium measurements may not reflect ionized hypocalcemia.
Other drugs associated with hypocalcemia include antimicrobial
agents (pentamidine, ketoconazole) and chemotherapeutic drugs
(asparaginase, cisplatin, and doxorubicin).
Critical Illness
In critically ill patients, total calcium measurements may be
poor indicators of the ionized calcium concentration (hypo-
proteinemia, acid-base disturbances, dialysis therapy). Thus,
it is particularly important to measure ionized calcium in this
setting. Hypocalcemia has been reported to be present in 70%
of intensive care unit patients. Hypocalcemia is frequently
noted in gram-negative sepsis and toxic shock syndrome, the
mechanism of which is unknown, but which may involve
direct effects of interleukin-1 on parathyroid function.
Miscellaneous
Hypocalcemia is commonly seen in acute pancreatitis, and is a
poor prognostic factor. It is probably due to calcium chelation
by free fatty acids generated by the action of pancreatic
lipase. Severe hyperphosphatemia may cause hypocalcemia,
particularly in patients with renal failure. The use of phosphate 175
enemas and phosphate-supplemented infant formula has been
reported to cause hypocalcemia. Hypophosphatemia may also
be associated with massive tumor lysis and the early phase of
rhabdomyolysis. CH 8
Genetic Disorders of Parathyroid Hormone
Treatment of Hypocalcemia
Treatment of acute hypocalcemia depends on the severity of
the depression in serum calcium and the presence of clinical
manifestations. Oral calcium supplementation may be suffi-
cient treatment for mild hypocalcemia; severe hypocalcemia
with evidence of neuromuscular effects or tetany requires
intravenous calcium. Typically, 1 to 3 g of intravenous calcium
gluconate is given over a period of 10 to 20 minutes, followed
by slow intravenous infusion. Dialysis (with a high calcium
dialysate) may be the appropriate treatment if severe hyper-
phosphatemia is also present. Correction of hypomagnesemia
and hyperphosphatemia should also be undertaken when pres-
ent. Treatment of chronic hypocalcemia depends on the under-
lying cause. The principal therapy for primary disorders of
parathyroid dysfunction or PTH resistance is dietary calcium
supplementation and vitamin D therapy. Correction of serum
calcium to the low-normal range is generally advised; correc-
tion to normal levels may lead to frank hypercalciuria.
Extrarenal Causes
Nutritional Deficiency. Induction of magnesium deficiency
by dietary means in normal individuals is surprisingly diffi-
cult, as the majority of foods contain significant amounts of
magnesium, and the renal adaptation to conserve Mg2þ is very
efficient. Nonetheless, magnesium deficiency of nutritional
origin is characteristically seen in two clinical settings: alco-
holism and parenteral feeding. Approximately 20% to 25%
of alcoholics are frankly hypomagnesemic. Some evidence
suggests that alcohol may also impair renal magnesium con-
servation. Patients receiving parenteral nutrition have a high
incidence of hypomagnesemia due to associated medical con-
ditions, a poorly understood increase in daily Mg2þ require-
ments, and the refeeding syndrome, whereby overzealous
parenteral feeding of severely malnourished patients causes
hyperinsulinemia and a rapid cellular uptake of Mg2þ.
Intestinal Malabsorption. Generalized malabsorption syn-
dromes caused by conditions such as celiac disease, Whipple
disease, and inflammatory bowel disease are frequently asso-
ciated with intestinal Mg2þ wasting and Mg2þ deficiency. In
fat malabsorption with concomitant steatorrhea, free fatty
acids in the intestinal lumen may combine with Mg2þ to form
nonabsorbable soaps; in rare patients reduction of dietary fat
intake, which reduces steatorrhea, can correct the hypomagne-
semia. Previous intestinal resection, particularly of the distal
part of the small intestine, is also an important cause of
Mg2þ malabsorption. Similarly, Mg2þ deficiency can be a late
complication of jejunoileal bypass surgery performed for the
treatment of obesity.
Cutaneous Losses. Hypomagnesemia may be observed after
prolonged intense exertion. About a quarter of the decrement
in serum Mg2þ can be accounted for by losses in sweat, with
the remainder most likely being due to transient redistribution
into the intracellular space. Hypomagnesemia occurs in 40%
of patients with severe burn injuries during the early period
of recovery due to cutaneous losses, which can exceed 1 g/day.
Redistribution to Bone Compartment. Hypomagnesemia 177
may occasionally accompany the profound hypocalcemia of
hungry bone syndrome, observed in some patients with HPT
and severe bone disease immediately after parathyroidectomy,
when the sudden removal of excess PTH results in an immedi- CH 8
ate cessation of bone resorption, but continued high rate of
bone formation and consequent sequestration of both Ca2þ
Hypermagnesemia
Etiology
In states of Mg2þ excess, the kidney has a large capacity for
Mg2þ excretion. Once the apparent renal threshold is exceeded,
most of the excess filtered Mg2þ is excreted unchanged into the
urine; the serum Mg2þ is then determined by the GFR.
180 Renal Insufficiency. Significant hypermagnesemia is rare,
even in advanced kidney disease, unless the patient has
received exogenous Mg2þ in the form of antacids, cathartics,
or enemas.
2þ
II Excessive Mg Intake. Hypermagnesemia can occur in
individuals with a normal GFR when the rate of Mg2þ intake
Disturbances in Control of Body Fluid Volume and Composition
Clinical Manifestations
Initial manifestations, observed once the serum Mg2þ exceeds
4 to 6 mg/dL (1.75–2.76 mmol/L) are hypotension, nausea,
vomiting, facial flushing, urinary retention, and ileus. If
untreated, this may progress to flaccid skeletal muscular paral-
ysis and hyporeflexia, bradycardia and bradyarrhythmias,
respiratory depression, coma, and cardiac arrest. An abnor-
mally low (or even negative) serum anion gap may indicate
hypermagnesemia but is not consistently observed and proba-
bly depends on the nature of the accompanying anion.
Cardiovascular System. Manifestations include hypoten-
sion, cutaneous flushing, sinus or junctional bradycardia, and
sinoatrial, atrioventricular, and His bundle conduction block.
Cardiac arrest due to asystole is often the terminal event.
Nervous System. Flaccid skeletal muscle paralysis and
hyporeflexia are observed when serum Mg2þ exceeds 8 to
12 mg/dL, via inhibition of acetylcholine release from the neu-
romuscular endplate. Respiratory depression is a serious com-
plication of advanced Mg2þ toxicity. Smooth muscle paralysis
also occurs and is manifested as urinary retention, intestinal
ileus, and pupillary dilatation. Signs of central nervous sys-
tem depression, including lethargy, drowsiness, and eventu-
ally coma, are well described in severe hypermagnesemia
but may be entirely absent.
Treatment
Mild cases of Mg2þ toxicity in individuals with good renal
function may require no treatment other than cessation of
Mg2þ. In the event of serious toxicity, temporary antagonism
of the effect of Mg2þ may be achieved by the administration
of intravenous Ca2þ (1 g of calcium chloride infused via a cen-
tral vein over 2 to 5 minutes, or calcium gluconate, repeated
after 5 minutes if necessary). Renal excretion of Mg2þ can be
enhanced by saline diuresis and by the administration of furo-
semide. In patients with renal failure, hemodialysis efficiently
removes Mg2þ.
DISORDERS OF PHOSPHATE HOMEOSTASIS 181
Hyperphosphatemia
Hyperphosphatemia is generally defined as a serum phos- CH 8
phate level greater than 5 mg/dL (1.6 mmol/L) in the adult
Etiology
The clinical causes of hyperphosphatemia can be broadly clas-
sified into three groups: reduced phosphate excretion, excess
intake of phosphorus, and redistribution of cellular
phosphorus.
Decreased Phosphate Excretion
Renal Insufficiency. Chronic kidney disease is by far the most
common cause of hyperphosphatemia. A compensatory
increase in fractional excretion of PO4 occurs until the GFR
falls to the extent that normal PO4 excretion can no longer
be maintained. This is further discussed in Chapter 30, Min-
eral Bone Disease in Chronic Kidney Disease.
Endocrinopathies. Decreased renal excretion of phosphorus
may occur in the setting of reduced PTH secretion (hypopara-
thyroidism) or altered renal response to PTH (pseudohypopar-
athyroidism). Hyperphosphatemia is also seen in some
patients with acromegaly, and appears to result from direct
stimulation of proximal tubular phosphorus reabsorption by
growth hormone.
Increased Phosphorus Intake. Exogenous intake of phos-
phorus sufficient to cause hyperphosphatemia is rare in the
absence of renal insufficiency. Great caution in administration
of phosphate, particularly in the form of phosphate-containing
enemas, must be taken in individuals with renal insufficiency
and in children. The use of oral sodium phosphate for
bowel preparation prior to colonoscopy has been increasingly
recognized as a cause of acute kidney injury, so-called phos-
phate nephropathy, with intrarenal deposition of calcium
phosphate. This syndrome may occur in individuals with
good baseline kidney function, and typically does not recover.
Redistribution of Phosphorus
Respiratory Acidosis. Chronic respiratory acidosis can lead to
hyperphosphatemia, renal PTH resistance, and hypocalcemia.
The effect is more pronounced in acute respiratory acidosis.
Efflux of phosphate from cells into the extracellular space is
responsible.
182 Tumor Lysis Syndrome. Tumor lysis syndrome is a well-
described complication of the treatment of hematologic malig-
nancies associated with hyperphosphatemia. Lymphoblasts
are particularly high in phosphorus. The lactate dehydroge-
II nase (LDH) level prior to the initiation of therapy correlates
with the development of hyperphosphatemia and azotemia.
Disturbances in Control of Body Fluid Volume and Composition
Hypophosphatemia
Only a small percentage (about 1%) of total body phosphorus
is extracellular. Hypophosphatemia may therefore not neces-
sarily reflect total body phosphorus depletion. Hypophospha-
temia is relatively common in hospitalized patients and is
present in a significant proportion of chronic alcoholics.
Clinical Manifestations
Mild hypophosphatemia does not typically cause symptoms;
symptomatic patients usually have serum phosphate levels
below 1 mg/dL. The clinical manifestations of phosphorus
depletion generally result from a decrease in intracellular
adenosine triphosphate (ATP) levels. In addition, erythrocytes 183
experience an increase in 2,3-diphosphoglycerate levels,
which increases hemoglobin-oxygen affinity and alters oxygen
transport efficiency. Depletion of ATP by severe hypophos-
phatemia impairs muscle function; overt heart failure and CH 8
respiratory failure secondary to decreased muscle perfor-
Diagnosis
The probable cause of hypophosphatemia may be immediately
apparent from the clinical findings (e.g., a malnourished
patient with alcoholism or anorexia). Shifts of phosphorus
from the extracellular to the intracellular space generally
occur in the acute setting (respiratory alkalosis, treatment of
diabetic ketoacidosis). In hospitalized patients, hypophospha-
temia caused by shifts of phosphorus into the intracellular
compartment are much more common than hypophosphate-
mia caused by renal losses. If the underlying diagnosis is not
immediately apparent, it can be clinically useful to determine
the rate of urine phosphorus excretion. High urine phospho-
rus in the face of hypophosphatemia suggests HPT, a renal
tubule defect, or a form of rickets.
Causes of Hypophosphatemia
Increased Renal Excretion. Hypophosphatemia caused by
increased urinary phosphate excretion is generally due to
either excess PTH or an inherited disorder of renal phosphate
handling in the proximal tubule. Excess PTH directly
decreases renal phosphate reabsorption, leading to increased
renal phosphate excretion and hypophosphatemia. Phosphate
depletion itself decreases proximal tubular and distal nephron
reabsorption of phosphate.
Acute Kidney Injury and Recovery from Acute Tubular
Necrosis. AKI is typically associated with hyperphosphate-
mia. However, confounding factors in the setting of critical
illness may contribute to the development of hypophosphate-
mia in some instances: administration of phosphate-binding
184 antacids, refeeding syndrome, and mechanically induced
respiratory alkalosis. Moreover, the diuretic recovery phase
from acute tubular necrosis or postobstruction may cause sig-
nificant urinary losses of phosphate.
II Renal Transplantation. Hypophosphatemia is well described
in renal transplant patients, although severe hypophosphate-
Disturbances in Control of Body Fluid Volume and Composition
Treatment
Because serum levels of phosphorus are a poor reflection of
total body stores, it is difficult to predict the amount of phos-
phorus necessary to correct phosphorus deficiency. In mild or
moderate hypophosphatemia (>2 mg/dL), oral repletion with
low-fat milk (containing 0.9 mg phosphorus per milliliter) is
effective. In individuals intolerant of milk, potassium phos-
phate or sodium phosphate preparations can be used (up to
3.5 g/day in divided doses). Intravenous phosphorus repletion
is generally reserved for individuals with severe (<1 mg/dL)
hypophosphatemia. One standard regimen is to administer
2.5 mg/kg body mass of elemental phosphorus over a 6-hour
period for severe asymptomatic hypophosphatemia and
5 mg/kg body mass of elemental phosphorus over a 6-hour
period for severe symptomatic hypophosphatemia.
Chapter 9
Epidemiology of Kidney
Disease
A standardized definition and staging scheme for chronic kid-
ney disease (CKD), a term used to encompass the entire spec-
trum of renal dysfunction, has dramatically improved our
understanding of the occurrence and consequences of renal
disease. CKD is defined as the presence, for at least 3 months,
of evidence of kidney damage with an abnormal glomerular
filtration rate (GFR) or, alternatively, by a GFR below 60 mL/
min/1.73 m2 body surface area. In clinical practice, the assess-
ment of GFR is most readily and reliably achieved using esti-
mation equations, such as the Cockcroft-Gault equation or
the Modification of Diet in Renal Disease (MDRD) Study equa-
tion. The Cockcroft-Gault equation calculates unadjusted cre-
atinine clearance, using serum creatinine, age, gender, and
body weight. The formula uses an empirical adjustment factor
for women, based on a theoretical 15% lower muscle mass in
women relative to men; the equation tends to overestimate
renal function in subjects who are edematous or obese and
underestimates renal function in the elderly. The modified
MDRD equation was developed from subjects enrolled in the
baseline period of the MDRD Study. It estimates GFR adjusted
to body surface area and is calculated from the subject’s serum
creatinine, age, race, and gender. Although mathematically
somewhat complicated, it can be readily calculated with the
aid of a simple computer or at several Web sites (www.
nephron.com and www.kidney.org/professionals/KDOQI; see
also Chapter 2, Laboratory Assessment of Renal Disease).
The National Kidney Foundation (NKF) guidelines use a
five-stage schema based on the reduction in GFR to help clas-
sify the severity of CKD. An international position statement
added modifiers for noting whether a patient is treated with
dialysis or transplantation (Table 9-1). This staging system
represents a measure of the “azotemic burden” resulting from
the degree of kidney dysfunction. In essence, this staging sys-
tem recognizes that the progressive decrement in renal func-
tion gives rise to common complications (e.g., hypertension,
anemia, hyperparathyroidism) and management issues (e.g.,
hepatitis B vaccination, dietary modification, patient educa-
tion) that are independent of the underlying condition that
caused the kidney damage. This staging system complements,
189
190
Table 9-1 Stages of Chronic Kidney Disease
GFR (mL/min/
Stage Description 1.73 m2)
III 1 Kidney damage with normal or >90
↑ GFR
Epidemiology of Renal Disease
Prevalence of Stages 1 to 4
The occurrence of kidney damage and CKD in the general pop-
ulation is important because only a minority of patients prog-
ress to kidney failure and are thereby identified on national
ESRD registries. Instead, the majority of patients with CKD
die from concurrent disease or else maintain relatively stable,
although reduced, renal function and suffer the consequences
of CKD without ever progressing to the need for dialysis.
Thus, ESRD registries provide only limited insight into the
true burden of morbidity and death associated with CKD.
All prevalence estimates show a strong age dependence,
consistent with the most common forms of CKD being progres-
sive and increasing with age. Several of the initial studies
examining the prevalence of CKD were based on elevated
serum creatinine levels. With the increased recognition of
the many limitations of this approach, more recent surveys
have instead used estimation equations with attention to cre-
atinine assay calibration. The diagnosis of stages 1 and
2 CKD requires the presence of kidney damage in addition to
a reduced GFR. From an epidemiologic perspective, the most
commonly used surrogate for kidney damage in this setting
has been albuminuria. Other potential markers of kidney dam-
age include renal imaging or hematuria, although the latter is
less specific for CKD because the bleeding may often originate
from the lower genitourinary tract rather than the kidney.
Over the last several years, the National Health and Nutrition
Examination Survey (NHANES) has provided a wealth of infor-
mation regarding the prevalence of CKD and its complications
within the United States. In NHANES III, the mean prevalence
estimate for a GFR less than 60 mL/min/1.73 m2 was 4.4%. Inter-
nationally, it is clear that both proteinuria and decreased eGFR
are quite common in many settings. A focused comparison of
Norway to the United States revealed very similar prevalence
rates of albuminuria and CKD stage 3, despite markedly higher
treated ESRD incidence in the United States. This suggests that
factors determining progression from CKD to ESRD, not the least
of which are treatment availability and patient management, will
be important to understand.
192 End-Stage Renal Disease
Global Comparisons
The occurrence of ESRD varies widely between different
countries and, on many occasions, within different regions
of the same country. In addition to variability in the general
factors that determine the incidence of ESRD, which are dis-
cussed previously, international comparison of incidence
and prevalence rates may be complicated by different admin-
istrative definitions of ESRD and in the classification of the
underlying cause of kidney failure, as well as by variability
in the completeness and accuracy of the reported data. As a
result, direct comparison of the data from different national
registries must be undertaken with caution. However, within
194 these limitations, the increase in ESRD in Europe has mirrored
the U.S. experience, although absolute rates are lower. It is as
yet unclear whether the rising incidence of ESRD in Europe is
starting to slow, as has occurred in the United States in the
III last several years.
The age- and gender-adjusted incidence rates for Western
Epidemiology of Renal Disease
Dialysis Modality
In 2003, 91% of the incident U.S. ESRD population were trea-
ted with hemodialysis, 7% by peritoneal dialysis, and 2% by
preemptive transplantation. Of the prevalent population,
65.5% are treated by in-center hemodialysis, 0.3% by home
hemodialysis, 5.7% by peritoneal dialysis (2.5% with cycler-
based therapy, 3.2% with manual, noncycler therapy), and
28.5% with transplantation.
TRANSPLANTATION
Transplant Outcomes
The reduction in acute rejection rates and improvement in
short-term graft survival have been a dramatic success story
in the field of transplantation. The 1-year graft and patient
survival rates for a deceased donor transplant are 88% and 197
95%, respectively; the comparable figures for a living donor
are 94% and 98%. The cumulative rejection rates in the first
6 months are now less than 20%. Unfortunately, the long-term
graft outcome has failed to improve to a comparable degree. CH 9
One-year conditional graft half-life (the expected length for
201
202
Table 10-1 RIFLE Classification of Acute Kidney Injury
GFR Criteria Urine Output Criteria
Risk ↑ Serum Cr 1.5 UO < 0.5 mL/kg/hr 6 hr
IV Injury ↑ Serum Cr 2 UO < 0.5 mL/kg/hr 12 hr
Pathogenesis of Renal Disease
Postrenal Azotemia
Urinary tract obstruction accounts for fewer than 5% of cases of
AKI. Because one kidney has sufficient clearance capacity to
excrete the nitrogenous waste products generated daily, for
obstruction to cause AKI there must be either obstruction of
urine flow between the external urethral meatus and the blad-
der neck, bilateral ureteric obstruction, or unilateral ureteric
obstruction in a patient with only one functioning kidney or
with underlying chronic renal insufficiency. Obstruction of
the bladder neck, the most common cause of postrenal azote-
mia, may complicate prostatic disease (e.g., hypertrophy,
neoplasia, infection), neurogenic bladder, or therapy with anti-
cholinergic drugs. Less common causes of acute lower urinary
tract obstruction include blood clots, calculi, and urethritis
with spasm. Ureteric obstruction may result from intraluminal
obstruction (e.g., calculi, blood clots, sloughed renal papillae),
infiltration of the ureteric wall (e.g., neoplasia), or external 207
compression (e.g., retroperitoneal fibrosis, neoplasia, or
abscess, inadvertent surgical ligature). During the early stages
of obstruction (hours to days), continued glomerular filtration
leads to increased intraluminal pressure upstream of the site CH 10
of obstruction. This results in gradual distention of the proxi-
Electrolyte Disturbances
Hyponatremia due to a combination of impaired free-water
clearance and the ingestion of water or administration of hypo-
tonic intravenous solutions can cause hyponatremia, which
can be severe. Hyperkalemia is a common and potentially
life-threatening complication. The serum potassium typically
rises by 0.5 to 1 mEq/L/day in oligoanuric patients but the rate
of rise may be higher in rhabdomyolysis or the tumor lysis
syndrome. Mild hyperkalemia (<6 mEq/L) is usually asymp-
tomatic. Higher levels are frequently associated with elec-
trocardiographic (ECG) abnormalities, typically, peaked T
waves, prolongation of the PR interval, flattening of P waves,
widening of the QRS complex, and left-axis deviation. These 211
changes may precede the onset of life-threatening cardiac
arrhythmias such as bradycardia, heart block, ventricular
tachycardia or fibrillation, and asystole. Hypokalemia is
unusual in AKI but may complicate nonoliguric ATN caused CH 10
by aminoglycosides, cisplatin, or amphotericin B.
Acid-Base Disturbance
AKI is commonly complicated by metabolic acidosis, typically
with a widening of the serum anion gap. The acidosis may be
severe (daily fall in plasma HCO3 > 2 mEq/L) if the genera-
tion of Hþ is increased by additional mechanisms (e.g., dia-
betic or fasting ketoacidosis; lactic acidosis complicating
generalized tissue hypoperfusion, liver disease, or sepsis;
metabolism of ethylene glycol). Metabolic alkalosis is an infre-
quent finding but may complicate overzealous correction of
acidosis with bicarbonate or prerenal AKI triggered by loss of
gastric secretions by vomiting or nasogastric aspiration.
Uremic Syndrome
Protracted periods of severe AKI or short periods of catabolic,
anuric azotemia often lead to the development of the uremic
syndrome. Clinical manifestations of the uremic syndrome
include pericarditis, pericardial effusion, and cardiac tampo-
nade; gastrointestinal complications such as anorexia, nausea,
vomiting, and ileus; and neuropsychiatric disturbances
212 including lethargy, confusion, stupor, coma, agitation, psy-
chosis, asterixis, myoclonus, hyperreflexia, restless leg syn-
drome, focal neurologic deficit, and seizures.
IV
MANAGEMENT OF ACUTE KIDNEY INJURY
Pathogenesis of Renal Disease
Prerenal Azotemia
By definition, prerenal azotemia is rapidly reversible on resto-
ration of renal perfusion. Hypovolemia caused by hemorrhage
is ideally corrected with packed red blood cells if the patient
is hemodynamically unstable or if the hematocrit is danger-
ously low. In the absence of active bleeding or hemodynamic
instability, isotonic saline may suffice. Isotonic saline is the
appropriate replacement fluid for plasma losses (e.g., burns,
pancreatitis). Urinary or gastrointestinal fluids vary greatly in
composition but are usually hypotonic and, accordingly, ini-
tial replacement is best achieved with hypotonic solutions
(e.g., 0.45% saline). Colloid solutions should be used spar-
ingly in prerenal AKI with regular monitoring of renal func-
tion, and the risk of hyperoncotic renal failure minimized by
concomitant use of appropriate crystalloid solutions. Cardiac
failure may require aggressive management with loop diure-
tics, antiarrhythmic drugs, positive inotropes, and preload-
or afterload-reducing agents.
Fluid management may be particularly challenging in
patients with prerenal AKI and cirrhosis. These subjects typi-
cally have intense intrarenal vasoconstriction and expanded
total plasma volume because of pooling of blood in the
splanchnic circulation; the relative contribution of hypovole-
mia to AKI in this setting can be determined only by adminis-
tration of a fluid challenge. Fluids should be administered
slowly, because nonresponders may suffer an increase in
ascites formation or pulmonary edema, or both. Spontaneous
bacterial peritonitis is a common trigger factor for HRS
in patients with advanced cirrhosis and ascites. The adminis-
tration of albumin (1.5 g/kg on diagnosis and 1 g/kg on day 3)
in combination with standard antibiotic therapy in this
setting has been demonstrated to reduce the incidence of
HRS and improve patient survival. Paracentesis can be
employed to remove large volumes of ascitic fluid. Although
it is controversial, simultaneous administration of albumin
intravenously is thought by some investigators to minimize
the risk of prerenal AKI and full-blown HRS during large-volume
paracentesis. Indeed, large-volume paracentesis may occa-
sionally improve GFR, possibly by lowering intra-abdominal
pressure and promoting blood flow in renal veins. Vasopres-
sin (V1) receptor agonists, either alone or in combination
with the a-agonist midodrine, have shown promise in the rever- 213
sal of established HRS. In a small randomized trial, terlipressin
(1 mg IV twice daily) combined with albumin resuscitation
(goal, central venous pressure 10–12 mm Hg) resulted in 5 of
12 patients surviving 15 days as opposed to none of the placebo CH 10
group. Predictors of nonresponse include older age and more
Prevention
Optimization of cardiovascular function and intravascular vol-
ume is the single most important maneuver in the management
of acute intrinsic azotemia. There is compelling evidence that
aggressive restoration of intravascular volume dramatically
reduces the incidence of ATN after major surgery, trauma, and
burns. Recent studies have emphasized two salient features of
successful management of sepsis that may be of importance in
the prevention of AKI. Early goal-directed resuscitation to
defined hemodymanic targets (mean arterial pressure >
65 mm Hg, central venous pressure 10–12, urine output >
0.5 mL/kg/hour, SCVO2 > 70%) using a combination of crystal-
loid solutions, red blood cell transfusion, and vasopressors
results in a significant reduction in organ dysfunction and mor-
tality rate in patients with the sepsis syndrome.
The importance of maintaining euvolemia in high-risk clin-
ical situations has been demonstrated most convincingly with
contrast nephropathy. Prophylactic infusion of half-normal
saline (1 mL/kg for 12 hours before and after procedure)
appears to be more effective in preventing AKI than other
commonly used agents such as mannitol and furosemide. Pro-
phylactic administration of oral acetylcysteine (600 mg twice
daily, 24 hours before and 24 hours after the procedure), in
combination with hydration, reduced the incidence of con-
trast nephropathy in patients with moderate renal insuffi-
ciency in several trials.
Diuretics, NSAIDs (including COX-2 inhibitors), ACE inhi-
bitors, and other vasodilators should be avoided in patients
with suspected true or effective hypovolemia, because they
may convert prerenal azotemia to ischemic ATN. Careful mon-
itoring of circulating drug levels appears to reduce the inci-
dence of AKI associated with aminoglycoside antibiotics.
There is convincing evidence that once-daily dosing with
these agents affords equal antimicrobial activity and less
nephrotoxicity than do conventional regimens. The use of
lipid-encapsulated formulations of amphotericin B may offer
some protection against renal injury. Several other agents are
commonly employed to prevent AKI in specific clinical
214 settings. Allopurinol is useful for limiting uric acid generation
in patients at high risk for acute urate nephropathy; Amifostine,
an organic thiophosphate, has been demonstrated to ameliorate
cisplatin nephrotoxicity in patients with solid organ or hemato-
IV logic malignancies. Forced diuresis and alkalinization of urine
may attenuate renal injury caused by uric acid or methotrexate.
Pathogenesis of Renal Disease
Specific Therapies
Despite intensive investigation no specific therapy exists that
accelerates recovery from ATN. Judicious volume manage-
ment, treatment of complications, and avoidance of further
injury are the mainstays of therapy. “Renal dose dopamine”
(1–3 mg/kg/min) has been widely advocated for the manage-
ment of oliguric AKI; however, it has not been demonstrated
to prevent or alter the course of ischemic or nephrotoxic
ATN in prospective, controlled clinical trials. The administra-
tion of high-dose intravenous diuretics to individuals with
oliguric AKI is commonly practiced. Although this strategy
may minimize fluid overload, there is no evidence that it
alters the mortality rate or the dialysis-free survival rate. Sim-
ilarly, no adequate data exist to support the routine adminis-
tration of mannitol, fenoldopam, or natriuretic peptides to
oliguric patients. AKI caused by other intrinsic renal diseases,
such as acute glomerulonephritis or vasculitis, may respond to
corticosteroids, alkylating agents, or plasmapheresis, depend-
ing on the primary disease.
Management of Complications
Metabolic complications such as intravascular volume over-
load, hyperkalemia, hyperphosphatemia, and metabolic aci-
dosis are almost invariable in oliguric AKI, and preventive
measures should be taken from the time of diagnosis. Prescrip-
tion of nutrition should be designed to meet caloric require-
ments and minimize catabolism. In addition, doses of drugs
excreted via the kidney must be adjusted for the degree of
renal impairment.
Intravascular Volume Management. After correction of
intravascular volume deficits, salt and water intake should
be adjusted to match losses (urinary, gastrointestinal, drainage
sites, insensible losses). Intravascular volume overload can
usually be managed by restriction of salt and water intake
and the use of diuretics. In the volume-overloaded patient,
high doses of loop diuretics such as furosemide (bolus doses
of up to 200 mg or up to 20 mg/hour as an intravenous infu- 215
sion) or sequential thiazide and loop diuretic administration
may be required if there is no response to conventional doses.
Diuretic therapy should be discontinued in resistant patients
to avoid complications such as ototoxicity. Ultrafiltration or CH 10
dialysis may be required for removal of volume if conservative
Indications
Absolute indications for RRT in AKI include the following:
• Symptomatic uremia (asterixis, pericardial rub,
encephalopathy)
• Metabolic acidosis/hyperkalemia/volume overload
refractory to medical management
Relative indications include a rapidly rising BUN and creat-
inine without evidence of imminent renal recovery when the
development of uremic or other complications can reasonably
be expected to supervene without intervention. “Renal sup-
port” indications involve using RRT to facilitate the adminis-
tration of total parenteral nutrition, fluid removal in
congestive heart failure, and total fluid management in the
patient with multiorgan failure. The decision regarding the
timing of initiation of RRT in the intensive care unit (ICU) is
a complex one, and has traditionally been dictated by the 217
presence of a life-threatening indication. However, when one
considers renal support requirements, and the extremely high
mortality rate in these patients, earlier intervention may be
appropriate in selected patients. CH 10
Postrenal Azotemia
OUTCOME
The mortality rate among patients with acute intrinsic renal
azotemia varies from less than 10% in obstetric-related AKI
to over 70% in cases associated with multiple organ failure.
Factors associated with a poor prognosis include male sex, 221
advanced age, oliguria (<400 mL/day), and a rise in the serum
creatinine value of more than 3 mg/dL (265 mmol/L). Most
patients who survive an episode of AKI recover sufficient renal
function to live normal lives. However, AKI is irreversible in CH 10
approximately 5% of patients, usually as a consequence of
Proteinuria
Proteinuria can be caused by systemic overproduction (e.g.,
multiple myeloma with Bence Jones proteinuria), tubular dys-
function (e.g., Fanconi syndrome), or glomerular dysfunction.
It is important to identify patients in whom the proteinuria is
a manifestation of substantial glomerular disease as opposed
to those patients who have benign transient or postural (ortho-
static) proteinuria.
Isolated proteinuria is a mild, transient proteinuria that typ-
ically accompanies physiologically stressful conditions,
including fever, exercise, and congestive heart failure.
Orthostatic proteinuria is defined by the absence of protein-
uria while the patient is in a recumbent posture and its appear-
ance during upright posture, especially during exercise. It is
most common in adolescents. The total amount of protein excre-
tion in a 24-hour period is generally less than 1 g. The diagnosis
is made by comparing the protein excretion in two 12-hour urine
collections, one recumbent and one ambulatory. Alternatively,
the protein excretion in a split collection of 16 ambulatory hours
may be compared to that of an 8-hour overnight collection.
Importantly, patients should be recumbent for at least 2 hours
before their “ambulatory” collection is completed to avoid the
possibility of contamination of the “recumbent” collection by
urine formed during ambulation. The diagnosis of orthostatic
proteinuria requires that protein excretion be less than 50 mg
during those 8 recumbant hours. Patients should be followed
on an annual basis until the proteinuria resolves; the long-term
prognosis is typically excellent.
Fixed proteinuria is present whether the patient is upright
or recumbent. The proteinuria disappears in some patients,
whereas others have a more ominous glomerular lesion that
portends an adverse long-term outcome. The prognosis
depends on the persistence and severity of the proteinuria.
If proteinuria disappears, it is less likely that the patient will
develop hypertension or reduced glomerular filtration rate
(GFR). These patients must be evaluated periodically for as
long as the proteinuria persists.
222
Plasma cell dyscrasias can produce monoclonal proteins, 223
immunoglobulin, free light chains, and combinations of these.
Light chains are filtered at the glomerulus and may appear in
the urine as Bence Jones protein. The detection of urine immu-
noglobulin light chains can be the first clue to a number of CH 11
important clinical syndromes associated with plasma cell dys-
Nephrotic Syndrome
The nephrotic syndrome is characterized by over 3.5 g/day
proteinuria in association with edema, hyperlipidemia, and
hypoalbuminemia. In addition to primary (idiopathic) glomeru-
lar diseases discussed later in this chapter, the nephrotic syn-
drome may be secondary to a large number of identifiable
disease states (Table 11-1).
Hematuria
Hematuria is the presence of an excessive number of red blood
cells in the urine, and is categorized as either microscopic (visi-
ble only with the aid of a microscope) or macroscopic (urine that
is tea-colored or cola-colored, pink, or even red). An acceptable
definition of microscopic hematuria is more than two red blood
cells per high-power field in centrifuged urine. The urinary dip-
stick detects one to two red blood cells per high-power field and a
negative dipstick examination virtually excludes hematuria.
Glomerular hematuria: Dysmorphic red blood cells on urine
microscopy provide strong evidence for glomerular bleeding.
The findings of proteinuria (especially >2 g/day) or red blood cell
casts enhance the possibility that hematuria is of glomerular ori-
gin. The differential pathologic diagnosis of glomerular hematuria
without proteinuria, renal insufficiency, or red blood cell casts is
IgA nephropathy, thin basement membrane nephropathy, heredi-
tary nephritis, or histologically normal glomeruli. When hematu-
ria is accompanied by 1 to 3 g/day proteinuria but no significant
renal insufficiency, IgA nephropathy is the most likely cause.
Patients with hematuria and serum creatinine greater than 3 mg/dL
(260 mmol/L) usually have aggressive glomerulonephritis with
crescents. However, a definitive diagnosis requires a renal biopsy.
224 Table 11-1 Causes of the Nephrotic Syndrome
Idiopathic nephrotic syndrome due to primary glomerular disease
Nephrotic syndrome associated with specific etiologic events or in
which glomerular disease arises as a complication of other diseases
IV Medications
Organic, inorganic, elemental mercury
Pathogenesis of Renal Disease
Organic gold
Penicillamine, bucillamine
“Street” heroin
Probenecid
Captopril
NSAIDs
Lithium
Interferon
Allergens, Venoms, Immunizations
Bee sting, pollens
Infections
Bacterial
PSGN, infective endocarditis, “shunt nephritis,” leprosy, syphilis
(congenital and secondary), Mycoplasma infection, tuberculosis,
chronic bacterial pyelonephritis with vesicoureteral reflux
Viral
Hepatitis B, hepatitis C, cytomegalovirus infection, infectious
mononucleosis (Epstein-Barr virus infection), herpes zoster,
vaccinia, human immunodeficiency virus type I infection
Protozoal
Malaria (especially quartan malaria), toxoplasmosis
Helminthic
Schistosomiasis, trypanosomiasis, filariasis
Neoplastic
Solid tumors (carcinoma and sarcoma): lung, colon, stomach, breast
Leukemia and lymphoma: Hodgkin disease
Graft-versus-host disease after bone marrow transplantation
Multisystem Disease
Systemic lupus erythematosus
Henoch-Schönlein purpura/IgA nephropathy
Amyloidosis (primary and secondary)
Heredofamilial and Metabolic Disease
Diabetes mellitus
Hypothyroidism (myxedema)
Graves disease
Amyloidosis (familial Mediterranean fever and other hereditary
forms, Muckle-Wells syndrome)
Podocyte mutations
Congenital nephrotic syndrome (Finnish type)
Miscellaneous
Pregnancy-associated (preeclampsia, recurrent, transient)
Chronic renal allograft failure
PSGN, poststreptococcal glomerulonephritis.
The potential benefits of renal biopsy in patients with hematuria 225
and no proteinuria or renal insufficiency (“isolated hematuria”)
include a reduction of patient and physician uncertainty and the
accompanying anxiety by establishing a specific diagnosis. How-
ever, in many cases, isolated glomerular hematuria may not war- CH 11
rant a renal biopsy because the findings often do not affect
Nephritic Syndrome
The nephritic syndrome is characterized by inflammatory
injury to the glomerular capillary wall. It presents clinically
as abrupt onset renal dysfunction with oliguria, hematuria
with red blood cell casts, hypertension, and subnephrotic pro-
teinuria. The distinction between the nephritic and nephrotic
syndrome is generally easily made based on clinical and labo-
ratory features. Common diseases that present as the nephritic
syndrome include poststreptococcal glomerulonephritis, IgA
nephropathy, lupus nephritis, and immune complex glomeru-
lonephritis associated with infection.
ANTIBODY-MEDIATED GLOMERULONEPHRITIS
lgA and no lgA and systemic SLE Acute strep/ Mesangio-capillary GBM dense Sub-epithelial 20 nm Other
vasculitis vasculitis staph infection changes deposits deposits fibrils features
lgA H-S Lupus Acute post- Type I Type II Membranous Fibrillary Many
nephropathy purpura nephritis infectious GN MPGN MPGN GN GN others
227
Figure 11-1. Algorithm for categorizing glomerulonephritis
that is known or suspected of being mediated by antibodies.
This categorization applies to glomerulonephritis with crescents
as well as to glomerulonephritis without crescents. The diseases CH 11
with stars above them can be considered primary glomerular
Pathology
Minimal change glomerulopathy has no glomerular lesions by
light microscopy, or only minimal focal segmental mesangial
prominence. Immunofluoresence staining in minimal change
disease is negative for immunoglobulins and complement
components. The pathologic sine qua non of minimal change
glomerulopathy is effacement of visceral epithelial cell foot
processes observed by electron microscopy.
Laboratory Findings
The ubiquitous laboratory feature of minimal change glomeru-
lopathy is severe proteinuria. Microscopic hematuria is seen
in fewer than 15% of patients. Volume contraction may lead
to a rise in both the hematocrit and hemoglobin. The erythro-
cyte sedimentation rate is increased as a consequence of
hyperfibrinogenemia as well as hypoalbuminemia. The serum
albumin concentration is generally less than 2 g/dL and, in
more severe cases, less than 1 g/dL. Total cholesterol, low-
density lipoprotein (LDL), and triglyceride levels are
increased. Pseudohyponatremia has been observed in the
setting of marked hyperlipidemia. Renal function is usually
normal, although a minority of patients have substantial acute
kidney injury, as discussed earlier. IgG levels may be pro-
foundly decreased—a factor that may result in susceptibility
to infections. Complement levels are typically normal in
patients with minimal change glomerulopathy.
Treatment
Children. Prednisone 60 mg/m2/day will induce a remission
in over 90% of patients within 4 to 6 weeks of therapy. Once
remission has been obtained, an alternate-day schedule
should begin within at least 4 weeks of the response in order
to decrease the incidence of steroid-induced side effects. In
children who have received empirical treatment, a renal
biopsy is indicated when there is failure to respond to a
4- to 6-week course of prednisone.
Adults. For an adult, the dose of prednisone is 1 mg/kg body
weight, not to exceed 80 mg/day. In adult patients, response
rates are typically lower and a full response to corticosteroid
treatment may take up to 15 weeks.
Management of Relapse. As few as 25% of patients have a
long-term remission, 25% to 30% have infrequent relapses (no
more than one a year), and the remainder have frequent relapses,
steroid dependency, or steroid resistance. Frequently relapsing
or steroid-dependent nephrotic patients typically require cyto-
toxic therapy with either cyclophosphamide or chlorambucil.
Both cyclophosphamide and chlorambucil have profound side
effects that include life-threatening infection, gonadal dysfunc- 229
tion, hemorrhagic cystitis, bone marrow suppression, and muta-
genic events. In patients unresponsive to alkylating therapy, the
question is whether other forms of therapy are indicated. End-
stage renal failure is rare in minimal change glomerulopathy, CH 11
and in light of this fact, additional forms of therapy must be con-
Pathology
FSGS is by definition a focal process; thus, not all glomeruli
are involved, the glomeruli are segmentally sclerotic, and por-
tions of the involved glomeruli may appear normal by light
microscopy. Nonsclerotic glomeruli and segments usually
have no staining for immunoglobulins or complement. The
ultrastructural features of FSGS on electron microscopy
include focal foot process effacement.
Laboratory Findings
Hypoproteinemia is common in patients with FSGS and the
serum albumin concentration may fall to below 2 g/dL, espe-
cially in patients with the collapsing variant. Hypogammaglo-
bulinema and hyperlipidemia are typical; serum complement
components are generally in the normal range. Serologic test-
ing for HIV infection should be obtained for all patients with
FSGS, especially those with the collapsing pattern.
Treatment 231
Angiotensin-converting enzyme (ACE) inhibitors decrease
proteinuria and the rate of progression to end-stage renal dis-
ease in proteinuric renal disease including FSGS. ACE inhi-
bition may provide a substantial reduction in proteinuria CH 11
and a long-term renoprotective effect that may be equal to,
Membranous Glomerulopathy
Idiopathic membranous glomerulopathy is the most common
cause of nephrotic syndrome in adults (25% of adult cases) and
can occur as an idiopathic (primary) or secondary disease. Sec-
ondary membranous glomerulopathy is caused by autoimmune
diseases (e.g., lupus erythematosus, autoimmune thyroiditis),
infection (e.g., hepatitis B, hepatitis C), drugs (e.g., penicilla-
mine, gold), and malignancies (e.g., colon cancer, lung cancer).
In patients over the age of 60, membranous glomerulopathy is
associated with a malignancy in 20% to 30% of patients. The
peak incidence of membranous glomerulopathy is in the fourth
or fifth decade of life. Although most patients with membranous
glomerulopathy present with the nephrotic syndrome, 10% to
20% of patients have less than 2 g/day proteinuria.
Pathology
The characteristic histologic abnormality in membranous
glomerulopathy is diffuse global capillary wall thickening
and the presence of subepithelial immune complex deposits.
Laboratory Findings
Proteinuria is usually more than 3 g of protein per 24 hours and
may exceed 10 g/day in 30% of patients. Microscopic hematu-
ria is present in 30% to 50% of patients, while macroscopic
hematuria is distinctly uncommon. Renal function is typically
preserved at presentation. Hypoalbuminemia is observed if
proteinuria is severe. Complement levels are normal; however,
the complex of terminal complement components known as
C5b-9 is found in the urine in some patients. Tests for hepatitis
B, hepatitis C, syphilis, and immunologic disorders such as
lupus, mixed connective tissue disease, and cryoglobulinemia
should be obtained to exclude secondary causes.
Treatment
The management of primary membranous glomerulopathy is
controversial. Common therapeutic approaches include the
following:
• Supportive care including ACE inhibition, lipid-lowering
therapy, and anticoagulation, if required
• Corticosteroids (usually prednisone or methylprednisolone)
• Alkylating agents, such as chlorambucil or cyclophospha-
mide, with or without concurrent corticosteroid treatment
• Cyclosporine
All patients should receive supportive care, including the use
of ACE inhibitors or adrenergic receptor blockers, lipid-lower-
ing agents, and consideration of the use of prophylactic
anticoagulation.
Corticosteroids. There have been three large, prospective,
randomized trials examining the efficacy of oral corticosteroid
therapy in adult patients, but they have differed in outcome.
A pooled analysis of randomized trials and prospective
234 studies has suggested a lack of benefit of corticosteroid ther-
apy in inducing a remission of the nephrotic syndrome. It
has been argued that higher does (60–200 mg every other
day) of prednisone and longer course of therapy (up to 1 year)
IV are required to effect a response. However, the side effects of
extended high-dose corticosteroid therapy are substantial
Pathogenesis of Renal Disease
Membranoproliferative Glomerulonephritis CH 11
(Mesangial Capillary Glomerulonephritis)
Type III
Secondary
Infections
Hepatitis B and C
Visceral abscesses
Infective endocarditis
Shunt nephritis
Quartan malaria
Schistosoma nephropathy
Mycoplasma infection
Rheumatologic Diseases
Systemic lupus erythematosus
Scleroderma
Sjögren syndrome
Sarcoidosis
Mixed essential cryoglobulinemia with or without hepatitis C
infection
Anti–smooth muscle syndrome
Malignancy
Carcinoma
Lymphoma
Leukemia
Inherited
a1-Antitrypsin deficiency
Complement deficiency (C2 or C3), with or without partial
lipodystrophy
Laboratory Findings
Hematuria is the hallmark of patients presenting with MGPN,
and may be microscopic or macroscopic. The degree of protein-
uria varies widely. Renal insufficiency occurs in a variable
number of cases, but it is the most ominous feature of the acute
nephritic syndrome. Serologic and clinical evidence of cryoglo-
bulinemia, hepatitis C, hepatitis B, osteomyelitis, subacute
bacterial endocarditis, or infected ventriculoatrial shunt should
be sought in type I MGPN. C3 is persistently depressed in 237
approximately 75% to 90% of MPGN patients. C3 nephritic fac-
tor is found in 60% of cases of type II MPGN.
Treatment CH 11
The treatment of type I MPGN is based on the underlying
GLOMERULONEPHRITIS
The syndrome of glomerulonephritis is characterized as
follows:
• Hematuria with or without red blood cell casts
• Proteinuria
• Hypertension
• Renal insufficiency
The spectrum of clinical presentation ranges from asymptom-
atic hematuria to the acute nephritic syndrome. A diagnostic
algorithm is outlined in Figure 11-1.
Laboratory Findings
Hematuria, microscopic or gross, is nearly always present in
acute PSGN. Microscopic examination of urine typically
reveals the presence of dysmorphic red blood cells or red
blood cell casts. Proteinuria is nearly always present, typically
in the subnephrotic range. Nephrotic-range proteinuria may
occur in as many as 20% of patients and is more frequent in
adults than in children. A pronounced decline in the GFR
is unusual in children and more common in the elderly
population. Throat or skin cultures may reveal group A strepto- 239
cocci, but serologic studies to evaluate the presence of recent
streptococcal infection are superior. The antibodies most
commonly studied for the detection of a recent streptococcal
infection are antistreptolysin O (ASO), antistreptokinase, anti- CH 11
hyaluronidase, antideoxyribonuclease B, and antinicotinylade-
Treatment
Treatment of acute PSGN is largely that of supportive care.
Children almost invariably recover from the initial episode.
Indeed, even the presence of acute kidney injury in adults is
not necessarily associated with a poor prognosis. Thus, there
is little evidence to suggest the need for any form of immuno-
suppressive therapy. Supportive therapy may require the use
of loop diuretics such as furosemide to ameliorate volume
expansion and hypertension. In patients with substantial vol-
ume expansion and marked pulmonary congestion who do not
respond to diuretics, dialytic support may be appropriate.
Importantly, potassium-sparing agents, including triamterene,
spironolactone, and amiloride, should not be used in this dis-
ease state as patients can develop substantial hyperkalemia.
Usually, patients undergo a spontaneous diuresis within 7 to
10 days after onset of their illness and no longer require sup-
portive care. There is no evidence to date that the early treat-
ment of streptococcal disease, either pharyngitic or cellulitic,
alters the risk of developing PSGN. The long-term prognosis
of patients with PSGN is not as benign as was previously con-
sidered. Widespread crescentic glomerulonephritis results in
an increased number of obsolescent glomeruli associated with
tubulointerstitial disease and may herald a progressive loss of
functional renal mass over time.
IgA Nephropathy
IgA nephropathy is one of the most common forms of glomer-
ulonephritis, if not the most common. The disease process was
initially considered a benign form of hematuria. It is most
240 common in the second and third decades of life, and is much more
common in males than females. IgA nephropathy can only be
definitively diagnosed by the immunohistologic demonstration
of mesangial immune deposits that stain dominantly or codomi-
IV nantly for IgA. The mechanisms responsible for the glomerular
injury in IgA nephropathy are poorly understood but may involve
Pathogenesis of Renal Disease
Laboratory Findings CH 11
Typical findings include microscopic hematuria on urinalysis
Treatment
As in any form of chronic renal insufficiency, antihyperten-
sive therapy is essential in preventing progressive glomerular
injury. ACE inhibition is specifically indicated in proteinuric
patients. Furthermore, combination therapy with trandolapril
and losartan was significantly more effective in preventing
disease progression than either agent alone. Recent studies
suggest that corticosteroids may have important beneficial
effects. A prospective, randomized trial has demonstrated that
in patients with urine protein excretion of 1 to 3.5 g daily, and
plasma creatinine concentrations of 1.5 mg/dL (133 mmol/L) or
less, intravenous methylprednisolone for 3 consecutive days
in months 1, 3, and 5 combined with oral prednisone given
at a dose of 0.5 mg/kg every other day for months 1 through
6 protected against loss of renal function. Patients with IgA
nephropathy who have concurrent minimal change glomeru-
lopathy also benefit from corticosteroid therapy. More aggres-
sive treatment may be appropriate in patients with rapidly
progressive IgA nephropathy. Treatment options in this
setting include low-dose oral prednisone and cyclophospha-
mide for 3 months followed by 2 years of azathioprine, which
has been demonstrated to improve renal survival in patients
with baseline creatinine greater than 1.5 mg/dL (133 mmol/L).
It is reasonable to treat crescentic disease in IgA nephropathy
in a manner similar to other forms of crescentic glomerulone-
phritis using pulse methylprednisolone, oral prednisone, or
cyclophosphamide, individually or in combination.
The advent of treatment of IgA nephropathy with fish oil is
based on a study that demonstrated a marked improvement in
renal outcome in patients treated with 12 g of fish oil contain-
ing omega-3 fatty acids daily for 2 years. The enthusiasm for
this approach has been tempered by two other much smaller
trials that showed absolutely no benefit of fish oil, and a recent
meta-analysis of the available trials that suggested there was
242 no significant benefit of fish oil therapy in most patients. If any
effect is to be observed with fish oil therapy, it is probably in
those individuals who have heavier proteinuria.
IV
Other Glomerular Diseases That Cause
Pathogenesis of Renal Disease
Hematuria
The clinical designation of benign familial hematuria often
refers to thin basement membrane nephropathy. The preva-
lence of thin basement membrane nephropathy in the general
population has been estimated to be approximately 5% to
10%. Males and females are equally affected and are typically
found to have microscopic hematuria when they are adoles-
cents or young adults. Macroscopic hematuria and proteinuria
are uncommon. The pattern of hematuria is sometimes famil-
ial, and assessing the urine of family members can further
support a diagnosis. Persistent isolated hematuria is also pres-
ent in hereditary nephritis associated with Alport syndrome,
which is usually associated with an X-linked dominant form
of inheritance and is associated with hearing loss and ocular
abnormalities. The syndrome of loin pain hematuria is
another condition associated with hematuria. This uncommon
syndrome occurs primarily in young women. The clinical pic-
ture is reminiscent of IgA nephropathy. There are recurrent
episodes of gross hematuria, usually with flank pain that is
typically described as dull or aching. Patients sometimes have
fever, malaise, and anorexia. Hypertension and proteinuria are
uncommon. The treatment of loin pain hematuria usually
begins with cessation of oral contraceptives, which have been
associated with disease development, or treatment with anti-
coagulant drugs.
Nomenclature
Fibrillary glomerulonephritis and immunotactoid glomerulopa-
thy are glomerular diseases that are characterized by patterned
deposits seen by electron microscopy. There is controversy
over how to categorize these diseases. Most renal pathologists
distinguish fibrillary glomerulonephritis from immunotactoid
glomerulopathy based on the presence of fibrils of approxi-
mately 20-nm diameter in the former and larger 30- to 40-nm
diameter microtubular structures in the latter. The etiology
and pathogenesis of fibrillary glomerulonephritis and immuno-
tactoid glomerulopathy are not known, but both conditions
have been associated with lymphoproliferative diseases.
Epidemiology and Clinical Features 243
Fibrillary glomerulonephritis is relatively uncommon. It is
observed in less than 1% of native renal biopsies. Patients typi-
cally present with a mixture of the nephrotic and nephritic syn-
drome features. Proteinuria is typically in the nephrotic range. CH 11
Renal insufficiency, hematuria, and hypertension are common
Treatment
At this time, there is no convincingly effective form of treat-
ment for patients with either fibrillary glomerulonephritis
or immunotactoid glomerulopathy. Efforts at treatment with
either glucocorticoids or alkylating agents such as cyclo-
phosphamide have proved unsuccessful. Nonetheless, it is
possible that the treatment of the underlying malignancy, if
one is detected, may improve the renal outcome. Fibrillary
glomerulonephritis recurs in the majority of renal allografts,
although the rate of deterioration in the allograft appears to
be slower.
Treatment
Therapy for crescentic immune complex glomerulonephritis is
influenced by the nature of the underlying category of immune
complex glomerulonephritis. For example, acute PSGN with
50% crescents might not prompt the same therapy as IgA
nephropathy with 50% crescents. However, controlled pro-
spective data are inadequate to guide therapy for most forms
of crescentic immune complex glomerulonephritis. Some
nephrologists extrapolate from the lupus nephritis experience
and choose to use immunosuppressive drugs in patients with
crescentic immune complex disease, a strategy that would not
be employed if the glomerular lesions appeared less aggressive.
For the minority of patients who have idiopathic immune
complex crescentic glomerulonephritis, the most common
treatment is immunosuppressive therapy with pulse methyl-
prednisolone followed by prednisone at a dose of 1 mg/kg/
day, and then tapered over the second to third month to an alter-
nate-day regimen until completely discontinued. In patients
with a rapid decline in renal function, cytotoxic agents in addi-
tion to corticosteroids may be considered. There is evidence
that immune complex crescentic glomerulonephritis is less
responsive to immunosuppressive therapy than either anti-
GBM or ANCA crescentic glomerulonephritis.
Laboratory Findings
Renal involvement by anti-GBM disease typically causes an
acute nephritic syndrome with hematuria, including dysmor-
phic erythrocyturia and red blood cell casts. The diagnostic
laboratory finding in anti-GBM disease is detection of circu-
lating antibodies to GBM, specifically to the alpha-3 chain
of type IV collagen. These antibodies are detected by radio-
immunoassay or enzyme immunoassay in approximately
90% of patients. Up to 30% of patients also have a
circulating ANCA.
Treatment
The standard treatment for anti-GBM disease includes inten-
sive plasmapheresis combined with corticosteroids and cyclo-
phosphamide or azathioprine. Plasmapheresis consists of
removal of 2 to 4 L of plasma and replacement with a 5% albu-
min solution, continued on a daily basis until circulating anti-
body levels become undetectable. In those patients with
pulmonary hemorrhage, clotting factors should be replaced
by administrating fresh-frozen plasma at the end of each treat-
ment. Prednisone should be administered at a dose of 1 mg/kg
body weight for at least the first month and then tapered to
alternate-day therapy during the second and third months of
treatment. Cyclophosphamide is administered either orally
(at a dose of 2 mg/kg/day) or intravenously at a starting dose
of 0.5 g/m2 body surface area. The dose of cyclophosphamide
must be adjusted with consideration for the degree of
impairment of renal function and the white blood cell count.
246 Cytotoxic therapy is usually continued for about 6 to 12
months. Aggressive plasmapheresis, even in patients with
severe renal insufficiency, may have an ameliorative effect
and provide improved long-term patient and renal survival.
IV The major prognostic marker for the progression to end-stage
renal disease is the serum creatinine level at the time of initi-
Pathogenesis of Renal Disease
Laboratory Findings
Approximately 80% to 90% of patients with pauci-immune
necrotizing and crescentic glomerulonephritis will have a circu-
lating ANCA. By indirect fluorescence microscopy on alcohol-
fixed neutrophils, ANCA yields two patterns of staining:
perinuclear (P-ANCA) and cytoplasmic (C-ANCA). The two
major antigen specificities for ANCA are MPO and PR3. With
rare exceptions, anti-MPO antibodies produce a P-ANCA pat-
tern of staining on indirect immunofluorescence microscopy,
whereas anti-PR3 antibodies cause a C-ANCA pattern of stain-
ing. About two thirds of patients with pauci-immune necrotiz-
ing crescentic glomerulonephritis without clinical evidence of
systemic vasculitis will have MPO-ANCA or P-ANCA, and
approximately 30% will have PR3-ANCA or C-ANCA. The fre-
quency of MPO-ANCA relative to PR3-ANCA is higher in
patients with renal-limited disease than in patients with micro-
scopic polyangiitis or Wegener granulomatosis. Maximal sensi-
tivity and specificity with ANCA testing is best achieved when
both immunofluorescence and antigen-specific assays are per-
formed. Antigen-specific assays may be either an enzyme-
linked immunosorbent assay (ELISA) or radioimmune assay.
The positive predictive value (PPV) of a positive ANCA result
depends on the signs and symptoms of disease in the patient
who is tested. The PPV of a positive ANCA result in a patient
with classic features of RPGN is 95%. Although the PPV is
not good in patients with hematuria and normal renal function,
the negative predictive value is greater than 95%.
248 Urinalysis findings in pauci-immune crescentic glomeru-
lonephritis include hematuria with dysmorphic red blood
cells, with or without red blood cell casts, and proteinuria.
The proteinuria ranges widely. Serum creatinine usually is
IV elevated at the time of diagnosis and rising, although a
minority of patients will have relatively indolent disease.
Pathogenesis of Renal Disease
Treatment
The treatment of pauci-immune crescentic glomerulonephritis
involves varying regimens of corticosteroids and cyclophos-
phamide. In view of the potentially explosive and fulminant
nature of this disease, induction therapy should be instituted
using pulse methylprednisolone at a dose of 7 mg/kg/day for
3 consecutive days followed by daily oral prednisone, as well
as cyclophosphamide, either orally or intravenously. Predni-
sone is usually started at a dose of 1 mg/kg/day for the first
month, then tapered to an alternate-day regimen, and then dis-
continued by the end of third to fourth month of treatment.
When a regimen of monthly intravenous doses of cyclophos-
phamide is used, the starting dose should be about 0.5 g/m2
and adjusted upward to 1 g/m2 based on the 2-week leukocyte
count nadir. A regimen based on daily oral cyclophosphamide
should begin at a dose of 2 mg/kg/day and adjusted downward
as needed to keep a nadir leukocyte count above 3000 m3. The
usual length of therapy with cyclophosphamide is for 6 to 12
months. For patients who have not achieved remission by that
time, continuing for a longer duration is a reasonable
approach. In some patients, the monthly intravenous regimen
is not sufficiently immunosuppressive, necessitating daily
oral cyclophosphamide treatment (which results in a higher
cumulative dosage). An alternative proposed regimen is based
on the use of cyclophosphamide for the first 3 months of treat-
ment followed by azathioprine, 2 mg/kg/day, for an additional
6 to 12 months. Plasmapheresis does not provide any added
benefit over immunosuppressive treatment alone in patients
with renal-limited disease or in patients with mild to moder-
ate renal dysfunction. However, the use of plasmapheresis in
addition to immunosuppressive therapy may be beneficial in
the subset of patients who require dialysis at the time of pre-
sentation. Trimethoprim-sulfamethoxazole has been suggested
to be of benefit in the treatment of patients with Wegener
granulomatosis. The beneficial effect, if any, seems to be
limited to the upper respiratory tract and this antibiotic
combination is unlikely to have a role in the treatment of
pauci-immune crescentic glomerulonephritis alone.
Other agents currently undergoing evaluation in the manage-
ment of pauci-immune RPGN include rituximab, alemtuzumab
(Campath-1H), and infliximab. Definitive data regarding their 249
benefit is lacking at this time.
The chance of recovery of renal function in patients present-
ing with advanced renal failure requiring renal replacement
therapy is diminished when compared to patients who do not CH 11
require dialysis at presentation (50% versus 70%). It appears
Secondary Glomerular
Disease
SYSTEMIC LUPUS ERYTHEMATOSUS
Lupus nephritis (LN) is a frequent and potentially serious
complication of systemic lupus erythematosus (SLE). Renal
involvement worsens morbidity and mortality rates in lupus;
patient outcomes are also adversely affected through compli-
cations of therapy. Approximately 25% to 50% of unselected
lupus patients have clinical renal disease at disease onset
and up to 60% of adults with SLE develop renal disease dur-
ing their lifetime. Renal involvement in SLE is defined for
diagnostic purposes as persistent proteinuria exceeding
500 mg daily or the presence of cellular casts. The deposition
of circulating immune complexes plays a major role in the
development of LN. Glomerular and vascular damage may
also be potentiated by hypertension and a thrombotic micro-
angiopathy triggered by the presence of antiphospholipid
(APL) antibodies.
Clinical Manifestations
The clinical manifestations of kidney involvement in SLE are
varied. Renal involvement often develops concurrently or
shortly following the onset of SLE, and may follow a
250
251
International Society of Nephrology/Renal
Table 12-1 Pathology Society (2003) Classification of
Lupus Nephritis
Designation Description CH 12
Class I Minimal mesangial LN
and the 5-year renal survival rate is higher than 90% in some
series of patients treated with modern immunosuppressive
therapy. Clinical risk factors for a poor outcome in diffuse prolif-
erative disease include age over 30, male sex, African-American
race, nephrotic range proteinuria, disease relapse, and elevated
creatinine. Patients with combined severe activity and chronicity,
as well as those with the combination of cellular crescents and
interstitial fibrosis, appear to have a worse prognosis.
Pathogenesis
The vasculitis of polyarteritis may be mediated by a number of
diverse pathogenetic factors including humoral vascular
immune deposits, cellular immunity, endothelial cytopathic
factors, and ANCAs. ANCA may play a pathogenetic role in
a manner similar to in Wegener granulomatosis.
Renal Features
In the microscopic form of the disease, features of vasculitis
and glomerulonephritis manifest, whereas in the classic pat-
tern, features of renal ischemia and infarction predominate
due to larger vessel disease. Hypertension is common in poly-
arteritis (50%) and most patients have laboratory evidence of
their renal involvement at presentation. The majority of cases
have urinary sediment changes with microscopic hematuria
and often RBC casts. Proteinuria is found in most patients,
but the nephrotic syndrome is rarely present. In microscopic
polyarteritis, the severity of the clinical renal findings corre-
lates with the degree of glomerular involvement. Patients with
a normal creatinine clearance are likely to have normal
glomeruli on biopsy or only ischemic glomerular changes. 259
Presenting symptoms related to kidney disease are uncommon
in classic polyarteritis with the exception of hypertension but
may include hemorrhage from a renal artery aneurysm, flank
pain, and gross hematuria. Angiographic examination reveals CH 12
multiple rounded, saccular aneurysms of medium-sized
Laboratory Tests
The erythrocyte sedimentation rate (ESR) is elevated in almost
all patients and is usually associated with anemia, leukocyto-
sis, eosinophilia, and thrombocytosis. Most patients are ANA
negative and have normal serum complement levels. Tests
for circulating immune complexes and rheumatoid factor are
often positive. Cryoglobulins may reflect associated hepatitis
B infection (<10% of cases). Patients with classic PAN are
ANCA-negative and a positive test result suggests either
microscopic polyarteritis or Wegener granulomatosis.
Pathology
IV
The spectrum of glomerular involvement in Churg-Strauss
Pathogonesis of Renal Disease
Pathogenesis
Although the pathogenesis of Churg-Strauss syndrome is
unclear, an allergic or hypersensitive mechanism is suggested
by the presence of asthma, hypereosinophilia, and elevated
plasma levels of IgE. It is likely that ANCAs may play a role akin
to that in Wegener granulomatosis and microscopic polyarteritis.
Takayasu Arteritis
Takayasu arteritis is a rare vasculitic disease of unknown
pathogenesis characterized by inflammation and stenosis of
medium-sized and large arteries, with a predilection for the
262 aortic arch and its branches. The disease most commonly
affects young women between 10 and 40 years of age, and
Asians are much more commonly affected. Renal involvement
is characterized by an obliterative arteritis of the main renal
IV artery or narrowing of the renal ostia by abdominal aortitis
leading to renovascular hypertension. Arteriography is most
Pathogonesis of Renal Disease
Treatment
In most patients, corticosteroids are effective therapy for the
vasculitis and systemic symptoms and further vascular deteri-
oration is suppressed. Other immunosuppressive agents
including methotrexate, cyclophosphamide, and mycopheno-
late have also been used successfully.
HENOCH-SCHÖNLEIN PURPURA
Henoch-Schönlein purpura (HSP) is a systemic vasculitis syn-
drome with involvement of the skin, gastrointestinal tract, and
joints in association with a glomerulonephritis characterized
by prominent IgA deposition. IgA immune complexes deposit
in the skin, kidney, and other organs in association with an
inflammatory reaction of the vessels. Children are far more
commonly affected than adults, although the disease can
occur at any age. More severe renal disease occurs in older
children and adults.
Clinical Findings
SJÖGREN SYNDROME
SARCOIDOSIS
The most common renal manifestations of sarcoidosis are
interstitial nephritis (typically granulomatous), nephrolithia-
sis, and functional abnormalities of the tubule. Glomerular
disease is infrequent and may be the coincidental expression
of two unrelated disease processes in one individual rather
than secondary to the sarcoidosis itself. A variety of glomeru-
lar lesions have been described in patients with sarcoidosis
including minimal change disease, focal segmental glomerulo-
sclerosis, membranous nephropathy, IgA nephropathy,
MPGN, and proliferative and crescentic glomerulonephritis.
Some patients have granulomatous renal interstitial nephritis
in addition to the glomerular lesions, whereas others have
only extrarenal histologic documentation of the sarcoidosis.
The clinical presentation of glomerular disease in sarcoidosis
is usually that of proteinuria, active urinary sediment at times,
and most commonly the nephrotic syndrome. Patients have
been treated with various forms of immunosuppression,
including steroids, depending on their glomerular lesions.
AMYLOIDOSIS
MONOCLONAL IMMUNOGLOBULIN
DEPOSITION DISEASE
Myeloma Kidney
Myeloma cast nephropathy (myeloma kidney) is an important
cause of acute kidney injury in myeloma. The underlying
pathogenesis involves the precipitation of filtered light chains
within the tubule lumen and the subsequent obstruction of
urine flow. Light chains may also be directly toxic to the prox-
imal tubule cells and can trigger the development of the Fan-
coni syndrome. Patients are equally susceptible to cast
nephropathy whether the filtered light chain is of the k or l
variety; an inherent ability to bind with Tamm-Horsfall pro-
tein is an important determinant of whether or not the light
chain precipitates. Other factors favoring the development of
cast nephropathy include a low urine flow rate as may occur
during volume depletion, hypercalcemia, and diuretic or
NSAID use. Clinical findings include features of myeloma,
including a serum and urine paraprotein, and, occasionally,
evidence of Fanconi syndrome (proximal RTA, glycosuria).
Of note, a routine urine dipstick test may not detect the posi-
tively charged light chains, and hence quantitative determina-
tion of urine protein should be performed if cast nephropathy
is suspected. The definitive diagnosis requires a renal biopsy.
The pathologic findings include preservation of the normal
glomerular architecture and tubular casts that stain positive
for either k or l light chains on immunofluoresence. Manage-
ment involves treatment of exacerbating factors including
removal of offending agents (diuretics, NSAIDs, ACE inhibi-
tors), volume expansion, treatment of hypercalcemia, and,
possibly, the induction of an alkaline diuresis, though this last 269
point remains controversial. Ultimately, clearance of the para-
protein is required and this may be achieved by chemotherapy
aimed at the underlying plasma cell dyscrasia. Plasmapheresis
had been suggested in the management of patients with a high CH 12
paraprotein burden and acute kidney injury in whom conser-
WALDENSTRÖM MACROGLOBULINEMIA
Waldenström macroglobulinemia is a syndrome character-
ized by a circulating monoclonal IgM protein in association
with a B-cell lymphoproliferative disorder. This slowly
progressive disorder occurs in older patients who present
with fatigue, weight loss, bleeding, visual disturbances,
peripheral neuropathy, hepatosplenomegaly, lymphade-
nopathy, anemia, and often a hyperviscosity syndrome.
Renal involvement is uncommon but may manifest as
microscopic hematuria and proteinuria, which may be
nephrotic. Patients may have enlarged kidneys. The pathol-
ogy seen in Waldenström macroglobulinemia is varied.
Some patients have invasion of the renal parenchyma by
neoplastic lymphoplasmacytic cells. Acute kidney injury
associated with intraglomerular occlusive thrombi of the
IgM paraprotein has also been reported. By IF, these glomer-
ular “thrombi” stain for IgM and a single light chain, consis-
tent with monoclonal IgM deposits. By EM, the deposits
contain nonamyloid fibrillar or amorphous electron-dense
material. Other potential presentations include MPGN
with an associated type I or II cryoglobulinemia, LCDD,
intratubule casts deposition similar to myeloma cast
nephropathy, and amyloidosis. Treatment of Waldenström
macroglobulinemia consists of therapy directed against the
lymphoproliferative disease with alkylating agents and, at
times, plasmapheresis for hyperviscosity signs and symp-
toms. Newer therapies include fludarabine, cladribine,
interferon alfa, rituximab, and marrow transplantation.
MIXED CRYOGLOBULINEMIA
Cryoglobulinemia refers to a pathologic condition caused by
the production of circulating immunoglobulins that precipi-
tate on cooling and resolubilize on warming. It is associated
with a variety of infections as well as collagen-vascular
disease, and lymphoproliferative diseases. Cryoglobulins have
270 been divided into three major groups based on the nature of
the circulating immunoglobulin:
• Type I: The cryoglobulin is a single monoclonal immuno-
globulin often found associated with Waldenström macro-
IV globulinemia or myeloma.
• Type II: The cryoglobulin is a monoclonal immunoglobulin
Pathogonesis of Renal Disease
Clinical Features
The disease usually manifests in children or young adults as
microscopic hematuria, with episodic gross hematuria that
may be exacerbated by respiratory infections or exercise.
Proteinuria is usually mild at first and increases progressively
with age. Hypertension is a late manifestation. Slowly progres-
sive renal failure is common and ESRD usually occurs in
males between the ages of 16 and 35. As this is usually an
X-linked disorder, most females have only mild disease. More
severe disease in females suggests an autosomal pattern of
inheritance. High-frequency sensorineural deafness occurs in
30% to 50% of patients and is always accompanied by renal
involvement. Ocular abnormalities occur in 15% to 30% of
patients. Anterior lenticonus is virtually pathognomonic of
Alport syndrome.
272 Course and Treatment
Clinical Features
Patients usually present in childhood with microhematuria.
Hematuria is usually persistent but may be intermittent in
some patients. Episodic gross hematuria may occur, particu-
larly with upper respiratory infections. Patients do not
typically have overt proteinuria, but when present, this may
suggest progression of disease.
Pathogenesis
In most kindreds with benign familial hematuria, the disorder
appears to be transmitted in an autosomal dominant pattern.
Thin GBM disease has been linked to the COL4A3 and
COL4A4 genes suggesting that type IV collagen defects can
cause both benign hematuria and Alport syndrome.
INHERITED MUTATIONS OF PODOCYTE 273
PROTEINS
Two novel proteins have been associated with the steroid-resistant
nephrotic syndrome in childhood: nephrin and podocin. CH 12
Treatment
Treatment strategies to support infants include intravenous
albumin substitution, optimizing nutrition, administration of
thyroxin, and anticoagulation, until bilateral nephrectomy
can be performed (at around 1 year of life). Patients are main-
tained on dialysis until renal transplantation (at around
2 years of age). Other authors have reported success in reduc-
ing proteinuria, thus avoiding nephrectomy, with ACE inhibi-
tion in combination with indomethacin.
Clinical Features
The estimated incidence in males is 1 in 40,000 to 1 in 60,000.
The initial clinical presentation begins in childhood with epi-
sodic pain in the extremities and acroparesthesias. Renal
involvement presents with hematuria and proteinuria, which
often progress to nephrotic levels with progressive renal fail-
ure by the fifth decade. The skin is commonly involved with
reddish purple macules (angiokeratomas) typically found on
the abdomen, buttocks, hips, genitalia, and upper thighs.
The nervous system is involved, with peripheral and auto-
nomic neuropathy. Premature arterial disease of coronary ves-
sels leads to myocardial ischemia and arrhythmias at a young
age. Corneal opacities are seen in virtually all homozygotes
and most heterozygotes. Posterior capsular cataracts, edema
of the retina and eyelids, and tortuous retinal and conjunctival
vessels may also been seen in the eye. Up to one third of
female carriers have been reported to have significant disease
manifestations.
Pathogenesis 275
Treatment
Two randomized, controlled trials have shown that recombi-
nant human a-galactosidase A replacement therapy is safe
and can improve clinical parameters including neuropathic
pain and creatinine clearance. Treatment has also been shown
to decrease microvascular endothelial deposits of globotriao-
sylceramide in the kidney. Enzyme replacement therapy
should be administered as early as possible in all males with
Fabry disease (including those with ESRD) and female carriers
with substantial disease manifestations.
LECITHIN-CHOLESTEROL ACYLTRANSFERASE
DEFICIENCY
This familial disorder is characterized by proteinuria, anemia,
hyperlipidemia, and corneal opacity. Most patients are of
Scandinavian origin; however, subsequent reports have been
from other countries.
Clinical Features
The triad of anemia, nephrotic syndrome, and corneal opacities
suggests lecithin-cholesterol acyltransferase (LCAT) deficiency.
Renal disease is a universal finding, with albuminuria noted
276 early in life. Proteinuria increases in severity during the fourth
and fifth decades, often with development of nephrotic syn-
drome and progressive renal failure. Most patients are mildly
anemic with target cells and poikilocytes on the peripheral
IV smear. There is evidence of low-grade hemolysis. Corneal opa-
cities are noted during childhood, which appear as grayish
Pathogonesis of Renal Disease
Diagnosis
Patients have little or no LCAT activity in their blood circula-
tion because of mutations in the LCAT gene. In patients sus-
pected of having LCAT deficiency, measurements of plasma
enzyme should be performed. Other abnormalities of lipids fre-
quently accompany LCAT deficiency. The plasma is turbid, total
cholesterol varies, triglycerides are increased, HDL is reduced,
and all fractions contain higher amounts of cholesterol.
Treatment
Treatment
With the initiation of antibiotic therapy, the manifestations of
glomerulonephritis begin to subside. Plasmapheresis and cor-
ticosteroids have been reported to promote renal recovery in
some patients with renal failure. However, the risk of worsen-
ing infectious aspects of the disease while ameliorating immu-
nologic manifestations should be kept in mind while using
this approach.
Shunt Nephritis
Ventriculovascular (ventriculoatrial, ventriculojugular) and
ventriculoperitoneal shunts used for the treatment of hydro-
cephalus may become colonized with microorganisms, most
commonly Staphylococcus albus (75%). Patients commonly
present with fever, arthralgia, and malaise. Anemia, hepato-
splenomegaly, and lymphadenopathy are found on examina-
tion. Renal manifestations include hematuria (microscopic or
gross), proteinuria (nephrotic syndrome in 30% of patients),
azotemia, and hypertension. Laboratory abnormalities include
presence of rheumatoid factor, cryoglobulins, elevated ESR
and C-reactive protein levels, hypocomplementemia, and
presence of circulating immune complexes.
Treatment
Antibiotic therapy and prompt removal of the infected
catheter lead to remission of the glomerulonephritis.
Leishmaniasis
Leishmaniasis, also known as kala-azar, is caused by
Leishmania donovani. Renal involvement in kala-azar appears
to be mild and reverts with antileishmanial treatment. Renal
biopsies show mesangial proliferation or focal proliferation.
IgG, IgM, and C3 may be observed in areas of proliferation.
Amyloidosis may also complicate kala-azar.
HIV-Associated Nephropathy
Clinical Features
HIV-associated nephropathy (HIVAN) was first reported in
1984 and is characterized by a collapsing form of focal
glomerulosclerosis. There is a strong predilection for HIVAN
among black HIV-infected patients with a black-white ratio
280 of 12:1. Although intravenous drug use has been the most
common risk factor for HIVAN, the disease has been seen in
all groups at risk for AIDS. HIVAN usually occurs in patients
with a low CD4 count, but full-blown AIDS is certainly not a
IV prerequisite for the disease. The prevalence of HIVAN in
patients who test positive for HIV is reported to be
Pathogonesis of Renal Disease
Pathogenesis
HIV appears to be able to infect glomerular endothelial cells
and, to a lesser degree, mesangial cells in vitro. HIV-1 RNA
is detectable in renal tubule epithelial cells and glomerular
epithelial cells (visceral and parietal) by in situ hybridization
in human subjects. Based on animal models, it appears likely
that a viral gene product or indirect effects on host cytokine
production mediate glomerular injury.
Treatment
In children with a mild endemic form of hepatitis B–
associated nephropathy, no treatment other than supportive
care is advocated and spontaneous recovery is common. In
patients with progressive renal dysfunction, interferon alfa
has been used with mixed results. Steroids do not signifi-
cantly improve proteinuria and may potentially enhance viral
replication. Nucleoside analogs including lamivudine (3TC),
adefovir, and lobucavir have also demonstrated clinical utility
in treating hepatitis B infection; their role in treating the
nephropathy remains to be established. Preemptive lamivu-
dine therapy in renal transplant recipients has shown
improved survival compared to historical control subjects.
Hepatitis C
Renal disease associated with HCV infection includes MPGN,
with or without associated mixed cryoglobulinemia, and mem-
branous glomerulopathy (see Chapter 11, Primary Glomerular
Disease, and previous discussion in this chapter). The MPGN
is most often type I, with fewer cases of type III. Rare cases of dif-
fuse proliferative and exudative glomerulonephritis, polyarter-
itis, and fibrillary and immunotactoid glomerulopathy have
also been described in association with HCV. Most patients
have evidence of liver disease as reflected by elevated plasma
transaminase levels. However, transaminase levels are normal
in some cases, and a history of acute hepatitis is often absent.
Pathogenesis
The pathogenesis of HCV-related nephropathies is immune
complex–mediated. HCV-specific proteins have been isolated
282 from glomerular lesions. The disappearance of viremia in
response to interferon (see later) is associated with a diminu-
tion of proteinuria; a relapse of viremia is accompanied by
rising proteinuria.
IV
Treatment
Pathogonesis of Renal Disease
Cirrhosis
Cirrhotic glomerulonephritis is usually a clinically silent
disease; however, the diagnosis can be suspected by finding
proteinuria or abnormalities of the urine sediment. Glomeru-
lar morphologic abnormalities with IgA deposition have been
noted in more than 50% of patients with cirrhosis at both nec-
ropsy and biopsy, although this has also been found in some
autopsies of noncirrhotic kidneys. Clinically, there may be
mild proteinuria or hematuria, or both. Rarely, HSP with rap-
idly progressive glomerulonephritis has been described in
association with cirrhosis.
Membranous Nephropathy
Lesions of membranous nephropathy may be associated with
malignancies in 10% to 40% of cases. These include carci-
noma of bronchus, breast, colon, stomach, and Hodgkin dis-
ease, among others. In some instances, successful treatment
of the neoplasm has induced a partial or complete remission
of the associated glomerulopathy.
Microvascular Diseases
of the Kidney
HEMOLYTIC UREMIC SYNDROME AND
THROMBOTIC THROMBOCYTOPENIC
PURPURA
Thrombotic microangiopathy (TMA) represents a group of disor-
ders with common pathologic features including alteration in the
microvasculature with detachment and swelling of the endothe-
lium, deposition of amorphous material in the subendothelial
space, and luminal platelet aggregation leading to microthrom-
bosis. Laboratory features include thrombocytopenia, hemolytic
anemia, and schistocytes. Among TMAs, hemolytic uremic syn-
drome (HUS) and thrombotic thrombocytopenic purpura (TTP)
are the most prominent diseases. Given the overlap in clinical
manifestations, the two syndromes were considered as a contin-
uum of a single disease entity. Newly identified pathophysio-
logic mechanisms, however, have allowed differentiation of the
two syndromes on a molecular basis.
Clinical Features
Laboratory Findings
The hallmark laboratory finding, essential for the diagnosis of
HUS/TTP, is a microangiopathic hemolytic anemia. The labo-
ratory findings include the following:
• Schistocytes on the peripheral smear (burr cells, helmet
cells, and other fragments)
• Anemia (hemoglobin levels < 6.5 mg/dL in 40%)
• Reticulocytosis
• Elevated lactate dehydrogenase (LDH)/low haptoglobin level
• Negative Coombs test
• Thrombocytopenia (cell count usually < 60,000/mm3)
Moderate leukocytosis may accompany the hemolytic ane-
mia, but white blood cell counts rarely exceed 20,000/mm3.
In contrast to disseminated intravascular coagulation, the pro-
thrombin time (PT), partial thromboplastin time (PTT), fibri-
nogen level, and coagulation factors are normal.
Renal Involvement
Etiology
Hemolytic Uremic Syndrome
Diarrhea-associated HUS (DþHUS) is associated with infection
by shiga-toxin–producing E. coli serotype O157:H7 and has an
excellent prognosis. Transmission can occur through contami- 287
nated foodstuffs or through municipal water, airborne trans-
mission, and person-to-person contact. Hemolytic uremic
syndrome can also follow non-shiga-toxin–producing E. coli
(STEC) O15:H7 infections, and such infections are almost cer- CH 13
tainly undetected. Diarrhea starts 2 to 12 days after ingestion
Clinical Features
Systemic sclerosis is a rare disease affecting predominantly CH 13
women between the ages of 30 and 50 years. The overall annual
Laboratory Findings
About 70% of the patients with systemic sclerosis have a pos-
itive antinuclear antibody titer (ANA 1:16), typically in a
speckled or nucleolar pattern. Antibodies to DNA topoisomer-
ase I (anti-Scl-70) are more specific, but they are found in only
30% of patients with diffuse cutaneous involvement and in
only 15% of those with the limited form. Anticentromere anti-
bodies are present in half of the patients, most of whom have
limited systemic sclerosis. Approximately 30% of the patients
have positive tests for rheumatoid factor. Antibodies to dou-
ble-stranded DNA are rarely noted.
Renal Involvement
Kidney involvement in systemic sclerosis (80%) manifests as
a slowly progressing chronic renal disease or as scleroderma
renal crisis (SRC), which is characterized by malignant hyper-
tension and acute azotemia. Clinical indicators of chronic
renal involvement in systemic sclerosis include proteinuria,
hypertension, and decreased glomerular filtration rate (GFR).
Renal manifestations rarely antedate the other features of sys-
temic sclerosis.
292 Scleroderma renal crisis is defined by the sudden onset of
accelerated or malignant arterial hypertension, followed by
rapidly progressive oliguric renal failure. Ten percent of
patients with scleroderma, in general, and 25% of those with
IV diffuse scleroderma develop SRC typically within the first 4
years of the disease. Patients with the diffuse cutaneous form
Pathogenesis of Renal Disease
are at much higher risk for development of SRC than are those
with limited cutaneous systemic sclerosis, and black patients
are also at higher risk compared with white patients.
The symptomatology is predominantly that of accelerated/
malignant hypertension. Oliguria and a rapidly rising serum
creatinine concentration follow shortly thereafter. The urinal-
ysis reveals proteinuria, microscopic hematuria, and granular
casts. Plasma renin activity is markedly elevated during SRC.
SRC progresses rapidly to severe renal failure that requires
dialysis. Other clinical manifestations of SRC include micro-
angiopathic hemolytic anemia with thrombocytopenia.
Pathogenesis
The pathogenesis of systemic sclerosis is poorly understood.
Postulated mechanisms include abnormal vasomotor control,
enhanced collagen production, immune-mediated injury, and
primary endothelial abnormalities. Although several antinu-
clear autoantibodies have been detected in patients with
systemic sclerosis, it is unclear whether these immunologic
changes constitute primary events in systemic sclerosis or
are epiphenomena.
Clinical Features
The mode of onset of clinical manifestations varies greatly. It
may be sudden, developing in a few days after a precipitating
factor, or insidious, over weeks or months. Clinical manifesta-
tions include the following:
• Livedo reticularis, “purple” toes or toe gangrene (40–50%)
• Fever, myalgias, headaches, and weight loss (<50%)
• Abdominal pain (intestinal embolization)
• Transient cerebral ischemia
• Renal failure (50%)
A high degree of suspicion is required to diagnose atheroem-
bolic renal disease. The differential diagnosis includes sys-
temic vasculitis, subacute bacterial endocarditis, polymyositis,
myoglobinuric renal failure, drug-induced interstitial nephritis,
and renal artery thrombosis or thromboembolism. The time
course of decline in renal function may aid in the diagnosis
of atheroembolic renal disease. Renal failure due to proce-
dure-induced atheroembolic renal disease is characterized by
a decline in renal function over 3 to 8 weeks. Radiocontrast-
induced nephropathy, conversely, usually manifests earlier
and often resolves within 2 to 3 weeks after appropriate inter-
vention. Histologic demonstration of cholesterol crystals in
small arteries and arterioles of target organs is the most defini-
tive method of diagnosing atheroembolic renal disease.
294 Laboratory Features
Outcome
Treatment
No effective therapy for atheroembolic renal disease has been
reported. Anticoagulants should be avoided because of the
risk of precipitating more atheroembolization. In fact, with-
drawal of anticoagulation may be beneficial. Despite the high
mortality rate and the absence of effective therapy, kidney
function improves in a minority of patients even after pro-
longed periods of renal insufficiency. An aggressive therapeu-
tic approach with patient-tailored supportive measures,
including statin therapy, withdrawal of anticoagulants, post-
ponement of aortic procedures, control of hypertension and
heart failure, dialysis therapy, and adequate nutritional sup-
port, may be associated with favorable clinical outcomes.
Pathogenesis
Hb-SS polymer formation is promoted by higher degrees of
deoxygenation, increased intracellular hemoglobin concentra-
tion, and the absence of hemoglobin F. The pathogenesis of
medullary renal lesions in sickle cell disease is attributed
largely to microvascular occlusion. Erythrocytes passing
through the vessels of the inner renal medulla and the renal
papillae are vulnerable to sickling because of relative hypoxia
and the high osmolality of the blood, which leads to cell
shrinkage and increased hemoglobin concentration. The path-
ogenesis of sickle cell glomerulopathy is generally attributed
to secondary hyperfiltration.
Treatment
The management of patients with sickle cell disease is targeted
at limiting sickle cell crises and end-organ damage. Factors that
trigger sickling, such as infection and dehydration, should be
treated aggressively. Exposure to hypoxia, cold, or medications
that may induce sickle cell crisis should be avoided. Treatment
options include transfusion therapy and, more recently, bone
marrow transplantation. Hydroxyurea increases the hemoglobin
F concentration, which results in over 40% reduction in the
median annual rate of pain crises. However, it is not known
296 whether a reduction in the frequency of sickle cell crises trans-
lates to a lower incidence of renal disease. ACE inhibitors
should be used in the presence of proteinuric renal insufficiency
to retard disease progression. Patients with sickle cell disease
IV who reach ESRD have a 60% survival rate at 2 years after the
administration of renal replacement therapy. Dialysis is the
Pathogenesis of Renal Disease
Tubulointerstitial Diseases
Tubulointerstitial disease is common to all chronic progres-
sive renal diseases, irrespective of the initial trigger or site of
injury. Progressive inflammation or injury to the tubulointer-
stitial region typically destroys extensive amounts of kidney
tissue and, as a result, usually produces irreversible chronic
kidney disease (CKD). Interstitial inflammation can begin
either from within the interstitial compartment or as a second-
ary event following glomerular or vascular injury and, if left
unchecked, can evolve into irreversible tubulointerstitial
fibrosis. Although some forms of injury to the tubulointersti-
tial compartment are the result of toxic insult or exposure to
infection and drugs, much of the inflammatory process is
immunologically mediated. Many studies have pointed to
the degree of tubulointerstitial fibrosis as an accurate prognos-
tic marker of severe interstitial disease in a variety of glomer-
ular diseases.
Etiology
Drugs
Drugs are frequently recognized as etiologic factors in AIN
because of the increased use of renal biopsy and the character-
istic clinical presentation. Approximately a third of cases of
drug-related AIN are due to antibiotics. Tubulointerstitial dis-
ease is more commonly seen with b-lactam antibiotics (includ-
ing cephalosporins), but other antibiotics (sulfonamides,
297
298
Acute Interstitial Nephritis: Causative
Table 14-1
Factors
Drugs
IV Antibiotics Cephalosporins, ciprofloxacin, ethambutol,
isoniazid, macrolides, penicillins, rifampin,
Pathogenesis of Renal Disease
Tubulointerstitial Diseases
Infections
AIN is associated with primary renal infections such as
acute bacterial pyelonephritis, renal tuberculosis, and fungal
nephritis. Systemic infections can cause direct injury
because of pathologic processes in the kidney or can be asso-
ciated with indirect injury caused by medications used in
the treatment of infections. For example, human immunode-
ficiency virus (HIV) can be responsible for AIN caused
by opportunistic infections or by using drugs such as indin-
avir, sulfonamide antibiotics, and others. Sometimes,
depressed cell-mediated immunity may protect the patients
from developing AIN.
Clinical Features
Tubulointerstitial Diseases
in acute interstitial nephritis unless there is a coexisting glo-
merular lesion after exposure to NSAIDs. The fractional
excretion of Naþ is usually greater than 1. Affected patients
are often oliguric, but nonoliguric renal failure also occurs.
Oliguria may be related to interstitial inflammation severe
enough to cause tubular obstruction and impede urine flow.
The kidney in AIN is usually normal or slightly increased
in size by ultrasonographic criteria. Many features of the
patient’s history, presentation, urinalysis, and laboratory
evaluation may suggest the diagnosis of AIN. Unfortunately,
none of these findings are pathognomonic, and ultimately
the diagnosis can be established with certainty only by renal
biopsy. Renal biopsy is the “gold standard” for diagnosis of
AIN; it is not, however, required in those patients for whom
a probable precipitating drug can be easily withdrawn, or
who improve readily after withdrawal of a potentially offend-
ing drug. Supportive management can proceed safely with-
out renal biopsy. Patients who do not improve after
withdrawal of likely precipitating medications, who have
no contraindications to renal biopsy and do not refuse the
procedure, and who are being considered for steroid therapy
are good candidates for renal biopsy.
Analgesic Nephropathy
Analgesic nephropathy (AN) is a specific form of renal
disease characterized by renal papillary necrosis (RPN) and
chronic interstitial nephritis caused by prolonged and exces-
sive consumption of analgesic mixtures. It is caused by
compound analgesic mixtures containing aspirin or antipyrine
in combination with phenacetin, paracetamol, or salicylamide
and caffeine or codeine in popular over-the-counter proprietary
mixtures.
AN has been one of the more common causes of chronic
kidney disease (CKD), particularly in Australia and parts of
303
Common Causes of Chronic Interstitial
Table 14-2
Nephritis
Primary Infection
Metabolic Disturbances Bacterial pyelonephritis CH 14
Hypercalcemia/ Hantavirus
Tubulointerstitial Diseases
nephrocalcinosis Leptospirosis
Hyperoxaluria Malacoplakia
Hypokalemia Xanthogranulomatous pyelonephritis
Hyperuricemia Hematologic Disorders
Drugs and Toxins Sickle cell disease
Analgesics Light chain nephropathy
Cadmium Amyloidosis
Lead Secondary
Nitrosoureas Secondary chronic tubulointerstitial
Chinese herbs nephritis encompasses disease in
Lithium which the primary pathogenic process
Cyclosporine begins in vascular, glomerular, or tubular
5-Aminosalicylic acid systems, and is followed by damage to
(5-ASA) the tubulointerstitial compartment
NSAIDs
Balkan endemic
nephropathy
Immune-Mediated
Renal allograft rejection
Sjögren syndrome
Sarcoidosis
Clinical Features
The renal manifestations of AN include slowly progressive
CKD, sterile pyuria, and mild proteinuria (<1.5 g/day). Hyper-
tension and anemia are commonly seen with moderate to
advanced disease; more prominent proteinuria that can exceed
3.5 g/day may also occur at this time, a probable reflection of
secondary hemodynamically mediated glomerular injury. Most
patients have no symptoms referable to the urinary tract,
although there may be flank pain or macroscopic/microscopic
hematuria from a sloughed or obstructing papilla. Urinary tract
infection is also somewhat more common in women with this
disorder. Most patients are between the ages of 30 and 70 years.
Careful questioning often reveals a history of chronic head-
aches or low back pain that leads to the analgesic use.
Renal function stabilizes or mildly improves in most patients
if analgesic consumption is discontinued. Eight percent to 10%
of patients with AN will develop urinary tract malignancy. The
tumors generally become apparent after 15 to 25 years of anal-
gesic abuse, usually, but not always, in patients with clinically
evident AN. The major presenting symptom of urinary tract
304 malignancy in AN is microscopic or gross hematuria. Thus,
continued monitoring is essential, and new hematuria should
be evaluated with urinary cytologic examination, and if indi-
cated, cystoscopy with retrograde pyelography.
IV
Diagnosis and Treatment
Pathogenesis of Renal Disease
5-Aminosalicylic Acid
Clinical Features
The disease is more prevalent in men, with a male-female
ratio of 15:2. The age of reported cases ranged from 14 to 45
years. In contrast to AN, in which renal lesions are observed
Table 14-3 Differential Diagnosis of Some Forms of Chronic Interstitial Nephritis
Analgesic Chinese Herb Balkan Endemic 5-Aminosalicylic
Nephropathy Disease Nephropathy Acid Nephritis
Clinical course >10–15 yr 6 mo to 2 yr >20 yr >6 mo
Kidney imaging Shrunken Shrunken Shrunken Slightly shrunken
Irregular contours Irregular contours Smooth surface Smooth
Papillary No calcification No calcification No calcification
calcifications
Histology
Cellular infiltration þþ þ þ þþþ
Fibrosis þþ þþ þþ þþ
Atrophy þþ þþ þþþ þ
Capillarosclerosis þ þ/? þ /?
Apoptosis ? ? þ ?
Urothelial þ* þ þ þ
malignancies
Familial occurrence þ
Etiology Analgesics Aristolochic acid ?Aristolochia clematis 5-Aminosalicylic acid
þAddictive þDiuretics þ/?
substances þVasoconstrictive
substances
*As long as phenacetin was part of the analgesic mixture.
305
306 only after several years of analgesic abuse, interstitial nephri-
tis associated with 5-ASA was already observed during the
first year of treatment in 7 out of 17 reported cases, most of
whom had started 5-ASA therapy with documented normal
IV renal function. The cumulative dose of 5-ASA is not predic-
tive for development of interstitial nephritis.
Pathogenesis of Renal Disease
Clinical Features
Patients present with renal insufficiency and other features
indicating a tubulointerstitial disease. The blood pressure is
either normal or only mildly elevated, and the urine sediment
reveals only a few red and white blood cells. The urine con-
tains subnephrotic proteinuria and evidence of proximal tubu-
lar dysfunction. Stable renal function may be anticipated in
most patients with an initial plasma creatinine concentration
below 2 mg/dL. However, progressive renal failure resulting
in dialysis or transplantation may ensue in patients with more
severe disease.
Tubulointerstitial Diseases
nephrotic syndrome, and focal segmental glomerular sclerosis/
global glomerular sclerosis.
Clinical Features
Renal failure becomes apparent years after the exposure and
is associated with gout in most, if not all, cases. Hyperten-
sion is a very common feature of lead nephropathy. Although
hyperuricemia is common in renal failure, gout is unusual
and its presence should raise the possiblity of lead
nephropathy.
Tubulointerstitial Diseases
severe cases, progressive CKD. The extent to which chronic
low-level environmental exposure to cadmium affects renal
function is less clear. A number of studies have demonstrated
an increased prevalence of kidney stones among individuals
occupationally exposed to cadmium. Minimizing exposure to
cadmium is the most important therapeutic measure. Occupa-
tional exposure should be kept as low as technically feasible.
Other than general supportive therapy, no specific methods
are available for treating acute cadmium poisoning. Although
various chelating agents have been tried in animals, none
has been shown to be efficient in humans.
Clinical Features
BEN is a slowly progressive tubulointerstitial disease that may
culminate in ESRD. Clinical manifestations first appear in
patients 30 to 50 years of age. Initially characterized by
tubular dysfunction, a progressive decrease in concentrating
310 ability and in the GFR follows over many years. Patients are
usually nonedematous and normotensive, hypertension devel-
oping only with end-stage disease. Intrarenal calcifications
are not observed. BEN is also associated with the development
IV of transitional cell carcinoma of the renal pelvis or ureter,
with studies noting a wide range in incidence (2% to nearly
Pathogenesis of Renal Disease
Chronic Hypokalemia
Persistent hypokalemia can induce a variety of changes in renal
function, impairing tubular transport, and possibly inducing
chronic tubulointerstitial disease and cyst formation. Hypoka-
lemic nephropathy in humans produces characteristic vacuolar
lesions in the epithelial cells of the proximal tubule and, occa-
sionally, the distal tubule. More severe changes, including
interstitial fibrosis, tubular atrophy, and cyst formation that is
most prominent in the renal medulla, occur if prolonged
hypokalemia is maintained. Renal cyst formation as a conse- 311
quence of chronic hypokalemia has now been reported in a
patient with Bartter syndrome resulting from a gene defect in
CLC-KC.
CH 14
Sarcoidosis
Tubulointerstitial Diseases
Clinically important renal involvement in sarcoid is an occa-
sional problem—hypercalciuria and hypercalcemia are most
often responsible, although granulomatous interstitial disease,
glomerular disease, obstructive uropathy, and, rarely, ESRD
may also occur. Most affected patients have clear evidence of
diffuse active sarcoidosis, although some patients present
with only minimal extrarenal manifestations.
Clinical Features
Hypercalciuria, hypercalcemia, nephrolithiasis, granuloma-
tous interstitial nephritis, glomerular disease, and urinary
tract disorders can all be observed in patients with sarcoido-
sis. Macrophages in a sarcoid granuloma contain a 1a-hydrox-
ylase enzyme, capable of converting vitamin D to its active
form. The resultant increase in the absorption of calcium from
the gut leads to hypercalciuria and, in roughly 2.5% to 20% of
cases, to hypercalcemia. Most patients remain asymptomatic,
but nephrolithiasis, nephrocalcinosis, renal insufficiency,
and polyuria are important complications. Nephrocalcinosis,
observed in over half of those with renal insufficiency, is the
most common cause of CKD in sarcoidosis.
An interstitial nephritis with granuloma formation is
common in sarcoidosis, but the development of clinical disease
manifested by renal insufficiency is unusual. Renal biopsy
reveals normal glomeruli, interstitial infiltration mostly with
mononuclear cells, noncaseating granulomas in the interstitium,
tubular atrophy, and, with more chronic disease, interstitial
fibrosis. Glomerular involvement is rare in sarcoidosis. Occa-
sionally, retroperitoneal lymph node involvement, retroperito-
neal fibrosis, or renal stones may produce ureteral obstruction.
313
314 per cubic millimeter are found, there is a high probability of
clinical infection. Most symptomatic women with pyuria
without significant bacteriuria have urinary infection with
either bacterial uropathogens present in colony counts of less
5
IV than 10 CFU/mL (which will respond to appropriate antimi-
crobial therapy) or with some other condition. Possibilities
Pathogenesis of Renal Disease
Etiologic Agents
Bacterial Pathogens
• Enterobacteriaceae (including Escherichia coli) and Entero-
coccus faecalis account for over 95% of UTIs.
• Previous antimicrobial therapy, instrumentation, and uri-
nary obstruction favor other organisms including Serratia
marcescens and Pseudomonas aeruginosa.
• Staphylococcus saprophyticus is an important cause of
symptomatic UTI in young, sexually active women.
• In contrast, the organisms that commonly colonize the dis-
tal urethra and skin of both men and women, and the vagina
of women, rarely cause UTI (Staphylococcus epidermidis,
corynebacteria, lactobacilli, Gardnerella vaginalis).
• Hematogenous seeding (<5%) is most commonly observed in
association with bacteremia resulting from Staphylococcus
aureus, P. aeruginosa, and Salmonella species.
• The kidney is the most common extrapulmonary site of
tuberculosis; the tubercle bacilli reach the kidney from the
lung by the hematogenous route.
Fungal Pathogens
• Candida species are the most common cause of fungal
infection of the urinary tract. Most such infections occur
in patients with indwelling Foley catheters who have been
receiving broad-spectrum antibacterial therapy, particularly
if diabetes mellitus is also present or corticosteroids are
being administered.
Other Pathogens
• C. trachomatis has been clearly shown to be an important
cause of the acute urethral syndrome.
• Ureaplasma urealyticum also causes a significant number of
cases of urethritis (albeit fewer than C. trachomatis).
Pathogenesis 315
Vesicoureteral Reflux
An important host defense against ascending infection from the
bladder to the kidneys is the competency of the vesicoureteral
valve. Indeed, the combination of VUR and infected urine is
the most common factor predisposing to chronic pyelonephritic
scarring, particularly in infants and children. Failure of this
vesicoureteric valve mechanism is most commonly due to
shortening of the intravesical portion of the ureter caused by
abnormal lateral localization of the ureteral orifices (primary
VUR). In children, VUR may also be secondary, occurring in
association with other anomalies including meningomyelocele,
paraurethral diverticulum, posterior urethral valves, ureteral
duplications, hypospadias, and ureteroceles. VUR occurs in
316 18% of adults who have spinal cord injuries and in a variable
percentage of adults with bladder tumors, prostatic hypertro-
phy, and urinary tract stones.
VUR, which can be unilateral or bilateral, may vary consid-
IV erably in severity. Severity of reflux is graded as follows:
• Grade I: reflux partly up the ureter
Pathogenesis of Renal Disease
Intrarenal Reflux
Whereas VUR is responsible for the ascent of bacteria into the
renal pelvis, considerable evidence now suggests that the
spread of infection from the pelvis into the cortex occurs by
virtue of a phenomenon known as intrarenal reflux. In this
setting, contrast medium instilled into the bladder during
voiding cystourethrography permeates the renal parenchyma
as far as the renal capsule. VUR and intrarenal reflux, in com-
bination, are almost certainly the major mechanisms respon-
sible for the renal inflammation and scarring characteristic of
chronic pyelonephritis. Scarring appears to occur early in
life, possibly even in utero. Indeed, the development of
new scars in children is unusual beyond the age of 5 years
(and possibly the age of 2 years), regardless of proven epi-
sodes of UTI, suggesting that the early detection of UTI and
the gross forms of VUR is essential if renal scarring is to be
prevented.
Frequency and Epidemiology of Urinary Tract 317
Infection
CLINICAL PRESENTATIONS
In dealing with the patient who presents with possible UTI,
the tasks of the clinician are the following:
• To identify the microbial etiologic agent of the symptoms
and the ideal form of antimicrobial management
• To make a judgment as to the anatomic site within the uri-
nary tract that is the site of infection
318
WOMEN WHO PRESENT
WITH COMPLAINTS OF
DYSURIA AND FREQUENCY
IV
Pathogenesis of Renal Disease
Follow-up 4–7
days later
Asymptomatic Symptomatic
No further Urinalysis,
intervention urine culture
Recurrent Cystitis
Recurrent symptoms of lower urinary tract inflammation may
be due to either relapsing infection or reinfection. Relapse is
caused by reappearance of the same organism from a seques-
tered focus, usually within the kidney, or in men, the prostate,
shortly after completion of therapy. In reinfection, the course
of therapy has successfully eradicated the original infection,
and there is no sequestered focus, but organisms are reintro-
duced from the fecal reservoir. More than 80% of all recur-
rences are due to reinfection. The most important cause of
recurrent symptoms of lower urinary tract inflammation in
adult men is prostatitis. Acute bacterial prostatitis is a febrile
illness associated with chills, perineal, back, or pelvic pain,
dysuria, and urinary frequency and urgency. There may be
bladder outlet obstruction; on physical examination, the pros-
tate is enlarged, tender, and indurated. Chronic prostatitis, in
contrast, may be more occult; asymptomatic infection is man-
ifested as recurrent bacteriuria or variable low-grade fever
with back or pelvic discomfort. Urinary symptoms usually
result from reintroduction of infection into the bladder from
a chronic prostatic focus that has been inadequately treated,
and only temporarily suppressed, by a previous course of
antimicrobial therapy.
320 Acute Pyelonephritis
The clinical findings associated with full-blown acute pyelo-
nephritis are familiar: rigors, fever, back and loin pain (with
exquisite tenderness on percussion of the costovertebral
IV angle), often with colicky abdominal pain, nausea and vomit-
ing, dysuria, frequency, and nocturia. Although bacteremia
Pathogenesis of Renal Disease
DIAGNOSTIC EVALUATION
TREATMENT
Acute Uncomplicated Cystitis in Young Women
The treatment of choice is short-course therapy with trimetho-
prim-sulfamethoxazole or a fluoroquinolone, both of which
are superior to b-lactam in the treatment of UTI. The antibacter-
ial spectrum of activity of these drugs is such that the normal
324 anaerobic and microaerophilic vaginal flora, which provide
colonization resistance against the major uropathogens, are
left intact. In contast, b-lactam drugs, such as amoxicillin, appear
to promote vaginal colonization with uropathogenic E. coli.
IV Unfortunately, antimicrobial resistance has increased signifi-
cantly since the early 1990s, particularly to trimethoprim-
Pathogenesis of Renal Disease
CH 15
Xanthogranulomatous Pyelonephritis
Xanthogranulomatous pyelonephritis is an uncommon form of
chronic bacterial pyelonephritis characterized by the destruc-
tion of renal parenchyma and the presence of granulomas,
abscesses, and collections of lipid-filled macrophages. Women
are affected more often than men (2:1), and the lesions typi- 331
cally affect only one kidney. The majority of patients present
with renal pain, recurrent UTI, fever (of undetermined
nature), malaise, anorexia, weight loss, and constipation. Most
patients have a history of previous calculous disease, obstruc- CH 15
tive uropathy, or diabetes mellitus, and 38% have undergone
Malakoplakia
ETIOLOGY
Intrinsic Causes
Nephrolithiasis represents the most common cause of ureteral
obstruction in younger men. Twelve percent of the U.S. popu-
lation forms a symptomatic stone at some time in their lives,
with a male-female predominance of 3:1. When they cause
obstruction, it tends to be acute, unilateral, and intermittent,
usually without a long-term impact on renal function. Less
common types of stones, such as struvite (ammonium-magne-
sium-sulfate) and cystine stones, are more frequently asso-
ciated with renal damage because these substances
accumulate over time, and often form staghorn calculi.
Intrinsic intramural processes that cause obstruction
include functional abnormalities, such as those associated
with the neurologic dysfunction of diabetes mellitus, multiple
sclerosis, and spinal cord injury. Lower spinal tract injury
may result in a flaccid, atonic bladder and failure of micturi-
tion. When the bladder does not void normally, renal damage
may develop as a consequence of recurrent urinary tract infec-
tions and back-pressure produced by the accumulation of
residual urine. Various drugs can cause intrinsic intramural
obstruction by disrupting the normal function of the smooth
muscle of the urinary tract (see Table 16-2).
336 Acquired anatomic abnormalities of the wall of the urinary
tract include ureteral strictures, and both benign and malignant
tumors of the renal pelvis, ureter, bladder, and urethra. Ure-
teral strictures may occur as a result of radiation therapy for
IV local cancers, such as cervical cancer, or as a result of analgesic
abuse. In addition, strictures may develop as a complication
Pathogenesis of Renal Disease
Extrinsic Causes
A wide variety of diseases cause acquired extrinsic urinary
tract obstruction. Because processes affecting the female
reproductive tract (e.g., pregnancy, pelvic neoplasms) often
cause obstructive uropathy, urinary tract obstruction occurs
more frequently in younger women than in younger men.
Noninvasive imaging studies have shown that more than two
thirds of women entering their third trimester demonstrate
some degree of dilation of the collecting system. The vast
majority of these are subclinical and appear to completely
resolve soon after delivery. Pelvic malignant neoplasms repre-
sent the second most common cause of extrinsic obstructive uro-
pathy in women. In older women, uterine prolapse may cause
obstruction, with hydronephrosis developing in 5% of patients.
Pelvic inflammatory disease, particularly a tubo-ovarian abscess,
can also cause obstruction. Although endometriosis only rarely
results in ureteral obstruction, it should be excluded in all pre-
menopausal women presenting with unilateral obstruction.
The onset of obstruction may be insidious, and the process is
usually confined to the pelvic portion of the ureter. Inadvertent
ligation of the ureter in abdominal and retroperitoneal operations
during gynecologic procedures is also a cause of ureteral
obstruction.
Benign prostatic hyperplasia, the most common cause of
urinary tract obstruction in men, produces some symptoms
of bladder outlet obstruction in 75% of men aged 50 years
and older. Presenting symptoms include urgency, difficulty
initiating micturition, dribbling at the end of micturition,
incomplete bladder emptying, and nocturia. The diagnosis
may be established by history and urodynamic studies. Malig-
nant genitourinary tumors occasionally result in urinary tract
obstruction. Bladder cancer is the second most common cause
(after cervical cancer) of malignant obstruction of the ureter.
Prostate cancer may cause obstruction by compression of the
bladder neck, invasion of the ureteral orifices, or metastatic
involvement of the ureter or pelvic nodes. Although urothelial 337
tumors of the renal pelvis, ureter, and urethra are rare, they
also may lead to urinary obstruction.
Several gastrointestinal processes, including Crohn disease,
may extend into the retroperitoneum causing ureteric obstruc- CH 16
tion, usually on the right side. An abdominal aortic aneurysm
CLINICAL ASPECTS
DIAGNOSIS
History and Physical Examination
A careful history and a well-directed and complete physical
examination often reveal the specific cause of urinary obstruc-
tion. Important information in the history includes the type
and duration of symptoms (voiding difficulties, flank pain,
decreased urine output), number of urinary tract infections
(especially in children), pattern of fluid intake and urine out-
put, history of stone disease, malignancies, gynecologic dis-
eases, history of recent surgery, and prescription medication
use. The abdominal examination may reveal hydronephrosis
presenting as a flank mass or a distended bladder. A pelvic
examination in women and a rectal examination in all patients
are mandatory.
Laboratory Evaluation
Unexplained renal failure with benign urinary sediment
should suggest urinary tract obstruction. Microscopic hematu-
ria without proteinuria or casts suggests a calculus or tumor.
Pyuria and bacteriuria may indicate pyelonephritis; bacteri-
uria alone may suggest stasis. Serum electrolytes, blood urea
nitrogen concentration, creatinine, Ca2þ, phosphorus, Mg2þ,
uric acid, and albumin levels should be measured. These
levels will help identify disorders of distal nephron function
(impaired osmoregulation or acid excretion) and uremia. Uri-
nary chemistries may also suggest distal tubular dysfunction
(isosthenuric urine, high urine pH), and/or inability to reab-
sorb sodium normally (urinary Naþ > 20 mEq/L, fractional
excretion of Naþ [FENa] > 1%, and osmolality < 350 mOsm).
Alternatively, in acute obstruction, urinary chemistry values
may be consistent with prerenal azotemia (urinary Naþ < 20
mEq/L, FENa < 1%, and osmolality > 500 mOsm).
Radiologic Evaluation 339
Ultrasonography
When obstruction is suspected, ultrasonography is the pre-
ferred screening modality because it is safe, cost effective, and
lacks ionizing radiation, making it ideal for pregnant patients.
Moreover, because no contrast agent is involved, it is well
suited to patients with an elevated or rising serum creatinine
level. Utrasonography can determine the size and shape of the
kidney, show dilation of the pelvis and calyces, and may dem-
onstrate thinned cortex in the case of severe long-standing
hydronephrosis. It has both high sensitivity and specificity for
detecting hydronephrosis. However, it may fail to detect
obstruction in the first 48 hours when hydronephrosis has
not, as yet, developed. False-positive conclusions may be the
result of a large extrarenal pelvis, parapelvic cysts, vesicouret-
eral reflux, or high urine flow rate.
Antenatal Ultrasonography
Prenatal hydronephrosis is diagnosed with an incidence of 1
in 100 to 1 in 500 maternal-fetal ultrasonographic studies.
Both obstructive and nonobstructive processes can cause dila-
tion of the urinary tract (see earlier discussion). The long-term
morbidity of mild hydronephrosis (pelviectasis without caly-
ceal dilation) is low. Cases of severe hydronephrosis (pelvical-
yceal dilation with parenchymal thinning) may require
postnatal surgical intervention for declining renal function,
infection, or symptoms. Overall, approximately 5% to 25%
of patients with antenatal hydronephrosis will ultimately
require surgical intervention. Therefore, long-term follow-up
of these patients is required. Functional imaging is required
for patients with persistent postnatal hydronephrosis. All
infants with prenatally detected hydronephrosis, confirmed by
postnatal studies, should be placed on antibiotic prophylaxis
pending the outcome of further evaluation. An infection in
340 the setting of ureteral obstruction can cause significant mor-
bidity in the uroseptic infant, and renal damage is a potential
comorbidity. Oral amoxicillin (10 mg/kg/day) is the most com-
monly used prophylactic antibiotic.
IV
Intravenous Urography
Pathogenesis of Renal Disease
Computed Tomography
CT has the distinct advantage of being able to visualize a dilated
collecting system, even without contrast enhancement, and can
also be performed more quickly than IVU. Non–contrast-
enhanced CT is more effective than IVU in precisely identifying
ureteral stones; it is as effective as IVU in determining the presence
or absence of ureteral obstruction and can identify even radiolu-
cent stones. CT is useful in identifying extrinsic causes of obstruc-
tion (e.g., retroperitoneal fibrosis, lymphadenopathy, hematoma).
CT can also detect extraurinary pathology and can establish non-
urogenital causes of pain. All of these advantages establish non–
contrast-enhanced helical CT as the diagnostic study of choice
for the evaluation of the patient with acute flank pain.
Isotopic Renography
Isotopic renography, or renal scintigraphy, can diagnose
upper urinary tract obstruction while avoiding the risk of
radiocontrast agents. Although it provides a functional assess-
ment of the obstructed kidney, anatomic definition is poor.
Isotopic renography is typically used to estimate the fractional
contribution of each kidney to overall renal function, and
repeat studies can gauge the extent to which relief of the
obstruction has restored renal function.
Diabetic Nephropathy
Persistent albuminuria (>300 mg/24 hours) is the hallmark of
diabetic nephropathy, which can be diagnosed clinically if
the following additional criteria are fulfilled: the presence of
diabetic retinopathy and the absence of clinical or laboratory
evidence of other kidney or renal tract disease. This clinical
definition of diabetic nephropathy is valid in both type 1
and type 2 diabetes. During the last decade longitudinal stud-
ies have shown that microalbuminuria strongly predicts the
development of diabetic nephropathy in both type 1 and type
2 diabetes. Microalbuminuria is defined as urinary albumin
excretion greater than 30 mg/24 hours (20 µg/min) and less
than or equal to 300 mg/24 hours (200 µg/min), irrespective
of how the urine is collected.
Diabetic nephropathy is the single most common cause of
end-stage renal disease (ESRD) in Europe and the United
States, accounting for 25% to 45% of patients enrolled in
ESRD programs. Nephropathy is a major cause of illness and
death in diabetes and is associated with strikingly high rates
of cardiovascular disease (CVD), particularly in type 2 diabetic
patients.
EPIDEMIOLOGY OF MICROALBUMINURIA
AND DIABETIC NEPHROPATHY
345
346 Microalbuminuria Predicts Nephropathy
Prognosis in Microalbuminuria
Microalbuminuria is a strong predictor of total and cardio-
vascular fatality and cardiovascular morbidity in diabetic
patients. The mechanisms linking microalbuminuria and
death from CVD are poorly understood. Microalbuminuria
has been proposed as a marker of widespread endothelial
dysfunction, which might predispose to enhanced penetra-
tions in the arterial wall of atherogenic lipoprotein particles
and as a marker of established cardiovascular disease. It is
associated with an excess of well-known and potential
cardiovascular risk factors: raised blood pressure, dyslipo-
proteinemia, increased platelet aggregability, endothelial
dysfunction, insulin resistance, and hyperinsulinemia have
all been demonstrated in microalbuminuric diabetic patients.
Recent echocardiographic studies have revealed impaired
diastolic function and cardiac hypertrophy in microalbumi-
nuric insulin-dependent (IDDM) and non–insulin-dependent
diabetes mellitis (NIDDM) patients. Left ventricular hypertro-
phy predisposes the individual to ischemic heart disease,
ventricular arrhythmia, sudden death, and heart failure.
Diabetic Nephropathy
gression of diabetic nephropathy.
Normoalbuminuria
Approximately one third of type 1 diabetic patients have a glo-
merular filtration rate (GFR) above the upper normal range of
age-matched healthy nondiabetic subjects. The degree of
hyperfiltration is less in type 2 diabetic patients. The GFR ele-
vation is particularly pronounced in newly diagnosed diabetic
patients and during other intervals with poor metabolic control.
Intensified insulin treatment and near-normal blood glucose
Systemic blood
pressure
Dietary protein
intake
Hyperlipidemia
Glycemic
control
Proteinuria
Smoking
Glomerular
hypertension
ACE/ID
polymorphism
Oligonephropathy
Figure 17-1. Putative promoters for progression of diabetic
nephropathy. ACE/ID, angiotensin-converting enzyme insertion/
deletion. (From Parving H-H, Mauer M, Ritz E: Diabetic
nephropathy. In Brenner BM: Brenner & Rector’s The Kidney,
8th ed. Philadelphia, WB Saunders, 2008.)
348 control reduce GFR toward normal levels after a period of days
to weeks in both type 1 and type 2 diabetic patients.
Longitudinal studies suggest that hyperfiltration is a risk
factor for subsequent increase in urinary albumin excretion
IV and development of diabetic nephropathy in type 1 diabetic
patients, but this has not been conclusively established. The
Pathogenesis of Renal Disease
Microalbuminuria
Subclinical albumin excretion rate has been termed microalbu-
minuria and can be normalized by improved glycemic control.
In addition to hyperglycemia, many other factors can induce
microalbuminuria in diabetic patients such as hypertension,
massive obesity, heavy exercise, various acute or chronic ill-
nesses, and cardiac failure. Furthermore, the day-to-day varia-
tion in the urinary albumin excretion ratio (AER) is high, 30%
to 50%, and consequently more than one urine sample is needed
to determine whether an individual patient has persistent micro-
albuminuria. Urinary albumin excretion within the microalbu-
minuric range (30–300 mg/24 hours) in at least two out of three
consecutive nonketotic sterile urine samples is the generally
accepted definition of persistent microalbuminuria. Persistent
microalbuminuria is exceptional in the first 5 years of diabetes.
The annual rate of rise of urinary albumin excretion is about
20% in both type 1 and type 2 diabetic patients with persistent
microalbuminuria. The prevalence of arterial hypertension
(140/90 mm Hg) in adult type 1 diabetic patients is 42%,
52%, and 79% in subjects with normo-, micro-, and macroalbu-
minuria, respectively. The prevalence of hypertension in type
2 diabetes is 71%, 90%, and 93% in the normo-, micro-, and
macroalbuminuria groups, respectively.
Diabetic Nephropathy
Impaired or abolished renal autoregulation of renal plasma flow
(RPF), as demonstrated in type 1 and type 2 diabetic patients
with nephropathy, contributes to increased glomerular pres-
sures in diabetic nephropathy: glomerular hypertension. Pro-
teinuria itself may contribute to renal damage. Indeed, type 1
diabetic patients with diabetic nephropathy and nephrotic-
range proteinuria (>3 g/24 hours) have the worst prognosis.
For many years it was believed that once albuminuria had
become persistent, then glycemic control was unimportant
because a “point of no return” had been reached. This is a
misconception and studies dealing with large numbers of type
1 diabetic patients have documented the important impact of
glycemic control on progression of diabetic nephropathy. In
contrast, most of the studies dealing with proteinuric type
2 diabetic patients have failed to demonstrate any significant
impact of glycemic control on disease progression.
Extrarenal Complications
Diabetic retinopathy is present in virtually all type 1 diabetic
patients with nephropathy, whereas only 50% to 60% of pro-
teinuric NIDDM patients suffer from retinopathy. Absence of
retinopathy should prompt further investigation for nondia-
betic glomerulopathies (see later discussion). Blindness due
to severe proliferative retinopathy or maculopathy is approxi-
mately five times greater in type 1 and type 2 diabetic patients
with nephropathy compared to normoalbuminuric patients.
Macroangiopathies—for example, stroke, carotid artery steno-
sis, congestive heart failure, and peripheral vascular dis-
ease—are two to five times more common in nephropathic
patients. Peripheral neuropathy is present in almost all
patients with advanced nephropathy. Foot ulcers with sepsis
leading to amputation occur frequently (>25%), probably
due to a combination of neural and arterial disease. Auto-
nomic neuropathy may be asymptomatic and simply manifest
as abnormal cardiovascular reflexes, or it may result in debili-
tating symptoms. Over half of the patients with advanced
nephropathy have symptoms of autonomic neuropathy: gusta-
tory sweating, impotence, postural hypotension, and diarrhea.
Diabetic cystopathy is also a frequent (>30%) problem in
these patients (Table 17-1).
350
Major Microvascular and Macrovascular
Table 17-1 Complications in Patients with Diabetic
Nephropathy
IV Microvascular Complications
Retinopathy
Pathogenesis of Renal Disease
TREATMENT
Glycemic Control
Primary Prevention
Intensive blood glucose control has a significant beneficial effect
on the progression from normo- to microalbuminuria in type 1
diabetic patients. A worsening of diabetic retinopathy may be
observed during the initial months of intensive therapy, but in
the longer term, the rate of deterioration is slower than in conven-
tionally treated type 1 diabetic patients. Side effects are a major
concern with intensive therapy and the frequency of severe
hypoglycemia is higher in intensively treated patients. In the
Diabetes Control and Complications Trial (DCCT) intensive ther-
apy reduced the occurrence of microalbuminuria by 39% and
that of albuminuria by 54%. Despite these impressive results,
16% of subjects in the primary prevention cohort and 26% in
the secondary prevention cohort developed microalbuminuria
during the 9 years of intensive treatment. This clearly documents
the need for additional treatment modalities to avoid or reduce
the burden of diabetic nephropathy. Intensive metabolic control
has been confirmed to have a beneficial effect on progression of
normoalbuminuria to micro- and macroalbuminuria in type
2 diabetes by the U.K. Prospective Diabetes Study (UKPDS).
Secondary Prevention
The impact of intensive versus conventional diabetic treatment
on the progression or regression of microalbuminuria in type 1
diabetic patients has shown conflicting outcomes. These disap- 351
pointing results might partly be due to the relatively short
length of the follow-up period, because the UKPDS study
with 15 years of follow-up documented a progressive beneficial
effect with time on the development of proteinuria and a two- CH 17
fold increase in plasma creatinine. Furthermore, pancreatic
Diabetic Nephropathy
transplantation can reverse glomerulopathy in patients with
type 1 diabetes, but reversal requires more than 5 years of nor-
moglycemia. Recently, intensified multifactorial intervention
(pharmacologic therapy targeting hyperglycemia, hypertension,
dyslipidemia, and microalbuminuria) in patients with type
2 diabetes and microalbuminuria has been demonstrated to
substantially slow progression to nephropathy, retinopathy,
and autonomic neuropathy.
Secondary Prevention
ACE inhibitors significantly reduce the risk of progression to
macroalbuminuria compared to placebo in type 1 patients with
microalbuminuria (odds ratio, 0.38). In addition, regression to
normoalbuminuria occurs more frequently, and urinary albu-
min excretion ratio is 50% lower in patients taking ACE
352 inhibitors. Furthermore, the beneficial effect of ACE inhibitors
in preventing progression from microalbuminuria to overt
nephropathy is long-lasting and is associated with preser-
vation of normal GFR. Antihypertensive treatment has a
IV renoprotective effect in hypertensive patients with type 2 dia-
betes and microalbuminuria, particularly when achieved
Pathogenesis of Renal Disease
Established Nephropathy
Control of hypertension and blockade of the renin-angiotensin
system are key therapeutic interventions in established diabetic
nephropathy. Indeed, the prognosis of type 1 diabetic patients
suffering from diabetic nephropathy has improved during the
past decade, largely because of effective antihypertensive treat-
ment with conventional drugs (b-blockers, diuretics) and ACE
inhibitors. Early and aggressive antihypertensive treatment
reduces albuminuria and the rate of decline in GFR in young
men and women with type 1 diabetes and nephropathy. In
addition, regression of kidney disease (DGFR 1 mL/min/year)
or remission of proteinuria for at least 1 year (proteinuria 1 g/
24 hours) has been documented in up to 20% of type 1 diabetic
patients receiving aggressive antihypertensive therapy for dia-
betic nephropathy. The renoprotective effect of interruption of
the renin-angiotensin blockade on the progression of diabetic
nephropathy has been conclusively proved in both type 1
(ACE inhibition) and type 2 (ARB) diabetes mellitus. Moreover,
these agents offer an additional significant mortality benefit in
this patient population.
Initiation of antihypertensive treatment usually induces an
initial drop in GFR. This phenomenon occurs with conven-
tional antihypertensive treatment with b-blockers, diuretics,
and when ACE inhibitors or ARBs are used. This initial decline
in GFR is due to a functional (hemodynamic) effect of antihy-
pertensive treatment; however, this is accompanied thereafter
by a slower decline in kidney function reflecting the beneficial
effect on progression of nephropathy. This is an important
clinical point. Many patients with diabetic nephropathy will
experience a modest increment in serum creatinine following
initiation of ACE inhibition or ARB therapy. These changes
should be anticipated and should not trigger withdrawal of
the agent. However, the development acute kidney injury
should prompt consideration of the possibility of coexisting
bilateral renal artery stenosis or effective or actual volume
depletion (e.g., congestive heart failure or excessive diuresis).
Lipid Lowering 353
Diabetic Nephropathy
type 2 diabetes with micro- or macroalbuminuria appears to
be highly variable. These agents should be prescribed only if
a coexisting indication is present.
Hypertension
Blood pressure tends to be higher in diabetic compared to
nondiabetic patients with renal failure. Because of their ben-
eficial effect on cardiovascular complications and disease
progression, ACE inhibitors or ARBs are obligatory in all
patients unless there are contraindications (e.g., renal artery
stenosis or resistant hyperkalemia). Patients with diabetic
nephropathy are sodium avid and have a marked tendency
to develop hypervolemia and edema. Therefore, dietary salt
restriction and the use of loop diuretics are usually indi-
cated. Thiazides are not sufficient as monotherapy once
GFR is below 40 to 50 mL/min. When the creatinine concen-
tration is elevated, multidrug therapy is usually necessary to
normalize blood pressure with, on average, three to five anti-
hypertensive agents. In these patients hypertension is also
characterized by a wide pulse pressure (as a result of
increased aortic stiffness) and by an attenuated nighttime
decrease in blood pressure, which in itself is a potent risk
predictor.
Glycemic Control
The half-life of insulin is prolonged in advanced kidney dis-
ease causing a tendency to develop hypoglycemia. This risk
is further compounded by anorexia and by accumulation of
most sulfonylurea compounds. Glinides and glitazones do
not accumulate, but long-term safety data in renal failure are
not available.
Malnutrition 355
Patients with ESRD due to diabetic nephropathy are typically
catabolic and are predisposed to develop malnutrition, particu-
larly during periods of intercurrent illness and fasting. There-
fore, protein-restricted diets are discouraged in advanced CH 17
renal insufficiency, particularly in anorectic patients. Anorectic
Diabetic Nephropathy
obese patients with type 2 diabetes and advanced renal failure
often undergo massive weight loss leading to normalization of
fasting and even postloading glycemia. Wasting with low mus-
cle mass is an important reason why physicians misjudge the
severity of renal failure, because at any given level of GFR,
serum creatinine concentrations are spuriously low.
Vascular Access
Timely creation of vascular access is of overriding importance.
It should be considered when the GFR is approximately 20 to
25 mL/min. Although venous runoff problems are not
unusual, inadequate arterial inflow is increasingly recognized
as the major cause of fistula malfunction. If distal arteries are
severely sclerotic, anastomosis at a more proximal level may
be necessary. Arteriosclerosis of arm arteries not only jeopar-
dizes fistula flow but also predisposes to the steal phenome-
non with digital ischemia.
Hemodialysis
In recent years, survival of diabetic patients on HD has
improved, with a 5-year survival rate in type 2 diabetic
patients on HD of approximately 30%.
356 Intradialytic and Interdialytic Blood Pressure
Diabetic hemodialysis patients are more hypertensive than
nondiabetic patients, and the blood pressure is exquisitely
volume-dependent. The problem is compounded by the fact
IV that patients are predisposed to intradialytic hypotension,
so that it is difficult to reach the target “dry weight” by ultrafi-
Pathogenesis of Renal Disease
Cardiovascular Problems
Cardiovascular disease accounts for over half of all deaths in
diabetic patients on HD. The prevalence of CHD is signifi-
cantly higher in diabetic compared to nondiabetic patients
entering ESRD programs. In addition, the diabetic patient is
at higher risk when coronary complications supervene. The
impact of ischemic heart disease is amplified by coexisting
cardiac abnormalities such as congestive heart failure, left
ventricular hypertrophy, and disturbed sympathetic innerva-
tion, as well as microvessel disease with diminished coronary
reserve. Observational studies suggest that good glycemic con-
trol before or during dialysis reduces overall and cardiovascu-
lar mortality rates. It is sensible to reduce afterload (blood
pressure control) and preload (hypervolemia). The value of
lipid lowering by statins has not been proved but is currently
being investigated in type 2 diabetic patients on dialysis. Dia-
betic patients with renal failure are characterized by prema-
ture and more pronounced anemia, so that timely and
effective treatment with recombinant human erythropoietin
(rhEPO) is advisable. Pharmacologic blockade of the renin-
angiotensin system using ACE inhibitors or ARBs is also
advised based on an extrapolation of the results of the Heart
Outcome Prevention Evaluation (HOPE) study. In the patient
with symptomatic CHD, active intervention, for example, per-
cutaneous transluminal coronary angioplasty (PTCA) or CABG
(coronary artery bypass graft), has been shown to be superior
to medical treatment alone. A recent retrospective analysis of
dialysed diabetics suggested that CABG using internal mam-
mary grafts (but not CABG using venous grafts) yielded supe-
rior outcome compared to PTCA with or without stenting.
Malnutrition
Because of anorexia and prolonged habituation to dietary
restriction, the dietary intake of diabetic patients on HD often
falls short of adequate energy (30–35 kcal/kg/day) and protein
(1.3 g/kg/day) intake. This is particularly undesirable because 357
malnutrition is a potent predictor of death. All patients should
be reviewed on a regular basis by a clinical nutrition service.
Peritoneal Dialysis CH 17
Diabetic Nephropathy
In the United States, 7% of all patients with diabetes receiving
renal replacement therapy are treated with peritoneal dialysis
(PD), but these rates are much higher in Western Europe.
There are very good a priori reasons to initially offer CAPD
treatment to diabetic patients including difficulties in vascu-
lar access placement, improved survival during the first
2 years, survival in patients treated with PD compared to HD
(excluding the very elderly), and avoidance of rapid fluctua-
tions of fluid volumes and electrolyte concentrations. Some
evidence suggests that patients who start on PD and then
transfer to HD when residual renal function declines have
better long-term survival than patients who started on HD.
Although protein is lost across the peritoneal membrane, the
main nutritional problem is gain of glucose and calories
because high glucose concentrations in the dialysate are nec-
essary for osmotic removal of excess body fluid. This leads
to weight gain and obesity.
Transplantation
Kidney Transplantation
Although survival of the diabetic patient with a kidney graft is
worse compared with a grafted nondiabetic patient, the gain in
life expectancy of the diabetic patient with a graft, compared
with the dialyzed diabetic patient on the waiting list, is propor-
tionally much greater than in the nondiabetic patient, because
survival of the diabetic patient is so much poorer on dialysis.
The higher mortality rate of the diabetic with a kidney graft is
mainly explained as the consequence of preexisting vascular
disease, left ventricular hypertrophy, and post-transplant
hypertension. Diabetic patients must be subjected to rigorous
pretransplantation evaluation, which in most centers includes
routine coronary angiography. Patients should also be exam-
ined by Doppler sonography of pelvic arteries and, if necessary,
angiography, to avoid placement of a renal allograft into an iliac
artery with compromised arterial flow at risk of ischemia of the
extremity and amputation.
Kidney-Plus-Pancreas Transplantation
Survival of patients with simultaneous pancreas-kidney trans-
plantation (SPK) approaches that of patients transplanted for
nondiabetic renal disease and is clearly superior to that for
358 diabetic recipients of living donor kidney-only grafts and par-
ticularly of cadaver kidney-only grafts. Reversibility of estab-
lished microvascular complications after SPK is minor at
best, with the important exception of autonomic polyneu-
IV ropathy, particularly improved cardiorespiratory reflexes,
potentially contributing to increased survival, and some
Pathogenesis of Renal Disease
Pancreas-After-Kidney Transplantation
An alternative strategy must be considered in the diabetic
patient who has a live kidney donor: to first transplant the liv-
ing donor kidney, and subsequently, once stable renal func-
tion is achieved (GFR > 50 mL/min), to transplant a cadaver
donor pancreas. Recent data suggest a poorer outcome in such
patients compared to conventional treatment.
BLADDER DYSFUNCTION
Bladder dysfunction as a sequela of autonomous diabetic poly-
neuropathy is frequent in diabetic patients, leading to straining,
hesitancy, and the sensation of incomplete emptying of the blad-
der; disabling symptoms, however, are rare (with the exception
of the frail elderly). Because of its association with autonomous
polyneuropathy, it is not surprising that bladder dysfunction is
frequently associated with postural hypotension, gastroparesis,
constipation, and nocturnal diarrhea. Cystometry shows
increased bladder volume at first desire to void and increased
maximal bladder capacity associated with decreased detrusor
contractility. Cystopathy with residual volume after voiding
renders eradication of urinary tract infection (UTI) difficult.
Diabetic Nephropathy
Extrarenal bacterial metastases are common, particularly
after UTI with methicillin-resistant staphylococci. In commu-
nity-acquired UTI, the predominant microbe is E. coli, but
Klebsiella is more frequently found in diabetic patients than
in control subjects. The reasons for the potentially higher fre-
quency and the definitely higher severity of UTI in diabetes
are not known but may include more favorable conditions
for bacterial growth (glucosuria), defective neutrophil func-
tion, increased adherence to uroepithelial cells, and impaired
bladder evacuation (detrusor paresis). As to the management
of UTI, no clear benefits of antibiotic treatment have been
demonstrated for treatment of asymptomatic bacteriuria in
diabetic patients. Community-acquired symptomatic lower
UTI may be managed with trimethoprim, trimethoprim with
sulfamethoxazole, or gyrase inhibitors. For nosocomially
acquired UTI, sensitivity tests and sensitivity-directed antibi-
otic intervention are necessary. Invasive candiduria can be
managed with amphotericin by irrigation or systemic adminis-
tration of fungicidal substances.
Nephrolithiasis
CLINICAL PRESENTATION
Pain
The classic presentation of pain in patients with nephrolithia-
sis is severe ureteral colic. This pain is often of abrupt onset
and intensifies over time into an excruciating, severe flank
pain that resolves with stone passage or removal. The pain
may migrate anteriorly along the abdomen and inferiorly to
the groin, penis, or labia majora as the stone moves toward
the ureterovesical junction. Gross hematuria, urinary urgency,
frequency, nausea, and vomiting may be also present. Stones
smaller than 2 mm have a 97% likelihood of spontaneous pas-
sage, at 3 mm an 86% chance of passage, at 4 to 6 mm a 50%
chance, but if larger than 6 mm, it has only a 1% chance of
spontaneous passage and will almost certainly require uro-
logic intervention.
Hematuria
Stone disease commonly causes hematuria, both microscopic
and macroscopic. In general, macroscopic hematuria occurs
most commonly with large calculi and during urinary infection
and colic. Although typically associated with loin pain or
360
ureteric colic, nephrolithiasis may cause hematuria in the 361
absence of pain. The clinical differential diagnosis of hematuria
is therefore wide and includes tumor, infection, and stones, as
well as glomerular and interstitial renal parenchymal disease.
Painless microscopic hematuria in children may occur with CH 18
hypercalciuria in the absence of demonstrable stones.
Nephrolithiasis
Loin Pain Hematuria Syndrome
The combination of loin pain with hematuria syndrome (LPHS)
in the absence of renal stones is a poorly understood condition
that must always be considered in the differential diagnosis of
patients presenting with the clinical manifestations of nephro-
lithiasis. This diagnosis is reached by exclusion when the
patients, often young to middle-aged females, present with loin
pain and persistent microscopic or intermittent macroscopic
hematuria. Careful evaluation is required to exclude small
stones, tumor, and urinary tract infection as a cause of the pain.
Inconsistent angiographic abnormalities implying intrarenal
vasospasm or occlusion have been reported, as have renal biopsy
abnormalities typified by deposition of complement C3 in arteri-
olar walls. Denervation of the kidney by autotransplantation is
rarely successful, and although nephrectomy has been
attempted, often the pain recurs promptly in the contralateral
kidney.
Pregnancy
Complications of pregnancy are not increased above those of
the general population in patients with nephrolithiasis except
for a slightly higher rate of urinary tract infection. Further-
more, the rate of stone formation during pregnancy is no
higher than that observed in nongravid stone formers.
Radiologic Evaluation
Nephrolithiasis
Calcium phosphate (apatite; brushite)
Uric acid Radiolucent
Rarely staghorn
Struvite (magnesium ammonium phosphate) Can be staghorn
Cystine Mildly opaque
“Ground-glass” look
Can be staghorn
Laboratory Studies
A simple urinalysis can offer important information. Urine
crystals are of variable assistance in the diagnosis, because
crystalluria can be encountered in the absence of kidney
stones. However, the presence of distinctive hexagonal cystine
stones is extremely valuable in prompting the diagnosis of
cystinuria and cystine stones. Specific gravity and osmolality
provide a clue to the habitual fluid intake of a given individ-
ual. A low urinary pH (<5.5) signifies the possibility of uric
acid stones. A moderately high pH (6.5–7.2) may reflect com-
plete or incomplete distal RTA. An extremely high pH (>7.4)
usually indicates splitting of urea into ammonium and
Stone Analysis
Stone analysis assumes a central role in the evaluation of
stone formers. In the majority of cases, knowledge of the
stone composition can disclose the underlying diagnosis or
at least streamline the diagnostic process. Identification of
calcareous stones is less definitive in terms of narrowing 365
down the diagnosis but is still helpful. Mixed urate/calcium
stones may suggest hyperuricosuric calcium urolithiasis,
and primarily calcium phosphate stones may suggest acid-
ification defects such as RTA and carbonic anhydrase CH 18
inhibitors.
Nephrolithiasis
In addition to diagnosis, stone analysis can also assist in
prognosis and treatment. A higher recurrence rate has been
described for calcareous stones with higher calcium phosphate
content; with recurrent stone formation, the proportion of cal-
cium phosphate also increases in the stone.
Renal Colic
General Therapy
Therapy to minimize stone recurrence should ideally be
guided by determination of stone type. However, passage of
a single stone in an apparently healthy young adult often does
not lead to extensive metabolic evaluation, and the stone may
not be available for analysis. Nonpharmacologic measures in
such patients should include an increase in fluid intake;
restriction of dietary sodium, which leads to a reduction of
urine calcium excretion; restriction of animal protein, which
also leads to a reduction of urine calcium excretion and an
increase in excretion of the calcification inhibitor citrate;
and ingestion of an age- and gender-appropriate amount
of dietary calcium. With this general advice, in the absence
of pharmacologic therapy, stone recurrence rates of 60% over
5 years are typical.
CALCIUM STONES
Calcium oxalate and calcium phosphate stones account for
the majority of renal stones, and because they are so com-
mon much is known about their natural history and
pathogenesis.
Primary Hyperparathyroidism
Approximately 20% of patients with hyperparathyroidism will
develop nephrolithiasis, usually calcium oxalate stones. CH 18
Despite the fact that PTH stimulates distal tubule calcium reab-
Nephrolithiasis
sorption, urinary calcium excretion may be greatly elevated in
those patients with primary hyperparathyroidism who form
renal stones even when hypercalcemia is slight. Stones often
recur and become bilateral if the diagnosis is not made early
in the course of the disease. Nephrocalcinosis may be the only
renal manifestation of hyperparathyroidism. Less commonly,
parenchymal calcification may be accompanied by calculi in
the renal pelvis and ureters. The presence of nephrocalcinosis
should prompt a diagnostic evaluation to exclude
hyperparathyroidism.
Diagnosis. Immunometric assays distinguish hyperparathy-
roidism and hypercalcemia of malignancy with a high level
of reliability, and show high (or absence of suppression)
PTH levels in 90% of patients with hyperparathyroidism.
Despite advances in the measurement of immunoreactive
PTH (iPTH), the diagnosis of primary hyperparathyroidism
still requires the demonstration of hypercalcemia and the
exclusion of other causes. In general, multiple serum samples
should be studied, and even modest elevations of calcium
concentration should be accorded considerable weight, if
consistent. Humoral hypercalcemia of malignancy may be
difficult to distinguish from hyperparathyroidism, as both
present as hypercalcemia with hypercalciuria. PTH-related
peptide (PTHrP) has been identified as a mediator of humoral
hypercalcemia of malignancy, the diagnosis of which can be
confirmed by demonstration of a high serum concentration
of PTHrP. This finding is present in most hypercalcemic
patients with solid tumors.
Treatment. Removal of the adenoma or hyperplastic glands
is indicated in patients with renal stone disease. Medical
therapy may be used for patients deemed not to be surgical
candidates. Dietary salt restriction reduces urine calcium
excretion and may be helpful in preventing stones in
patients not having surgery. Bisphosphonates, which inhibit
osteoclast function, are effective in controlling hypercalce-
mia with short-term use. However, hypercalciuria does not
improve with these agents. After successful surgery, serum
calcium becomes normal and cessation of hypercalciuria
presumably accounts for the marked decrease in the rate of
stone formation compared with that observed in the preoper-
ative period. Patients with osteitis fibrosa appear to suffer
more severe renal damage than those presenting with renal
calculi alone.
368 Idiopathic Hypercalciuria
Between 30% and 50% of calcium stone formers excrete more
calcium in their urine than normal people customarily do,
with levels exceeding 300 mg/24 hours in men, 250 mg/24
IV hours in women, or 4 mg/kg body weight/24 hours (either
sex), and are therefore labeled hypercalciuric. Hypercalciuria
Pathogenesis of Renal Disease
DIET
As with any type of stone, high water intake is always the cor-
nerstone of the therapeutic regimen. A high-fluid intake (2–2.5
L/day) results in a greater than 50% reduction in stone recur-
rence over 5 years. Dietary sodium restriction reduces urine
calcium excretion, thereby lowering the risk of stone forma-
tion. A high-protein intake increases urine calcium excretion
and causes negative calcium balance, so dietary protein
restriction would also seem to be a prudent recommendation.
A low-calcium diet has long been advocated for the treatment
of hypercalciuric stone disease and has been shown to be
effective in reducing urine calcium excretion. However, given
the risks of osteopenia and the absence of compelling prospec-
tive data suggesting that calcium restriction reduces stone fre-
quency, this therapeutic approach should be avoided. A
recent study compared the effectiveness of a low-calcium diet
to a low-sodium, low-protein, normal-calcium diet. One hun-
dred and twenty male hypercalciuric recurrent calcium stone
formers were randomized to either a low-calcium (400 mg/day)
diet with no sodium or protein restriction or a 1200-mg
calcium, low-sodium, low-protein diet. The patients were fol-
lowed for 5 years. In the low-salt, low-protein diet group the uri-
nary calcium-oxalate supersaturation fell, and stone recurrence
was significantly lower compared to the calcium-restricted
group. Based on this study, sodium restriction is now favored
over calcium restriction in the prevention of recurrent 369
nephrolithiasis.
THIAZIDE DIURETICS CH 18
Nephrolithiasis
Thiazide diuretics are the first-line therapy for idiopathic
hypercalciuria. They inhibit tubule resorption of NaCl,
stimulate calcium reabsorption by the distal convoluted tubule,
and trigger a fall in urine supersaturation of calcium salts. Mul-
tiple randomized studies of thiazide diuretics show a benefit in
the treatment of recurrent calcium oxalate nephrolithiasis with
respect to the incidence of recurrent stones. Chlorthalidone 25
to 50 mg daily is usually sufficient. Diuretic-induced hypokale-
mia can predispose to hypocitraturia, a known risk factor for
stone pathogenesis; therefore, serum potassium levels should
be checked after several days and if hypokalemia develops then
potassium citrate supplements (Uro-cit K 20–40 mmol daily)
can be administered.
Hyperuricosuria
The usual upper limits of daily urine uric acid excretion, 800 mg
(men) and 750 mg (women), are exceeded more frequently by
calcium stone formers than by normal people. In hyperuri-
cosuric patients who form calcium stones, stone disease
begins at a later age and is unusually active and severe. The
pathogenetic link between hyperuricosuria and the tendency
to develop calcium stones likely involves seed crystals of
urate initiating calcium oxalate precipitation from the urine.
Urinary uric acid crystals are commonly found in the setting
of volume depletion, emphasizing the need to maintain a brisk
urine flow in patients at risk of stone formation. Low urine pH
is also a risk factor. A reduction of new stone formation during
allopurinol administration is the most compelling evidence
for the role of hyperuricosuria in calcium oxalate stone dis-
ease. Allopurinol dramatically reduces new stone formation
in patients with combined uric acid–calcium stones and may
be combined with a thiazide diuretic in patients with idio-
pathic hypercalciuria and hyperuricosuria. Allopurinol
should be commenced at 100 mg/day and increased gradually
to 300 mg/day. A low-protein, low-purine diet can decrease
uric acid secretion and raise urinary pH, but compliance with
this diet is often poor. All patients should maintain a brisk
oral fluid intake; alkalinization of the urine with potassium
citrate to achieve a urine pH of 6.5 to 7.0 is also helpful. The
urine pH should not exceed 7.0, as this may trigger precipita-
tion of calcium phosphate salts.
370 Hypocitraturia
Nephrolithiasis
patients. Hydration, restriction of dietary protein and sodium,
and avoidance of foods that contain excessive oxalate are pru-
dent management measures. Pharmacologic therapy to further
reduce urine supersaturation may be useful if hydration and
diet fail to control stone formation. However, small scale stud-
ies suggest that thiazide diuretics and allopurinol are signifi-
cantly less effective in patients with idiopathic calcium
stones than in patients with established hypercalciuria or
hyperuricosuria. In this setting, citrate supplementation has
also been used with some success.
Hyperoxaluria
Hyperoxaluria causes stones by raising the saturation of the
urine with respect to calcium oxalate and is found in 5% to
25% of stone formers. The upper limit of normal for oxalate
excretion is usually considered to be 45 mg/day in an adult.
Hyperoxaluria can result from one of the following problems:
• Excessive dietary intake
• Overabsorption (enteric oxaluria)
• Crohn disease, ileal resection, celiac disease, pancreatic
insufficiency
• Metabolic overproduction
• Primary oxaluria types I and II
• Ethylene glycol intoxication
Oxalate is an end product of several metabolic pathways;
the amount of oxalate in the urine reflects the sum total of
intestinal absorption plus de novo synthesis. Dietary oxalate
intake is estimated to be 50 to 200 mg/day with about 10%
absorption; a liberal intake of high-oxalate foods can cause
frank hyperoxaluria. Calcium and magnesium complex oxa-
late in the intestinal tract; diets low in calcium have been
shown to increase urine oxalate excretion even when oxalate
intake is fixed. Increased luminal free fatty acids may promote
oxalate overabsorption by increasing the permeability of colon
epithelium to oxalate (Crohn disease, celiac sprue, pancreatic
insufficiency, and small intestinal bypass surgery for obesity).
In general, a low-fat, low-oxalate diet should be tried in the
first instance, followed by oral calcium carbonate or cholestyr-
amine, which both bind intestinal oxalate, if dietary manipu-
lation proves unsuccessful. Treatment needs to be aggressive
372 as patients can develop renal failure and systemic oxalosis
from severe enteric hyperoxaluria.
Hyperoxaluria may also be inherited as an autosomal reces-
sive trait. Primary hyperoxaluria is characterized by urinary
IV oxalate excretion of 100 to 300 mg/day, recurrent calcium oxa-
late calculi, progressive renal failure, and oxalosis, beginning
Pathogenesis of Renal Disease
Natural History
Nephrolithiasis
Gout
Patients with primary gout may also have uric acid stones.
The frequency of uric acid stones is directly related to the
degree of uricosuria. The disease may be heterogeneous,
because uric acid overexcretion persists despite a low-purine
diet in some 21% to 28% of gouty subjects. In addition, urine
pH tends to be low, suggesting a defect in ammonium produc-
tion. The majority of patients also have a defect in renal urate
excretion, such that hyperuricemia is required to excrete even
normal amounts of uric acid.
Malignant Disease
Myeloproliferative disease and chronic granulocytic leukemia
in adults and acute leukemia in childhood are the common
neoplastic disorders that cause hyperuricosuria. Massive cell
necrosis in response to chemotherapy abruptly increases urine
uric acid excretion, which may cause extensive precipitation
and urinary tract obstruction. In the absence of chemotherapy,
less marked uricosuria may cause uric acid stones.
Gastrointestinal Diseases
Acute diarrheal states and chronic inflammatory bowel dis-
ease may increase urine uric acid concentration through
excessive water loss and dehydration. Urine pH tends to fall
with extracellular volume contraction, increasing the possibil-
ity of stone formation. Patients with ileostomy are particularly
at risk, and associated small bowel disease (proximal ileum)
may contribute to the lowered urine pH through signifi-
cant bicarbonate loss. Hyperoxaluria may also be present
in patients with ileal resection, leading to mixed stones
composed of both uric acid and calcium oxalate.
Drug-Induced Stones
Probenecid and aspirin in large doses are both common urico-
suric drugs. Hyperuricemic patients respond to these agents
with a transient increase in uric acid excretion. Excretion then
falls but remains higher than pretreatment levels, owing to
reduced intestinal uricolysis. In patients with high dietary
purine intake, the efficient excretion of uric acid induced by
the drugs may increase the risk of uric acid stone formation
or calcium oxalate stone formation.
374 Treatment
CYSTINURIA
See Chapter 20, Inherited Disorders of the Kidney.
Nephrolithiasis
In addition to Proteus species, Haemophilus, Corynebacte-
rium, and Ureaplasma are also frequently shown to cause
struvite stones. The common urinary pathogen, Escherichia
coli, does not produce urease.
Therapy
Surgery
Struvite staghorn calculi generally require surgical removal
and, if not properly treated, may result in nephrectomy in
up to 50% of cases. Initially, struvite stones were treated with
open surgical stone removal; however, almost one quarter of
patients so treated had recurrence following surgery. Rather
than open surgical stone removal, percutaneous nephrolithot-
omy can completely remove struvite stones in up to 90% of
cases, with a recurrence rate approaching only 10% in
kidneys rendered stone-free. Extracorporeal shock wave litho-
tripsy with ureteral stenting alone will result in stone-free
rates of 50% to 75%. The American Urological Association
suggested that a combined approach of percutaneous nephro-
lithotomy and shock wave lithotripsy was preferred. Other
approaches include ureteroscopy with holmium:YAG laser
stone disruption.
Antimicrobial Agents
In the absence of ongoing infection with urease-producing
bacteria, stones cannot grow and, if urine can be sterilized,
may actually regress in size. Long-term, culture-specific anti-
microbial drugs must be used. Optimally, the urine will be
sterilized; however, this will rarely occur because it is diffi-
cult to eradicate infections in the presence of the struvite
stone, owing to bacteria lodging in sites relatively inaccessible
to antibiotics and white blood cells. However, the reduction of
bacterial counts will result in reduced urease production and
should reduce stone growth.
After surgery, the urine should be cultured, as should
stone fragments. After 1 to 2 weeks of full-dose antibiotic
therapy, the urine may become sterilized; the dose of antibio-
tics can then be decreased by 50%. This dose of antibiotics
should be continued while monthly urine cultures are taken,
and can be discontinued when there are three successive
376 negative monthly urine cultures. The urine should continue
to be cultured on a monthly basis for another year, with re-
treatment of any recurrent infection. In patients who cannot
tolerate surgery, chronic suppressive antibiotics can be used
IV in an effort to retard stone growth.
Pathogenesis of Renal Disease
Chapter 19
Renal Neoplasia
Malignant neoplasms involving the renal parenchyma and
renal pelvis may be primary or secondary in origin, although
the latter are typically of little clinical consequence. The main
primary renal tumors are the following:
• Renal cell carcinomas (80–85%)
• Transitional carcinomas (7–8%)
• Nephroblastoma (Wilms tumor) in children (5–6%)
• Other parenchymal epithelial tumors, including oncocyto-
mas, collecting duct tumors, and renal sarcomas, are
uncommon but are becoming more frequently recognized
pathologically.
377
378 locally advanced disease at diagnosis. The most common pre-
senting symptom is hematuria, followed by abdominal mass,
pain, and weight loss. The classic triad of flank pain, hematu-
ria, and a palpable abdominal renal mass occurs in only about
IV 10% of cases. Hematuria, gross or microscopic, is usually
observed only if the tumor has invaded the collecting system.
Pathogenesis of Renal Disease
Renal Neoplasia
sonography are the mainstays of evaluation of a suspected
renal mass. As seen on CT, the typical RCC is generally larger
than 4 cm in diameter, has a heterogeneous density, and
enhances with contrast material. Ultrasonography, though less
sensitive than CT, is particularly useful in differentiating
between a simple benign cyst and a more complex cyst or
a solid tumor. It has a sensitivity of 97%, a specificity of
97%, and a false-negative rate of only 1% in differentiating a
benign cyst from a potentially malignant tumor. MRI with gad-
olinium contrast agent is superior to CT for evaluating the
inferior vena cava if tumor extension into this vessel is sus-
pected. MRI is also a useful adjunct to ultrasonography in
the evaluation of renal masses if radiographic contrast mate-
rial cannot be administered because of allergy or inadequate
renal function. Although most solid renal masses are RCCs,
some benign lesions complicate the diagnosis. These lesions
include angiomyolipomas and renal oncocytomas. Selective
renal arteriography, a mainstay of diagnosis in the past, is
now rarely used. Renal arteriography is generally reserved
for selected cases in which preoperative mapping of the vas-
culature is necessary, such as when nephron-sparing surgery
is contemplated.
Surgical Management
Nephrectomy
The mainstay of treatment of primary RCC is surgical excision
or nephrectomy. This procedure may involve a radical
nephrectomy, which includes early ligation of the renal artery
and renal vein and en bloc excision of the kidney with the sur-
rounding Gerota fascia and ipsilateral adrenal gland. The early
ligation of the vascular pedicle is important to prevent
381
Table 19-3 Correlation of Stage Grouping with Survival
in Patients with Renal Cell Carcinoma
Stage Grouping 5-Year Survival Rate (%)
I T1 N0 M0 90–95 CH 19
II T2 N0 M0 70–85
Renal Neoplasia
III T3a N0 M0 50–65
T3b N0 M0 50–65
T3c N0 M0 45–50
T1 N1 M0 25–30
T2 N1 M0 25–30
T3 N1 M0 15–20
IV T4 Any N M0 10
Any T N2 M0 10
Any T Any N M1 —
M, distant metastasis; N, nodes; T, tumor.
Nephron-Sparing Surgery
The generally accepted criteria for consideration of nephron-
sparing or partial nephrectomy include patients with bilateral
tumors, tumor in a solitary kidney, or compromised renal func-
tion. The rate of recurrence in the partially resected kidney
ranges from 4% to 10%. Complications of nephron-sparing sur-
gery include urinary fistulas, acute tubular necrosis, the need
for temporary or permanent dialysis, and hemorrhage. Because
of the favorable results seen with nephron-sparing surgery and
the increasing number of smaller, incidentally discovered
tumors, nephron-sparing surgery has been increasingly used to
treat patients with small (<4 cm), polar tumors and a normal
382 contralateral kidney. The primary concern with this approach is
that a multicentric tumor would go unrecognized and result in
recurrent disease in the salvaged kidney. With highly sensitive
preoperative staging, increasing use of three-dimensional recon-
IV struction of CT images, and the use of intraoperative ultrasound,
such an occurrence should be rare.
Pathogenesis of Renal Disease
Laparoscopic Nephrectomy
Although no randomized study has been conducted, the clin-
ical data to date suggest that laparoscopic radical nephrec-
tomy may be a viable alternative to an open procedure, with
equivalent surgical efficacy and safety and substantially
reduced postoperative recovery time.
Angioinfarction
Angioinfarction is performed with or without nephrectomy for
the treatment of patients with metastatic or locally advanced
RCC. This approach has been used to reduce vascularity and
the consequent risk of hemorrhage during nephrectomy in
patients with large, marginally resectable primaries and to
control symptoms such as bleeding or pain in patients with
unresectable tumors or distant metastases. Most patients expe-
rience pain, fever, and nausea after the procedure that may
last several days.
Renal Neoplasia
tomy. Venal caval obstruction may produce various clinical
manifestations, including abdominal distention with ascites
and hepatic dysfunction—possibly related to Budd-Chiari
syndrome, nephrotic syndrome, caput medusa, varicocele,
malabsorption, and pulmonary emboli. Survival rates in
patients with subdiaphragmatic lesions approach 50%;
patients with supradiaphragmatic thrombi do considerably
less well. A team of specialists is usually required for the sur-
gical management of these patients, as the operative mortal-
ity rate may be as high as 5% to 10%, particularly if
thrombectomy of an intracardiac tumor is contemplated.
Palliative Surgery
“Palliative nephrectomies” are rarely necessary. Pain and
bleeding can be controlled with systemic pain medication
and angioinfarction, clot colic can be minimized with ureteral
stents and hydration, and hypercalcemia, fatigue, fever, and
other systemic symptoms can often be controlled with
NSAIDs, bisphosphonates, hydration, and appetite stimulants
such as medroxyprogesterone.
Radiation Therapy
The major sites of systemic metastases include lung, bone, and
brain. Radiation treatment of disease in these areas can provide
palliation of bone pain, prevention of cord compression or frac-
ture, regression of central nervous system metastases, or control
of hemoptysis or airway obstruction. Objective responses occur
in about 50% of patients with symptomatic skeletal metastases.
Palliation of large renal bed recurrences by external-beam irra-
diation has been unsatisfactory. Stereotactic radiation surgery
has been reported to be effective therapy for selected patients
with small (3 cm) central nervous system metastases from
renal cell carcinoma.
384 Systemic Therapy
Chemotherapy
Single-agent chemotherapy has limited or no activity against
RCC. Gemcitabine chemotherapy has been studied as a single
agent, with response rates reported between 6% and 30%.
Response rates with combination chemotherapy regimens are
slightly better. The combination of gemcitabine and 5-FU
demonstrated a response rate of 17% in 41 patients with met-
astatic RCC. Median progression-free survival time in this pre-
treated group of patients was 28.7 weeks. Follow-up studies
using gemcitabine and capecitabine, the oral prodrug form of
5-FU, demonstrated response rates of 11% and overall sur-
vival of 14 months.
Immunotherapy
The most successful immunotherapeutic strategies for RCC
involve the administration of interferon-a (IFN-a) and inter-
leukin-2 (IL-2). The mechanism of action of these cytokines
is incompletely understood but may involve the direct killing
of tumor cells by activated T and natural killer cells, as well as
antiangiogenic effects.
Interferon-a. IFN-a has undergone extensive clinical evalua-
tion for the treatment of metastatic RCC over the past two dec-
ades. Most studies have demonstrated some antitumor effect,
with the overall response rate being approximately 15%. The
median time to response is approximately 4 months. However,
most responses are partial and short-lived (median response
duration, 6 to 7 months) and only about 2% of patients have
had complete responses. The toxicity of IFN-a includes flulike
symptoms such as fever, chills, myalgia, and fatigue, as well
as weight loss, altered taste, depression, anemia, leukopenia,
and elevated liver function test results. Most side effects, espe-
cially the flulike symptoms, tend to diminish with time during
chronic therapy. Efforts to improve the clinical activity of IFN-
a have included combinations with 5-FU, cis-retinoic acid,
IFN-g, thalidomide, and IL-2.
Interleukin-2 Therapy. High-dose bolus IL-2 has received
U.S. Food and Drug Administration (FDA) approval for treat-
ment of metastatic RCC. Because of considerable toxicity
associated with high-dose IL-2 regimens (hypotension, capil- 385
lary leak syndrome), treatment should be administered in a
setting capable of providing a level of care comparable to that
in an intensive care unit, and restricted to carefully selected
patients with excellent organ function treated at experienced CH 19
treatment centers. The clinical result of this approach is a com-
Renal Neoplasia
plete response in approximately 5% of patients and a partial
response in 9%. Attempts to improve efficacy have included
the addition of IFN-a and then 5-FU to IL-2, with variable
reported success rates. Factors that have been variably
associated with response to IL-2 include performance status,
number of organs with metastases (one versus two or more),
absence of bone metastases, prior nephrectomy, degree of
treatment-related thrombocytopenia, absence of prior interferon
therapy, thyroid dysfunction, rebound lymphocytosis, erythro-
poietin production, and post-treatment elevations of blood
tumor necrosis factor-a (TNF-a) and IL-1 levels.
Targeted Agents
Given the frequency of biallelic loss of the VHL gene and asso-
ciated dysregulation of hypoxia-inducible genes, including
proangiogenic growth factors VEGF (vascular endothelial
growth factor) and PDGF (platelet-derived growth factor),
renal cell carcinoma is a particularly promising target for
antiangiogenic therapy.
Bevacizumab
Bevacizumab, a recombinant humanized anti-VEGF monoclo-
nal antibody, demonstrated several responses in patients with
RCC. Progression-free survival of 4.8 months versus 2.4
months for the patients on placebo has been demonstrated.
Sorafenib
Sorafenib possesses inhibitory activity against VEGF and PDGF
receptors (VEGFR, PDGFR). Based on phase II and III trials demon-
strating prolongation of progression-free survival (4 months),
sorafenib received approval by the FDA in late 2005.
Sunitinib
Sunitinib is a small molecule inhibitor of VEGFR, PDGFR,
c-KIT, and FLT-3. Based on phase II data showing response
rates of 25% to 40%, sunitinib was approved for use in
patients with advanced renal cancer in early 2006. A phase
III trial comparing sunitinib and interferon-a showed a
response rate of 31% and a median progression-free survival
of 11 months for sunitinib-treated patients versus 6%
response rate and 5 months median progression-free survival
386 for patients treated with interferon. No significant difference
in overall survival was observed.
Temsirolimus (CCI-779)
IV Temsirolium is a rapamycin analog that inhibits mammalian
target of rapamycin (mTOR) downstream of AKT, resulting
Pathogenesis of Renal Disease
Renal Neoplasia
monly, a filling defect of the caliceal system, or renal pelvis, on
intravenous pyelography. Exfoliative cytologic testing is com-
monly positive, as it is in bladder cancers. Positive cytologic
findings in the presence of a filling defect of the renal pelvis or
ureter confirm the diagnosis. If the diagnosis is still uncertain
after pyelography, ureteroscopy may facilitate diagnosis.
Management
Renal Sarcomas
Renal sarcomas account for approximately 1% to 2% of pri-
mary renal cancers. Fibrosarcomas are the most common and
388 have a poor prognosis as a result of late diagnosis and the
presence of locally advanced involvement into the renal vein
or metastatic disease at initial evaluation. Five-year survival
rates are less than 20%. Other, rarer, sarcoma variants may
IV occur and include leiomyosarcoma, rhabdomyosarcoma,
osteogenic sarcoma, and liposarcoma.
Pathogenesis of Renal Disease
Wilms Tumor
Initial Features
An abdominal mass, with or without abdominal pain, is the most
common finding and occurs in 80% and 40% of cases, respec-
tively. Other physical abnormalities, including aniridia, genito-
urinary abnormalities, and hemihypertrophy, may occasionally
be detected. Hematuria, anemia, hypertension, and acute severe
abdominal pain may also be present. An abdominal ultrasound
is an important diagnostic test to further evaluate the mass and
its anatomic extension, which may include inferior or superior
extension into the vena cava. Intravenous pyelography and CT
are also warranted. Metastatic evaluation of liver, chest, and bone
complement the evaluation. The diagnosis is usually established
by surgery. If the diagnostic tests and clinical features suggest the
presence of a Wilms tumor, preoperative needle biopsy should
be avoided because of the attendant risk of tumor spillage.
Multimodality Management
High cure rates have been achieved with the concerted effort
of multimodality teams performing surgery, radiation therapy,
and chemotherapy. Removal of all gross tumor by radical
resection should be attempted. Most patients receive radiation
therapy as an adjunct to surgical removal. Chemotherapy is an 389
important component of therapy in Wilms tumors. In addition
to adjuvant chemotherapy in conjunction with radiation ther-
apy, neoadjuvant chemotherapy can diminish the size of the
primary tumor and induce regression of metastatic lesions. CH 19
Agents that have activity against Wilms tumor include vincris-
Renal Neoplasia
tine, dactinomycin, doxorubicin, etoposide, ifosfamide, and
cisplatin. Cure rates approach 80% to 90% with survival rates
of 92% to 97% in early stage disease. For patients who experi-
ence relapse or for those with poor prognostic features, bone
marrow transplantation has been offered with good results.
Chapter 20
Clinical Presentation
All amino acids are filtered by the glomerulus; greater than 98%
are subsequently reabsorbed by multiple transporters in the
proximal tubule. In Fanconi syndrome, all amino acids are
excreted in excess. Clinically, amino acid losses are relatively
modest; they do not lead to specific deficiencies and affected
patients do not require supplementation. Phosphate wasting
is a cardinal feature; serum phosphate levels are usually
decreased. Rickets and osteomalacia result from increased uri-
nary losses of phosphate as well as impaired 1a-hydroxylation
of 25-hydroxyvitamin D3 by proximal tubule cells. A hyper-
chloremic metabolic acidosis (type II) is a frequent finding
and is caused by defective bicarbonate reabsorption by the
393
394
Table 20-1 Causes of Inherited and Acquired Fanconi
Syndrome
Inherited
V Idiopathic (AD)
Dent disease (X-linked hypophosphatemic rickets, X-linked
Genetic Basis of Kidney Disease
recessive nephrolithiasis
Sporadic
Cystinosis (AR)
Tyrosinemia type 1 (AR)
Galactosemia (AR)
Glycogen storage disease
Wilson disease
Mitochondrial disease (cytochrome c oxidase deficiency)
Oculocerebral syndrome of Lowe
Hereditary fructose intolerance
Acquired
Paraproteinemias (multiple myeloma)
Nephrotic syndrome
Chronic tubulointerstitial nephritis
Renal transplantation
Malignancy
Exogenous Factors
Heavy metals (cadmium, mercury, lead, uranium, platinum)
Drugs (cisplatin, aminoglycosides, 6-mercaptopurine, valproate,
ifosfamide, outdated tetracyclines, methyl-3-chrome)
Chemical compounds (toluene, maleate, paraquat, Lysol)
AD, autosomal dominant; AR, autosomal recessive.
Pathogenesis
Dent disease, X-linked recessive hypophosphatemic rickets,
and X-linked recessive nephrolithiasis (OMIM 300009) repre-
sent the same inherited disorder caused by mutations in the
CLCN5 gene (chromosome Xp11.22) encoding a renal chloride
channel, ClC-5. This X-linked recessive disease is associated
with a primary renal Fanconi syndrome.
Clinical Presentation
The clinical spectrum of CLCN5 mutations includes hypercal-
ciuria with calcium phosphate nephrolithiasis, rickets,
nephrocalcinosis, low-molecular-weight proteinuria, and
renal failure. The same mutation can induce different pheno-
types in different families, probably because of genetic or
environmental modifiers or both. The disease affects males
predominantly but females frequently have an attenuated phe-
notype. Renal failure is seen only in males. The degree of pro-
teinuria is relatively constant and amounts to 0.5 to 2 g/day in
adults and up to 1 g/day in children. The nephrotic syndrome
does not occur and albumin excretion represents less than half
of the proteins excreted. Affected males usually excrete
b2-microglobulin in amounts exceeding 100 times the upper
limit of normal. Hypercalciuria is characteristic and is present
in most cases, beginning in childhood, with overt hypercal-
ciuria (>7.5 mmol/day) usually seen in males. Females are also
frequently hypercalciuric, but with values closer to the upper
end of the normal range. Kidney stones are present in 50% of
males, and are composed of calcium phosphate or a mixture
of calcium phosphate and calcium oxalate. Radiologic nephro-
calcinosis of the medullary type is seen in most affected males
and occasionally females. Serum phosphate levels are usually
below normal values and rickets or osteomalacia may occur.
Serum levels of 1,25(OH)D3 are normal or slightly raised,
whereas 25(OH)D levels are normal. Systemic acidosis is usu-
ally not seen before renal function deteriorates significantly.
396 Spontaneous hypokalemia is common in males and there is an
inability to maximally concentrate the urine. Aminoaciduria
and glucosuria are also frequent. Progressive renal failure
occurs in 50% of males with end-stage renal failure occurring
V in the fifth decade on average. Renal biopsy specimens show a
pattern of chronic interstitial nephritis with scattered calcium
Genetic Basis of Kidney Disease
Treatment
Renal stones and hypercalciuria are treated with supportive
measures (particularly by increasing fluid intake). Dietary
restriction of calcium reduces calcium excretion but is not
recommended as it may exacerbate bone disease. Thiazide diure-
tics may be given in small doses, but may trigger hypotension and
excessive diuresis, as these patients tend to have a salt-losing
nephropathy. Rickets and osteomalacia are treated with small
doses of vitamin D, but this should be administered with caution
as it might increase urine calcium excretion and the risk of
nephrolithiasis. Assessment of urinary calcium excretion before
and after vitamin D therapy may be useful.
Cystinosis
Pathogenesis
Cystinosis (OMIM 219800) is a rare autosomal recessive disease
(incidence 1 in 100,000–200,000) caused by defective transport
of the disulfide amino acid cystine across lysosomal membranes,
with consequent intracellular accumulation and crystallization,
causing cell death. Cystinosis is due to inactivating mutations
in CTNS, which encodes an integral lysosomal membrane
protein, termed cystinosin.
Clinical Presentation
Cystinosis is the most frequent cause of the renal Fanconi syn-
drome in children. The clinical spectrum of disease is variable,
encompassing classic nephropathic cystinosis, a rare adolescent
variant, and a mild adult-onset variant. Nephropathic cystinosis 397
usually presents in the first year of life with failure to thrive,
increased thirst, polyuria, poor feeding, and hypophosphatemic
rickets. In whites, affected subjects frequently have blond hair
and blue eyes, and are more lightly pigmented. Renal wasting CH 20
of sodium, calcium, and magnesium is frequently seen, as well
Treatment
Early diagnosis, and appropriate treatment with cysteamine,
dialysis, and renal transplantation has improved the outcome
of patients with nephropathic cystinosis, and most patients
now reach adulthood. Symptomatic treatment involves rehy-
dration, particularly during episodes of gastroenteritis.
Replacement of bicarbonate losses with citrate or bicarbon-
ate-containing salts is frequently indicated. Phosphate losses
are replaced with phosphate salts and oral vitamin D therapy.
Indomethacin has been used for decreasing the renal salt- and
water-wasting syndrome. Recombinant human growth hor-
mone can also be given to increase growth, and does not
increase the rate of progression of renal failure. The cystine-
depleting drug cysteamine slows the rate of progression of
renal failure, increases growth in affected patients, and is
now widely used for cystinosis. Kidney function stabilizes
upon initiation of therapy and may allow patients treated at
an early age to reach adulthood without developing end-stage
renal failure. Topical cysteamine eyedrops can be used to treat
398 ocular complications of cystinosis, and results in dissolution
of corneal crystals. Transplantation is now routinely per-
formed in cystinotic patients.
V
Lowe Oculocerebrorenal Syndrome
Genetic Basis of Kidney Disease
Cystinuria
Cystinuria (OMIM 220200) is an autosomal recessive disorder
associated with defective transport of cystine and the dibasic
amino acids ornithine, lysine, and arginine, involving the epi-
thelial cells of the renal tubule and gastrointestinal tract. The
formation of cystine calculi in the urinary tract, leading to
infection and renal failure, is the hallmark of the disorder.
Cystine is the least soluble of the naturally occurring amino
acids, particularly at low pH. The prevalence is approximately
1 in 7000 but varies depending on the geographic location.
Pathogenesis
Cystinuria is caused by mutations in either of two genes
implicated in dibasic amino acid luminal transport by the
proximal tubule.
Type A (or type 1, OMIM 220100) cystinuria is a completely
recessive disease caused by mutations in SLC3A1on chromosome
2, which encodes the renal proximal tubule S3 segment and intes-
tinal dibasic amino acid transporter. Jejunal uptake of cystine
and dibasic amino acids is absent and there is no plasma response
to an oral cystine load. The risk of nephrolithiasis is very high.
Type B (or non-type 1, OMIM 600918) cystinuria is an
incompletely recessive form in which both parents usually
excrete intermediate amounts of cystine (100–600 mmol/g cre-
atinine) but may also have normal excretory function. The
disease is caused by mutations in the SLC7A9 gene located on
chromosome 19q13, which encodes a protein BAT1. It belongs
to a family of light subunits of amino acid transporters,
expressed in the kidney, liver, small intestine, and placenta.
Clinical Presentation
The only known manifestation of cystinuria is nephrolithiasis.
Clinical expression of the disease typically starts during the
first to third decades. Males tend to be more severely affected
than females, although the incidence is equal in both sexes.
Cystine stones are made of a yellow-brown substance (sulfur-
containing), are very hard, and appear radiopaque. Stones
are frequently multiple, have a staghorn configuration, and
tend to be smoother than calcium stones. Magnesium ammo-
nium phosphate and calcium stones can also form as a result
of infection.
Diagnosis can be made by demonstration of the presence of 401
characteristic hexagonal cystine crystals in the urine. Acidifi-
cation of concentrated urine with acetic acid can precipitate
crystals not visible on initial urine microscopy. Diagnosis is
ultimately made by measurement of cystine excretion in the CH 20
urine, usually performed in specialized centers using chro-
Treatment
Management involves maintaining a high urine flow rate and
reducing sodium in the diet, which results in lower urinary
cystine concentrations. Fluid intake should ideally reach
4 L/day because many patients excrete 1 g or more of cystine
daily. Cystine solubility can also be increased by alkaliniza-
tion of the urine with potassium citrate, but the solubility of
cystine does not increase until the pH reaches 7.0 to 7.5; the
requirements for alkali may reach 3 to 4 mmol/kg. Patients
who are unable to comply with a regimen of high-fluid intake
and urine alkalinization or who fail despite adequate treat-
ment can be given D-penicillamine in doses of 30 mg/kg up to
a maximum of 2 g/day. Through a disulfide exchange reaction
D-penicillamine forms the disulfide cysteine-penicillamine,
which is much more soluble than cystine. This drug has
variable tolerability and frequent side effects (including rash,
fever, membranous nephropathy, epidermolysis, and loss of
taste) complicate therapy. Another drug that may be useful
in cystinuria is mercaptopropionylglycine, whose mechanism
of action is identical to that of D-penicillamine. This drug is
as effective as D-penicillamine in reducing urine cystine excre-
tion but this agent also has substantial side effects includ-
ing skin rash, fever, nausea, proteinuria, and membranous
nephropathy.
The introduction of extracorporeal shock wave lithotripsy
has not been of great benefit to cystinuric patients as cys-
tine stones are difficult to pulverize. Consequently, percutane-
ous lithotripsy is more effective. Urinary alkalinization with
direct irrigation of the urinary tract with D-penicillamine or
N-acetylpenicillamine to form disulfide compounds has
resulted in dissolution of stones, although dissolution may
require several weeks of therapy with the attendant complica-
tions of catheterization. Transplantation is sometimes neces-
sary for patients who develop end-stage renal disease from
chronic obstruction or infection. A kidney from an unaffected
donor will not form cystine stones.
402 Hartnup Disease
Pathogenesis
X-linked hypophosphatemic rickets (OMIM 307800) is an
X-linked dominant disorder and is the most common inherited CH 20
hypophosphatemic disorder, accounting for 80% of cases of
Clinical Presentation
The hallmark of X-linked hypophosphatemic rickets (XLH) is
inappropriately normal 1,25(OH)2D3 levels in the presence of
hypophosphatemia and rickets. There is no renal wasting of
amino acids and glucose. The patients demonstrate growth
retardation, femoral or tibial bowing presenting early in life,
and evidence of rickets and osteomalacia. Serum phosphate
levels are usually lower than 2.5 mg/dL (0.8 mmol/L). The ear-
liest sign of the disease in children may be increased serum
alkaline phosphatase levels. Males are usually more severely
affected than females and there is variable penetrance.
Treatment
Early therapy with 1,25(OH)2D3 (1–3 mg/day) and phosphate
(1–2 g/day in divided doses) has a beneficial effect on growth
and bone disease. Nephrocalcinosis due to vitamin D and
phosphate therapy can lead to deterioration of renal function.
Renal Glucosuria
Familial renal glucosuria (FRG; OMIM 233100) is generally a
benign clinical condition that denotes a renal tubular abnormal-
ity characterized by persistent isolated glucosuria in the absence
of hyperglycemia. FRG is transmitted as a codominant trait with
incomplete penetrance. Homozygotes may demonstrate gluco-
suria above 60 g/day, evidence of renal sodium wasting, mild
volume depletion, and raised basal plasma renin and serum aldo-
sterone levels. Selective aminoaciduria may occasionally be
seen, unlike the generalized aminoaciduria seen in the Fanconi
syndrome. Mutations in the sodium/glucose co-transporter
SGLT2 coding gene, SLC5A2, are responsible for the disorder.
Mutations in the GLUT2 glucose transporter are thought to be
responsible in some Japanese kindreds.
A currently accepted stringent definition of glucosuria pro-
poses the following diagnostic criteria:
1. The oral glucose tolerance test, levels of plasma insulin and
free fatty acids, and glycosylated hemoglobin levels should
all be normal.
2. The amount of glucose in the urine (10–100 g/day) should
be relatively stable except during pregnancy, when it may
increase.
3. The degree of glucosuria should be largely independent of diet
but may fluctuate according to the amount of carbohydrates
ingested. All specimens of urine should contain glucose.
4. The carbohydrate excreted should be glucose. Other sugars
(e.g., fructose, sucrose, galactose, lactose) are not found.
5. Subjects with renal glucosuria should be able to store and
utilize carbohydrates normally.
406 INHERITED HYPOKALEMIC HYPOTENSIVE
DISORDERS
Familial hypokalemic, hypochloremic metabolic alkalosis is not
V a single entity but rather a set of closely related disorders. The dis-
tinguishing features of these disorders are outlined in Table 20-3.
Genetic Basis of Kidney Disease
Bartter Syndrome
Pathogenesis
Bartter syndrome (OMIM 601678, 241200, 607364, and 602522)
is a group of autosomal recessive disorders affecting the func-
tion of the thick ascending limb of the loop of Henle, giving a
clinical picture of salt-wasting and hypokalemic metabolic
alkalosis. Hyperplasia and hypertrophy of the juxtaglomerular
apparatus is seen. It is caused by inactivating mutations in
one of at least four genes encoding membrane proteins (Bartter
syndrome I–IV) expressed in this nephron segment:
1. The Naþ/Kþ/2Cl co-transporter (SLC12A1 encoding NKCC2)
2. The apical inward-rectifying potassium channel (KCNJ1
encoding ROMK)
3. ClC-Kb, a basolateral chloride channel (CLCNK encoding
ClC-Kb)
4. Barttin (BSND), a protein that acts as an essential activator
b-subunit of ClC-Ka and ClC-Kb
Gain-of-function mutations in the extracellular calcium
ion–sensing receptor (CaSR) cause a variant of Bartter syn-
drome with hypocalcemia.
Clinical Presentation
Most cases of Bartter syndrome present antenatally or in the
neonatal period. Polyhydramnios and premature labor are com-
monly found. Polyuria and polydipsia are invariable. Postnatal
findings include failure to thrive, growth retardation, volume
depletion, hypotension, muscle weakness, seizures and tetany,
paresthesias, and joint pain due to chondrocalcinosis. In con-
trast to patients with Gitelman syndrome, those with Bartter
syndrome are virtually always hypercalciuric and normomag-
nesemic. Nephrocalcinosis occurs almost universally in
patients with NKCC2 and ROMK mutations but in only 20%
of those with ClC-Kb mutations. Patients with ROMK mutations
may present with hyperkalemia at birth, which converts to
hypokalemia within the first weeks of life, and may be misdiag-
nosed with pseudohypoaldosteronism type I. In contrast to
other Bartter patients, they do not need potassium supplemen-
tation. The type III Bartter syndrome (ClC-Kb) phenotype is
highly variable, and may present either as a typical antenatal
Table 20-3 Clinical Differences between Bartter and Gitelman Syndromes
Bartter Syndrome
Type 1 (NKCC2) Type II (ROMK) Type III (ClC-Kb) Type IV (Barttin) Gitelman Syndrome
Polyhydramnios þ þ þ þ
Failure to thrive þ þ þ þ
Growth retardation þ þ þ þ
Polyuria þ þ þ þ
Polydipsia þ þ þ þ
Muscle cramps/spasm
Chondrocalcinosis
Nephrocalcinosis þ þ þ
Sensorineural deafness þ
407
408 variant or as a “classic” Bartter variant characterized by onset in
early childhood and less severe or absent hypercalciuria and
nephrocalcinosis. Barttin mutations are usually associated with
an extremely severe phenotype of intrauterine onset that
V includes profound renal salt and water wasting, renal failure,
sensorineural deafness, and motor retardation. Sensorineural
Genetic Basis of Kidney Disease
Treatment
The treatment of Bartter syndrome involves oral potassium
supplementation combined with interventions to reduce dis-
tal potassium secretion including spironolactone and nonste-
roidal anti-inflammatory drugs in addition to oral potassium
supplementation. Adjunctive use of angiotensin-converting
enzyme inhibitors has also been successful. Therapy should
lead to catch-up growth for infants.
Gitelman Syndrome
Pathogenesis
Gitelman syndrome (OMIM 263800) is an autosomal recessive
disorder usually diagnosed in adults. It results from inactivat-
ing mutations in the SLC12A3 gene encoding the thiazide sen-
sitive Naþ/Cl co-transporter, or NCCT. This results in sodium
and chloride wasting with secondary activation of the renin-
angiotensin-aldosterone system. The increased sodium load to
the cortical collecting duct leads to increased sodium reabsorp-
tion by the epithelial sodium channel (ENaC), counterbalanced
by increased potassium and hydrogen excretion, resulting in
hypokalemia and a metabolic alkalosis. Hypocalciuria is due
to enhanced passive Ca2þ transport in the proximal tubule,
rather than active Ca2þ transport in the distal convoluted
tubule. Hypomagnesemia remains unexplained. Down-regula-
tion of the epithelial Mg2þ channel transient receptor potential
channel subfamily M, member 6 (TRPM6) has been recently
demonstrated.
Clinical Presentation
Unlike Bartter syndrome (see Table 20-3), Gitelman syndrome
does not present symptomatically in the neonatal period and
is often discovered incidentally. Patients have a hypokalemic
metabolic alkalosis, but in contrast with Bartter syndrome,
they are hypocalciuric and hypomagnesemic and may not
have signs of overt volume depletion. Polyuria and polydipsia
are not features of Gitelman syndrome. Urinary prostaglandin
E2 levels are normal. The major differential diagnosis of
Gitelman syndrome is diuretic abuse and chronic bulemia.
A careful history, as well as measurement of urinary chloride 409
(low in surreptitious vomiting) and a urinary diuretic screen,
should help differentiate these conditions.
Treatment CH 20
The treatment of Gitelman syndrome includes potassium supple-
11b-Hydroxylase Deficiency
Inactivating mutations in the gene encoding 11b-hydroxylase
(OMIM 202010) are responsible for 5% of cases of congenital
adrenal hyperplasia (90% of cases are caused by 21-hydroxylase
410 deficiency, which is not associated with hypertension). This dis-
ease is associated with excess production of deoxycortisone
(DOC), 18-deoxycortisol, and androgens. DOC has significant
intrinsic mineralocorticoid activity, and high levels trigger
V hypokalemic hypertension. Because the androgen pathway is
unaffected, prenatal masculinization occurs in females and
Genetic Basis of Kidney Disease
17a-Hydroxylase Deficiency
17a-hydroxylase deficiency (OMIM 202110) results in reduced
conversion of pregnenolone to progesterone and androgens,
with absent sex hormone production. The resulting hypogo-
nadism and male pseudohermaphroditism is usually detected
at adolescence because of failure to undergo puberty. Elevated
glucocorticoid-suppressible levels of DOC and corticosterone,
as well as their 18-hydroxylated products, are responsible for
hypertension, hypokalemia, and renin-aldosterone suppression.
In severe 17a-hydroxylase deficiency, both the 17a-hydroxylase
and 17,20-lyase activities are reduced or absent, resulting in
excess mineralocorticoid activity, hypertension, and a universal
female phenotype due to absent sex steroid production in both
the adrenal and gonad. Partial 17a-hydroxylase deficiency
occurs and can present as sexual ambiguity in males, without
hypertension. Corticosteroid replacement corrects ACTH levels
and hypertension. Females usually require hormone replace-
ment, as do genetic males reared as females. Genetic males reared
as males require surgical correction of their external genitalia and
androgen replacement therapy.
Liddle Syndrome
Pathogenesis
Liddle syndrome (OMIM 177200) is an autosomal dominant
form of hypertension characterized by hypokalemia and low
levels of plasma renin and aldosterone, resulting from mutations
in the b- or g-subunits of the amiloride-sensitive epithelial
sodium channel (ENaC) in the distal convoluted tubule and col-
lecting duct. ENaC activity in the kidney is tightly controlled
by several distinct hormonal systems, including aldosterone.
In Liddle syndrome, mutations within the b- and g-subunits of
ENaC lead to constitutive activation of the channel. SCNN1B
b-subunit mutations or SCNN1G g-subunit mutations could lead
to an increase in the number of channels in the membrane or an
increased probability of the channels being open.
Clinical Presentation 411
Constitutive activation of the ENaC causes inappropriate renal
Naþ reabsorption, blunted Naþ excretion, and low-renin
hypertension. Affected individuals are at increased risk of
cerebrovascular and cardiovascular accidents, but renal fail- CH 20
ure is notoriously rare. Liddle syndrome can be differentiated
Treatment
The treatment of AME is sodium restriction and either triamter-
ene or amiloride. Spironolactone is not effective. Additional
antihypertensive agents can be used as needed, particularly in
older patients.
Glucocorticoid-Remediable Hyperaldosteronism
Pathogenesis
Glucocorticoid-remediable hyperaldosteronism (GRA) or familial
hyperaldosteronism type 1 (OMIM 103900) is an autosomal dom-
inant form of hypertension caused by a chimeric gene duplication
arising from unequal crossover between aldosterone synthase and
11b-hydroxylase, two highly similar genes with the same tran-
scriptional orientation lying 45,000 base pairs apart on chromo-
some 8. Normally 11b-hydroxylase is expressed at high levels
and is regulated by ACTH, whereas aldosterone synthase is
expressed at low levels and is regulated by angiotensin II. The
genetic defect in this disorder results in the aldosterone synthase
gene coming under the control of regulatory promoter sequences
of the 11b-hydroxylase. The chimeric gene product is expressed
at high levels in both the zona glomerulosa and zona fasciculata,
and is controlled by ACTH. This leads to increased production of
18-hydroxycortisol and aldosterone metabolites and subsequent
hypokalemic, hyporeninemic hypertension.
Clinical Presentation
The phenotypic spectrum of disease is broad, ranging from
patients with mild hypertension and normal biochemistry to
patients with early onset of severe hypertension, hypokalemia,
and metabolic alkalosis. GRA is associated with high morbidity
and mortality rates from early onset of hemorrhagic stroke and
ruptured intracranial aneurysms (20%). The diagnosis is usually
established by demonstrating high levels of 18-hydroxycortisol
or 18-oxocortisol metabolites in the urine (which are normally
secreted in negligible amounts) or with the dexamethasone sup- 413
pression test. Inhibition of ACTH via glucocorticoid administra-
tion can suppress excessive aldosterone secretion. The diagnosis
of GRA can be definitively established demonstrating the chime-
ric gene by molecular techniques. CH 20
Pseudohypoaldosteronism Type I
Pathogenesis
Pseudohypoaldosteronism type I (PHA-I) is a rare genetically
heterogeneous disorder of which there are two subtypes—an
autosomal recessive form (OMIM 264350 and 177735) with
severe manifestations that persist into adulthood, and an auto-
somal dominant form (OMIM 177735) with milder manifesta-
tions that remit with age. The autosomal recessive form is
caused by inactivating mutations in any of the three subunits
(a, b, g) of ENaC, resulting in resistance to the effects of aldo-
sterone; the autosomal dominant form is due to mutations in
the mineralocorticoid receptor (MR) gene.
Clinical Presentation
Autosomal recessive PHA-I presents in early life with renal salt
wasting, hypotension, hyperkalemia, metabolic acidosis, and on
occasion, failure to thrive. Biochemical features include hypona-
tremia, high plasma and urinary aldosterone levels despite hyper-
kalemia, and elevated plasma renin activity. The differential
diagnosis includes aldosterone synthase deficiency, salt-wasting
forms of CAH, and adrenal hypoplasia congenita. Bartter syn-
drome resulting from mutations in the ROMK gene may present
in the neonatal period with a similar (transient) clinical picture.
Autosomal dominant PHA-I presents with milder manifestations
with remission of the syndrome with age. This is consistent with
progressively reduced dependence on aldosterone.
Treatment
Treatment consists of salt supplementation. Administration of
aldosterone, fludrocortisone, and deoxycorticosterone is not
helpful. Patients with the recessive form usually need lifelong
treatment for salt wasting and hyperkalemia, whereas in the dom-
inant form, treatment can usually be withdrawn in adulthood.
414 INHERITED HYPERKALEMIC HYPERTENSIVE
DISORDERS
Pseudohypoaldosteronism Type II
V
Pathogenesis
Genetic Basis of Kidney Disease
Clinical Presentation
PHA-II is usually diagnosed in adults, but it may also be seen in
the neonatal period. The severity of hyperkalemia varies greatly
and is influenced by prior intake of diuretics and salt. In its
most severe form, it is associated with muscle weakness (from
hyperkalemia), short stature, and intellectual impairment. Mild
hyperchloremia, metabolic acidosis, and suppressed plasma
renin activity are findings variably associated with the trait.
The plasma renin response to upright posture or to a low-
sodium diet is blunted. Aldosterone levels vary from low to high
depending on the level of hyperkalemia. Urinary concentrating
ability, acid excretion, and proximal tubular function are all
normal.
Treatment
Treatment with thiazide diuretics reverses all the biochemical
abnormalities. Lower than average doses can be given if over-
correction is seen.
DIABETES INSIPIDUS 415
Pathogenesis
The major action of arginine vasopressin (AVP) is to facilitate CH 20
urinary concentration by allowing water to be transported pas-
Clinical Presentation
Loss-of-Function Mutations of the AVPR2
X-linked NDI (OMIM 304800) is secondary to AVPR2 muta-
tions that result in loss-of-function or dysregulation of the V2
receptor. Males who have an AVPR2 mutation have a pheno-
type characterized by early dehydration episodes, hypernatre-
mia, and hyperthermia as early as the first week of life.
Dehydration episodes can be life-threatening. The infants are
irritable, cry almost constantly, and although eager to suck,
will vomit milk soon after ingestion unless prefed with water.
The history given by the mothers often includes persistent
constipation, erratic unexplained fever, and failure to gain
weight. Heterozygous females exhibit variable degrees of poly-
uria and polydipsia because of skewed X chromosome inacti-
vation. Historically, mental retardation consequent to
repeated episodes of dehydration was a prevalent feature.
416 Early recognition and treatment of X-linked NDI with an abun-
dant intake of water allows a normal life span with normal
physical and mental development. A variant of this disorder
is autosomal dominant NDI, which occurs secondary to muta-
V tions in the prepro-arginine-vasopressin-neurophysin II gene.
Patients with autosomal dominant NDI retain some limited
Genetic Basis of Kidney Disease
Orofaciodigital syndrome
Tuberous sclerosis
von Hippel-Lindau syndrome
Familial renal hamartomas associated with hyperparathyroidism–
jaw tumor syndrome
Autosomal recessive disease in the differential diagnosis of ARPKD
Meckel-Gruber syndrome
Other multiple malformation syndromes
Hereditary cystic disease with interstitial nephritis
Nephronophthisis
Joubert syndrome
Bardet-Biedl syndrome
Alström syndrome
Medullary cystic kidney disease
Cystic renal dysplasia
Multicystic kidney dysplasia
Hepatocyte nuclear factor-1b mutations
Other cystic kidney disorders
Simple cysts
Localized or unilateral renal cystic disease
Medullary sponge kidney
Acquired cystic kidney disease
Renal cystic neoplasms
Cystic renal cell carcinoma
Multilocular cystic nephroma
Mixed epithelial and stromal tumor
Cystic partially differentiated nephroblastoma
Cysts of nontubular origin
Cystic disease of the renal sinus
Perirenal lymphangiomas
Subcapsular and perirenal urinomas
Pyelocalyceal cysts
Extrarenal Manifestations
Vascular Manifestations. Vascular manifestations include
intracerebral aneurysms (ICAs) and dolichoectasia, thoracic
aortic and cervicocephalic artery dissections, and coronary
424 artery aneurysms, caused by alterations in the vasculature
directly related to mutations in PKD1 or PKD2. ICAs occur
in approximately 6% of patients with a negative family history
and approximately 16% of patients with a clear family his-
V tory of cerebral aneurysm; angiographic screening (usually mag-
netic resonance angiography) is reserved for individuals with a
Genetic Basis of Kidney Disease
Novel Therapies
Improved understanding of the pathophysiology of ADPKD
has facilitated the development of preclinical trials, with
identification of promising targets for therapy and candidate
drugs.
Vasopressin V2 receptor (VPV2R) antagonists have been
undergoing trials, given the inhibitive effect of vasopressin
on cAMP levels in the collecting duct, the major site of cyst
formation in ADPKD, and the role of cAMP in cystogenesis,
resulting in reduction of renal cysts in rodent models. Phase
III clinical trials are underway.
cAMP accumulation in the liver and kidney is inhibited by
somatostatin acting on SST2 receptors. Octreotide, a synthetic
metabolically stable somatostatin analog, has been shown to
halt the expansion of both hepatic and renal cysts in the
PKD rat.
Recently, mTOR (mammalian target of rapamycin) activa-
tion in polycystic kidneys and an interaction between poly-
cystin-1 and the tuberous sclerosis protein tuberin have been
reported. Rapamycin has been shown to significantly inhibit
cyst expansion and protect renal function. Phase II clinical
trials of the mTOR inhibitors rapamycin and everolimus are
being implemented.
Material to educate patients and their families about
ADPKD can be obtained through the Polycystic Kidney Dis-
ease Foundation (www.PKDcure.org).
426 Autosomal Recessive Polycystic Kidney Disease
Therapy
The newborn with pulmonary hypoplasia usually succumbs
to pulmonary insufficiency within the first few days. Nonethe-
less, until the degree of the pulmonary insufficiency and its
cause can be assessed fully, artificial ventilation and aggres-
sive resuscitative measures are indicated. Severely affected
neonates may require unilateral or bilateral nephrectomies
because of nutritional and respiratory compromise. Early
institution of dialysis has been used successfully, with perito-
neal dialysis the modality of choice in infants with ESRD.
Patients with less severe ARPKD who survive the newborn
period invariably develop progressive renal failure. Aggres-
sive nutritional supplementation and correction of acid-base
and electrolyte disorders are required to optimize linear
growth. Renal transplantation is the treatment of choice. Pre-
transplant splenectomy may be required in patients with
severe leukopenia or thrombocytopenia due to hypersplenism.
Biliary sepsis is a frequent complication in ARPKD patients
who undergo transplant surgery. Combined kidney/liver
transplant has been advocated for ESRD patients with signifi-
cant bile duct dilatation and recurrent cholangitis.
Emotional support and educational material for families
can be obtained through the Polycystic Kidney Foundation
(www.PKDcure.org).
Diagnosis
ACKD develops insidiously. Most patients are asymptomatic,
but when symptoms do occur, gross hematuria, flank pain,
renal colic, fever, palpable renal mass, and rising hematocrit
are most common. Retroperitoneal hemorrhage may present
with acute pain, hypotension, and shock. Sonography reveals
the bilateral cystic process in advanced cases and is useful in
the detection of neoplasms. However, CT, with or without
contrast enhancement, is the preferred diagnostic technique
and is better at distinguishing between simple cysts and
ACKD. MRI may be particularly useful for the diagnosis of
neoplasms, without the attendant risk of contrast nephro-
pathy, and when CT findings are indeterminate. Distinction
from ADPKD and from multiple simple cysts usually is sug-
gested by the generally smaller size of the kidneys and of the
individual cysts in ACKD, by the usual absence of hepatic
cysts, and by the family and patient histories.
Therapy
Bleeding episodes, either intrarenal or perirenal, often may be
treated conservatively with bed rest and analgesics. Persistent
hemorrhage, however, may require nephrectomy or therapeutic
renal embolization and infarction. Because the risk of unde-
tected renal cell carcinoma is high in patients with
retroperitoneal hemorrhage, nephrectomy is recommended in 429
those cases in which carcinoma cannot be ruled out. Due to
the associated risk of renal cell carcinoma, CT screening has
been recommended after 3 years of dialysis, followed by
screening for neoplasm at 1- or 2-year intervals thereafter. Renal CH 21
masses larger than 3 cm detected in ACKD are treated by exci-
V
Medullary Cystic Kidney Disease
Genetic Basis of Kidney Disease
SIMPLE CYSTS
RENAL DYSPLASIA
Hypertension
High blood pressure (BP) is a leading risk factor for heart dis-
ease, stroke, and kidney failure. It is estimated that 50 million
people in the United States are hypertensive. However, fewer
than 30% of all hypertensive patients have adequate BP con-
trol. In general, the upper limits of normal BP in older persons
have been considered to be a systolic value of 140 mm Hg and
a diastolic value of 90 mm Hg. These figures may be adjusted
downward for younger patients to the point that readings in
excess of 120/80 mm Hg may be considered hypertensive.
Clinical studies indicate that relatively higher BPs that are
casually recorded, even those that are within the normal
range, are statistically associated with increased mortality rate
from cardiovascular complications. It is well established that
antihypertensive treatment provides a significant degree of
protection against such complications as congestive heart fail-
ure (CHF), renal failure, and stroke, but not coronary artery
disease. Nonetheless, the risks of death and disability asso-
ciated with hypertension are increased only in the broad sta-
tistical sense; a large majority of patients with hypertension
live lives of normal longevity and health. Thus, risks are
apparently not distributed randomly but are concentrated in
subgroups of patients that have proved difficult to accurately
identify. For these and other reasons, hypertension cannot be
considered a discrete disease entity but must be considered a
factor common to the development of several pathologic
events. Thus, hypertension is a physical sign and a risk factor
to be assessed in conjunction with other physiologic and envi-
ronmental factors.
NOMENCLATURE
439
440 However, it should be noted that the relationship between
blood pressure and cardiovascular risk moves along a contin-
uum; thus, any discrete numeric criteria for the classification
of hypertension should be considered arbitrary.
VI Essential hypertension: The pathophysiologic mechanism
underlying hypertension is unknown in approximately 90%
Hypertension and the Kidney
Hypertension
nephrocalcinosis; neoplasms; glomerulosclerosis
Obstructive uropathies and hydronephrosis
Renin-secreting renal tumors
Congenital defect in renal sodium transport (Liddle syndrome)
Renovascular
Renal arterial lesions, occlusions, stenoses, aneurysms,
thromboses
Coarctation of the aorta with renal ischemia
Adrenocortical disorders
Cushing syndrome (cortisol excess)
Primary aldosteronism (Conn syndrome)
Pseudoprimary aldosteronism (bilateral adrenocortical hyperplasia)
Congenital or acquired enzymatic defects with excess Naþ-retaining
steroids (11b-hydroxylase deficiency, 11b-hydroxysteroid
dehydrogenase deficiency, 17-hydroxylase deficiency)
Adrenal carcinoma
Ectopic corticotropin-secreting tumor
Pheochromocytoma
Other endocrine causes
Hypothyroidism (diastolic hypertension)
Hyperthyroidism (systolic hypertension)
Hypercalcemic states
Acromegaly
Toxemias of pregnancy
Neurogenic factors
Increased intracranial pressure
Familial dysautonomia
Acute porphyria, buffer denervation, poliomyelitis, spinal cord
injuries
COMPLICATIONS OF HYPERTENSION
Defining the Risk of Hypertensive Complications
Practice guidelines for the treatment of hypertension are tradi-
tionally based on the premise that a discrete cut point sepa-
rates normotension and hypertension. There is, in fact, a
continuous, graded, and independent relationship between
the height of the BP and the incidence of cardiovascular dis-
ease and stroke. Hypertension is not the sole determinant of
cardiovascular risk and whether, and how soon, these compli-
cations occur in an individual hypertensive patient appears to
be strongly determined by the concurrence of other risk fac-
tors, such as left ventricular hypertrophy (LVH), glucose intol-
erance, smoking, hypercholesterolemia, and obesity. In fact,
only some hypertensive individuals will have a heart attack
or stroke even at the highest end of the BP range and more
than half of all heart attacks, and almost half of all strokes,
occur in normotensive individuals. Thus, there is no thresh-
old BP that distinguishes patients at risk.
Cardiovascular Disease
The Framingham Heart Study confirmed the finding that high
BP is a leading risk factor predisposing to stroke, heart failure
(HF), heart attack, and kidney failure.
The relative importance of systolic, diastolic, and more
recently, pulse pressure components of BP as predictors of
cardiovascular risk have been analyzed. Under age 50 years,
diastolic BP is the strongest predictor. Between ages 50 and
59 years, all three BP components are comparable predictors.
However, from age 60 years onward, both systolic BP and
pulse pressure are significant predictors of the risk of illness
and death due to cardiovascular disease (CVD).
Electrocardiographic evidence of LVH (ECG-LVH) is pres-
ent in about 3% to 8% of hypertensive individuals. When
ECG-LVH is identified, clinical manifestations of CVD occur
at a rate that is about threefold higher than that in the general
population. About 12% to 30% of unselected hypertensive
adult patients will have echocardiographic increases in LV
mass. As compared with hypertensive persons with a normal 443
LV geometry, those with concentric LVH had about 10-fold
greater total mortality rate and about 5-fold higher rate of car-
diovascular events. It is notable that studies have demon-
strated that the risk of having LVH is almost twice as high CH 22
for blacks as for whites.
Hypertension
Stroke
Stroke is the third most common cause of death in the United
States and is the most feared and devastating complication of
hypertension. Ischemic strokes predominate in hypertensive
individuals, accounting for 80% of all strokes, followed by
the hemorrhagic type. There is a direct, graded, positive asso-
ciation between BP and stroke risk, down to at least 115 mm
Hg systolic BP and 75 mm Hg diastolic BP, below which there
is little evidence. In the Framingham study, definite hyperten-
sion (160/95 mm Hg) was associated with a 2.5-fold higher
relative risk of stroke, after adjustment for other known car-
diac risk factors.
Heart Failure
Hypertension is the most common condition antedating HF,
with a two- to threefold higher risk than for normotensive sub-
jects and with a graded increase in risk at higher pressure.
This risk is amplified further when ECG-LVH or echo-LVH
findings are present. Diastolic dysfunction plays an important
role in the pathogenesis of HF in the hypertensive population.
Treatment of hypertension decreases the risk of HF, with an
approximately 50% reduction in the occurrence of HF in
hypertensive patients who received medication compared
with those who receive placebo.
Microalbuminuria
Microalbuminuria occurs in approximately 6% to 40% of
individuals with primary hypertension, with the prevalence
increasing with age and duration of hypertension. The pres-
ence of microalbuminuria is associated with a significantly
higher prevalence of LVH, coronary artery disease, myocardial
infarction (MI), hyperlipidemia, and peripheral vascular
disease.
Effective reduction in BP with antihypertensive medication
can decrease the urinary excretion of albumin. Although there
is evidence that angiotensin-converting enzyme (ACE) inhibi-
tors may be more effective in accomplishing this goal, this
effect has been reported with several different classes of anti-
hypertensive agents. It has not been established whether the
treatment-related reduction in albumin excretion, per se, is
associated with a decline in cardiovascular risk in patients
with essential hypertension, or whether this change simply
reflects the decline in BP.
Hypertension
tensive medications. The benefit was manifested by a reduced
frequency of strokes, CHF, and dissection of the aorta but not of
ischemic cardiac events. Notably, no benefit was achieved among
the patients with diastolic BP below 105 mm Hg. Furthermore,
a particularly relevant finding was that the major benefit in the
group with diastolic BPs between 105 and 115 mm Hg was rea-
lized by those patients who had displayed evidence of preexisting
cardiovascular disease on entering the study, or who were
50 years of age or older. Subsequent trials have confirmed the
benefit of antihypertensive treatment in patients with milder
forms of hypertension. Once again the primary benefit is a reduc-
tion in stroke incidence, but beneficial effects on the development
of CHF and ischemic cardiac events have also been demonstrated.
Antihypertensive treatment in the elderly significantly
reduces all-cause and cardiovascular mortality rates. These
benefits are greater in male patients with higher baseline risk
status, such as prior cardiovascular complications. In a more
recent meta-analysis of treatment trials encompassing 80,000
patients, prevention of coronary heart disease was attributed
primarily to the reduction in systolic BP and to ACE inhibitor
use, whereas prevention of stroke was most closely associated
with systolic BP reduction and calcium channel blocker use.
Ischemic Stroke
BP rises during acute stroke in previously treated hypertensive
patients and even in previously normotensive patients. Cere-
bral autoregulation is disrupted during acute ischemic stroke
and marked decrements in cerebral blood flow can occur with
inappropriate reductions in BP. When left untreated during an
ischemic stroke, BP decreases to baseline level within 1 to 4
days. Although severe hypertension during an ischemic stroke
has been reported to augur a poor prognosis, there is no con-
vincing evidence to support acute pharmacologic reduction in
BP in this setting. Randomized, controlled clinical trials indi-
cate that antihypertensive drug treatment during an ischemic
stroke does not improve clinical outcome and, in fact, may
worsen it. Precipitous declines in BP during treatment with
direct vasodilators (e.g., nitroprusside, nifedipine, hydralazine)
may cause catastrophic consequences.
Therefore, BP should be allowed to decrease spontaneously
during the first few days after an ischemic stroke. Antihyper-
tensive treatment may be indicated when a concurrent medi-
cal condition exists, such as acute aortic dissection or MI.
Hemorrhagic Stroke
Hypertension occurs commonly in the early period following
intracerebral hemorrhage. It is more severe and, in contrast
to the BP elevation during ischemic stroke, is less likely to
spontaneously improve during the first few days after presen-
tation. Severe hypertension is a common feature of subarach-
noid hemorrhage. Nimodipine, a dihydropyridine calcium
channel blocker, significantly improves outcome in patients
with subarachnoid hemorrhage. However, transient hypoten-
sion is a relatively common side effect of nimodipine, particu-
larly when it is administered intravenously.
Treatment with a dihydropyridine calcium channel blocker
during the early period after intracerebral or subarachnoid
hemorrhage causes a significant reduction in mean arterial
pressure and mean cerebral perfusion pressure, while simulta-
neously increasing mean intracerebral pressure. The adverse
hemodynamic responses to dihydropyridine calcium channel
blockers may account for their limited therapeutic efficacy 447
reported in treatment trials.
Hypertension
General Principles
The evaluation of a new patient with high BP relies on a
complete history and physical examination and the routine
application of appropriately chosen laboratory tests. A thor-
ough initial evaluation can avoid the prescription of needless
or inappropriate drugs for the lifetime commitment that
hypertension may often require, and can reveal surgically
curable hypertension or other important medical diseases.
Multiple visits have the advantage of defining the persistence
or lability of the hypertensive process. In general, the milder
or more labile the hypertension is, the longer the evaluation
period will be before commitment to therapy. Unless the
hypertension is severe or complications are impending or
present, treatment should be withheld throughout the
evaluation.
Medical History
Hypertension
the hypertension. An abrupt onset of hypertension with rapid
progression, especially in young or old patients, should lead
the physician to a strong suspicion of renovascular hyperten-
sion due to either fibromuscular hyperplasia or an atheroscle-
rotic plaque, respectively. This suspicion is reinforced by
retinopathy or by cardiac or renal involvement, all of which
are likely to be more prominent in renovascular hypertension.
Polyuria or nocturia may indicate more severe renal hyperten-
sion or a metabolic abnormality such as hypokalemia or
hypercalcemia. Inability to concentrate the urine, with poly-
dipsia, polyuria, and nocturia, commonly occurs in patients
with primary aldosteronism or malignant hypertension or in
chronic renal disorders, including glomerulonephritis, tubu-
lointerstitial nephropathy, or obstructive uropathy. Muscle
weakness may accompany hypokalemia or hypercalcemia.
Patients should be asked about their smoking, drinking,
exercise, and dietary habits. Obesity can be an important fac-
tor in producing or amplifying hypertension. Excessive regu-
lar consumption of alcohol can also induce or aggravate
hypertension, and in some patients, cessation of the habit
may correct the hypertensive process. Tobacco, because it is
a known vasoconstrictor, is especially contraindicated in
hypertensive subjects, even though no causal relationship
between smoking and the development of essential hyperten-
sion has been defined. The risk factor analysis is completed
by the identification of any target organ damage and of any
other coexisting diseases.
Physical Examination
Special Aspects
The general appearance is unrevealing in most patients with
hypertension. However, a florid facies—with or without a ten-
dency for rapid color changes, which would suggest vasomo-
tor instability—may signify an underlying metabolic process,
perhaps pheochromocytoma, a hyperdynamic circulation, or
hyperthyroidism. A ruddy complexion with a bluish tinge
characterizes some patients with essential hypertension and
reactive polycythemia (Gaisböck syndrome). Truncal obesity
with moon facies, frontal baldness, atrophic extremities with
abdominal striae, atrophy of the skin, and spontaneous ecchy-
moses suggests Cushing syndrome.
450 Blood Pressure
In the vast majority of hypertensive patients, elevated BP is the
only abnormal finding. Hence, the way in which the BP is
measured assumes great importance. The patient should be
VI seated quietly, and a cuff size appropriate to the arm diameter
should be chosen. Several readings should be taken, and it is
Hypertension and the Kidney
Fundus
Ophthalmoscopic examination of the optic fundi is one of the
most valuable clinical tools for assessing target organ damage,
the severity and duration of the hypertension, and the urgency
for applying treatment.
Heart
A forceful apical thrust is common even in early hypertensive
disease and may be exaggerated in the so-called hyperdynamic
state. In contrast, a sustained, heaving LV pulse indicates sign-
ificant hypertrophy due to pressure overload. Probably the ear-
liest physical sign of cardiac involvement is the fourth heart
sound, the atrial gallop, which is occasionally heard in normal
patients. It is usually audible before cardiac enlargement is
detectable, and is said to reflect a reduced ventricular compli-
ance leading to a more forceful atrial contraction. The third
heart sound may be a late manifestation of hypertensive heart
disease and reflects the early diastolic compliance abnormality
of LV failure. In severe hypertension, an accentuated aortic sec-
ond sound may be accompanied by an aortic insufficiency mur-
mur. It suggests dilation of the aortic root and may indicate the
need for more urgent therapy.
Vascular System 451
Bruits and thrills, indicative of occlusive disease, are more
prevalent in hypertensive patients and may occur throughout
the arterial tree. Accordingly, the physician should examine
the carotid arteries, abdominal aorta, renal arteries, and femo- CH 22
ral arteries. A diastolic component to a bruit or palpable thrill
Hypertension
over a peripheral vessel usually suggests a higher-grade steno-
sis. When pulses in the lower extremities are absent or damp-
ened, coarctation of the aorta should be suspected in a young
person, and occlusive aortic femoral disease should be sus-
pected in an older one.
Abdomen
The aorta should be palpated carefully in all patients inas-
much as possible, as aortic dilation or aneurysm is a highly
treatable condition best identified at the initial physical exam-
ination. A systolic and diastolic bruit in the upper epigastrium
or in one or both upper quadrants of the abdomen suggests
renal artery stenosis. A palpable enlargement of one or both
kidneys may suggest polycystic renal disease, hydronephro-
sis, or a renal tumor.
Neurologic Examination
Gross neurologic deficits in sensory or motor function, menta-
tion, or mood are not likely to be ignored. More subtle deficits
suggesting transient cerebral ischemia or autonomic dysfunc-
tion may be overlooked and should be sought clinically, espe-
cially when the history is suggestive.
Hypertension
tial hypertension or when it is measured during antihyperten-
sive treatment with agents that affect renin secretion. If the
biochemistry is suggestive of primary aldosterone excess, then
a thin-slice adrenal CT can help identify an adenoma. The
approach to the patient with suspected renovascular hyper-
tension is outlined in Chapter 23, Renovascular Hypertension
and Ischemic Nephropathy.
RENIN-DEPENDENT FORMS OF
HYPERTENSION
Unilateral Renovascular Hypertension
Unilateral renovascular hypertension is discussed in Chapter 23.
Pheochromocytoma
Pheochromocytoma (PHEO) is a catecholamine-producing
tumor arising from chromaffin cells of the adrenal medulla
or extra-adrenal paraganglia. The hemodynamic and meta-
bolic manifestations of PHEO are caused by catecholamine
excess in addition to high plasma renin levels that are a conse-
quence of catecholamine-induced renal ischemia. In hyper-
tension referral clinics, the prevalence is approximately 0.5%.
Many of the signs and symptoms of PHEO are related to the
direct actions of catecholamines. Although the classic triad of
headache, paroxysmal sweating, and tachycardia in a hyperten-
sive patient has a diagnostic sensitivity and specificity exceeding
90%, fewer than 10% of patients present in this way. Metabolic
effects include hyperglycemia, lactic acidosis, and weight loss.
Although hypertension is usually present, BP may be quite vari-
able and some cases are now detected incidentally by imaging.
Sustained hypertension with paroxysmal increases is relatively
common and may be associated with a hypertensive crisis. The
occurrence of unexplained orthostatic hypotension in patients
with sustained hypertension is a clue that PHEO may be present.
Hypotension and shock may be the presenting clinical signs.
Cardiovascular complications are common, most notably
atrial and ventricular fibrillation, myocarditis with dilated
cardiomyopathy, vasospastic coronary artery disease, and
cardiogenic or noncardiogenic pulmonary edema. During
pregnancy, PHEO can cause severe hypertension, with
454 cardiovascular and neurologic complications. The diagnosis
of PHEO during pregnancy, the presentation of which can
mimic preeclampsia, is associated with maternal mortality
rate of 4% and fetal loss rate of 11%.
VI Germline mutations in five genes have been identified to be
responsible for familial PHEOs: the von Hippel-Lindau syn-
Hypertension and the Kidney
Laboratory Tests
All patients with suspected PHEO should undergo biochemi-
cal evaluation. Indications for testing include (1) episodic
headaches, tachycardia, diaphoresis (regardless of whether
hypertension is present), (2) family history of PHEO, (3) his-
tory, signs, or symptoms of a multiple endocrine neoplasia
(MEN) syndrome (e.g., medullary thyroid carcinoma), (4) inci-
dentally discovered adrenal mass, (5) hypertension with
equivocal increases in catecholamine production, and (6)
markedly elevated BP or hemodynamic instability, especially
during induction of anesthesia or surgical procedure.
Plasma and Urinary Free Metanephrines. Plasma free meta-
nephrines and normetanephrines have a diagnostic sensitivity
exceeding 95% and specificity of approximately 85%. In compar-
ison, 24-hour urinary total metanephrines and catecholamines
have a sensitivity of 90% and specificity of 98%. The higher spec-
ificity of the urinary measurements yield fewer false-positive
results and, thus, may be preferable for screening low-risk
patients. Plasma concentrations of free metanephrines are rela-
tively independent of renal function and are, therefore, more
suitable for screening patients with concurrent kidney disease.
Catecholamines. There is no relationship between the
height of the BP and the plasma catecholamine levels. There-
fore, plasma catecholamine levels can have diagnostic value
regardless of whether the patient is symptomatic or hyperten-
sive at the time the sample is obtained. Resting plasma cate-
cholamine levels (sum of norepinephrine and epinephrine)
are abnormal when elevated above 2000 pg/mL and are nor-
mal below 500 pg/mL. PHEO is very unlikely to be present
when catecholamine levels are normal in the patient with a
markedly elevated BP. Values between 500 and 2000 pg/mL
are equivocal and the sampling should be repeated.
Clonidine Suppression Test. In most cases of PHEO, cate-
cholamine and plasma free metanephrine levels are markedly
elevated. However, when equivocal levels of plasma catecho-
lamines or plasma metanephrines are found, then further eval-
uation with a clonidine suppression test is indicated. Failure
to suppress plasma catecholamine levels after acute clonidine 455
administration is highly predictive of PHEO, with both false-
positive and false-negative rates of 2%.
Several relatively common disorders, including HF, stroke,
autonomic dysfunction, alcohol withdrawal, cocaine use, clo- CH 22
nidine withdrawal, and vasodilator therapy are associated
Hypertension
with increased levels of catecholamines and, thus, can lead
to a false-positive screening test for PHEO.
b-Adrenergic receptor blockers (b-blockers), including the
combined a1- and b-blocker labetalol, have been associated with
60% of all false-positive elevations of plasma metanephrines;
phenoxybenzamine and tricyclic antidepressants have been
associated with up to 45% of all false-positive elevations of
plasma normetanephrine and norepinephrine (NE). Calcium
channel blockers have been associated with a significantly higher
prevalence of false-positive elevations of plasma and urinary NE
levels as well as the urinary epinephrine level. By contrast, other
antihypertensive agents, including ACE inhibitors, ARBs, and
diuretics, had little influence on the frequency of false-positive
biochemical results of these plasma and urinary analytes.
Tumor Localization
To avoid unnecessary radiographic procedures, tumor locali-
zation should be attempted only after the diagnosis of PHEO
has been confirmed by biochemical testing. Most tumors
(95%) are found within the abdomen. The most common
extra-adrenal locations are the superior and inferior paraortic
areas (75% of extra-adrenal tumors), the bladder (10%), the
thorax (10%), and the head, neck, and pelvis (5%). Extra-adrenal
PHEOs probably represent up to 15% of adult and 30% of
childhood PHEOs.
MRI with gadolinium enhancement and CT scans identify
lesions with a diameter greater than 0.5 cm with diagnostic
sensitivities approaching 100% and specificities ranging from
70% to 80%. However, MRI is superior for detecting extra-
adrenal PHEO. Metaiodobenzylguanidine (MIBG) scintigra-
phy employs radioisotopes with chemical similarities to NE
that allow it to enter the metabolic pathway into and out of
storage granules. However, false-negative MIBG scan results
can occur when patients are also treated with drugs that block
the catecholamine transport mechanism (e.g., tricyclic antide-
pressants, guanethidine, phenylpropranolamine).
Medical Treatment
Surgical resection of PHEO is the definitive treatment. The goal
of preoperative treatment is to optimize the patient’s cardiovas-
cular status and, thus, prevent perioperative complications.
Prospective clinical trials of various drug treatment regimens
456 have not been performed. However, we utilize the following
preoperative medical regimen in patients with PHEO:
a-Adrenergic Receptor Blockade. Phenoxybenzamine
should be commenced 2 to 4 weeks prior to surgery, with an ini-
VI tial dose of 20 mg/day, increasing to 40 to 100 mg daily as neces-
sary. If postural hypotension occurs preoperatively during
Hypertension and the Kidney
Hypertension
OF HYPERTENSION
Primary Hyperaldosteronism
Primary hyperaldosteronism (PAL) describes the clinical syn-
drome characterized by hypertension, hypokalemia, hyperna-
tremia, alkalosis, and periodic paralysis caused by an
aldosterone-secreting adenoma. There are distinct subsets of
PAL. The majority of patients with PAL can have hyperten-
sion and metabolic abnormalities ameliorated by unilateral
adrenalectomy due to an aldosterone-producing adenoma. A
subset of patients with autonomous aldosterone production
do not manifest adrenal adenomas. This variant has been
referred to as primary adrenal hyperplasia (PAH).
Glucocorticoid-Remediable Aldosteronism
Glucocorticoid-remediable aldosteronism (GRA), also termed
familial hyperaldosteronism type 1 (FH-1), is an autosomal
dominant disorder in which aldosterone biosynthesis is regu-
lated by adrenocorticotropic hormone (ACTH), rather than by
the RAAS. The exaggerated aldosterone responsiveness to
ACTH in GRA can be corrected by glucocorticoid treatment.
Clinical features include a strong family history of hyperten-
sion, early-onset hypertension, and an increased risk of intra-
cerebral hemorrhage or aortic dissection.
The most common routine laboratory finding is a low plasma
renin activity (PRA) level; however, other biochemical evi-
dence of aldosterone excess may be absent (e.g., hypokalemia).
A key diagnostic feature is the overproduction of 18-
hydroxycortisol and 18-oxocortisol, which are formed when
cortisol is accepted by aldosterone synthase as a substrate for
methyloxidation.
GRA is caused by a chimeric gene duplication resulting
from the fusion of the ACTH-responsive promoter region of
the 11-hydroxylase gene and coding sequences of the aldoste-
rone synthase gene. It results in ectopic expression of aldoste-
rone synthase activity in the cortisol-producing zona
fasciculata that is stimulated by ACTH instead of angiotensin
II. Treatment of this syndrome with low doses of exogenous
glucocorticoid inhibits ACTH secretion, suppresses aldoste-
rone production, thereby promoting natriuresis, normalizes
PRA, and consequently reduces BP and corrects the metabolic
abnormalities caused by mineralocorticoid excess.
458 The preferred diagnostic test for GRA is direct genetic analy-
sis to identify the chimeric CYP11B1/CYP11B2 gene. Other tests
include 24-hour urine collection demonstrating overproduction
of cortisol C-18 oxidation metabolites (i.e., 18-hydroxycortisol,
VI 18-oxocortisol), and the dexamethasone suppression test.
Hypertension and the Kidney
Liddle System
Liddle syndrome is an autosomal dominant condition charac-
terized by low renin hypertension, hypokalemia, renal potas-
sium wasting, and low levels of aldosterone. The genetic
defects responsible for this syndrome are mutations in the
C-terminus of the b/g-subunits of the renal epithelial Na
channel (ENaC). These gain-of-function mutations lead to con-
stitutive activation of ENaC, resulting in electrogenic Na reab-
sorption and kaliuresis. Amiloride, which blocks the apical
Na channel, is effective treatment.
Epidemiology 459
Hypertension
of plasma aldosterone to plasma renin activity (PRA), suggest that
the prevalence of PAL may be higher than previously believed.
Clinical Characteristics
Symptoms include nocturia and urinary frequency, reflecting the
urinary concentrating defect induced by the potassium deficit.
In patients with more severe hypokalemia, other manifestations
including muscular weakness, frontal headaches, polydipsia,
paresthesias, visual disturbances, temporary paralysis, cramps,
and tetany may occur. If the patient is normokalemic, these
characteristic symptoms are usually mild or absent.
Patients with an adenoma, however, usually have more exten-
sive manifestations of mineralocorticoid excess than those with
hyperplasia, including more severe hypertension. The physical
examination is not usually distinguishable from primary hyperten-
sion, unless hypokalemia is severe. Serum potassium levels are
significantly lower in adenoma patients (<2.8 mEq/L in >40%)
compared with patients with hyperplasia (<2.8 mEq/L in <10%).
The profound hypokalemia that occurs in patients with an ade-
noma contributes to the development of a metabolic alkalosis.
Diagnostic Tests
The diagnostic tests described are designed to (1) screen the
large hypertensive population for PAL and (2) identify
patients with surgically remediable subtypes of PAL.
Unprovoked hypokalemia is the hallmark of hyperaldosteron-
ism, but as already discussed, serum Kþ levels between 3.5 and
4 mEq/L are relatively common in patients subsequently proven
to have PAL. Moreover, patients with primary hypertension may
exhibit hypokalemia, especially during treatment with thiazide
and loop diuretics. Monitoring serum Kþ following salt loading
is required to identify the entity of normokalemic PAL.
VI Aldosterone-Renin Ratio
An elevated aldosterone-renin ratio (ARR) is an indicator of
Hypertension and the Kidney
Hypertension
therefore, additional volume expansion does not decrease
aldosterone levels to the same extent as in normal subjects
or patients with primary hypertension.
1. Oral Na loading for 3 to 5 days with 200 mEq/day or more
(5 g Na/day)
2. Intravenous saline loading: Plasma aldosterone is
measured after the infusion of 2 L 0.9% NaCl over 4 hours.
3. Fludrocortisone suppression test: Plasma aldosterone and
cortisol levels are measured in an upright position at
10:00 AM after 4 days of administration of fludrocortisone
(0.1 mg every 6 hours) and NaCl supplementation
(30 mEq thrice daily) with a corresponding 24-hour urine
Na excretion rate of 3 mEq/kg/day.
Lateralizing Tests
Adrenal Vein Sampling
The diagnostic tests reviewed previously provide the bio-
chemical evidence necessary to confirm the diagnosis of
PAL. Adrenal CT and MRI scanning lack sufficient sensitivity
and specificity to identify adrenal tumors less than 1.5 cm
diameter and thus cannot reliably distinguish APA from bilat-
eral adrenal hyperplasia.
The ability to measure plasma aldosterone concentration
(PAC) from selectively catheterized adrenal veins has added
an important dimension to the localization of APAs. Techni-
cal problems that are encountered during adrenal vein sam-
pling include (1) difficulty in catheterizing the short right
adrenal vein, (2) trauma, including adrenal hemorrhage that
can result in acute adrenal insufficiency, (3) dilution of the
sample by blood from nonadrenal sources, and (4) the epi-
sodic changes in aldosterone secretion coincident with
changes in cortisol. Most of these problems can be controlled
by careful catheter localization, simultaneous plasma cortisol
measurements to document appropriate catheter placement,
and collection of blood during ACTH administration.
Diagnostic Strategy
The results of diagnostic screening of patients with this syn-
drome are often ambiguous, especially when the serum
462 potassium level is in the normal range. Some relatively simple
tests can improve the diagnostic accuracy:
• 24-hour urinary aldosterone excretion rate 14 mg or greater
and a PRA less than 1 ng/mL/hour, after Na loading for at
VI least 3 days (urinary Na content > 200 mEq/day)
• ARR greater than 50, with a concurrent serum aldosterone
Hypertension and the Kidney
Treatment
Idiopathic Hyperaldosteronism (Bilateral Adrenal
Hyperplasia)
The cornerstone of medical therapy in PAL caused by idio-
pathic hyperaldosteronism is a mineralocorticoid receptor
antagonist (i.e., spironolactone, eplerenone). Side effects of
PRA
CH 22
Hypertension
<0.65 mg/hr ≥0.65 mg/hr
Yes
Na loading
K repletion
24 hr urine:
• Na > 200 mEq No Check cortisol
• Aldosterone ≥ 15 mg DOC
Plasma aldosterone > 15
Yes
Positive
GRA screen Medication
Negative
Adrenal CT scan
Ancillary tests
Postural stimulation
Unilateral Plasma 18-OHB
adrenalectomy 24 hr urine 18-OHF
Positive Negative
Aldosterone-Producing Adenoma
Laparoscopic unilateral adrenalectomy is now the standard of
care for patients with an APA. Although more than 90% of
patients will have their BP controlled postoperatively, antihy-
pertensive medication is required in 40% to 70%. Factors that
have been associated with persistent hypertension after uni-
lateral adrenalectomy include age older than 50 years, dura-
tion of hypertension, increased serum creatinine, one first-
degree relative with hypertension, and preoperative use of
more than two antihypertensive medications.
Hypertension
study, a diet rich in fruits, vegetables, and low-fat dairy products,
in addition to dietary sodium restriction intake, significantly low-
ered systolic BP (8–14 mm Hg). These BP lowering effects were
observed in both black and white subjects and were comparable
in obese and nonobese subjects. However, only a relatively small
percentage of patients will achieve a goal BP of less than 140/90
mm Hg with nonpharmacologic intervention alone; therefore,
pharmacologic therapy is required in most cases.
The drug treatment of the hypertensive patient requires a
complex decision-making process. It is complicated by the
fact that there are many pharmacologically distinct drug
classes available, all of which effectively lower the BP
and have been demonstrated to reduce the complications
of hypertension. In uncomplicated patients, the initial drug
of choice according to Joint National Committee on Preven-
tion, Detection, Evaluation, and Treatment of High Blood
Pressure (JNC) VII guidelines should be a thiazide diuretic
either alone or in combination with an agent previously
demonstrated to have a beneficial affect on cardiovascular out-
comes (ACE inhibitor, ARB, b-blocker, or calcium channel
blocker). If the BP is considerably above goal (>160/100 mm Hg),
consideration should be given to commencing two agents
from the outset. Indeed, most patients will require at least
two medications to achieve adequate control. In certain clinical
circumstances, specific antihypertensive agents are indicated
(Table 22-2). An algorithm outlining the approach to treat-
ment of essential hypertension is given in Figure 22-2.
The class effects and side effects of the individual agents
are discussed in Chapter 26, Diuretics, and Chapter 25, Antihy-
pertensive Drugs. The management of hypertensive emergen-
cies is discussed in Chapter 25, Antihypertensive Drugs.
b-Blocker
Aldosterone antagonist
Angina pectoris b-Blocker
Long-acting CCB
Post-myocardial infarction ACE inhibitor
b-Blocker
Aldosterone antagonist
Left ventricular hypertrophy All classes except a-blockers and
hydralazine
Diabetes mellitus ACE inhibitor
ARB
CCB
Thiazide diuretic
b-Blocker
Diabetic microalbuminuria Type 1: ACE inhibitor
Type 2: ARB
Chronic kidney disease ACE inhibitor
(especially if proteinuric) ARB
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CCB,
calcium channel blocker.
REFRACTORY HYPERTENSION
See Chapter 25, Antihypertensive Drugs.
Lifestyle modifications 467
Not at goal BP
CH 22
(<140/90 mm Hg or <130/80 mm Hg
Hypertension
for patients with diabetes mellitus or CKD)
Not at goal
Renovascular Hypertension
and Ischemic Nephropathy
The clinical manifestations of renovascular disease include
the following:
• Asymptomatic “incidental” renal artery stenosis (RAS)
• Renovascular hypertension
• Ischemic nephropathy
• Accelerated cardiovascular disease
• Congestive heart failure/stroke/secondary hyperaldosteronism
Each of these clinical manifestations presents different
co-morbid and risk factor management issues. Even though
renal artery stenosis can accelerate cardiovascular disease
and threaten the viability of the kidney, renal revasculariza-
tion, either surgical or percutaneous, is not always indicated.
The benefits of renal artery interventional procedures include
the potential to improve systemic blood pressure and to pre-
serve or salvage renal function. Selecting patients to whom
these benefits apply without excessive risk is rarely simple.
The procedures themselves may threaten the viability of the
affected kidney through vascular thrombosis, dissection, reste-
nosis, or atheroemboli and can precipitate the need for life-
long renal replacement therapy. It is therefore important that
clinicians understand the risks and benefits of both medical
management and intervention for the restoration of renal
perfusion pressure.
PATHOPHYSIOLOGY
Renal Artery Stenosis versus Renovascular
Hypertension
RAS is identified in 20% to 45% of patients undergoing vas-
cular imaging for other reasons, such as coronary angiography
or lower extremity peripheral vascular disease. However, the
majority of the observed stenoses are of little or no hemody-
namic significance. The term renovascular hypertension
refers to a rise in arterial pressure induced by a reduction in
renal perfusion that can be triggered by a variety of lesions
(Table 23-1). Luminal narrowing must approach 70% to 80%
468
469
Examples of Vascular Lesions Producing
Table 23-1 Renal Hypoperfusion and the Syndrome
of Renovascular Hypertension
Unilateral Disease CH 23
Unilateral atherosclerotic renal artery stenosis
VI
Hypertension and the Kidney
Angiotensin II
dependent hypertension
Diagnostic tests
Plasma renin activity elevated
Lateralized features, e.g., renin levels in renal veins,
A captopril-enhanced renography
Figure 23-1. Schematic views of one-kidney (A) and two-
kidney (B) renovascular hypertension. These models differ by the
presence of a contralateral kidney exposed to elevated perfusion
pressures in two-kidney hypertension. The nonstenotic kidney
tends to allow pressure natriuresis to ensue and produces
ongoing stimulation of renin release from the stenotic kidney. The
one-kidney model eventually produces sodium retention and a fall
in renin with minimal evidence of angiotensin dependency unless
sodium depletion is achieved. (From Textor SC: Renovascular
hypertension. In Johnson RJ, Feehally J [eds]: Comprehensive
Clinical Nephrology. London, Mosby, 2000, pp 41.1–41.12.)
Continued
CH 23
Diagnostic tests
Plasma renin activity normal or low
B Lateralized features: none
Figure 23-1, cont’d.
Fibromuscular Disease
Atherosclerosis
Atherosclerosis affecting the renal arteries is the most common
cause of renovascular disease (75–85% of cases). Atheroscle-
rotic renal artery stenosis (ARAS) is commonly associated with
vascular disease in other vascular beds. Approximately 20% of
patients undergoing coronary angiography, and up to 50% of
patients undergoing aortography for peripheral vascular dis-
ease, have renal artery lesions of some degree. The prevalence
of such lesions increases with age and with the presence of ath-
erosclerotic risk factors such as elevated cholesterol, smoking,
and hypertension. Indeed, the probability of identifying high-
grade RAS in hypertensive patients with chronic kidney
disease rises from 3.2% in the sixth decade to above 23% in the
eighth decade. The location of atherosclerotic disease is most
often at the origin of the artery, usually representing a direct
extension of an aortic plaque into the renal arterial segment.
Goals of Evaluation
The goals of the diagnostic evaluation in the patient with sus-
pected renovascular disease are outlined in Table 23-3.
476
Goals of Diagnostic Evaluation and
Table 23-3 Therapeutic Intervention in Renovascular
Hypertension and Ischemic Nephropathy
VI Goals of Diagnostic Evaluation
Establish presence of renal artery stenosis: location and type of
Hypertension and the Kidney
lesion
Establish whether unilateral or bilateral stenosis (or stenosis to a
solitary kidney) is present
Establish presence and function of stenotic and nonstenotic
kidneys
Establish hemodynamic severity of renal arterial disease
Plan vascular intervention: degree and location of atherosclerotic
disease
Goals of Therapy
I. Improved blood pressure control
Prevent morbidity and mortality of high blood pressure
Improve blood pressure control and reduce medication
requirement
II. Preservation of renal function
Reduce risk of renal-adverse perfusion from use of
antihypertensive agents
Reduce episodes of circulatory congestion (“flash” pulmonary
edema)
Reduce risk of progressive vascular occlusion causing loss of
renal function
Salvage renal function (i.e., recover glomerular filtration rate)
Captopril Renography
Imaging the kidneys using the radiopharmaceuticals technetium
Tc 99m pentetate and technetium 99m mertiatide provides useful
information regarding the size and glomerular filtration rates of
both kidneys. The change in glomerular filtration characteristics
after ACE inhibition allows inferences regarding the dependence
of glomerular filtration upon A-II. Captopril renography has a rea-
sonably high specificity, and thus can be used in populations at
low pretest probability, with an expectation that a normal study
will exclude significant renovascular hypertension in more than
95% of cases. Important considerations in the use of captopril
renography include a lower sensitivity and specificity in the pres-
ence of renal insufficiency (usually defined as creatinine > 2 mg/
dL, 175 mmol/L) and the need to withdraw diuretics and ACE inhi-
bitors for 4 to 14 days before the study. It should be emphasized
that renography provides functional information but no direct
anatomic information, that is, the location of renal arterial disease,
the number of renal arteries, or associated aortic or ostial disease.
hypertension
2. Preservation of kidney function
3. Facilitation of volume management in congestive cardiac
failure
Newer antihypertensive agents and the expanding use of
agents that block the renin-angiotensin system for indications
other than hypertension have fundamentally changed the
presentation and clinical management of renovascular disease.
“Uncontrollable” hypertension is now rarely the main reason
for considering renal revascularization. Rather, the hazards of
underperfusion of kidney tissue, leading to irreversible renal
failure, have led many to consider revascularization for “preser-
vation” of renal function. Importantly, it must be emphasized
that long-term clinical outcomes in patients with atheroscle-
rotic renovascular disease are commonly determined by other
disease entities (termed competing risk), and this has important
implications for decisions concerning invasive therapy. The
burden of atherosclerotic disease associated with RAS is often
widespread and the causes of death include a broad array of
cardiovascular events. An algorithm for managing these
patients is illustrated in Figure 23-2.
Low High
Low
Stable renal function Non-invasive imaging: RAS present
Excellent blood pressure ? Comorbid disease risk
? Indications for revascularization
• Circulatory congestion
• Deteriorating kidney function
ACE inhibitor
Advanced renal failure
Optimize • Bilateral high-grade RAS
antihypertensive • Solitary functioning kidney
and medical therapy • Uncontrolled hypertension
Moderate High:
Repeat assessment: Rx failure
3–6 months
? Significant Renal intervention
disease progression PTRA/stent
Stable Progression Surgical revascularization
Nephrectomy (nonsalvageable
Stable renal function pressor kidney)
Excellent blood pressure No
May
Repeat assessment: 6–12 weeks need
? Excellent blood pressure control repeat
? Stable renal function procedure
No
? Recheck for vessel patency
? Restenosis
Yes ? Technical failure
? De novo/contralateral lesions
? Atheroemboli
SUMMARY
Clinical Features
The clinical onset of preeclampsia may be insidious and
not accompanied by overt symptoms. The laboratory
abnormalities seen may frequently mimic other conditions, 493
and a high clinical index of suspicion may be required early
in the course of disease.
Hypertension. For the diagnosis of preeclampsia, hyperten-
sion is defined as a systolic blood pressure of 140 mm Hg or CH 24
higher, or a diastolic blood pressure of 90 mm Hg or higher
Postpartum Recovery
Generally, preeclampsia begins to remit soon after delivery of
the fetus and placenta; complete recovery is the rule, although
normalization of blood pressure and proteinuria may take
weeks. Postpartum monitoring is important as eclampsia
may occur after delivery.
Screening
Risk assessment early in pregnancy is important to identify
those who require close monitoring after 20 weeks. Women
with first pregnancies or any of the previously discussed risk
factors should be assessed every 2 to 3 weeks during the third
trimester for development of symptoms of preeclampsia.
Higher systolic and diastolic blood pressure at the initiation
of prenatal care, even in the absence of overt hypertension,
is associated with elevated risk of preeclampsia in healthy
nulliparous women; the elevations in midtrimester blood
pressure are usually subtle, however, limiting its use as a
screening tool. Preeclampsia is associated with increased
placental vascular resistance in the second trimester, as
measured by uterine artery Doppler ultrasound. However,
test performance varies widely, limiting its diagnostic accu-
racy. Recent data suggest there may be promise in combining
uterine artery Doppler with serum markers. Alterations in
circulating levels of angiogenic factors occur weeks prior to
the development of preeclampsia. Significant elevations in
maternal soluble fms-like tyrosine kinase 1 (sFlt1) appear
to rise 5 to 8 weeks prior to onset of preeclampsia, and are
particularly elevated in severe preeclampsia, early-onset
disease, and preeclampsia associated with a small-for-
gestational-age infant. Serum and urine levels of placental
growth factor (PIGF) are lower in women who develop pre-
eclampsia, from the first and early second, and late second
trimester, respectively.
Prevention
Despite intensive investigation of potential preventive strate-
gies, no intervention to date has proved unequivocally
effective.
496 Because of prominent alterations in prostacyclin-thromboxane
balance in preeclampsia, aspirin has been proposed as a prophy-
lactic agent and, along with other antiplatelet agents, has been
evaluated in multiple trials. Despite some disparity in results of
VI individual trials, two large meta-analyses have suggested a mod-
est benefit with the use of antiplatelet agents, with the greatest
Hypertension and the Kidney
Management
Blood pressure control should be optimized prior to concep-
tion where possible, and women should be appropriately
counseled regarding potential adverse outcomes. When
hypertension is severe (diastolic blood pressure > 100 mm 501
Hg), antihypertensive therapy is clearly indicated for the pre-
vention of stroke and cardiovascular complications. However,
as discussed previously, there is little evidence that treatment
of mild-moderate hypertension is of clear benefit to either CH 24
mother or fetus, and although it reduces the risk of developing
Antihypertensive Drugs
INDIVIDUAL AGENTS
Class Members
There are currently more than 15 ACE inhibitors in clinical
use. Each drug has a unique structure but they all have
remarkably similar clinical effects. The pharmacodynamic
properties of the ACE inhibitors are outlined in Table 25-2.
Antihypertensive Drugs
normal response if restricted sodium
intake
Inhibit tubule sodium
resorption
Decrease arterial pressure
Decrease aldosterone Correlates with decreased
production potassium excretion
Decrease proteinuria Variable individual response rates;
antiproteinuric effects abolished by
high salt intake
Improve altered lipid
profiles
Decrease renal blood flow
Decrease filtration fraction
Decrease renal vascular
resistance
Reduce scarring and
fibrosis
Attenuate oxidative stress
and free radicals
Antihypertensive Drugs
or diabetes or those taking potassium-sparing drugs. The most
common side effect of ACE inhibitors is a dry, hacking, nonpro-
ductive, and often intolerable cough that is reported in up to
20% of patients, thought to be secondary to hypersensitivity
to bradykinins, which are normally degraded by ACE. This is
managed by switching to an ARB (see later discussion). Angioe-
dema is a rare but potentially life-threatening complication of
ACE inhibitor therapy, thought to be due to tissue accumula-
tion of bradykinins and inhibition of C1 esterase activity. It
occurs in less than 0.2% of patients within hours of the first
dose of ACE inhibitor or occasionally after prolonged use.
First-dose hypotension occurs more commonly in volume-
depleted states, patients with high-renin hypertension, and
those with systolic heart failure. In elderly patients, ACE inhib-
itor therapy more frequently causes nocturnal hypotension. In
high-risk patients, therapy should be initiated with lower doses
and preferably after discontinuation of diuretics. Other compli-
cations include a metallic taste sensation, leucopenia, and ane-
mia. Fatal agranulocytosis has been reported. ACE inhibitors
have been demonstrated to interfere with the response to eryth-
ropoietin, an effect that has been utilized therapeutically for
post-transplant erythrocytosis.
Antihypertensive Drugs
Class Efficacy and Safety
All ARBs have been demonstrated to lower BP effectively
and safely in patients with mild, moderate, and severe
hypertension regardless of age, gender, or race. They are
indicated as first-line monotherapy or add-on therapy for
hypertension and are comparable in efficacy to ACE inhibi-
tor therapy. They are safe and effective in patients with
chronic kidney disease, diabetes, heart failure, renal trans-
plants, coronary artery disease (CAD), and left ventricular
hypertrophy (LVH), and have been shown to protect against
hypertensive end-organ damage, such as LVH, stroke, end-
stage renal disease (ESRD), and possibly diabetes. Although
they may not be the most efficacious agents in terms of BP
reduction in black hypertensive patients, they are equally
or more efficacious in offering target organ protection and
arresting disease progression than agents that do not inhibit
the RAAS.
The long onset of action of 4 to 6 weeks avoids the first-
dose hypotension and rebound hypertension commonly seen
with other drugs. The addition of thiazide diuretics potenti-
ates the therapeutic effect and increases response rates to
70% to 80%, and is more effective than increasing the dose
of ARB. ARBs may cause fetal or neonatal death when used
during the second and third trimesters of pregnancy. As with
ACE inhibitors an abrupt decline in GFR may be observed in
the setting of renal hypoperfusion; this typically responds to
withdrawal of the drug or optimization of renal perfusion. In
clinical trials, hyperkalemia occurs in less than 1.5% of
patients and is comparable to that observed with ACE inhibi-
tor therapy. It is more likely to develop in patients with renal
insufficiency, those with diabetes, or those taking potassium-
sparing drugs. ARBs tend to lower brain natriuretic peptide
levels, which may explain their benefit in heart failure. They
have no effect on serum lipids in hypertensive patients but
may improve the abnormal lipoprotein profile of patients
with proteinuric renal disease. Clinically relevant side effects
are not observed more frequently than in placebo-treated
patients. Because ARBs do not interfere with kinin metabo-
lism, cough is rare and the incidence of cough in patients
with a history of ACE inhibitor–induced cough is no greater
than in those receiving placebo. Similarly, the incidence
of angioedema and facial swelling is no greater than with
placebo.
518 b-Adrenergic Antagonists
Mechanisms of Action
b-Adrenergic blocking drugs act via attenuation of sympathetic
VI stimulation through competitive antagonism of catecholamines
at the b-adrenergic receptor. In addition to b-blockade proper-
Hypertension and the Kidney
Class Members
The b-adrenergic antagonists are classified and reviewed on
the basis of the following subclasses: nonselective b-adrener-
gic antagonism, nonselective b-adrenergic antagonism with
partial agonist activity, and b1-selective adrenergic antago-
nism. Their pharmacodynamic properties are outlined in
Table 25-5.
Renal Effects
Both a- and b-adrenergic receptors in the kidney mediate
vasoconstriction, vasodilatation, and renin secretion. In gen-
eral, the acute administration of a b-adrenergic blocker usually
results in reduction of GFR. The degree of reduction in GFR is
typically modest and not of clinical significance in most cases.
b-Adrenergic antagonist therapy is usually associated with
suppression of plasma renin activity.
Calcium Antagonists
Mechanisms of Action
Calcium antagonists (CAs) have emerged as an important ther-
apeutic class of medications for a variety of cardiovascular
disorders. Initially introduced in the 1970s as antianginal
agents, they are now widely advocated as first-line therapy for 521
hypertension. CAs do not directly antagonize the effects of
calcium, but they inhibit the entry of calcium or its mobiliza-
tion from intracellular stores. Each class of CA is quantita-
tively and qualitatively unique, possessing differential CH 25
sensitivity and selectivity for binding pharmacologic receptors
Antihypertensive Drugs
as well as the slow calcium channel in various vascular tis-
sues. This differential selectivity of action has important clin-
ical implications for the use of these drugs and explains why
the CAs vary considerably in their effects on regional circula-
tory beds, sinus and atrioventricular (AV) nodal function, and
myocardial contractility. It further explains the diversity of
indications for clinical use, ancillary effects, and side effects.
CAs uniformly lower peripheral vascular resistance in
patients regardless of race, salt sensitivity, age, or co-morbid
conditions. CAs decrease vascular responsiveness to A-II,
and the synthesis and secretion of aldosterone. Interestingly,
the maximal vasodilatory response to the CAs is inversely
related to the patient’s plasma renin activity. Thus, it is possi-
ble that these agents are of specific benefit in patients with
low-renin hypertension, such as black hypertensive patients.
CAs may also induce a mild diuresis.
Class Members
CAs are a very heterogeneous group of compounds and differ
with respect to pharmacologic profile, pharmacokinetic
profile, clinical indications, and side effect profile (Table 25-6).
Antihypertensive Drugs
capillary pressure that perpetuates renal disease progression.
CAs represent an important treatment option for renal trans-
plant recipients. Administration of CAs may help preserve
long-term renal function by protecting against cyclosporine
nephrotoxicity and, possibly, by contributing to immunomo-
dulation (Table 25-7).
Antihypertensive Drugs
CAs may be associated with an increased risk of gastrointes-
tinal hemorrhage, particularly in elderly persons. There is
clear evidence that CAs reduce cardiovascular mortality and
morbidity rates, particularly for stroke; however, short-acting
agents such as nifedipine have been associated with a small
increased risk for myocardial infarction in meta-analyses
when compared with other agents. Currently, there is no evi-
dence to prove the existence of either additional beneficial
or detrimental effects of CAs on coronary disease events,
including fatal or nonfatal myocardial infarctions and other
deaths from coronary heart disease. Because of a potential
risk, however, as well as simplicity and improved compliance,
longer-acting agents should be considered over short-acting
CAs for the treatment of hypertension.
Mechanisms of Action
Central adrenergic agonists act by crossing the blood-brain
barrier and have a direct effect on a2-adrenergic receptors
located in the midbrain and brainstem, or the more recently
described I1 imidazole receptors. In addition to decreasing
total sympathetic outflow, binding to these receptors results
in increases in vagal activity. Clonidine is a stimulant of both
a2- and I1 receptors, while a-methlydopa acts on the former.
The classical a2-receptor agonists such as clonidine and
a-methyldopa trigger vasodilatation in resistance vessels and
hence a reduction in peripheral vascular resistance and BP.
Despite the vasodilatory action, reflex tachycardia generally
does not occur due to peripheral sympathetic inhibition. The
selective I1 receptor agonists moxonidine and rilmenidine
are predominantly arterial vasodilators, resulting in a reduc-
tion in peripheral vascular resistance. Moxonidine is also
associated with reduction in plasma renin activity. The cen-
tral a2-adrenergic agonists may also stimulate peripheral
a2-adrenergic agonists, which mediate vasoconstriction,
resulting in a paradoxic increase in BP.
Direct-Acting Vasodilators
Mechanisms of Action
The direct-acting vasodilators reduce systolic and diastolic BP
by decreasing peripheral vascular resistance. Decreases in arte-
rial pressure are associated with a fall in peripheral resistance
and a reflex increase in cardiac output. Sodium and water reten-
tion is promoted secondary to the stimulation of renin release.
Class Members
Hydralazine is a direct-acting arteriole vasodilator. Initial oral
doses in hypertension should be 10 mg four times daily
increasing to 50 mg four times daily over several weeks.
Patients may require doses of up to 300 mg/day. Dosing can
be changed to twice daily for maintenance. The drug may also
be used as an intravenous bolus injection or as a continuous
infusion. Oral absorption is 50% to 90% of the dose and the 527
drug is up 90% protein bound. Patients with mild to moderate
renal insufficiency should have the dosing interval increased
to every 8 hours. In severe renal failure, the dose interval
should increase to every 8 to 24 hours. CH 25
Minoxidil is a direct vasodilator. It is more potent than
Antihypertensive Drugs
hydralazine and induces a more marked activation of adrener-
gic drive. For severe hypertension the initial recommended
dose is 5 mg as a single daily dose, increasing to 10 to 20 mg
or 40 mg in single or divided doses. Minoxidil is usually used
in conjunction with salt restriction and diuretics to prevent
sodium retention. Concomitant therapy with a b-adrenergic
blocking agent is often required to prevent increases in heart
rate. The elimination half-life varies with the acetylation rate
in the liver, and both slow and fast acetylators have been
described. Renal excretion is 90%. Dosage adjustments may
be required in patients with renal failure, although the mean
daily doses required to control BP have been reported to be
similar in patients with normal renal function.
Mechanisms of Action
The nonselective agents phentolamine and phenoxybenza-
mine have an occasional role in hypertension management.
Phentolamine is utilized parenterally, and the longer acting
agent phenoxybenzamine has been used orally for the manage-
ment of hypertension associated with pheochromocytoma.
Class Members
Phenoxybenzamine irreversibly binds to the a-receptors, low-
ering peripheral resistance and increasing cardiac output.
The usual oral dose of phenoxybenzamine for pheochromo-
cytoma is 10 mg twice daily, gradually increasing every other
day to doses ranging between 20 and 40 mg two or three times
a day. A b-blocker may be administered if tachycardia
becomes excessive during therapy; however, the pressor
effects of a pheochromocytoma must be controlled by a-blockade 529
before b-blockers are initiated. With oral use, symptoms of
pheochromocytoma decrease after several days. Administra-
tion of phenoxybenzamine to patients with renal impairment
should be done cautiously. Specific dosage recommendations CH 25
are not available. Phentolamine is an a-adrenergic blocking
Antihypertensive Drugs
agent that produces peripheral vasodilatation in cardiac stim-
ulation with a resulting fall in BP in most patients. The drug is
used parenterally. The usual dose is 5 mg repeated as needed.
The onset of activity with intravenous dosing is immediate.
The drug is metabolized in the liver, with 10% excreted in
the urine as unchanged drug.
Renal Effects
Phenoxybenzamine has no clear effect on the renin-angioten-
sin-aldosterone axis. Salt and water retention does not occur.
GFR and effective renal plasma flow would be expected to
increase, and renal vascular resistance to decrease in propor-
tion to the degree of blockade of a-adrenergic receptors.
Renal Effects
GFR and renal blood flow are maintained during long-term
treatment with these agents. Renal vascular resistance may
be reduced. No dosage adjustment is necessary in patients
with renal disease.
Renin Inhibitors
The development of renin inhibitors has been limited by diffi-
culty with oral bioavailability, and as a result development on
several drugs was canceled.
Antihypertensive Drugs
Selective Aldosterone Receptor Antagonists
Class Mechanism and Class Member
Eplerenone is a selective aldosterone receptor antagonist that
may have antihypertensive effects distinct from its diuretic
properties. Although it is a much less potent mineralocorti-
coid receptor blocker than spironolactone, it is much more
specific and has little agonist activity for estrogen and proges-
terone receptors. Therefore, it is associated with a lower inci-
dence of gynecomastia, breast pain, and impotence in men
and diminished libido and menstrual irregularities in women.
Antihypertensive Drugs
ceptor responses in older patients and worsen orthostasis
and should be used with caution. Treatment of isolated sys-
tolic hypertension in older patients frequently requires multi-
ple drugs. Regardless of the agents that are utilized, a slow
careful titration approach is recommended, preferably not
more frequently than every 3 months.
Differences in gender may be important with regard to
the selection of antihypertensive therapy. Women should
avoid the use of ACE inhibitors and ARBs in pregnancy
because of their possible teratogenic effects. Optimal therapy
in a pregnant woman includes a-methyldopa, hydralazine, or
b-blockers as they have a proven safety record with minimal
risk of teratogenic effects. The treatment of pregnancy-
related hypertension is discussed further in Chapter 24,
The Kidney in Hypertension and Pregnancy. In women with
osteoporosis, thiazide diuretics are ideal agents because they
antagonize calciuria and facilitate bone mineralization.
Women experience more cough with ACE inhibitors and
more pedal edema with calcium channel blockers compared
with men.
Race may play a role in the choice of antihypertensive
agents. Blacks typically present with hypertension at an ear-
lier age, have more substantial elevations in BP, and experi-
ence earlier development of target organ damage than similar
demographically matched white counterparts. In addition,
significant racial differences in the response to antihyperten-
sive medications exist, possibly due to higher salt sensitivity
in black patients. In general, thiazide diuretics and calcium
channel blockers have more robust antihypertensive proper-
ties in lower doses in blacks than other commonly used thera-
peutic classes. Higher doses of ACE inhibitors or ARBs are
frequently required in order to achieve the same level of BP
reduction as seen in other racial groups. It is not uncommon
for multiple drugs to be required to reach the target BP. Conse-
quently, fixed-dose combinations may prove to be most useful
in this population group as part of the strategy to simplify the
approach. Hispanic and Asian populations do not appear to
have different hypertensive responses to commonly used
drugs compared with whites.
Obese hypertensive patients frequently have other medical
problems that complicate their hypertensive management.
b-Blockers may be helpful in diminishing sympathoadrenal
drive. Vasodilators, such as HCTZ and ACE inhibitors, ARBs,
534 and calcium channel blockers, are useful for reducing periph-
eral vascular resistance. Combinations of these drugs may also
be helpful. Because of the tendency toward expanded plasma
volume, thiazide diuretics can be helpful as they provide an
VI opportunity to cause both vasodilation and mild volume
reduction. Frequently, these patients require multiple drugs
Hypertension and the Kidney
Refractory Hypertension
Refractory hypertension is a term used to characterize hyper-
tension that fails to respond to what the clinician considers
an adequate antihypertensive regimen. True refractory hyper-
tension is unusual, and a methodologic approach should be
taken to help achieve BP control in these patients. A variety
of factors interfere with the ability to normalize BP, the most
important of which is noncompliance. This problem derives
from many factors including inadequate education, poor
clinician-patient relationship, lack of understanding about 535
side effects, and the complexity of multidrug regimens.
Pseudohypertension is commonly observed in older hyper-
tensive patients who have hardened atherosclerotic arteries,
which are not easily compressible. This interferes with aus- CH 25
cultatory measurements of BP and greater apparent pressure
Antihypertensive Drugs
is required to compress the sclerotic vessel than the intra-arte-
rial BP requires. Another common cause of pseudohyperten-
sion is improper measurement. This occurs when the BP is
taken with an inappropriately small cuff in people with large
arm circumference. Because of the substantial proportion of
hypertensive patients who are obese, it is critical to have the
appropriate cuff size for determining auscultatory pressure.
Some clinicians may view white coat hypertension as a
cause of refractory hypertension. This is an area of contentious
debate in that elevated office readings, despite lower home
readings, still provide important predictive value for the devel-
opment of cardiovascular events. Some clinical studies indicate
that patients with so-called white coat hypertension also have
LVH and may not have an appropriate nocturnal dip in BP.
Volume overload is an important and common cause of
refractory hypertension. It may be related to excessive salt
intake or inability of the kidney to excrete an appropriate salt
and water load because of either endocrine abnormalities or
intrinsic renal disease. Salt sensitivity is particularly common
in patients of African-American descent. A careful clinical
examination coupled with judicious use of either thiazide or
loop diuretics is critical in achieving ideal blood volume in
order to restore the antihypertensive efficacy of most classes
of drugs. It is also appropriate to consider educating the
patient about avoiding foods that are rich in salt content, such
as processed foods.
Drug-related causes of refractory hypertension are common
and need to be carefully assessed in each patient. Perhaps the
most common drugs that cause refractory hypertension are
over-the-counter preparations of sympathomimetics such as
nasal decongestants, appetite suppressants, and NSAIDs.
Unfortunately, patients may not always recognize over-
the-counter preparations as a medication. Therefore, careful
questioning specifically focusing on these types of medica-
tions should be routine during the evaluation for refractory
hypertension. In addition, oral contraceptives, ethanol, cigar-
ettes, and cocaine can be complicating factors that interfere
with the ability of medications to lower BP.
Obesity is an oft-overlooked cause of refractory hyperten-
sion and is commonly associated with obstructive sleep apnea.
Nighttime ventilation techniques enhance the control of BP.
Secondary causes of hypertension might also be considered
as a cause of refractory hypertension. CKD and renal vascular
536 disease are not uncommon and are easily investigated. Addi-
tional endocrine abnormalities include hyperaldosteronism,
pheochromocytoma, or hypo- or hyperthyroidism and hyper-
parathyroidism; rarely, aortic coarctation can be a cause of
VI refractory hypertension. Often patients with subtle hyperal-
dosteronism will respond to the addition of a selective aldo-
Hypertension and the Kidney
Antihypertensive Drugs
Labetolol 100–400 mg 1–2 hr 2–4 8–12
every 12 hr
(max 2400 mg)
Clonidine 0.2 mg initially, 30–60 2–4 6–8
then 0.1 mg/hr min
(max 0.8 mg)
Diltiazem 30–120 mg every <15 min 2–3 8
8 hr (max 480
mg)
Enalapril 2.5–10 mg every <60 min 4–8 12–24
6 hr
Captopril 12.5–25 mg <15 min 1 6–12
every hr (max
150 mg)
Prazosin 1–5 mg every <60 min 2–4 6–12
2 hr (max
20 mg)
Antihypertensive Drugs
Labetalol
a-Adrenergic Antagonist
Phentolamine mesylate is a nonselective a-adrenergic antago-
nist used primarily in the treatment of hypertension associated
with pheochromocytoma. It has a rapid onset of action when
administered intravenously as either a bolus or a continuous
infusion (see Table 25-8). The duration of action is 10 to
15 minutes. It has a plasma half-life of 19 minutes; approxi-
mately 13% of a single dose appears in the urine as unchanged
drug. Adverse effects include those associated with nonselec-
tive a-adrenergic blockade, as discussed previously.
542 Calcium Antagonists
steady state does not occur for about 50 hours (see Table 25-8).
Discontinuation of infusion is followed by a 50% offset of
action in 30 minutes, but gradually decreasing antihyperten-
sive effects exist for about 50 hours. It has been shown to be
safe and effective in pediatric hypertensive emergencies.
Antihypertensive Drugs
BP can also interfere with coronary perfusion during diastole
and result in myocardial ischemia, infarction, or arrhythmia.
In addition, rapid reduction of BP may result in a reflex
increase in heart rate, which would also interfere with coro-
nary perfusion. For these reasons, careful, cautious, and con-
trolled reduction in BP is necessary in these patients. For
most hypertension emergencies, a parenteral drug such as
sodium nitroprusside is ideal. However, if the patient has cor-
onary disease, intravenous nitroglycerin or esmolol, or both, is
a useful approach as they can induce coronary dilation or
slow heart rate, respectively. Intravenous nicardipine could
also be used because it facilitates coronary vasodilation.
Patients with acute aortic dissection are best treated with a
b-adrenergic antagonist plus nitroprusside or a ganglionic
blocker such as trimethaphan. Patients with hypertensive
encephalopathy or central nervous system hemorrhage may
be best treated with drugs that do not cause cerebral vasodila-
tion such as hydralazine, nitroprusside, nicardipine, or fenol-
dopam. Fenoldopam may be helpful in patients with kidney
diseases, as it maintains renal blood flow (Table 25-10).
544
Diuretics
INDIVIDUAL CLASSES OF DIURETICS
Mechanism of Action
CAIs work by inhibition of luminal and cellular carbonic anhy-
drase, resulting in an alkaline diuresis with impaired reabsorption
of Naþ, Cl, and HCO3 and decreased excretion of titratable acid
and NH4þ. There is substantial kaliuresis, although hypokalemia
is uncommon. Diuretic efficacy is limited by distal Naþ and
HCO3 reabsorption and development of metabolic acidosis,
which limits the filtered load to HCO3, thereby curtailing natri-
uresis. Most diuretics have some carbonic anhydrase activity.
Pharmacokinetics
Acetazolamide (Diamox) is readily absorbed. It is eliminated by
tubular secretion (which is diminished by hypoalbuminemia),
and has a half-life (t1/2) of 13 hours. Methazolamide (Neptazane)
has less plasma protein binding, a longer t1/2, and greater lipid
solubility, all of which favor penetration into aqueous humor
and cerebrospinal fluid (CSF). It has fewer renal effects and there-
fore is preferred for treatment of glaucoma.
Clinical Indications
The use of CAIs is limited by their transient action, develop-
ment of metabolic acidosis, and a spectrum of adverse effects.
They can be used with NaHCO3 infusion to cause an alkaline
diuresis that increases the excretion of weakly acidic drugs
(e.g., salicylates and phenobarbital) or acidic metabolites
(urate). Chloride-responsive metabolic alkalosis is best treated
by administering Cl with Kþ or Naþ. However, if this produces
unacceptable extracellular volume (ECV) expansion, acetazol-
amide (250–500 mg/day) and KCl can be used to increase
HCO3 excretion. These agents are useful in glaucoma by
diminishing the transport of HCO3 and Naþ by the ciliary pro-
cess, thereby reducing the intraocular pressure. CAIs also limit
546
formation of CSF and endolymph. Acetazolamide is used in a 547
dose of 250 mg twice daily as prophylaxis against mountain
sickness, probably through stimulating respiration and dimin-
ishing cerebral blood flow. In established mountain sickness,
it improves oxygenation and pulmonary gas exchange. It can CH 26
stimulate ventilation in patients with central sleep apnea. CAIs
Diuretics
are effective in prophylaxis of hypokalemic periodic paralysis
due to diminished influx of Kþ into cells. Paradoxically,
they are also useful in the treatment of hyperkalemic periodic
paralysis.
Adverse Effects
Lethargy, abnormal taste, paresthesia, gastrointestinal distress,
malaise, and decreased libido are among the adverse effects
seen with treatment. Administration of NaHCO3 may amelio-
rate symptoms, but increases the risk of nephrocalcinosis
and nephrolithiasis, which is tenfold higher in patients
receiving acetazolamide. Symptomatic metabolic acidosis
develops in 50%; the elderly, diabetics, and patients with
chronic kidney disease (CKD) may develop serious metabolic
acidosis. An alkaline urine favors partitioning of renal ammo-
nia into blood, rather than its elimination in urine, and may
precipitate encephalopathy in patients with liver failure.
Osmotic Diuretics
Site of Action
Osmotic diuretics do not act on any specific transport path-
way. They act as osmotic particles in tubule fluid and are
freely filtered but poorly reabsorbed.
Mechanism of Action
Filtered mannitol is concentrated sufficiently to diminish
tubular fluid reabsorption. Ongoing Naþ reabsorption creates
an osmotic gradient for back-flux of reabsorbed Naþ into the
tubule. Increased distal flow stimulates Kþ secretion. Manni-
tol increases the total renal and medullary blood flow and
decreases the medullary solute gradient, preventing urinary
concentration.
Adverse Effects
The osmotic abstraction of cell water initially causes hypona-
tremia and hypochloremia. Later, when the excess extracellular
fluid is excreted, the decrease in cell water concentrates Kþ and
Hþ within cells, which increases the gradient for their diffusion
into the extracellular fluid (ECF), leading to hyperkalemic aci-
dosis. If renal function is adequate, these electrolyte changes
are normally rapidly corrected by the kidney. Hypernatremic
dehydration may later develop if free water is not provided,
because urinary concentrating ability is inhibited. Importantly,
in patients with renal failure, administration of mannitol
causes expansion of ECV, hemodilution, and hyperkalemic
metabolic acidosis; the consequent circulatory overload, central
nervous system depression, and severe hyponatremia can
trigger the need for emergent hemodialysis.
Loop Diuretics
Site of Action
Loop diuretics work in the luminal aspect of the thick ascend-
ing limb of the loop of Henle (TAL).
Mechanism of Action
Loop diuretics are organic anions that inhibit the Naþ/Kþ/2Cl
co-transporter, a member of the solute carrier family 12
(SLC12A1), also termed NKCC2, which is expressed on the api-
cal membranes of medullary and cortical TAL cells and macula
densa segments. Expression of NKCC2 is increased by pro-
longed infusion of saline or furosemide. They are potent diure-
tics (25% of Naþ reabsorption occurs in TAL). Loop diuretics
also inhibit NaCl transport in short descending limbs of the
loop of Henle and collecting ducts. Reduction in the medullary
concentrating gradient due to inhibition of solute reabsorption
in the water-impermeable TAL leads to impaired free water
excretion during water loading and reabsorption during dehy-
dration. Loop diuretics increase the fractional excretion of
Ca2þ by up to 30% by decreasing the lumen-positive transep-
ithelial potential that promotes paracellular Ca2þ reabsorption
from the lumen. The loop of Henle is the major nephron 549
segment for reabsorption of Mg2þ; loop diuretics increase frac-
tional Mg2þ excretion by more than 60%, also by diminishing
voltage-dependent paracellular transport. Uniquely, furosemide
also has a venodilatory action mediated by an endothelium- CH 26
dependent hyperpolarizing action that can acutely lower central
Diuretics
filling pressures in the setting of congestive heart failure (CHF).
The total renal blood flow is maintained or increased, and the
glomerular filtration rate (GFR) is little changed during adminis-
tration of loop diuretics to normal subjects, although there is
marked redistribution of blood flow from the inner to the outer
cortex. Furosemide increases the renal generation of prostaglandins
(PGs); blockade of cyclooxygenase (COX) prevents furosemide-
induced renal vasodilatation. Loop diuretics stimulate renin secre-
tion, both acute and chronic, partly from ECV depletion, but also
from direct effects on the macula densa.
Pharmacokinetics
Loop diuretics are absorbed promptly after ingestion, but their
bioavailability varies. Loop diuretics are more than 90% albu-
min-bound, greatly limiting their clearance by glomerular
filtration. Diuretics gain access to tubular fluid almost exclu-
sively by proximal secretion; loop diuretics, thiazides, and
CAIs are all secreted avidly by a probenecid-sensitive organic
ion transporter (OAT) in proximal tubule cells. Furosemide is
variably absorbed, both between patients and over time;
approximately 50% is eliminated by renal metabolism to the
inactive glucuronide. In contrast, bumetanide and torsemide
have better oral bioavailability and are metabolized in the
liver. The duration of action of torsemide is approximately
twice as long as furosemide, whereas the duration of bumeta-
nide action is shorter; clinically relevant differences in salt-
depleting action are not evident. In patients with CKD, the
elimination of furosemide, unlike bumetanide or torsemide,
is greatly reduced because its metabolism to the inactive glu-
curonide occurs in the kidney, although the fraction of drug
excreted unchanged in CKD is greater for furosemide. There
is, therefore, a tradeoff when selecting a loop diuretic in
CKD: furosemide can accumulate and cause ototoxicity at high
doses, whereas bumetanide retains its metabolic inactivation
but is therefore somewhat less potent. Renal clearance of the
active form of loop diuretics falls in proportion to the creati-
nine clearance. In addition, there is competition for peritubu-
lar uptake and luminal secretion by other organic anions
(including urate), and impairment of organic anion secretion
by metabolic acidosis. These factors combine to explain why
diuretic secretion is often impaired in advanced CKD. Hypoal-
buminemia also decreases tubular secretion of active diuretic.
Natriuresis is related to the urinary, but not the plasma,
550 diuretic concentration. It is worth noting that a reduced die-
tary salt intake and repeated administration of furosemide
during salt restriction diminish the renal tubular response to
furosemide.
VI
Clinical Indications
Hypertension and the Kidney
Adverse Effects
These effects are discussed under “Adverse Effects of
Diuretics.”
Thiazides
Site of Action
Thiazides act at the early distal convoluted tubule (DCT).
Mechanism of Action
Thiazide diuretics inhibit the thiazide-sensitive Naþ/Cl co-
transporter (NCC, gene symbol SLC12A3), which mediates
40% of coupled reabsorption of Naþ and Cl. Thiazides
increase Kþ excretion, due to stimulation of aldosterone secre-
tion, increased distal flow, and increased calcium reabsorp-
tion. The mechanisms underlying decreased Ca2þ excretion
include enhanced basolateral Naþ/Ca2þ exchange and stimu-
lation of proximal reabsorption of Ca2þ in response to ECV
depletion. Mg2þ excretion is enhanced. Thiazides impair max-
imal urinary dilution, but not maximal urinary concentration,
thereby predisposing to hyponatremia, particularly in the
elderly. Thiazides also enhance water absorption from inner
medullary collecting ducts in a vasopressin-independent
manner, further contributing to the tendency toward hypona-
tremia. Urate clearance is diminished due to ECV depletion
and competition for tubular uptake.
Pharmacokinetics
Thiazides are readily absorbed and are extensively bound to
plasma proteins. They are eliminated largely by secretion
into the proximal tubule, mainly via OAT. The t1/2 is
prolonged in renal failure and in the elderly, which reduces
their natriuretic efficacy, as the secreted component is
clinically active. The more lipid-soluble drugs (e.g., bend-
roflumethiazide and polythiazide) are more potent, have a
more prolonged action, and are more extensively metabo-
lized. Chlorthalidone has a particularly prolonged action;
indapamide is sufficiently metabolized to limit accumulation
in renal failure.
Clinical Indications 551
These indications are described under “Clinical Uses of
Diuretics.”
Adverse Effects CH 26
These effects are described under “Adverse Effects of
Diuretics
Diuretics.”
Site of Action
Their site of action is the principal cells in the late DCT, the
initial connecting tubule, and the cortical collecting duct.
Mechanism of Action
Direct inhibition of ENaC from the luminal surface (triamter-
ene and amiloride) results in a natriuresis and diminished
electrochemical gradient for Kþ and Hþ secretion. Amiloride
also inhibits the Naþ/Hþ exchanger in the proximal tubule,
although distal effects predominate clinically. Trimethoprim
and pentamidine have amiloride-like actions and can cause
hyperkalemia. Spironolactone and eplerenone are competitive
antagonists of the mineralocorticoid receptor. Eplerenone has
fewer estrogenic side effects. Distal Kþ-sparing diuretics cause
a modest natriuresis; their more clinically relevant actions are
to reduce the excretion of Kþ and net acid.
Pharmakokinetics
Triamterene is well absorbed. The drug and its metabolites are
secreted in the proximal tubule with half-lives of 3 to 5 hours.
Triamterene and its active metabolites accumulate in patients
with cirrhosis because of decreased biliary secretion, in the
elderly, and in those with CKD because of decreased renal
excretion. Amiloride is incompletely absorbed, and has a dura-
tion of action of approximately 18 hours. It accumulates in renal
failure and may worsen renal function. Spironolactone is read-
ily absorbed, has a t1/2 of 20 hours, and takes 10 to 48 hours to
become maximally effective.
Clinical Indications
Distal Kþ-sparing agents are used to prevent or treat hypokalemic
alkalosis, especially in combination with a thiazide diuretic.
Amiloride can prevent amphoteracin-induced hypokalemia
552 and hypomagnesemia. Spironolactone is indicated as first-line
therapy for the treatment of ECV expansion in cirrhotic ascites,
for treatment of CHF with systolic dysfunction, and may also be
an effective adjunct to the treatment of resistant hypertension
VI and hypertension associated with hyperaldosteronism. Eplere-
none is indicated for systolic dysfunction in the setting of recent
Hypertension and the Kidney
myocardial infarction.
Adverse Effects
The risk of hyperkalemia is dose-dependent and increases consid-
erably in patients with CKD or in those receiving potassium
supplements, angiotensin-converting enzyme inhibitors (ACEIs),
angiotensin receptor blockers (ARBs), NSAIDs, b-blockers, hepa-
rin, or ketoconazole. Impaired net acid excretion can cause meta-
bolic acidosis, which worsens hyperkalemia. Amiloride and
triamterene accumulate in renal failure, and triamterene accumu-
lates in cirrhosis. Therefore, these drugs should be avoided in
these situations. Gynecomastia may occur in men, especially with
increasing doses (less with eplerenone); decreased libido and
impotence have also been reported. Menstrual irregularities,
hirsutism, breast swelling, and tenderness have been reported in
women.
Dopamine
Vasopressin Antagonists
Nonpeptide orally active vasopressin V2 receptor antagonists
(e.g., tolvaptan) cause free water diuresis without appreciable
natriuresis, and have been shown to increase urine volume,
free water clearance, and serum sodium concentration in
patients with syndrome of inappropriate secretion of anti-
diuretic hormone (SIADH), CHF, and cirrhosis. Despite these
effects, there is no evidence to date that the use of these agents
modifies CHF outcomes.
ADAPTATION TO DIURETIC THERAPY: 553
CLINICAL IMPLICATIONS
Diuretics entrain a set of homeostatic mechanisms that limit
their fluid-depleting actions and contribute to diuretic resis- CH 26
tance and adverse effects. The first dose of a diuretic normally
Diuretics
produces a brisk diuresis. However, in subjects on a normal
salt diet, a new equilibrium is attained within 24 hours when
body weight stabilizes and daily fluid and electrolyte excre-
tion no longer exceeds intake. This adjustment occurs as a
result of a combination of postdiuretic salt retention, contrac-
tion alkalosis that inhibits the efficacy of loop diuretics, and
diuretic tolerance (which is class-specific). In contrast, during
salt restriction, while the first dose of furosemide produces a
blunted natriuresis, Naþ balance cannot be restored because
of the low level of dietary Naþ intake, and the patient con-
tinues to lose both Naþ and body weight. Tolerance manifests
as a 40% reduction in the natriuretic response to the drug over
3 days. It is noteworthy that the natriuretic response to the
addition of a thiazide is augmented during furosemide ther-
apy. Tolerance to furosemide is thus class-specific, and is
dependent on increased NaCl reabsorption at a downstream,
thiazide-sensitive site.
There are a number of clinical implications from these find-
ings: first, that even in subjects receiving powerful loop diuretics,
dietary salt intake must be restricted to obviate postdiuretic
salt retention and to ensure the development of a negative NaCl
balance; second, during prolonged diuretic administration,
subjects may be particularly responsive to another class of
diuretic; third, diuretic therapy should not be stopped abruptly
unless dietary salt intake is effectively curtailed, because the
adaptive mechanisms limiting salt excretion persist for days
after diuretic use; fourth, selection of a diuretic with a prolonged
action, or more frequent administration of the diuretic, will
enhance NaCl loss by limiting the time available for postdiuretic
salt retention; fifth, prevention or reversal of diuretic-induced
metabolic alkalosis may enhance diuretic efficacy.
Diuretic Resistance
Diuretic resistance implies inadequate clearance of edema
despite a full dose of diuretic. The principal causes are sum-
marized in Table 26-1. The first step is to select the appropri-
ate target response (e.g., a specific body weight) and to ensure
that the edema is due to inappropriate renal NaCl and fluid
retention rather than lymphatic or venous obstruction. Diure-
tics do not prevent edema caused by dihydropyridine calcium
channel blockers. The next step is to exclude noncompliance
554
Table 26-1 Common Causes of Diuretic Resistance
Cause Example(s)
Incorrect diagnosis Venous or lymphatic edema
VI Inappropriate NaCl intake Naþ intake > 120 mmol/day
Hypertension and the Kidney
Diuretics
Loop Diuretics and Thiazides
A loop diuretic and a thiazide (e.g., hydrochlorothiazide or
metolazone) are synergistic in normal subjects and in those
with edema or renal insufficiency. Metolazone is equivalent
to bendrofluazide in enhancing NaCl and fluid losses in furose-
mide-resistant subjects with CHF or the nephrotic syndrome.
Patients with advanced CKD (GFR < 30 mL/min) who are
unresponsive to thiazide alone have a marked natriuresis
when the thiazide is added to loop diuretic therapy, probably
by blockade of enhanced distal tubular Naþ reabsorption.
However, close clinical surveillance is imperative when
combination therapy is initiated, because of a high incidence
of hypokalemia, excessive ECV depletion, and azotemia.
Hyponatremia
Hyponatremia is usually described with thiazide therapy. The
mechanisms include enhanced arginine vasopressin (AVP)
release in response to volume depletion and, more importantly,
specific effects on the urinary concentrating capacity. This
effect is relatively specific for thiazides, which inhibit urinary
dilution, whereas loop diuretics inhibit both urinary concentra-
tion and dilution. Mild, asymptomatic hyponatremia can be
treated by withdrawal of diuretics, restriction of daily free
556 water intake to 1 to 1.5 L, restoring any Kþ and Mg2þ losses,
and replenishing NaCl if the patient is clearly volume-depleted.
Severe, symptomatic hyponatremia complicated by seizures is
an emergency requiring intensive treatment. The ideal manage-
VI ment remains controversial but may involve the controlled
administration of hypertonic saline (see Chapter 5, Disorders
Hypertension and the Kidney
of Water Balance).
Hypokalemia
The serum Kþ concentration (SK) of patients not receiving KCl
supplements falls by an average of 0.3 mmol/L with furosemide
and by 0.6 mmol/L with thiazides. Mild diuretic-induced hypo-
kalemia (SK 3–3.5 mmol/L) increases the frequency of ventricu-
lar ectopy, the clinical significance of which is unknown in
otherwise healthy subjects. Severe hypokalemia (SK < 3
mmol/L) is associated with a doubling of serious ventricular
dysrhythmias, muscular weakness, and rhabdomyolysis. Lesser
degrees of hypokalemia can precipitate dysrhythmias in
patients with known ischemic heart disease or left ventricular
hypertrophy, those taking digoxin, or patients with a prolonged
QT interval. An increase in the daily intake of Kþ with Cl can
prevent hypokalemia, although this often requires 40 to 80
mmol daily. In the presence of alkalosis, hyperaldosteronism,
or Mg2þ depletion, hypokalemia is poorly responsive to dietary
KCl. A more effective, convenient, and predictable strategy is to
prescribe a combined therapy with a distal Kþ-sparing agent,
such as amiloride or triamterene, which prevents diuretic-
induced hypokalemia and alkalosis and provides further natri-
uresis and antihypertensive efficacy.
Hyperkalemia
Distal potassium-sparing diuretics decrease Kþ secretion and
predispose to hyperkalemia. Recently, trimethoprim and pent-
amidine have been identified as amiloride-like agents that
inhibit Kþ secretion in the collecting ducts.
Hypomagnesemia
During prolonged therapy with thiazides and loop diuretics,
serum Mg2þ concentration (SMg) falls by 5% to 10% and
diuretic-induced hyponatremia and hypokalemia cannot be
reversed fully until any Mg2þ deficit is replaced. Symptoms
of hypomagnesemia include depression, muscular weakness,
and atrial fibrillation and can be corrected by administration
of magnesium oxide or sulfate. Distal Kþ-sparing agents and
spironolactone diminish Mg2þ excretion.
Hypercalcemia
Thiazides increase the serum concentrations of total and ion-
ized calcium (SCa). Persistent hypercalcemia should prompt a
search for a specific cause, for example, an adenoma of the 557
parathyroid glands. In contrast, loop diuretics are used in asso-
ciation with saline volume expansion to treat hypercalcemia.
Acid-Base Changes CH 26
Metabolic alkalosis induced by thiazides or loop diuretics is
Diuretics
an important adverse factor in patients with hepatic cirrhosis
and ascites, in whom the alkalosis may provoke hepatic coma
by partitioning ammonia into the brain, and in those with
underlying pulmonary insufficiency, in whom the alkalosis
can impair ventilatory drive. Diuretic-induced metabolic alkalo-
sis is best managed by administration of Cl, usually as KCl, but a
distal Kþ-sparing diuretic, or occasionally a CAI, should also be
considered. Metabolic alkalosis impairs the natriuretic response
to loop diuretics, and may therefore contribute to diuretic resis-
tance. Spironolactone and distal Kþ-sparing diuretics can cause
hyperkalemic metabolic acidosis, especially in elderly patients,
those with renal impairment or cirrhosis, and those receiving
KCl supplements.
Metabolic Abnormalities
Hyperglycemia
Diuretic therapy, especially thiazide use, impairs carbohydrate
tolerance and occasionally precipitates diabetes mellitus. The
increase in blood glucose concentration is greatest during initia-
tion of therapy and is reversed rapidly after diuretic discontinu-
ation, even following many years of therapy. During sustained
thiazide therapy, there is decreased insulin secretion that can
be corrected by reversal of hypokalemia, hypomagnesemia, or
administration of spironolactone. Care should be taken to moni-
tor blood glucose following initiation of thiazide therapy, partic-
ularly in obese or diabetic patients. Measures to prevent this
complication include co-administration of a distal, Kþ-sparing
diuretic, spironolactone, ACEI, or ARB, prescribing extra KCl,
or reducing the thiazide dosage.
Hyperlipidemia
Administration of loop diuretics or thiazides increases the
plasma concentrations of total cholesterol, triglycerides,
and low-density lipoprotein (LDL) cholesterol, but reduces
high-density lipoprotein (HDL) cholesterol, thereby raising
the LDL/HDL cholesterol ratio. Importantly, most studies
have shown that serum cholesterol returns to baseline over
3 to 12 months of thiazide therapy, and when combined
with lifestyle management, 4 years of thiazide therapy for
hypertension is associated with a modest improvement in
lipid profile.
558 Hyperuricemia
Prolonged thiazide therapy for hypertension increases the
serum urate concentration by approximately 35%, due to
competition for secretion between urate and the diuretic,
VI and because of ECV depletion-induced urate reabsorption.
Hyperuricemia is dose related and may lead to gout.
Hypertension and the Kidney
Impotence
The incidence of impotence has been shown in some series
to be twice as high in patients receiving thiazides than in
normal subjects. Sildenafil use has been demonstrated to be
efficacious in hypertensive patients receiving multiple
antihypertensive agents, including diuretics.
Ototoxicity
Loop diuretics can cause deafness that may occasionally be
permanent. The risk is greater with ethacrynic acid and when
combined with another ototoxic drug (e.g., an aminoglyco-
side), during high-dose bolus intravenous therapy in patients
with renal failure where plasma levels are increased, and in
hypoalbuminemic subjects.
Drug Allergy
A reversible photosensitivity dermatitis occurs rarely during
thiazide or furosemide therapy. High-dose furosemide in renal
failure can cause bullous dermatitis. Diuretics may cause a more
generalized dermatitis, sometimes with eosinophilia, purpura,
or blood dyscrasia. Occasionally, they cause a necrotizing vasculi-
tis. Cross-sensitivity can occur with other sulfonamide drugs.
Acute interstitial nephritis with fever, skin rash, and eosinophilia
may develop abruptly some months after initiation of therapy
with a thiazide or, less often, furosemide. Ethacrynic acid is chem-
ically dissimilar from other loop diuretics and can be a substitute.
B Vitamin Deficiency
Diuretics increase the excretion of water-soluble vitamins.
Long-term diuretic therapy for CHF reduces folate and vitamin
B1 (thiamine) levels and increases plasma homocysteine. Thi- 559
amine can improve left ventricular function in some patients
with CHF treated with furosemide.
Diuretics
diuretics can be precipitated by concurrent therapy with
KCl, ACEIs, ARBs, heparin, ketoconazole, trimethoprim, or
pentamidine. Loop diuretics and aminoglycosides potentiate
ototoxicity and nephrotoxicity. Diuretic-induced hypokale-
mia increases digitalis toxicity fourfold. Plasma lithium
concentrations increase during thiazide therapy because of
increased proximal lithium reabsorption. NSAIDs may impair
the diuretic, natriuretic, antihypertensive, and venodilating
responses to diuretics and predispose to renal vasoconstric-
tion and a fall in GFR. Used together, indomethacin and triam-
terene may precipitate acute urinary obstruction and renal
failure.
Cardiac Failure
The therapeutic approach for cardiac failure depends on the
cause of the dysfunction.
Acute Ischemic Left Ventricular Failure. Intravenous furo-
semide for left ventricular failure (LVF) complicating acute
myocardial infarction can rapidly reduce the left ventricular
filling pressure, primarily by increasing venous capacitance,
an effect that antecedes any diuretic effect. The ensuing diure-
sis reduces left ventricular end-diastolic pressure further. It is
critical, however, that preload-dependent right-sided heart
failure, which may result from a right ventricular infarct,
and diastolic dysfunction are ruled out, because in this
setting, diuretic-induced volume losses can occasionally
reduce cardiac output to the point of hypotension and shock.
Decompensated Congestive Heart Failure. Acute decom-
pensation often results from an imbalance in the neurohu-
moral systems that regulate cardiac and renal function. It is
560 therefore rational to target these mechanisms with selective
therapy. These patients often respond to intravenous vasodila-
tors, which counteract the effects of baroreceptor-dependent
increases in sympathetic tone, angiotensin II and aldosterone,
VI endothelin, and AVP. Venodilation and diuresis evoked by
furosemide may be useful. Longer-acting loop diuretics (e.g.,
Hypertension and the Kidney
Diuretics
increased portal pressure, combined with preexisting diuretic
use, lead to true “underfill edema.” Diuretic therapy for this
group is complicated by hypotension, azotemia, and electro-
lyte dysfunction. Studies in patients with cirrhosis demon-
strate increases in proximal reabsorption in response to a
diminished effective arterial blood volume; there may also be
a blunted response to furosemide because of hypoalbumine-
mia leading to diminished tubular delivery. These patients
have an enhanced natriuretic response to diuretics acting
in the distal nephron. Thus, thiazides and, in particular,
spironolactone are a rational choice. Cirrhotic patients with
peripheral edema may tolerate a diuresis of 1 to 3 kg/day.
However, as the daily ascites drainage into the systemic
circulation is limited to 300 to 900 mL, the maximum daily
weight loss in nonedematous patients should not exceed 0.3
to 0.5 kg. Mild edema can be treated by dietary restriction of
Naþ (100 mmol/day). Guidelines developed by the American
Association for the Study of Liver Disease recommend fluid
restriction only if the SNa falls below 120 to 125 mmol/L.
Patients with moderate ascites require stricter reduction of salt
and diuretics. Spironolactone (50–200 mg/day), eplerenone
(50–200 mg/day), and occasionally amiloride (5–10 mg/day)
have been used as first-line agents. Guidelines suggest an
initial regimen of 40 mg furosemide with 100 mg spironolac-
tone, with titration upward, maintaining the same diuretic
ratio. Patients with diuretic resistance may be considered for
transjugular intrahepatic portosystemic shunting or repeated
large-volume paracentesis. Large-volume paracentesis is more
effective than diuretic therapy in relieving ascites
and reducing length of hospital stay and electrolyte complica-
tions, but does not influence mortality rates. Even repeated,
large-volume paracenteses (4–6 L/day) are safe if intravenous
albumin (8 g/L removed) is co-administered.
The most common problems with furosemide in cirrhosis
are electrolyte disturbances and volume depletion. Hypokalemia
is related to preexisting Kþ depletion and hyperaldosteronism.
It can be countered by the use of spironolactone or distal
Kþ-sparing agents. However, patients with cirrhosis can develop
hyperkalemic metabolic acidosis with spironolactone.
Nephrotic Syndrome
Diuretics, in combination with dietary salt restriction, are cen-
tral to the management of the nephrotic syndrome. These
562 patients typically have some degree of diuretic resistance;
loop diuretics by virtue of their more potent natriuretic effects
are therefore the agents of first choice. Decreased diuretic
delivery into tubular fluid, and diuretic binding to filtered
VI albumin within the tubule lumen contribute to the observed
diuretic resistance. The administration of albumin in combi-
Hypertension and the Kidney
Idiopathic Edema
Idiopathic edema predominantly affects women. It causes
fluctuating salt retention and edema, exacerbated by orthosta-
sis. The effects of diuretic therapy in this setting are unclear,
and patients are best treated by salt restriction.
Nonedematous Conditions
Hypertension
Hypertension is discussed in Chapter 22.
Diuretics
Thiazide diuretics, when used alone, become relatively inef-
fective in patients with a creatinine clearance less than
35 mL/min. When used in combination with a loop diuretic,
higher doses of thiazides, such as metolazone, retain some
efficacy in patients with moderate azotemia, although at the
expense of further deterioration in renal function and high
incidence of electrolyte disorders. High plasma levels of furo-
semide can cause ototoxicity and it is advisable to set a ceiling
dose in patients with CKD.
Hypercalcemia
Ca2þ excretion is increased by osmotic or loop diuretics.
Hypercalcemia activates a Ca2þ-sensing protein that inhibits
fluid and NaCl reabsorption in the TAL and impairs renal con-
centration. The ensuing ECV depletion further limits Ca2þ
excretion by reducing the GFR and enhancing proximal fluid
and Ca2þ reabsorption. Therefore, the initial therapy for
hypercalcemia is volume expansion with saline. Once volume
expansion is achieved, an infusion of a loop diuretic (e.g., 80–
120 mg of furosemide every 1–2 hours) causes the loss of
approximately 80 mg of Ca2þ per dose. Intermittent bolus ther-
apy may also be used. Fluid and electrolytes should be
replaced quantitatively.
Nephrolithiasis
Thiazides reduce stone formation in hypercalciuric and even
normocalciuric patients by reducing excretion of Ca2þ and
oxalate. Some patients continue to form stones and require
additional citrate therapy. Ca2þ excretion can be enhanced
by addition of amiloride or a low-salt diet. KHCO3 produces
a greater reduction in Ca2þ excretion than KCl when given
with hydrochlorothiazide.
Diabetes Insipidus
Thiazides can reduce urine flow by about 50% in patients with
central or nephrogenic diabetes insipidus. Antidiuresis is related
to a decreased GFR, enhanced water reabsorption in the proximal
and distal tubules, and an increase in papillary osmolarity.
Amiloride is effective treatment for lithium-induced diabetes
insipidus.
564 Osteoporosis
Bone cells express a Naþ/Cl co-transporter that, when
blocked by a thiazide, enhances bone Ca2þ uptake. Thiazides
inhibit osteocalcin, an osteoblast-specific protein that retards
VI bone formation. They inhibit bone reabsorption and augment
bone mineralization, independent of PTH. Indeed, thiazide
Hypertension and the Kidney
Cardiovascular Aspects of
Chronic Kidney Disease
BACKGROUND
Cardiovascular Disease
Cardiovascular disease is the predominant cause of death in
patients with chronic kidney disease (CKD). Heart disease
accounts for 40% to 45% of all deaths among both dialysis
and transplantation patients. Most clinical consequences of
cardiac disease result from either cardiomyopathy (systolic or
diastolic) or ischemic heart disease. Although myocardial
infarction and angina are most often attributable to the pres-
ence of critical coronary artery disease (CAD), they may also
result from decreased perfusion of the myocardium due to non-
atherosclerotic small vessel disease and left ventricular (LV)
hypertrophy. It has also become evident that the structure
of large arteries can be altered not only by atherogenesis, but
also by arteriosclerosis. Valvular heart disease due to dystro-
phic calcification of the aortic and mitral valves is another
significant cause of cardiac morbidity.
567
568 progress from LV hypertrophy with preserved systolic func-
tion to LV dilatation and symptomatic heart failure.
Cardiac Failure
Diastolic Dysfunction. Hemodialysis patients with LV
hypertrophy often have some impairment in LV diastolic func-
tion. Consequent to increased LV stiffness, small increases in
extracellular volume trigger large rises in LV pressure, predis-
posing to symptomatic pulmonary edema. The reverse is also
true: volume depletion results in a large fall in LV pressure
with symptomatic hypotension and hemodynamic instability,
as is frequently observed during rapid ultrafiltration during
hemodialysis. This is often a clinical clue to the presence of
diastolic dysfunction in a hemodialysis patient.
570 Systolic Dysfunction. Decreased systolic function is fre-
quently observed in patients in whom cardiac disease was
present before the onset of dialysis therapy, and in patients
who have experienced prolonged and marked hemodynamic
VII overload. Approximately 15% of patients have systolic
dysfunction at the time of initiation of dialysis. Diminished
The Consequences of Renal Failure
Dialysis Hypotension
The pathophysiology of the clinical manifestations of dialysis
hypotension is multifactorial and not fully understood. It may
occur in the presence of systolic failure, diastolic dysfunc-
tion, or ischemic disease. In the latter, it is usually associated
with chest pain, whether atherosclerotic or nonatherosclerotic
in origin. In dilated cardiomyopathy, hypotension during dial-
ysis occurs only in patients who are unable to increase resting
cardiac output in response to plasma volume depletion. Such
patients usually have severe systolic failure, because the dial-
ysis procedure actually improves myocardial performance in
most patients with depressed LV function. LV hypertrophy, 573
highly prevalent in this population, may also be a contributing
factor to dialysis hypotension. Because of diminished LV com-
pliance, the relationship between LV end-diastolic pressure
and volume is exaggerated. Consequently, during dialysis, rel- CH 27
ative hypovolemia may result in a disproportionately large
Arrhythmias
LV hypertrophy and coronary heart disease are associated
with an increased risk of arrhythmias. In addition, serum elec-
trolyte levels that can affect cardiac conduction, including
potassium, calcium, magnesium, and hydrogen, are often
abnormal or undergo rapid fluctuations during hemodialysis.
Hence, arrhythmias (or sudden death) are of particular con-
cern in patients undergoing dialysis. High-grade ventricular
arrhythmias such as multiple premature ventricular contrac-
tions, ventricular couplets, and ventricular tachycardia have
been observed in up to 30% of dialysis patients on 24-hour
Holter monitoring. Older age, dialysis-associated hypoten-
sion, preexisting heart disease, LV hypertrophy, and digoxin
therapy are associated with a higher prevalence and greater
severity of cardiac arrhythmias. There is considerable varia-
tion in the frequency and severity of arrhythmias during
hemodialysis, as well as in the interdialytic period. Because
of these factors, there is no consensus on the frequency of
arrhythmias in these patients or their clinical significance.
There are also conflicting data about the effect of dialysis and
of various dialysis compositions and dialysis protocols on the
occurrence of rhythm disturbances. Whereas the dialysis
method, membrane, and buffer used do not seem to have a direct
effect on the incidence of arrhythmias, dialysis-associated
hypotension seems to be an important factor in precipitating
high-grade ventricular arrhythmias.
Arrhythmias in peritoneal dialysis patients appear different
from those in hemodialysis patients, and consist mainly of
atrial and ventricular premature beats. Peritoneal dialysis by
itself does not appear to provoke or aggravate arrhythmias.
The arrhythmias seen in these patients are more a reflection
of the patient’s age, underlying ischemic heart disease, or an
association with LV hypertrophy. Most atrial arrhythmias are
of low clinical significance, although sustained, rate-related
(fast or slow) impairment of LV filling can trigger hypotension.
The use of digoxin in hemodialysis patients has also raised
concern regarding precipitation of arrhythmias, especially in
574 the immediate postdialysis period, when both hypokalemia
and relative hypercalcemia may occur. However, an asso-
ciated increase in the incidence of arrhythmias has not been
demonstrated in patients taking digoxin.
VII
Valvular Disease
The Consequences of Renal Failure
MANAGEMENT
Diagnosis
These diagnostic tools can often be applied across the spectrum
of CKD; they can be used to investigate both ischemic and
cardiomyopathic disease, and they are limited by the same
clinical considerations, both renal and cardiovascular. In a
practical context, it is, of course, assumed that careful clinical
assessment will always precede further diagnostic endeavors.
Cardiac Disease
Electrocardiography. The increasing prevalence of LV
hypertrophy with declining renal function predisposes to
abnormalities in resting and exercise electrocardiographic
(ECG) findings in patients with CKD. In dialysis patients, minor
incremental changes in the PR and QRS intervals, together with
nonspecific ST-T wave changes, are frequently seen in the rest-
ing ECG. Changes may be more prominent during dialysis due
to the substantial intracellular and extracellular electrolyte
shifts; the QRS amplitude has been shown to alter with reduc-
tion in extracellular fluid levels. In episodes of acute coronary
ischemia (unstable angina and myocardial infarction), classic
ECG changes occur. Exercise-related ECG changes should be
interpreted with caution. Resting abnormalities, a restricted
576 maximal pulse rate (autonomic neuropathy), and limited exer-
cise capacity in patients with CKD may either mask or errone-
ously predict underlying ischemia.
Biochemical Markers of Ischemia. Serial estimates of levels
VII of standard myocardial enzymes (creatine phosphokinase and
lactate dehydrogenase), when elevated, reliably diagnose acute
The Consequences of Renal Failure
Dyslipidemia
In short-term studies, statins have been recognized as being safe
and efficient for patients with CKD/ESRD. Recently published
results of longer-term studies support their use in the CKD pop-
ulation, where the use of pravastatin in a CKD stage 3 cohort was
associated with a reduction in the incidence of myocardial
infarction, coronary death, or revascularization. Experience of
fibrate use in CKD patients is limited, although subgroup analy-
sis of the Veterans’ Affairs High-Density Lipoprotein Interven-
tion Trial (VA-HIT) showed a reduction in the incidence of
coronary death or nonfatal infarction with the use of gemfibrozil
compared with placebo in male patients with CKD stage 2. The
use of fluvastatin in the transplant population was evaluated in
the Assessment of Lescol in Renal Transplantation (ALERT)
study, with effects on the primary end-points of cardiac death, 583
nonfatal MI, or coronary intervention investigated. Primary
analysis failed to show a difference, although post-hoc analysis
suggested a reduction in the incidence of cardiac death or defi-
nite myocardial infarction with the use of fluvastatin. Evidence CH 27
for the use of statins in the dialysis population, however, is less
Smoking
There are no studies demonstrating that cessation of smoking
improves the outcome of CKD at any stage. Nevertheless, it
is reasonable to extrapolate data from the general population
that indicates reduction of cardiovascular risk over time after
smoking cessation.
Diabetes
Tight glycemic control is an appropriate aim in predialysis
patients, given the proven attendant reduction in microvascu-
lar disease, unless hypoglycemic episodes are troublesome or
unpredictable. There is less support for near-euglycemic levels
in dialysis patients because of the inability to influence renal
function, and the propensity for hypoglycemia due to glucose
diffusion during dialysis. In transplantation patients, tight con-
trol may be difficult because of the hyperglycemic tendency of
immunosuppressive agents; however, strict glycemic control
after transplantation may reduce the development of new dia-
betic changes in the transplanted kidney and is a worthy goal.
Hematologic Aspects of
Kidney Disease and
Erythropoietin Therapy
ANEMIA IN CHRONIC KIDNEY DISEASE
Anemia is a state of deficient mass of red blood cells and
hemoglobin (Hgb), resulting in insufficient oxygen delivery
to the body’s tissues and organs. The anemia of kidney disease
is characterized by normocytic and normochromic RBCs, an
inappropriately low reticulocyte count for the degree of ane-
mia, and a hypoplastic erythroid bone marrow, with normal
leukopoiesis or megakaryocytopoiesis. Anemia is a cardinal
feature of chronic kidney disease (CKD) and the hematocrit
typically declines in parallel with the fall in the glomerular
filtration rate (GFR), although anemia is not typically a
frequent or severe complication until the GFR falls below
30 mL/min. Anemia develops earlier in CKD among patients
with diabetes mellitus, and tends to be more profound than
the anemia seen in nondiabetic patients. There is also
ethnic variation, with anemia a more prominent feature in
non-Hispanic blacks.
Normal Erythropoiesis
585
586 erythropoietic process. The interaction of erythropoietin with
colony-forming units-erythroid (CFU-E), a pre-normoblast cell
that expresses blood group and Rh antigen, is the key process
in determining net erythrocyte production. After this stage,
VII the number of erythropoietin receptors per cell progressively
declines, with none found on the surface of reticulocytes or
The Consequences of Renal Failure
mature erythrocytes.
Quality of Life
Anemia and its attendant symptoms of fatigue, dyspnea, and CH 28
reduced mental acuity have been shown to diminish the indi-
Mortality Risk
The relationship of anemia to mortality risk has been evalu-
ated through both observational and interventional studies,
although with limitations. Observational studies suffer partic-
ularly from the presence of multiple confounding factors,
including health status (sicker patients at greatest risk for
poor outcomes tend to be more anemic with lower Hgb levels),
co-morbidity, inflammation, and nutrition, and although
useful for describing the relationship between anemia and
mortality risk, do not establish causality.
Cardiac Health
The significant and deleterious impact of cardiovascular dis-
ease in CKD is discussed extensively in Chapter 27, Cardio-
vascular Aspects of Chronic Kidney Disease. Anemia results
in chronic compensatory changes in the cardiovascular sys-
tem, including increased cardiac output, reduced systemic
vascular resistance, vasodilatation, and neurohormonal acti-
vation. In the short term, these processes diminish the effect
of reduced oxygen carriage by the circulation, but in the long
term, maladaptive cardiac changes may occur. Left ventricular
hypertrophy (LVH) has been shown to be consistently asso-
ciated with chronic anemia, with increasing risk as Hgb
declines. LVH is a strong independent predictor of mortality
risk. However, interventional studies evaluating the effect of
treatment of anemia on left ventricular mass have had mixed
results.
Erythropoiesis-Stimulating Agents
The cloning and expression of the human EPO gene was
reported in 1985, and the clinical efficacy of rHuEPO in
reversing the anemia of chronic and end-stage kidney disease
was thereafter rapidly established. The impact of the use of
588 rHuEPO cannot be overstated: it is estimated that over 95%
of ESRD patients in the United States currently receive
replacement therapy with some form of recombinant erythro-
poietin. Transfusion dependence in ESRD has virtually been
VII eliminated, with reduction in attendant infectious sequelae
and sensitizing events, and marked enhancement in the
The Consequences of Renal Failure
Iron Status
In clinical practice, the iron status is most commonly assessed
using serum ferritin and the transferrin saturation (TSAT%).
The percentage of hypochromic red blood cells (PHR) and the
reticulocyte hemoglobin concentration (CHr) may, however, 591
offer greater overall utility.
Serum ferritin, a protein secreted into the plasma by the
reticuloendothelial cells under the regulation of intracellular
iron concentration, is an indirect measure of storage iron, CH 28
although its behavior as an acute phase reactant limits its
toneal dialysis, ongoing iron losses are less than those seen
in the hemodialysis population. Accordingly, iron balance
should be easier to attain, and there may be a role for oral iron
therapy, although the lack of controlled studies means that its
efficacy has yet to be established. K/DOQI guidelines recom-
mend that when oral iron is used in adults, 200 mg of elemen-
tal iron should be administered daily in two to three divided
doses. The efficacy of oral iron in patients with kidney disease
may be enhanced through several simple practices: first, the
dose should provide at least 200 mg of elemental iron per
day (for ferrous sulfate, this approximates to three 325-mg
tablets per day); second, iron administration should occur
between meals and should be spaced at least 1 hour apart from
the ingestion of phosphate binders; and third, because iron is
absorbed proximally in the gastrointestinal tract, delayed-
release iron supplements should be avoided.
Intravenous Iron
The efficacy of intravenous iron has been widely studied in
hemodialysis patients, and has been consistently shown to
result in higher hemoglobin levels or a reduced erythropoietin
requirement (>40%), or both. Several forms of intravenous
iron are available: iron dextran, iron sucrose, and ferric gluco-
nate. Iron dextran has been used for several decades and
although clearly effective, its use is associated with risk of
anaphylactoid reaction in approximately 0.6% of patients
treated. These reactions are believed to be related to the drug’s
dextran component and may be due to direct release of vaso-
active mediators by mast cells. Iron sucrose and ferric gluco-
nate are non-dextran forms of intravenous iron that appear to
be safer than iron dextran with lower risk of anaphylactoid
reactions, and a similar rate of serious adverse events when
compared to placebo.
Two strategies for administering intravenous iron to hemo-
dialysis patients are in common use. The first entails surveil-
lance for the presence of iron deficiency every 3 months and,
if detected, treatment with a short, repletive course of intrave-
nous iron. Typically, 1000 mg of either iron sucrose or ferric
gluconate can be given in divided doses over a period of
2 to 3 weeks. Patients will generally demonstrate a significant
improvement in responsiveness to rHuEPO thereafter. Many,
however, will remain iron deficient, so assessment of iron
stores should be repeated after completing such a course of
treatment. A second strategy is to anticipate iron deficiency
by administering small weekly doses to maintain stable iron 593
stores. Weekly doses of 12.5 to 100 mg of intravenous iron
may improve responsiveness to rHuEPO. The potential advan-
tage of such an approach lies in linking iron replacement tem-
porally with ongoing iron losses. Assessment of iron stores CH 28
should be performed quarterly, however, to ensure the adequacy
Seizures
The risk of precipitating seizures in patients receiving rHuEPO,
apart from that associated with hypertensive encephalopathy,
has not appeared to be increased once appropriate attention
is paid to dosing and titration guidelines. A previous history
of seizures should not preclude treatment with rHuEPO.
Thrombosis
In patients treated with rHuEPO, increases in factor VIII, von
Willebrand factor antigen, fibrinogen, and whole-blood plate-
let aggregation are observed. Despite this, multiple studies of
rHuEPO-treated patients, with mean hematocrit values of
34%, have revealed an average clotting incidence of only
7.5%. At present, there does not appear to be any added risk
of thrombosis in rHuEPO-treated patients with either grafts
or fistulas. Data from the U.S. Normalization of Hematocrit
trial demonstrated a higher rate of both fistula and graft throm-
bosis in patients randomized to the higher hemoglobin group
(Hgb 13g/dL), although no correlation between the hemoglobin
concentration attained, rHuEPO dose, and access thrombosis
was observed.
Pure Red Blood Cell Aplasia 595
Although reported only three times from the availability of
rHuEPO until 1998, from 1998 to 2001 Casadevall and collea-
gues* noted 21 patients in whom pure red blood cell aplasia
(PRCA) developed in the setting of rHuEPO treatment. These CH 28
patients possessed rHuEPO-neutralizing antibodies, which
Infection/inflammation
Malnutrition: folate or vitamin B12 deficiency
Aluminum toxicity
Severe secondary hyperparathyroidism
Hemoglobinopathies (e.g., a- and b-thalassemia, sickle cell anemia)
Malignancies
Hemolysis
Pure red blood cell aplasia
ACE inhibitor use
ACE, angiotensin-converting enzyme.
Iron Deficiency
A suboptimal response to rHuEPO most commonly results from
failure of delivery of an adequate amount of iron to the erythron,
either consequent to iron (blood) loss, iron consumption by the
growing erythron in an appropriate response to rHuEPO ther-
apy, or inadequate gastrointestinal absorption. In CKD or perito-
neal dialysis patients, issues of blood loss are far less common
because of the absence of extracorporeal circulation and repeti-
tive systemic anticoagulation. Most treated patients become iron
deficient and therefore require more rHuEPO to maintain the
same rate of RBC production, and if the iron balance is not
restored by administration of oral or parenteral iron, an initial
good response may falter.
Aluminum Overload
Aluminum toxicity has been seen with decreasing frequency
due to major improvements in water purification, declining
use of aluminum-based phosphate binders, and the availabil-
ity of non–aluminum-based agents. Mechanisms for the disor-
der have been variably ascribed to interference with
enzymatic insertion of iron and competition between alumi-
num and iron for binding to transferrin before substrate deliv-
ery to erythropoietic elements. Basal serum aluminum
concentrations greater than 50 ng/mL and aluminum levels
greater than 175 ng/mL following a desferoxamine challenge
test (a single dose of 500–1000 mg intravenously) suggest alu-
minum overload, although bone biopsy is the best method of
diagnosis. Increasing rHuEPO dosing has generally proved
effective in overcoming disruption in erythropoiesis, as has
exclusion of aluminum, or when necessary, desferoxamine
treatment of bone or central nervous system disease.
Infectious and Inflammatory Chronic Disease 597
and Malignancy
In states of active inflammation (infectious processes, surgical
insults, and malignancies), iron metabolism is directly altered,
and access to iron from the reticuloendothelial system by CH 28
hematopoietic cells is blocked due to increased iron uptake
Secondary Hyperparathyroidism
A correlation exists between rHuEPO requirements and the
degree of marrow fibrosis, osteoclastic and eroded surfaces
seen on bone biopsy specimens, and PTH levels. This has
been borne out in the Dialysis Outcomes and Practice Patterns
Study (DOPPS), which demonstrated a relationship between
attainment of a hemoglobin concentration of greater than
11 g/dL and local practices relating to the treatment of high-
turnover bone disease. A possible role for vitamin D has been
suggested in improving erythropoiesis, independent of its
effect on either serum calcium or PTH levels. Overall, effec-
tive management of high-turnover bone disease, either by sur-
gical or biochemical intervention, may have a beneficial effect
on the efficacy of rHuEPO treatment.
Carnitine Deficiency
L-Carnitine is an essential cofactor for transmitochondrial trans-
port for fatty acids for oxidation and is depleted by hemodialysis.
A role for carnitine in maintaining erythrocyte membrane integ-
rity and improving deformability, thereby increasing red blood
cell survival, has been postulated. Studies have shown modest
efficacy in raising hemoglobin levels or reducing rHuEPO
requirements. Variable benefit has been shown for dyslipidemia
or improvement in any specific abnormal lipid fraction.
Therapeutic Strategies
The treatment of uremic patients experiencing bleeding epi-
sodes requires the usual approach to a bleeding patient, includ-
ing hemodynamic stabilization, identification of the bleeding
source and etiology, and replacement of blood products as
required. Particular to uremic bleeding is the need to correct
platelet dysfunction and other contributing factors to the bleed-
ing diathesis. The intensity of interventions to correct uremic
platelet dysfunction is dictated by the severity of bleeding. Ini-
tiation of dialysis will lead to improvement in thrombasthenia
and bleeding risk, with over two thirds of dialyzed patients
demonstrating reduction in bleeding time. It is noteworthy,
however, that hemodialysis may induce a transient deterio-
ration in platelet dysfunction, thought to be multifactorial.
A transient decrease of platelet membrane expression of
glycoprotein 1b has been shown to occur after dialysis, with 599
other potential factors thought to include the removal of youn-
ger platelets with greater function and impaired platelet func-
tion due to a secondary effect of activated leukocytes. Clearly,
in the setting of acute bleeding, anticoagulation must be mini- CH 28
mized, or ideally avoided. The use of regional anticoagulation
Neurologic Complications
of Kidney Disease
End-stage renal disease (ESRD) is associated with at least five
well-described disorders of the nervous system:
• Uremic encephalopathy
• Dialysis dysequilibrium syndrome (DDS)
• Dialysis dementia
• Stroke
• Sexual dysfunction
In addition to these five manifestations of neurologic
dysfunction, which are specifically related to renal insuffi-
ciency, dialysis, or both, a number of other neurologic disorders
occur with increased frequency in patients who have ESRD and
are being treated with chronic hemodialysis. Subdural hema-
toma, acute stroke, certain electrolyte disorders (hyponatremia,
hypernatremia, hyperkalemia, phosphate depletion, hyper-
calcemia), vitamin deficiencies, Wernicke encephalopathy, drug
intoxication, hypertensive encephalopathy, and acute trace
element intoxication must be considered in patients with
chronic kidney disease (CKD) or ESRD who manifest an altered
mental state. Patients with renal failure are also at risk for
development of the same varieties of organic brain disease and
metabolic encephalopathy that can affect the general popula-
tion. Therefore, when a patient with ESRD presents with altered
mental status, a thorough and complete evaluation is necessary.
UREMIC ENCEPHALOPATHY
The term uremic encephalopathy is used to describe the early
appearance and dialysis-responsiveness of the nonspecific
neurologic symptoms of uremia. It is an acute or subacute
organic brain syndrome that regularly occurs in patients with
acute kidney injury (AKI) or CKD when the glomerular filtra-
tion rate (GFR) declines to less than 10% of normal. The causes
of uremic encephalopathy are doubtless multiple and com-
plex. As with other organic brain syndromes, these patients
display variable disorders of consciousness, psychomotor
behavior, thinking, memory, speech, perception, and emotion.
The symptoms of uremic encephalopathy are shown in
Table 29-1. Key early clinical features include daytime
601
602
Signs and Symptoms of Uremic
Table 29-1
Encephalopathy
Early Uremia
VII Anorexia
Malaise
The Consequences of Renal Failure
Insomnia
Diminished attention span
Decreased libido
Moderate Uremia
Emesis
Decreased activity
Easy fatigability
Decreased cognition
Impotence
Advanced Uremia
Severe weakness and fatigue
Pruritus
Disorientation
Confusion
Asterixis
Stupor, seizures, coma
EEG findings in patients with CKD are usually less severe than
those observed in patients with AKI. Several investigations have
shown a good correlation between the slow delta wave activity
and the decline of renal function as estimated by serum creati-
nine. After the initiation of dialysis, there may be an initial period
of clinical stabilization during which time the EEG deteriorates
(up to 6 months), but it subsequently approaches normal pat-
terns. Significant improvement is seen in the EEG abnormalities
following renal transplantation. The EEG abnormalities are likely
to be multifactorial; however, as discussed previously, there is
evidence to suggest that PTH may exert a direct effect on the
brain, by increasing the brain content of calcium Ca2þ.
NEUROLOGIC COMPLICATIONS OF
END-STAGE RENAL DISEASE
Dialysis Dementia
Dialysis dementia (also called dialysis encephalopathy) is a
progressive, frequently fatal neurologic disease that has been
reported almost exclusively in patients being treated with
chronic hemodialysis. Recent reports suggest that some forms
of dialysis dementia may be a part of a multisystem disease,
which may include encephalopathy, osteomalacic bone dis-
ease, proximal myopathy, and anemia. The syndrome is not
alleviated by increased frequency of dialysis or by renal trans-
plantation. The etiology has not been elucidated and although
an increase in brain aluminum content has been strongly impli-
cated in some cases of dialysis dementia, it is not the sole
607
Differential Diagnosis of Dialysis
Table 29-2
Disequilibrium Syndrome
Subdural hematoma
Uremia CH 29
Acute cerebrovascular accident
Hyperosmolality
Hyponatremia
Symptomatic uremia
Drug/trace metal intoxications
Hyperparathyroidism
Structural brain lesions
Subdural hematoma
Normal pressure hydrocephalus
Stroke
Other disorders
Hypertensive encephalopathy
Dialysis disequilibrium
Subdural Hematoma
Subdural hematoma is an infrequent cause of death in patients
maintained on chronic hemodialysis. This condition presents
with headache, drowsiness, nausea, and vomiting and may pro-
ceed to loss of consciousness with clinical signs of increased
intracranial pressure. On physical examination, there is often
evidence of localized neurologic disease; there may be signs of
meningeal irritation, and somnolence and focal seizures may
be observed. The diagnosis of subdural hematoma can usually
be made by CT or MRI and should be entertained as a possible
cause of altered mental status particularly in dialysis patients
612 taking anticoagulants. Rapid diagnosis and operative interven-
tion is required if a fatal outcome is to be averted.
Stroke
UREMIC NEUROPATHY
Clinical Manifestations
Metabolic Neuropathy
Uremic neuropathy is one of a group of central-peripheral axo-
nopathies, also known as dying-back polyneuropathies, which
include neuropathies associated with diabetes, multiple mye-
loma, and certain hereditary polyneuropathies. There is also
an associated degeneration of the spinal cord, particularly
involving posterior columns, as well as other portions of the
CNS (Table 29-6).
In addition to uremic neuropathy, uremic myopathy is a fre-
quent cause of weakness, exercise limitation, and rapid-onset
tiredness in dialysis patients. Later, muscle wasting occurs,
particularly in the limb muscles.
PHOSPHORUS
Inorganic phosphorus is critical for numerous physiologic
functions including skeletal development, mineral metabo-
lism, cell membrane phospholipid content and function, cell
signaling, platelet aggregation, and energy transfer through
616
617
Kidney Disease Improving Global Outcomes
(KDIGO) Classification of Chronic Kidney
Table 30-1 Disease (CKD)–Mineral Bone Disorder (MBD)
and Renal Osteodystrophy
CH 30
Definition of CKD-MBD
Phosphorus Homeostasis
Between 60% and 70% of dietary phosphate is absorbed by
the gastrointestinal tract, a process dependant both on passive
transport and active transport stimulated by calcitriol and, to a
much lesser extent, PTH. Most inorganic phosphate is freely
618 filtered by the glomerulus. Approximately 70% to 80% of
the filtered load is reabsorbed in the proximal tubule, the
remainder in the distal tubule. Phosphate excretion is increased
by increased plasma phosphate concentration, PTH, volume
VII expansion, metabolic acidosis, glucocorticoids, and calcitonin.
The majority of this regulation occurs in the proximal tubule
The Consequences of Renal Failure
CALCIUM
Serum calcium levels are normally tightly controlled within a
narrow range, usually 8.5 to 10.5 mg/dL (2.1–2.6 mmol/L),
although these levels are a poor reflection of overall total body
calcium. Ionized calcium is the physiologically active compo- 619
nent, and generally makes up approximately 40% of total
serum calcium levels. The nonionized component is bound to
albumin or anions such as citrate, bicarbonate, and phosphate.
Serum levels of ionized calcium are maintained within the nor- CH 30
mal range by alterations in the secretion of PTH, which acts to
Calcium Homeostasis
Calcium absorption across the intestinal membrane occurs via
both a vitamin D–dependent, saturable pathway and a vitamin
D–independent, nonsaturable pathway. The duodenum is the
major source of calcium absorption, although the remainder of
the small intestine and the colon also contribute. In the kid-
ney, approximately 60% to 70% of calcium is reabsorbed pas-
sively in the proximal tubule, driven by a transepithelial
electrochemical gradient generated by sodium and water reab-
sorption. A further 10% is absorbed in the thick ascending
limb by paracellular transport. The regulation of reabsorption
is via transcellular pathways that occur in the distal convo-
luted tubule, the connecting tubule, and the initial portion of
the cortical collecting duct.
Calcium-Sensing Receptor
VITAMIN D
PARATHYROID HORMONE
PTH at the skeletal level. PTH binds to the PTH1 receptor, which
is found in many tissues including osteoblasts and vascular
smooth muscle cells, and is widely expressed in the kidney.
Although PTH-related protein (PTHrp) also binds to the PTH1
receptor, its effects are autocrine, whereas the effects of PTH
are systemic.
Plasma PTH levels generally serve not only as a non-
invasive test for the initial diagnosis of renal bone disease,
but also as a useful index for monitoring evolution of the dis-
order, and as a surrogate marker of bone turnover in CKD, with
high levels associated usually with high-turnover bone dis-
ease, and low-turnover/adynamic bone disease with normal
or reduced plasma PTH levels. Interpretation of early immu-
noassays for PTH was complicated by the fact that PTH circu-
lates not only in the form of the intact 84-amino-acid peptide
but also as multiple fragments of the hormone, particularly from
the middle and COOH-terminal regions of the PTH molecule.
More recently, two-site immunoradiometric assays that only
detect intact PTH have been developed and are now widely
commercially available. Some recent studies have suggested that
PTH fragments may also have biologic actions.
BONE
The majority of total body stores of calcium and phosphorus
are located in bone. Trabecular (cancellous) bone is located
predominantly in the epiphyses of long bones, is 15% to
25% calcified, and serves a metabolic function with a rela-
tively short turnover rate of calcium, in contrast to cortical
(compact) bone in the shafts of long bones, which is 80% to
90% calcified, and has a calcium turnover rate of months.
The control of bone remodeling is highly complex but appears
to occur in distinct phases: (1) osteoblast activation, (2) osteo-
clast recruitment resorption, (3) preosteoblast migration and
differentiation, (4) osteoblast deposition of matrix, (5) mineral-
ization, and (6) quiescent stage. Osteoclasts, the bone-resorbing
cells, are derived from hematopoietic precursor cells, and act
via the release of degradative enzymes. PTH, cytokines, and
1,25(OH)2D are all important in the control of osteoclast
precursors.
Bone strength reflects the integration of two main features:
bone density and bone quality. These “quality” factors include
abnormal bone turnover or remodeling, and other indices of 623
bone architecture including mineralization and collagen cross-
linking. Impaired bone quality in CKD/ESRD is clinically mani-
fested by increased prevalence of hip fracture across all age
groups in the dialysis population compared to the general popu- CH 30
lation, with dialysis patients in their 40s shown to have a rela-
VASCULAR CALCIFICATION
Classically, atherosclerotic disease has been characterized
by fibrofatty plaque formation, associated with intimal calcifi-
cation, where calcification was thought to be a late feature
of the disease. More recent advances have demonstrated cir-
cumferential atherosclerosis, where calcification is an early
feature. The medial layer may also be affected, leading to
medial calcification of elastic arteries. This medial calcinosis,
or Monckeberg calcification, is seen in patients with diabetes
and kidney disease, and is associated with younger age, longer
duration of hemodialysis, and serum calcium phosphate
abnormalities. Medial calcification implies arteriosclerosis 625
with noncompliance of the large conduit vessels. It has been
clearly shown to be associated with increased all-cause and
cardiovascular calcification in CKD and in diabetic patients
in the absence of CKD. CH 30
Although initially believed to be a bystander process, recent
CALCIPHYLAXIS
Calciphylaxis is a small vessel vasculopathy largely confined
to patients with end-stage kidney disease and is also known
as calcific uremic arteriolopathy. Ischemia of the skin and
subcutaneous tissues is the most common clinical presenta-
tion, leading to necrosing skin ulcers, subcutaneous nodules
of infarction, and areas of poor wound healing. The most com-
mon sites of involvement are subcutaneous tissue with
increased adipose content, including the breast, abdominal
wall, and thigh. The overall prognosis is poor, with death due
to sepsis extremely common. The exact etiology of this disorder
is unclear. Risk factors include obesity, white ethnic race,
and diabetes mellitus. Much attention has also focused on the
roles of hypercalcemia, hyperphosphatemia, SHPT, and high
calcium phosphate product (Ca P). Sustained hyperphos-
phatemia in particular may be a risk factor for calciphylaxis.
Although associated with severe SHPT, many cases occur in
the absence of hyperparathyroidism at the time of diagnosis. 627
Protein calorie malnutrition, use of warfarin, vitamin K defi-
ciency, and protein C and S deficiency have also been postu-
lated as potential risk factors. Calciphylaxis is generally
diagnosed clinically by the presence of subcutaneous and cuta- CH 30
neous nodules, necrotic lesions, and eschar with hyperesthesia
Phosphate-Binding Agents
As discussed previously, we are increasingly aware of the
need for optimal control of hyperphosphatemia, as its role in
SHPT, vascular mineralization, and cardiovascular morbidity
628
Table 30-4 Radiographic Features of Mineral Bone Disease
Bone Disease Type Specific Feature(s)
High-turnover Subperiosteal bone resorption
VII Cystic lesions or brown tumors
(osteoclastomas)
The Consequences of Renal Failure
Osteosclerosis (“rugger-jersey”
appearance on lateral view of spine)
“Pepper-pot” skull
Osteomalacia Pseudofractures or Looser zones
(pathognomonic)
Stress fractures
Deformities of long bones (e.g., bowing)
May also see features of high-turnover
bone disease
Osteopenia Decreased bone mineral density
(nonspecific finding)
Metastatic Calcified large blood vessels; also
calcification calcifications in joints, skeletal muscle
Dialysis-related Cystic bone lesions (not pathognomonic)
amyloidosis Cysts of synovial joints, subchondral
cysts
Destructive Usually affects cervical spine; reduction
spondyloarthropathy of disk space with destruction or
sclerosis of adjacent end-plates (need to
distinguish from infective
osteomyelitis)
Vitamin D Sterols
Calcimimetic Agents
Calcimimetic agents are small organic molecules that func-
tion as allosteric activators of the calcium-sensing receptor
(CaR), which mediates calcium-regulated PTH secretion by
parathyroid cells. Cinacalcet hydrochloride is one such calci-
mimetic that is now commercially available. Cinacalcet is
rapidly absorbed from the gastrointestinal tract after oral
administration, reaching peak plasma levels 60 to 90 minutes
after dose, corresponding to maximum biologic effects, as
judged by reductions in plasma PTH levels. Treatment with
daily doses of cinacalcet produces an oscillating hormone
profile over the course of the day, a pattern that clearly
requires consideration when timing the sampling of plasma
levels of PTH taken to monitor biochemical response to ther-
apy. It is generally recommended that PTH levels be
measured at least 12 hours after the preceding dose. Serum
calcium concentrations also fall modestly, with a decrease
seen during the first 12 to 24 hours after commencement of
therapy, with subsequent stabilization within 24 to 48 hours,
but do not fall progressively if the dose remains unchanged.
Nevertheless, the use of large initial doses of cinacalcet or
continued administration of cinacalcet without periodic dose
adjustments based on measurements of serum calcium can
result in symptomatic hypocalcemia or overt tetany. There-
fore, a dose titration scheme is used, commencing at initial
doses of 30 mg daily, increasing in increments of 30 mg at
2- or 3-week intervals, to a maximum daily dose of 180 mg
if serum calcium concentrations remain within acceptable
limits. The efficacy of cinacalcet for lowering plasma
PTH appears to be equally effective among patients with
mild, moderate, or advanced SHPT. Although CaR expres-
sion is diminished in hyperplastic parathyroid tissue from
patients with overt SHPT, such changes do not affect the 633
ability of cinacalcet to produce clinically meaningful and
sustained reductions in serum PTH levels. Available data
also indicate that cinacalcet can be used either alone or
together with vitamin D sterols to control SHPT. Additional CH 30
studies are needed to ascertain the effect of cinacalcet on
Parathyroidectomy
637
638
Table 31-1 Dietary Recommendations for Patients with Chronic Kidney Disease
Dietary Factor Impact on GFR Decline Special Subgroups Recommendations Other Comments
Protein Restriction acutely Unknown Restriction to 0.8 g Protein-restricted diets should
lowers GFR protein/kg/day contain approx. 50%
Long-term restriction For symptomatic high-quality protein
may slow progression patients: restriction to
0.6 g protein/kg/day
Fat No impact concerned Unknown Restrict saturated and Polyunsaturated fats may
avoid trans fatty acids reduce risk of CHD
Carbohydrates Insufficient data Diabetics Avoid refined Energy needs can be met with
carbohydrates sugar polymers
Sodium Restriction may slow Elderly, African Intake 2 g/day Most effective for hypertension
progression Americans, diabetics with higher potassium intake
Potassium Insufficient data Elderly, African Encourage potassium-rich Monitor for hyperkalemia
Americans, diabetics diet as tolerated
Vitamins and Insufficient data Unknown Follow recommended Retinol may adversely affect
minerals dietary allowance bone health; vitamin D should
be used with care
CHD, coronary heart disease; GFR, glomerular filtration rate.
patients and correction of metabolic acidosis in predialy- 639
sis patients, as well as those treated by hemodialysis (HD) or
peritoneal dialysis (PD), sharply decreases the degradation of
body protein stores. More recently, chronic inflammatory
responses have been implicated in the development of PEM CH 31
and cardiovascular disease in CKD/ESRD.
Anthropometrics
Biochemical Markers
The concentration of serum albumin is frequently cited as an
index of the adequacy of the diet, with a low value being
equated with malnutrition. Although the serum albumin is a
reasonable marker of body protein stores and a reliable predic-
tor of mortality risk in dialysis patients, concluding that a low
serum albumin concentration is simply due to a low-protein
diet can be very misleading. The serum albumin concentration
is the result of a balance between synthesis and degradation
of albumin. The serum albumin responds relatively slowly
to changes in protein stores because of a half-life of about
20 days. A fall in plasma albumin levels may lag behind the
development of malnutrition by several months, and in mal-
nourished patients, albumin levels are only slowly restored to
normal during protein refeeding. In contrast, during states of
volume expansion the serum albumin concentration falls owing
to dilutional effects. Despite these drawbacks, given the strength
of association of hypoalbuminemia with poor outcomes, this
remains a widely used marker in nutritional assessment and
should be measured monthly in all dialysis patients.
Other serum markers of malnutrition in renal disease
include serum transferrin and prealbumin. The serum transfer-
rin may be a more reliable marker than albumin as an estimate
of protein nutrition because transferrin is more sensitive to pro-
tein deficiency and has a shorter half-life (10 days). Unfortu-
nately, serum transferrin levels, like serum albumin, change
with factors other than nutritional status. Serum transferrin
may rise when iron stores are depleted and diminish by
as much as 50% with chronic inflammatory disorders such
as malignant tumors, rheumatoid arthritis, and infections.
The serum concentration of prealbumin also has been touted as 641
an index of nutritional status. It has a half-life of about 2 days
and therefore changes more rapidly with variations in nutri-
tional status. However, as with serum albumin, a number of
other factors (e.g., inflammation) may also cause changes in CH 31
serum prealbumin. When compared with serum albumin and
Sodium
As CKD progresses, the ability to excrete the daily dietary
sodium intake diminishes. Sodium retention occurs in most
forms of CKD and contributes to the development of hyperten-
sion, and hence, progressive end-organ hypertensive injury.
The typical Western diet is high in sodium (100–300 mmol/day),
while the recommended sodium intake to limit hypertension
and edema in patients with CKD is less than 100 mmol/day
(43 mmol ¼ 1 g). In dialysis patients, excess sodium intake is
associated with higher interdialytic weight gains and intradia-
lytic hypotension as a result of the need to ultrafilter large fluid
volumes over a relatively short time interval. The degree of sodium
restriction in ESRD depends on the residual urine output—in
an anuric patient the intake should be less than 100 mmol/day,
but this restriction can be safely increased by 50 mmol/500 mL of
residual urine output. In rare cases of salt-wasting nephropathy,
sodium supplementation may be required to prevent intravascular
volume depletion.
Potassium 643
Dietary Lipids
Cardiovascular disease is the leading cause of death in end-stage
renal failure; the expert opinion is that the management of dys-
lipidemia in patients with CKD should be equivalent to that of
patients with known coronary heart disease. In addition, hyper-
lipidemia has been postulated to play a role in progression of
renal disease. Whether progression can be slowed by dietary or
pharmacologic modification of lipid levels is less clear. The
safety and efficacy of a low-fat, low-cholesterol diet in patients
with CKD has not been conclusively proved. Restriction of die-
tary fat should probably be avoided when there is evidence of
PEM. In general, the dietary recommendations regarding fat
intake mirror those given to the general population: 25% to
35% of the caloric intake should come from fat. Diet should
include less than 7% of calories as saturated fat, less than 10%
of calories as polyunsaturated fat, and the remainder of fat intake
as monounsaturated fat. According to Kidney Disease Outcomes
Quality Initiative (K/DOQI) guidelines, complex carbohydrates
should account for 50% to 60% of total calories.
Although statins are not a dietary component, these drugs
can modify serum cholesterol and support coronary heart dis-
ease (CHD) prevention, and thus, deserve mention. Multiple
randomized trials have demonstrated the beneficial effect of
statins on reducing low-density lipoprotein (LDL) cholesterol
and CHD. In individuals with preexisting CHD, pravastatin
has been shown to reduce secondary events just as effectively 645
when given to patients with CKD, as compared to those indi-
viduals without CKD. An important reduction in adverse out-
comes was also observed in diabetic patients treated with
pravastatin. The greatest absolute reduction in risk was CH 31
observed in those with both CKD and diabetes, emphasizing
Management of Malnutrition
Once the diagnosis of malnutrition is made, the initial evalua-
tion should include attempts to identify reversible causes
of diminished intake. Evaluation should include dietary
restrictions, drugs that interfere with taste, and depressive ill-
ness. In patients with gastroparesis (e.g., diabetic autonomic
neuropathy), metochlopramide and erythromycin have been
used with some success to improve gastric emptying. Uremia
is a leading cause of anorexia, and evidence of worsening
malnutrition (such as loss of lean body mass or a fall in serum
albumin concentration) is an indication to commence renal 647
replacement in subjects with advanced CKD. In those patients
established on maintenance HD or PD, evidence of underdia-
lysis should be specifically sought as suboptimal clearance
rates can lead to anorexia and weight loss. This is best identi- CH 31
fied by assessing dialysis adequacy as measured by the Kt/V
Nutritional Supplements
If the preceding interventions do not yield an improvement in
appetite and lean body mass, then nutritional supplementation
should be considered. Oral supplementation is the preferred
option and specially formulated supplements are available for
patients with stage 5 CKD/ESRD. Specialty supplements are
typically low in potassium and phosphate and have a high
caloric content relative to their volume. In patients with severe
malnutrition and persistent poor intake, consideration can be
given to overnight nasogastric feeding. Intradialytic parenteral
nutrition has been advocated as a treatment option in patients
with severe malnutrition with or without gastroparesis; how-
ever, definitive outcome data are lacking. Given its substantial
cost and the lack of compelling evidence of benefit, it should
probably be reserved for patients unable to tolerate oral supple-
mentation. The institution of total parenteral nutrition (TPN) is
reserved for those patients unable to consume more than 50%
of their prescribed caloric intake by the enteral route. Specially
formulated preparations are required in ESRD as most generic
TPN solutions are high in potassium, phosphate, and magne-
sium. Close attention to electrolyte serum levels during TPN
administration in ESRD is essential in order to prevent the
development of life-threatening electrolyte disturbances.
Other Options
Malnutrition in the PD patient may respond to a dialysate con-
taining amino acids rather than glucose as the osmotic agent.
Intraperitoneal amino acid administration is postulated to
enhance net nitrogen balance and overall nutritional status.
A commercially available formulation is available (Nutrineal)
648 in the United States and Europe but definitive guidelines for
its use are lacking at this time. A reasonable approach is to
use an amino acid solution equivalent to 1 to 2 exchanges
per day in malnourished patients who are resistant to or
VIII unable to tolerate oral supplementation. Serial biochemical
and anthropometric measurement can be used to assess the
Conservative and Pharmacologic Management of Kidney Disease
Specific Pharmacologic
Approaches to Clinical
Renoprotection
SPECIFIC PHARMACOLOGIC INTERVENTION:
A RISK FACTOR–BASED APPROACH
In many patients with chronic renal disease, progressive loss of
renal function occurs despite the absence of any overt activity of
the underlying renal disorder. The accepted hypothesis is that
common mechanisms account for the progressive loss of renal
function regardless of the underlying nature of the original dis-
ease. Systemic and glomerular hypertension, proteinuria, and
metabolic abnormalities, such as hyperlipidemia, are assumed
to be common mediators in the pathophysiology of focal glomer-
ulosclerosis, the probable final common pathway of progressive
renal damage. In many renal conditions, hypertension, protein-
uria, and metabolic abnormalities are simultaneously present.
This clustering of risk factors is presumably of prime importance
for renal outcome as the interaction of these risk factors likely
accelerates progressive renal damage. To prevent progressive loss
of renal function, as a matter of clinical common sense, any pre-
vailing primary damaging factors amenable to intervention
should be eliminated. However, in many patients no disease-spe-
cific factors accessible to intervention can be identified, and treat-
ment strategies should be aimed at ameliorating common renal
risk factors. Such interventions have been shown to effectively
slow the rate of loss of renal function in diabetic as well as nondi-
abetic patients. Importantly, clinical studies have consistently
demonstrated the importance of proteinuria as a promoter of pro-
gressive renal damage. Therefore, reduction of proteinuria is the
central element of any renoprotective regimen.
Glomerular Hypertension
Experimental studies have shown that glomerular hyperten-
sion/hyperfiltration occurs as a renal adaptive response to
loss of functional renal mass. This serves initially to main-
tain glomerular filtration rate (GFR) but ultimately it is mal-
adaptive and accelerates the decline in renal function.
Hyperfiltration is worsened by high protein intake, which
may further accelerate the progression of CKD. A reduction
in elevated glomerular capillary pressure, rather than a
reduction in systemic BP, closely correlates with protection
652 against the development of focal glomerulosclerosis in several
experimental renal conditions. Indirect data suggest that a
reduction in intraglomerular hydrostatic pressure may be rele-
vant to the outcome of renoprotective interventions in humans
VIII as well. In nondiabetic and diabetic renal disease, the early
renal hemodynamic response (but not the response of systemic
Conservative and Pharmacologic Management of Kidney Disease
60
58
56
GFR (mL/min)
54
52
50
48
46
0 50 100 150 200
Time (wk)
Figure 32-1. Time course of glomerular filtration rate (GFR)
before, during, and after withdrawal of antihypertensive therapy in
renal patients. Closed circles and continuous lines are patients who
initially showed a distinct fall in GFR (n ¼ 20). Open circles and
broken lines are patients in whom the GFR did not fall at the start
of therapy (n ¼ 20). After withdrawal of therapy, a rise in GFR
occurs in patients with an initial drop only, thus demonstrating the
functional nature of the initial drop in GFR. Interestingly,
withdrawal of treatment reveals that the GFR is better preserved in
patients with an initial drop. (Used with permission from Apperloo
AJ, de Zeeuw D, de Jong PE: A short-term antihypertensive
treatment induced fall in glomerular filtration rate predicts long
term stability of renal function. Kidney Int 51:793–797, 1997.)
Proteinuria 653
Reduction of Proteinuria
Antihypertensive regimens associated with a better reduction in
proteinuria typically provide better renoprotection in CKD. The
association between a reduction in proteinuria and renal progno-
sis applies not only to antihypertensive treatment but also to
remission of proteinuria attained spontaneously or by treatment
of the underlying renal disease (e.g., immunosuppressive treat-
ment). The consistent relationship between residual proteinuria
and long-term renal prognosis demonstrates, first and foremost,
that a reduction in proteinuria is a prerequisite for renoprotec-
tion. In individual patients, the long-term renal prognosis corre-
lates with the initial antiproteinuric response to therapy. For
clinical purposes, it is important that the response be apparent
early after the start of therapy to allow early distinction between
patients who will benefit from the intervention and those in
whom additional therapy may be required. Furthermore, in view
of the consistent relationship between a reduction in proteinuria
and renoprotection, as well as the absence of a J-shaped curve for
proteinuria, exploration of the renoprotective potential of a treat-
ment regimen titrated to obtain a maximally effective reduction
in proteinuria might be a fruitful approach.
Hyperlipidemia
Dyslipidemia is common in renal disease and lipid nephrotoxi-
city has been hypothesized to be involved in the progression of
renal damage. This association may be particularly relevant in
proteinuric renal disease that is associated with hyperlipidemia.
654 However, the common forms of primary hyperlipidemia do not
appear to initiate overt renal disease in normal individuals.
Nevertheless, several clinical studies have suggested that hyper-
lipidemia is associated with a faster rate of renal function loss in
VIII patients with CKD and in hypertensive individuals. A second-
ary analysis from the Modification of Diet in Renal Disease
Conservative and Pharmacologic Management of Kidney Disease
Reduction of Lipids
Genetic Factors
Miscellaneous
Morbid obesity has long been known to be associated with
focal glomerulosclerosis. Less extreme obesity is now increas-
ingly being recognized as a renal risk factor in CKD. The
mechanism underlying the renal risk of obesity is not well
characterized and may relate to its association with other 655
renal risk factors such as hypertension, diabetes mellitus,
lipid abnormalities, and possibly hyperfiltration.
Importantly, weight loss by ingestion of a hypocaloric diet
can result in significant reductions in proteinuria in obese CH 32
patients. An increasing body of evidence indicates that ciga-
PHARMACOLOGIC APPROACHES
Antihypertensive Treatment
Reduction in BP is of prime importance in the prevention
of disease progression in CKD and this can be achieved with
all of the currently available classes of antihypertensive
agents. Whether the choice of a particular antihypertensive
agent matters for long-term renoprotection, independent of
the reduction in BP achieved, is a matter of active debate.
Recent meta-analyses of ACE inhibitors support a renoprotec-
tive effect of renin-angiotensin-aldosterone system (RAAS)
blockade beyond BP control in nondiabetic and diabetic
patients; this finding is supported by recent data on the reno-
protective effects of angiotensin II type 1 (AT1) blockade.
b-Blockers
Diuretics
In many patients with CKD, diuretics are required for effec-
tive BP control, and are, accordingly, diuretics are part of
the therapeutic regimen in many studies. Nonetheless, their
long-term renoprotective effect in humans has not been
established. Not with standing this however, diuretics are
indispensable in renoprotective intervention in view of the
importance of control of volume status and BP in patients
with overt renal disease. Whether different diuretics are
equivalent for renoprotection is unknown. The specific cardi-
oprotective effects of aldosterone blockade by spironolactone
suggest that this issue may be relevant to renal patients as
well. Although spironolactone appears to have added antipro-
teinuric efficacy on top of ACE inhibition, it is unclear
whether this finding reflects specific aldosterone blockade or
just its effect on volume control. Of note, in renal patients
the combination of RAAS blockade and aldosterone blockade
will require close consideration of safety issues in light of
the risk of development of hyperkalemia.
CLINICAL MANAGEMENT
Primary Prevention CH 32
Secondary Prevention
VIII
In patients with established renal disease, primary causal factors
Conservative and Pharmacologic Management of Kidney Disease
Sodium Status
The disturbed sodium and volume homeostasis in most renal
patients leads to expanded extracellular volume and hyperten-
sion, particularly prominent in proteinuric patients. In specific
patient categories, such as African Americans and microalbu-
minuric diabetic patients, BP is often exquisitely sodium sen-
sitive and diuretic therapy is often required to obtain effective
BP control. This dependence of response on volume status
applies particularly to ACE inhibitors and AT1 receptor block-
ers. The effect of sodium status on antiproteinuric efficacy
may be partly related to its concomitant effects on BP, but the
intrarenal effects of sodium status may be important as well, as
suggested by the prominent effect of sodium restriction on pro-
teinuria in contrast to its relatively modest effect on BP. There-
fore, sodium restriction and diuretic therapy, if required, are
essential components of an optimal renoprotective regimen.
Protein Intake
Dietary protein restriction can reduce proteinuria in patients
with CKD; however, conclusive outcome data in terms of pre-
vention of end-stage renal disease are lacking. Nevertheless,
662
Circumvention of Treatment Resistance in
Table 32-2 Renoprotective Intervention by RAAS
Blockade
VIII General Measures
Check and, if necessary, improve compliance
Conservative and Pharmacologic Management of Kidney Disease
Dietary Measures
Restrict dietary sodium to 50 mEq/day
Restrict dietary protein in proteinuric patients
Pursue weight loss in excessively obese
Pharmacologic Measures
Consider dose response for proteinuria separately
Add diuretic
Add other antihypertensive if blood pressure is above target
Consider dual blockade if proteinuria persists
Consider higher dose of RAAS blockade if proteinuria persists
Add indomethacin if proteinuria persists
RAAS, renin-angiotensin-aldosterone system.
Combination Therapy
Combinations of drugs with different mechanisms of action
can exert additive effects. With regard to renal protection,
several combinations are of specific interest, as judged by
their effect on intermediate renal parameters. First, as noted
earlier, co-treatment with diuretics during ACE inhibition
can overcome the effects of high sodium intake on BP and
proteinuria. Thus, combination therapy provides a way to
overcome resistance to antiproteinuric efficacy. In light of
the different levels of RAAS blockade, a case may be made
for combining ACE inhibitors with ARBs. In renal popula-
tions, several studies thus far have reported that combined
therapy with an ACE inhibitor and an AT1 receptor blocker
exerts a more effective antiproteinuric response than either
agent alone in both diabetic and nondiabetic nephropathy.
However, dose considerations may be relevant. In studies
reporting an added effect of dual blockade, the doses used were
deliberately chosen to be submaximal—with the rationale of
possibly inducing fewer side effects than with the drugs used
separately. Thus, the efficacy of dual blockade could simply
be due to more effective RAAS blockade, and might also have
been achieved with a higher dose of either drug. For the pur-
pose of maximal reduction in proteinuria, it would also be rel-
evant to assess whether dual blockade, at optimal doses of both
drugs, would result in a further reduction in proteinuria. The
available data suggest an enhanced potential of dual blockade
over monotherapy, but this additive effect may not apply to
all conditions. Optimal dosing schedules, relative to other
optimizing measures such as volume control, will have to be
developed further.
Time Course
In nondiabetic patients, the reduction in proteinuria takes
several weeks to reach a maximum level, which should be
taken into account when titrating for optimal reduction of pro-
teinuria. In microalbuminuric IDDM, however, the time
course of reduction in albuminuria parallels the reduction in
BP, with maximal responses already taking place in the
664 first week of treatment, which may reflect the greater renal
impact of BP in these patients. The lack of similar data on
other antihypertensives, or in diabetics with overt nephropa-
thy, precludes recommendation of a fixed schedule for dose
VIII titration in these subgroups at the present time.
Conservative and Pharmacologic Management of Kidney Disease
Chapter 33
665
666 The hemodialysis clearance of a drug can be estimated from
the following relationship:
Cl HD ¼ Cl urea ð60=MW drug Þ
VIII
where ClHD is drug clearance by hemodialysis, Clurea is urea
Conservative and Pharmacologic Management of Kidney Disease
Antimicrobial Agents
Inappropriate loading dose reduction resulting in ineffectively
low plasma concentration is a significant danger in patients with
renal impairment. A single loading dose of antibiotic, equivalent
to the usual maintenance dose for patients with normal renal
function, should almost always be given to patients with 669
impaired renal function. Subsequent doses and dose intervals
can be individualized based on relative importance of maintain-
ing therapeutic peak or trough concentrations (see earlier discus-
sion). Uremia may mask the clinical presentation of infection CH 33
and the signs of antibiotic toxicity in patients with renal failure.
Hypoglycemic Drugs
Diabetic nephropathy is the leading cause of end-stage renal
disease (ESRD) in the United States. Careful consideration of
hypoglycemic drug selection and dosage is important for
patients with impaired renal function. The kidney accounts
for almost 30% of the elimination of insulin from the body
and as renal function decreases, insulin clearance also falls.
Diabetics with impaired renal function are at increased risk
of hypoglycemia when they are treated with insulin or oral
hypoglycemic drugs, and doses should be adjusted accord-
ingly. In renal failure, long-acting sulfonylureas (e.g., glybur-
ide) are accompanied by an enhanced risk of hypoglycemia
and metformin is associated with a higher risk of lactic acido-
sis, and therefore, their use is discouraged.
Continued
672
Table 33-1 Drug Dosing in Renal Failure—Cont’d
Dosage Modification/Recommendation
Dose
GFR (mL/min)
Adjustment
Drug Method >50 10–50 <10 HD CAPD CRRT
Alprazolam 100% 100% 100% Unknown Unknown NA
Alteplase (t-PA) 100% 100% 100% As for normal GFR As for normal As for normal GFR
GFR
Altretamine D Unknown Unknown Unknown No data No data Unknown
Amantadine I q24–48h q48–72h q7d As for GFR < 10 As for GFR < 10 As for GFR 10–50
Amikacin D, I 60–90% 30–70% 20–30% 5 mg/kg after HD 15–20 mg/L/day As for GFR 10–50
q12h q12–18h q24–48h
Amiloride D 100% 50% Avoid NA NA NA
Aminophylline D 100% 200– 200– As for GFR < 10 As for GFR < 10 As for GFR 10–50
400 mg 300 mg
q12h q12h
Amiodarone 100% 100% 100% As for normal GFR As for normal As for normal GFR
GFR
Amitriptyline 100% 100% 100% As for normal GFR As for normal As for normal GFR
GFR
Amlodipine 100% 100% 100% As for normal GFR As for normal As for normal GFR
GFR
Amoxapine 100% 100% 100% Unknown Unknown NA
Amoxicillin I q8h q8–12h q24h As for GFR < 10 250 mg q8h As for normal GFR
Give after HD
Amphotericin I q24h q24h q24–36h As for GFR < 10 As for GFR < 10 As for GFR 10–50
Amphotericin B I q24h q24h q24–36h As for GFR < 10 As for GFR < 10 As for GFR 10–50
colloidal
Amphotericin B I q24h q24h q24–36h As for GFR < 10 As for GFR < 10 As for GFR 10–50
lipid
Ampicillin I q6h q6–12h q12–24h As for GFR < 10 As for GFR < 10 As for GFR 10–50
Give after HD
Amrinone D 100% 100% 50–75% No data No data As for GFR 10–50
Anistreplase D 100% 100% 100% Unknown Unknown As for GFR 10–50
Astemizole D 100% 100% 100% Unknown Unknown NA
Atenolol D, I 100% 100% 50% As for GFR < 10 As for GFR < 10 As for normal GFR
q24h q24h q24h
Atovaquone 100% 100% 100% As for normal GFR As for normal As for normal GFR
GFR
Atracurium D 100% 100% 100% As for normal GFR As for normal As for normal GFR
GFR
Auranofin D 3–6 mg 3 mg Avoid Avoid Avoid As for GFR 10–50
q24h q24h
Azathioprine D 100% 75% 50% As for normal GFR As for GFR < 10 As for GFR 10–50
Azithromycin D 100% 100% 100% No data No data No data
Azlocillin I q4–6h q6–8h q8h As for GFR < 10 As for GFR < 10 As for GFR 10–50
Give after HD
Aztreonam D 100% 50–75% 25% As for GFR < 10 As for GFR < 10 As for GFR 10–50
Give after HD
Basiliximab 100% 100% 100% As for normal GFR As for normal As for normal GFR
GFR
Continued
673
674
Table 33-1 Drug Dosing in Renal Failure—Cont’d
Dosage Modification/Recommendation
Dose
GFR (mL/min)
Adjustment
Drug Method >50 10–50 <10 HD CAPD CRRT
Benazepril D 100% 50–75% 25–50% As for GFR < 10 As for GFR < 10 As for GFR 10–50
Betamethasone 100% 100% 100% As for normal GFR As for normal As for normal GFR
GFR
Betaxolol D 100% 100% 50% As for GFR < 10 As for GFR < 10 As for normal GFR
Bezafibrate D, I 70% 50% Avoid 200 mg q72h 200 mg q72h As for GFR 10–50
q24–48h
Bisoprolol D 100% 100% 50% As for GFR < 10 As for GFR < 10 As for GFR 10–50
Bleomycin D 100% 75% 50% As for GFR < 10 As for GFR < 10 As for GFR 10–50
Bopindolol 100% 100% 100% As for GFR < 10 As for GFR < 10 As for GFR 10–50
Bretylium D 100% 25–50% 25% As for GFR < 10 As for GFR < 10 As for GFR 10–50
Bromocriptine 100% 100% 100% As for normal GFR As for normal As for normal GFR
GFR
Brompheniramine 100% 100% 100% As for normal GFR As for normal As for normal GFR
GFR
Budesonide 100% 100% 100% As for normal GFR As for normal As for normal GFR
GFR
Bumetanide 100% 100% 100% As for normal GFR As for normal As for normal GFR
GFR
Bupropion D 100% 100% 100% As for GFR < 10 As for GFR < 10 As for GFR 10–50
q24h q24h q24h
Buspirone D 100% 100% 100% As for GFR < 10 As for GFR < 10 As for normal GFR
50% if anuric 50% if anuric
Busulfan 100% 100% 100% Unknown Unknown As for GFR 10–50
Butorphanol D 100% 75% 50% Unknown Unknown NA
Capreomycin I q24h q24h q48h As for GFR < 10 As for GFR < 10 As for normal GFR
Captopril D, I 100% 75% 50% q24h As for GFR < 10 As for GFR < 10 As for GFR 10–50
q8–12h q12–18h
Carbamazepine 100% 100% 100% As for normal GFR As for normal As for normal GFR
GFR
Carbidopa 100% 100% 100% Unknown Unknown Unknown
Carboplatin D 100% 50% 25% As for GFR < 10 As for GFR < 10 As for GFR 10–50
Carmustine 100% 100% 100% As for normal GFR As for normal As for normal GFR
GFR
Carteolol D 100% 50% 25% As for GFR < 10 As for GFR < 10 As for GFR 10–50
Carvedilol 100% 100% 100% As for normal GFR As for normal As for normal GFR
GFR
Cefaclor D 100% 50–100% 50% 250–500 mg q8h 250 mg q8–12h As for normal GFR
Cefadroxil I q12h q12–24h q24–48h 0.5–1 g after HD 0.5 g/day As for normal GFR
Cefamandole I q6h q6–8h q12h 0.5–1 g q12h 0.5–1 g q12h As for GFR 10–50
Give after HD
Cefazolin I q8h q12h q24–48h 0.5–1 g after HD 0.5 g q12h As for GFR 10–50
Cefepime I q12h q16–24h q24–48h 1 g after HD As for GFR < 10 Not recommended
Cefixime D 100% 75% 50% 200 mg q24h 200 mg q24h As for GFR 10–50
Give after HD
Cefmenoxime D, I 1g 0.75 g 0.75 g 0.75 g q12h 0.75 g q12h As for GFR 10–50
q8h q8h q12h Give after HD
Cefmetazole I q16h q24h q48h As for GFR < 10 As for GFR < 10 As for GFR 10–50
Give after HD
Continued
675
676
Hemodialysis
THE HEMODIALYSIS POPULATION
Demographics
Over 300,000 patients in the United States with end-stage renal
disease (ESRD) are on hemodialysis. The annual incidence of
patients entering hemodialysis programs is approximately 250
per 1 million people, representing over 70,000 new patients
per annum. Notably, the prevalence rate for African-American
patients with ESRD is approximately 4 times that of the general
population and 6.5-fold that of the white population.
Reducing Co-morbidity
Optimal pre-ESRD management includes treatment strategies
focused on the following clinical issues:
• Strict blood pressure and glycemic control
• Blockade of the renin-angiotensin-aldosterone system
• Management of anemia
703
704 • Avoidance of nephrotoxins (e.g., radiocontrast agents, NSAIDs)
• Prevention of renal osteodystrophy
• Dietary intervention to minimize malnutrition while
moderating protein intake
IX • Patient education regarding treatment options in ESRD
• Appropriate placement of vascular or peritoneal access
Invasive Therapy of Renal Failure
Starting Hemodialysis
Common indications for initiation of hemodialysis in acute
kidney injury include uncontrolled hypertension, pulmonary
edema, acidosis, hyperkalemia, pericarditis, and encephalopa-
thy. These indications should never be reasons for initiating
chronic maintenance hemodialysis, as the goal for patients is a
smooth transition from CKD to ESRD. Although there is no pre-
determined absolute level at which hemodialysis should be
initiated, therapy should be commenced at a level of residual
renal function below which the major symptoms of uremia
supervene. Among the criteria for initiating dialysis are residual
creatinine clearances of 15 and 10 mL/min, which roughly corre-
spond to serum creatinine concentrations of 6 and 8 mg/dL, for
diabetics and nondiabetics, respectively. These are general
guidelines and it may be necessary to initiate hemodialysis ear-
lier in patients who have otherwise uncorrectable symptoms or
signs of renal failure such as nausea and vomiting, weight loss,
intractable congestive heart failure, or hyperkalemia. The rest-
less leg syndrome, asterixis, and a reversal of the sleep-wake
cycle are early neurologic manifestations of uremia. If alternative
explanations for these symptoms and signs cannot be discerned,
they should be indications for initiating dialysis.
VASCULAR ACCESS
Arteriovenous Fistula
Hemodialysis
deep fascia, the vein must be dissected and transposed into a
more convenient subcutaneous position (basilic vein transposi-
tion). Compared with brachiocephalic fistulas, transposed
brachiobasilic fistulas are more likely to mature, but have a
higher long-term thrombosis rate. Better patency for upper
arm fistulas compared with lower arm fistulas or arteriovenous
grafts have been reported, supporting the trend toward creation
of upper arm arteriovenous fistulas as the access of choice in
patients with poor forearm venous anatomy. Preoperative ultra-
sonographic imaging can increase the success rate in the surgical
placement of arteriovenous fistulas. The chosen vein should
be at least 2.5 mm in diameter at the point of anastomosis to
increase the fistula success rate. Another strategy to increase
the prevalence of successful arteriovenous fistulas prevalence
involves ligation of tributary veins when arteriovenous fistulas
fail to mature promptly. The average time to first use of a fistula
is over 8 weeks, and because commencing hemodialysis using
an arteriovenous fistula is associated with better long-term
patient outcomes, timely insertion is essential.
Arteriovenous Grafts
Dialysis arteriovenous grafts made of expanded polytetrafluor-
oethylene (ePTFE) have the advantage of low early thrombosis
rate, surgical ease of placement, and a relatively short time
between access creation and successful cannulation. However,
short-term advantages are more than outweighed by the long-
term increased risk for infection and thrombosis compared to
native vein fistulas. The 1- and 2-year primary patency rates
for ePTFE grafts are only 50% and 25%, respectively. Graft
thrombosis accounts for 80% of all vascular access dysfunction,
and in more than 90% of thrombosed grafts, venous stenosis at
or distal to the graft vein anastomosis is detected. This can be
managed by either surgical revision or balloon angioplasty. Infec-
tion in the graft should be suspected when fever is accompanied
by pain over the graft or evidence of new onset graft dysfunction.
Graft infection should be treated as a matter of clinical urgency
and involves removal of the infected graft combined with
systemic antibiotic therapy for at least 3 weeks. There are no
compelling clinical trial data suggesting a benefit from either
antiplatelet or anticoagulant strategies in the prevention of
arteriovenous graft or fistula thrombosis.
706 Vascular Access Monitoring and Surveillance
Venous Catheters
Cuffed, tunneled dialysis catheters have the advantage of
immediate usability and relatively easy placement. However,
they are associated with strikingly high rates of patient mor-
bidity. They should only be used as a bridge to use of an arte-
riovenous access or as a permanent vascular access in patients
who have exhausted all other peripheral access options.Tun-
neled catheters are, unsurprisingly, associated with a high
rate of local exit site infections, bacteremia/septicemia (“line
sepsis”), and thrombotic complications. The importance of
line sepsis as a cause of death in ESRD patients cannot be
overemphasized. There is up to a 300-fold higher sepsis mor-
tality rate in all dialysis patients compared with the general
population, and the incidence of catheter-associated blood
stream infection is at least two to four episodes per 1000
patient-catheter days. The clinician needs to be ever vigilant
in the care of the patient with a tunneled line. Clinical find-
ings suggestive of a catheter infection include a fever, tender-
ness over the tunnel or exit site, and rigors during dialysis.
If infection is suspected, intravenous vancomycin and
gentamicin should be administered pending the results of blood 707
cultures. The coverage can be adjusted when the results of
bacteriologic evaluation are available. If infection is confirmed,
the treatment of catheter-related bacteremia is as follows:
• Removal of the catheter with delayed replacement until CH 34
defervescence in patients with severe clinical symptoms
Hemodialysis
• Catheter exchange by guidewire in patients with minimal
symptoms and normal-appearing tunnel and exit site
• Catheter replacement by guidewire with creation of a new
tunnel in patients with exit site or tunnel infection only
In all cases, patients should be treated with at least 3 weeks
of systemic antibiotic therapy. However, even employing
these conservative strategies, 15% to 20% of patients with
catheter-related bacteremias experience complicated infec-
tions, including osteomyelitis, discitis, endocarditis, and
septic arthritis. Catheter-related bacteremia due to Staphylo-
coccus aureus is particularly associated with metastatic infec-
tion. The use of mupirocin ointment at the catheter exit site
may decrease the incidence of S. aureus–associated bactere-
mias. Attempting to treat catheter-related bacteremia with
antibiotics but without catheter removal is unsuccessful in
most patients. Venous catheters are also subject to frequent
episodes of thrombosis requiring thrombolytic therapy or
replacement of the catheter. The long-term use of cuffed
venous catheters also leads to the development of central
venous stenosis and right atrial thrombi. Because subclavian
vein stenosis may preclude the subsequent successful place-
ment of ipsilateral arteriovenous fistulas or grafts, the use of
subclavian venous catheters is generally contraindicated in
dialysis patients unless used as a last resort.
Clearance
The clearance of a substance is the amount removed from plasma
divided by the average plasma concentration over the time of
measurement. Clearance is expressed in moles or weight of the
substance per volume per time, and can be thought of as the vol-
ume of plasma that can be completely cleared of the substance in
a unit of time. The goals of dialysis are straightforward: to remove
accumulated fluid and toxins. With respect to toxins, the goal is
to maintain their concentrations below the levels at which they
produce uremic symptoms. However, the toxic levels of retained
substances are not used as performance measures for dialysis
because their identities are unknown. Instead, the efficacy of
dialysis is primarily judged by the clearance of urea. Several vari-
ables affect clearance by the dialyzer including blood and dialy-
sate flow rates, dialyzer surface area, dialytic time, and the
inherent transport characteristics of the membrane for high-
and low-molecular-weight substances (Table 34-1).
Hemodialysis
Protein binding
Volume of distribution
Procedure-Related (in Order of Importance)
High-Molecular-Weight Toxin
Dialysate composition*
Blood flow
Dialysate flow
Membrane surface area
Time
Flux
Low-Molecular-Weight Toxin
Flux
Time
Membrane surface area
Blood flow
Dialysate flow
Dialysate composition*
*For potassium, calcium, sodium, and total CO2, this factor is nonapplicable.
Hemodialysis
poreal circuit
Dialyzer Choice
The blood flow and dialysate flow rates are critical elements of
the dialysis prescription that can be altered to modify solute
clearance. Blood and dialysate flow rates typically range from
300 to 500 mL/min and 500 to 800 mL/min, respectively. Stud-
ies have demonstrated that the practical upper limit of effective
dialysate flow is twice the blood flow rate, beyond which the
gain in solute removal is minimal. In clinical practice, the
efficacy of angioaccess may affect solute clearance obtained at
a given prescribed blood flow rate. Should venous outflow be
restricted, there is an increased likelihood of backflow (called
recirculation) from the venous to the arterial side of the access,
so that “dialyzed” blood re-enters the dialytic circuit, thereby
decreasing the efficiency of solute clearance.
The fractional recirculation (R) is calculated using the
formula:
R ¼ Cs Ca=Cs Cv
Hemodialysis
than 10% is considered significant and mandates evaluation
of the vascular access.
Dialysis Time
The clearance of any solute, such as urea, can be increased by
lengthening the dialysis treatment. Because the typical dialy-
sis prescription emphasizes optimal blood and dialysate
flows and the selection of dialyzers with large mass transfer
coefficient characteristics, the duration of dialysis is often
the sole variable that can be used to augment solute clearance
during an individual dialysis session. However, because diffu-
sive solute clearance depends on solute concentration on the
blood side, the efficiency of solute removal declines over the
course of the dialysis procedure. A longer duration of the dial-
ysis procedure also allows for a lower net ultrafiltration rate
per hour for a given targeted ultrafiltration goal. This may
result in fewer intradialytic symptoms such as hypotension
and cramping.
Dialysate Composition
Sodium
The sodium concentration of the dialysate plays a crucial role
in determining cardiovascular stability during hemodialysis.
Historically, the dialysate sodium concentration was main-
tained at hyponatremic levels (130–135 mEq/L) to favor diffu-
sive sodium loss during the dialysis procedure. However, this
favored fluid shifts from the extracellular to the intracellular
space, thereby exacerbating the plasma volume–depleting
effects of hemodialysis. In addition, the osmolar changes and
fluid shifts resulted in a high incidence of dialysis disequilib-
rium, characterized by headaches, nausea, vomiting, and in
severe cases, seizures. As a consequence, hyponatric dialysate
has largely been abandoned. The current standard is to have a
dialysate sodium concentration close to that of plasma. The
prescription of high-sodium dialysate has become a common
practice in an attempt to reduce intradialytic hypotension.
Unfortunately, this approach may lead to polydipsia,
increased interdialytic weight gain, and increased interdialy-
tic hypertension, thereby offsetting the beneficial effects of
714 increased intradialytic hemodynamic stability. Therefore,
strategies have evolved that involve varying the dialysate
sodium concentration over the course of a dialysis session,
referred to as sodium modeling. Sodium modeling is often
IX performed either in a stepwise fashion, in which the initial
dialysate sodium concentration is greater than or equal to
Invasive Therapy of Renal Failure
145 mEq/L and then abruptly reduced during the second half
of the dialysis session, or reduced gradually over the course
of the dialysis session (linear sodium modeling). Although
sodium modeling can reduce the frequency of hypotension
during dialysis, it is unclear whether this technique offers
any advantage over a fixed dialysate sodium concentration of
140 to 145 mEq/L.
Potassium
The fractional decline in the plasma potassium concentration
during hemodialysis is proportionately greater when there is
a higher predialysis potassium concentration. However, the
flux of potassium from the intracellular compartment to the
extracellular space lags behind the transfer of potassium
across the dialysis membrane. Hence, after the hemodialysis
session, there is an increase in the plasma potassium concen-
tration of approximately 30% over 4 to 5 hours due to move-
ment of potassium from the intracellular to the extracellular
space. Most of the cardiac arrhythmias that arise from the
fall in the serum potassium concentration occur during the
first half of the dialysis session. It is important to realize that
it is the rapidity of the fall in plasma potassium concentra-
tion, rather than the absolute plasma potassium level, that
determines the risk for interdialytic cardiac arrhythmias.
The selection of a dialysate potassium concentration is
empirical and guided by patient-specific factors. Generally,
a dialysate potassium concentration of 1 to 3 mEq/L is used
in most patients. Patients who have excessive potassium
loads from diet, medications, hemolysis, tissue breakdown,
or gastrointestinal bleeding may require a lower dialysate
potassium concentration. Low dialysate potassium concen-
trations should be used with caution, however, as an analysis
has found an association between low dialysate potassium
concentrations and sudden cardiac death in outpatient
hemodialysis patients.
Calcium
Given the use of calcium-based phosphate binders and the
aggressive use of vitamin D analogs, a standard dialysate cal-
cium concentration of 2.5 to 3 mEq/L is preferred in order to
prevent interdialytic hypercalcemia and elevations in the cal-
cium phosphate product, which are associated with vascular
calcification.
Buffers 715
Hemodialysis therapy cannot remove large quantities of free
hydrogen ions because their low concentration in the blood
precludes the development of a sufficiently large concentra-
tion gradient. As a result, correction of the acidosis is largely CH 34
achieved by using a dialysate with a higher concentration of
Hemodialysis
bicarbonate than is present in the blood (30–40 mmol/L), pro-
moting flux of base from the dialysate into the blood. Higher
dialysate bicarbonate concentrations are sometimes used to
fully correct metabolic acidosis due to the adverse effects of
metabolic acidosis on protein catabolism and nutritional sta-
tus in maintenance hemodialysis patients. Acetate-based dia-
sylates are no longer in routine use.
Glucose
In general, an optimal dialysate glucose concentration is 100 to
200 mg/dL for most patients. However, in diabetic patients, insulin
doses may require adjustment to account for this dialysis-imposed
“glucose clamp,” in which levels of plasma glucose may be kept
constant during dialysis due to the concentration in the dialysate.
Dialysate Temperature
Dialysate temperature is generally maintained between 36.5 C
and 38 C at the inlet of the dialyzer. Under normal circum-
stances, there is an increase in body temperature during dial-
ysis due to ultrafiltration-induced volume contraction during
hemodialysis, which results in peripheral vasoconstriction,
which in turn limits peripheral heat loss. Eventually, there is
a reflex dilatation of peripheral blood vessels, which allows
heat to escape but reduces peripheral vascular resistance,
resulting in an intradialytic fall in blood pressure. This led to
the suggestion that lowering dialysate solution temperature
might permit increased hemodynamic stability in hypoten-
sion-prone dialysis patients. Clinical trials have demonstrated
that the provision of low temperature dialysis (35 C) improves
cardiovascular stability during hemodialysis.
Ultrafiltration Rate
HEMODIALYSIS ADEQUACY
Hemodialysis
prior to drawing the sample from the “arterial” inflow access
port at the end of dialysis. The value obtained from the forego-
ing formula is known as a single pool, nonequilibrated Kt/V. A
postdialysis blood urea level drawn 30 to 60 minutes after
dialysis will be higher because of the equilibration of intracel-
lular and blood urea levels. A value derived from this figure is
known as a double pool, equilibrated Kt/V. The difference
between these two values is usually greater with shorter dial-
ysis treatment times; on average, however, the equilibrated
Kt/V is 0.2 Kt/V units lower than the single pool Kt/V. Despite
the apparent significance of the figure, clinical studies evalu-
ating the importance of Kt/V have used the single pool,
unequilibrated approach.
The simpler method for quantifying the delivered dose of
hemodialysis is the urea reduction ratio (URR) (i.e., predialy-
sis BUN postdialysis BUN/predialysis BUN). The URR
depends exclusively on the changes that occur in urea levels
during intermittent hemodialysis. Although URR has been
shown to correlate with survival in a fashion similar to
Kt/V and is recognized by Kidney Disease Outcomes
Quality Initiative (K/DOQI) guidelines as a valid index of
hemodialysis adequacy, Kt/V is a more precise index of small
molecule clearance.
Hemodialysis
phate, and volume control in small scale studies. No mortality
data is available.
Nocturnal hemodialysis (NHD) is also performed five to
seven times per week, with each treatment lasting 6 to 8 hours
and using biocompatible membranes at blood flow rate of 200
to 300 mL/min and dialysate flows of 200 to 300 mL/min.
Although the number of patients studied has been rather lim-
ited, multiple lines of evidence suggest that significant
improvements in nitrogen intake, caloric intake, and serum
albumin result. Once again, convincing outcome data are lack-
ing; however, one report described the use of NHD in children
with growth retardation and failure to thrive on peritoneal
dialysis: treatment with NHD was well tolerated and resulted
in improved nutritional status and quality of life and catch-
up growth.
Slow, long hemodialysis is given thrice weekly, with blood
flow rates of 200 to 250 mL/min and a dialysis time of 6 to
8 hours. The single pool Kt/V is typically 1.6 to 1.8. This
procedure is practiced in Tassin, France, and has been
associated with improvements in blood pressure control and
better overall nutritional status.
Hemodialysis
hemodialysis patients because of an increased risk for
influenza-related death. Household members and health care
workers in contact with hemodialysis patients should also be
vaccinated annually to decrease influenza transmission rates.
The influenza vaccine is also recommended for children on
hemodialysis.
Vaccines routinely administered in childhood (i.e., measles,
mumps, and rubella vaccines; varicella vaccine; inactivated
poliovirus vaccine; diphtheria, tetanus, and pertussis vaccine;
and Haemophilus influenzae type B conjugate vaccine) are
generally recommended for children on hemodialysis. Oral
poliovirus vaccine, which is no longer available in the United
States, is not recommended because of a theoretical risk of
producing paralytic poliomyelitis.
The pathogenesis and management of anemia, cardiovascu-
lar disease, calciphylaxis, and nutrition in the dialysis popu-
lation are discussed in detail in Chapter 27, Cardiovascular
Aspects of Chronic Kidney Disease; Chapter 28, Hematologic
Aspects of Chronic Kidney Disease and Erythropoietin
Therapy; Chapter 30, Mineral Bone Disease in Chronic Kidney
Disease; and Chapter 31, Diet and Kidney Disease.
COMPLICATIONS OF HEMODIALYSIS
Hemodialysis is a relatively safe procedure, with an estimated
1 death in 75,000 treatments as a result of technical error. The
age of the patient; the presence of underlying medical conditions
such as diabetes mellitus, coronary artery disease, or congestive
heart failure; and the patient’s degree of compliance with a com-
plex medical regimen necessary in end-stage disease influence
the frequency and severity of adverse events.
Hypotension
Hypotension is the most common acute complication of hemodi-
alysis (Table 34-2). The incidence of hypotension in the dialysis
population ranges between 15% and 30%. During ultrafiltration,
a protein-free ultrafiltrate of plasma is removed from the intravas-
cular space. The resultant rise in plasma oncotic pressure causes
fluid to move from the interstitial and intracellular spaces to
replenish plasma volume. Hypotension results when the rate of
intravascular volume depletion exceeds the rate of refilling of
722
Table 34-2 Causes of Intradialytic Hypotension
Common Causes
High ultrafiltration rate (>1 L/hr)
IX Excessive interdialytic weight gain
Invasive Therapy of Renal Failure
Hemodialysis
lality creates an osmotic gradient between the plasma and the
interstitial and intracellular spaces. Fluid moves from the
plasma into cells and the interstitium, resulting in a reduction
in plasma volume. This intravascular volume loss is superim-
posed on volume removed by ultrafiltration, and its magni-
tude can be as much as 1 to 1.5 L during the treatment. This
shift is opposed by an increase in oncotic pressure induced
by ultrafiltration. Increases in the concentration of sodium,
the principal osmotic agent in the dialysate, reduce this
osmotic gradient. The frequency of hypotension reported at a
dialysate sodium concentration of 140 mEq/L is substantially
lower than the frequency at 130 mEq/L. An increase in inter-
dialytic hypertension has not been a major problem at the
higher sodium concentration and the use of dialysate with a
sodium concentration of 140 mEq/L is common. The calcium
concentration of the dialysate has also been shown to affect
myocardial contractility. Higher calcium concentrations in
the dialysate, up to a concentration of 3.5 mEq/L, have been
associated with improved contractility, independent of the
nature of other factors in the dialysate. However, with the
increasing use of calcium salts to prevent hyperphosphatemia,
hypercalcemia is seen more often when the calcium concen-
tration of dialysate is this high. Dialysate temperature has
been shown to affect blood pressure during hemodialysis.
Dialysate cooled to 35 C reduces the frequency of hypotensive
episodes because vasoconstriction is potentiated at this
temperature.
Patients undergoing hemodialysis are often receiving anti-
hypertensive agents or other medications that can interfere
with the normal hemodynamic response to ultrafiltration and
loss of blood volume into the dialytic circuit. b-Adrenergic
receptor blockers reduce myocardial contractility and prevent
a compensatory increase in the heart rate, thus interfering
with a major defense supporting blood pressure during
dialysis. Verapamil can be expected to exert a similar effect.
Vasodilators can prevent vasoconstriction in response to
ultrafiltration. The development of several antihypertensive
agents formulated to be administered orally as a single
daily dose or by a transdermal delivery system (nifedipine
and clonidine, respectively) has reduced the incidence of
drug-induced hypotension. These agents are generally well
tolerated and may often be used on dialysis days because
high peak levels are avoided. Nitroglycerin ointment can
724 often aggravate the propensity for hypotension by inducing
peripheral vasodilatation.
Management of Hypotension
IX The immediate management of hypotension is achieved by
placing the patient in the Trendelenburg position, administer-
Invasive Therapy of Renal Failure
Hemodialysis
cellular volume contraction. Cramps are managed by reducing
the ultrafiltration rate and administering normal saline
(200 mL) or small volumes (5 mL) of 23% hypertonic saline,
or 50% dextrose in water (D50W). In nondiabetic patients,
D50W is especially useful, particularly near the conclusion of
the dialysis treatment, because as glucose is metabolized,
hyperosmolality and intravascular volume expansion in the
postdialysis period are avoided. The pain resulting from very
severe cramps may be alleviated by administration of agents
such as diazepam but at the risk of increased hypotension.
Quinine sulfate, an agent that increases the refractory period
and excitability of skeletal muscle, is effective in preventing
cramping if administered 1 to 2 hours before dialysis com-
mences. Patients using quinine must be observed for the devel-
opment of thrombocytopenia. In patients with excessive weight
gains, dialysis time must be increased to prevent cramps during
attempts to achieve the patient’s dry weight.
Hemodialysis
mias, with concomitant digoxin and hypokalemia, may be
greater.
Angina frequently occurs during dialysis. Coronary artery
disease is common in the dialysis population, and may be
exacerbated by the anemia associated with chronic kidney
disease and the increases in heart rate that commonly accom-
pany ultrafiltration, leading to episodes of overt angina.
Other potential precipitating factors include episodes
of hypotension, tachyarrythmias, and the possible need to
withhold b-blockers prior to the dialysis treatment. Supple-
mental oxygen should be administered if angina occurs, the
blood flow should be slowed, and hypotension treated if
present. If hypotension is not present, sublingual nitroglyc-
erin may be given, but the patient should be in the recumbent
position.
Hypoglycemia
Carbohydrate metabolism is quite abnormal in patients with
chronic kidney disease. Although there is peripheral resis-
tance to the effects of insulin in uremia, the half-life of
insulin is significantly prolonged when the GFR is less than
20 mL/min. It is noteworthy, however, that the initiation of
hemodialysis leads to an improvement in peripheral respon-
siveness to insulin, thereby enhancing the effect of a given
dose of insulin. The implication of this is that a diabetic
patient who takes a usual dose of insulin may experience
hypoglycemia when undergoing dialysis against a bath with
a fixed glucose concentration (i.e., glucose clamp) that is
too low for the amount of insulin being administered. It is fre-
quently necessary to decrease the dose of insulin on dialysis
days to prevent hypoglycemic episodes. Diabetic patients
should not be dialyzed against a bath that has a glucose
concentration less than 100 mg/dL.
Hemorrhage
The uremic environment produces impaired platelet func-
tioning, changes in capillary permeability, and anemia, all
of which can impair hemostasis. There may also be increased
blood loss from the gastrointestinal tract because of gastritis
728 or angiodysplasia, lesions associated with renal failure.
While the initiation of hemodialysis is reported to partially
correct the defects responsible for the platelet dysfunction
and capillary permeability, patients undergoing hemodialy-
IX sis still have a higher risk of hemorrhagic events because of
repeated exposure to heparin.
Invasive Therapy of Renal Failure
Hemodialysis
angioedema, and wheezing. A severe reaction is associated with
profound hypotension and cardiac arrest.
Many patients who have suffered from this reaction have
elevated levels of immunoglobulin E (IgE) directed against
serum proteins that have interacted with ethylene oxide, a
sterilizing agent used in the manufacture of dialyzers. Com-
plement activation also has been implicated. Noncellulosic
membranes, such as polyacrylonitrile, polysulfone, or poly-
methyl methacrylate, do not cause large amounts of comple-
ment to be released into the circulation, and appear to be
better tolerated. Anaphylactoid reactions have been reported
when patients taking ACE inhibitors undergo hemodialysis
using polyacrylonitrile (AN69) membranes or other reused
membranes of various kinds. These reactions occur despite
the fact that the biocompatibility profile of these membranes,
at least with respect to complement activation, is superior to
that of new cuprophane membranes. Evidence indicates that
AN69, because of its negative surface charge, is capable of
generating bradykinin by activation of Hageman factor and
the kallikrein-kininogen pathway. ACE is a potent kinase
responsible for degrading bradykinin. ACE inhibition may
lead to higher bradykinin levels and to the unopposed action
of this substance. Bradykinin-induced hypotension and
bronchoconstriction result. Treatment of mild forms of this
syndrome is symptomatic, but anaphylactoid reactions need
to be treated with epinephrine and steroids. Blood in the
extracorporeal circuit should not be returned to the patient.
Chapter 35
Peritoneal Dialysis
In the first decade of the 21st century, it is estimated that more
than 120,000 patients worldwide are being kept alive by peri-
toneal dialysis (PD), and this accounts for approximately 8%
of the world’s chronic dialysis population. The enormous suc-
cess of PD over the past 30 years has been made possible by
better understanding of the anatomy and physiology underly-
ing the modality and by greater appreciation of the complica-
tions of the therapy. This information has led to the
development of better technology, new delivery systems and
solutions, and better strategies for maintaining patients more
successfully on PD.
PERITONEAL TRANSPORT
With regard to PD, it is now recognized that the major site of
resistance to peritoneal transport is provided by the peritoneal
capillary. Understanding of peritoneal transport has been
greatly facilitated by the development of both the three-
pore model of peritoneal capillary transport and the
distributed model, which helps explain differences in trans-
port characteristics among PD patients. The three-pore model
states that solute and water transport across the peritoneal
capillary occurs through three different sets of pores. The
smallest of these, known as ultrapores, correspond to aqua-
porin I channels and transport only water and not solute.
Small pores are abundant, have a diameter of 4 to 6 nm, and
correspond to clefts in the endothelium. They transport small
solutes and water in proportion to their concentrations in
serum. Large pores have a diameter of 10 to 20 nm and also
correspond to clefts in the endothelium. These pores are much
fewer in number and are responsible for the transport of
macromolecules such as albumin. In standard glucose-based
PD, approximately half of peritoneal water transport is
accounted for by small pores and the other half by ultrapores.
Because the proportion of water transported by ultrapores is
solute free, the total ultrafiltrate in PD has a lower solute con-
centration than serum. This is the phenomenon of “sieving.”
The distribution of peritoneal capillaries within the sub-
mesothelial matrix of the membrane is the other major deter-
minant of differences between patients in their peritoneal
730
transport characteristics, such that peritoneal transport is 731
determined not so much by the peritoneal membrane surface
area but rather by the “effective peritoneal surface area.”
In other words, the vascularity of the membrane is more
important than its area. CH 35
Three distinct peritoneal transport processes occur during
Peritoneal Dialysis
PD and determine the success of fluid removal and solute
clearance. These three processes are diffusion, convective
ultrafiltration, and peritoneal fluid absorption.
Diffusion
The key factors determining diffusion for a given solute are, of
course, the concentration gradient and the mass transfer area
coefficient (MTAC) (Table 35-1). The MTAC for a given sol-
ute depends on the effective peritoneal surface area, which,
in turn, is determined by the size and vascularity of the
patient’s peritoneal membrane. At the start of a PD dwell,
the concentration gradient is maximal and solute removal is
fastest. As the dwell proceeds and the gradient decreases,
transport slows down. More frequent drainage and replenish-
ment of the cavity with fresh solution maintains the gradient
and maximizes peritoneal transport. The MTAC can also be
modified in the clinical setting but only to a modest degree.
Increased dwell volumes increase the surface area
of peritoneal membrane available for diffusion and so raise
the MTAC.
Peritoneal Dialysis
of water movement. Peritoneal capillary albumin concentra-
tions tend to hold fluid within the vasculature. In recent
years, peritoneal solutions based on polyglucose agent, ico-
dextrin, have become popular. These solutions have approxi-
mately the same osmolarity as serum and so do not remove
fluid by osmotic forces. However, the large icodextrin mole-
cules have an oncotic effect analogous to that of albumin
and remove fluid in this manner.
Fluid Absorption
During the course of a PD dwell, there is constant removal of
fluid from the peritoneal cavity through the lymphatics back
into the peritoneal circulation. It is now appreciated that
much of the absorption occurs not directly into the lymphatics
but rather into the tissues of the abdominal wall in a process
driven by peritoneal hydrostatic pressure. It is presumed that
much of this anterior abdominal wall fluid is subsequently
removed by subserosal lymphatics and by peritoneal capil-
laries. Peritoneal fluid absorption occurs at a rate in the range
of 1 to 2 mL/min or 250 to 500 mL during a 4-hour peritoneal
dwell. This fluid absorption is a “bulk flow” process, and so
results in both water and solute being restored to the systemic
circulation rather than being removed in the peritoneal efflu-
ent. It thus detracts from the ability of PD to clear solute and
remove fluid.
It should be noted that overall solute removal depends on
the combined contributions of diffusion and convection
minus the effect of peritoneal fluid absorption. The extent to
which ultrafiltration contributes to solute removal depends
not only on the net ultrafiltration, but also on the sieving co-
efficient of the solute concerned. This is the fraction of the
solute that passes through the membrane in association with
transported water. Because of the sieving effect of the ultra-
pores in glucose-driven peritoneal ultrafiltration, the siev-
ing coefficients for most small solutes, including urea and
sodium, are in the range of 0.6, meaning that the concentra-
tion of these solutes in pure ultrafiltrate is about 60% of what
it is in the serum. Overall, however, it can be said that convec-
tion is relatively more important in solute removal in PD as
compared with hemodialysis, accounting typically for 10%
to 20% of total solute removal.
734 Peritoneal Equilibration Test
Peritoneal Dialysis
catheters. The first is the predisposition to exit site and tunnel
infection and to biofilm formation on the intraperitoneal
segment, all of which may ultimately lead to peritonitis and
catheter loss. The second is impaired function, usually mani-
fested as poor or absent outflow, that is predisposed to by
migration of the catheter tip out of the pelvis and by wrapping
of omentum and bowel around the tip.
A basic chronic catheter design constitutes four compo-
nents: the extra-abdominal, subcutaneous, transmural, and
intraperitoneal segments (Fig. 35-1). All chronic catheters
now have a Dacron cuff at the point of entry into the cavity
between the transmural and intraperitoneal segments. A double-
cuff catheter has an additional cuff placed about 2 to
3 cm internal to the exit site, in the subcutaneous tunnel.
The extra-abdominal segment protrudes out of the exit site
and enables convenient safe handling of the catheter. The
subcutaneous segment sits in the tunnel and provides a pro-
tection against infection through in-growth of epithelial cells.
The intramural segment provides mechanical anchorage and a
watertight seal. The Dacron cuff stimulates fibrosis to provide
an antibacterial seal. Coiled catheter tips are designed to
reduce omental obstruction of the catheter and to minimize
inflow pain due to a jet effect caused by the dialysate flow.
Catheter Insertion
Patients should be evaluated for suitability for PD before cath-
eter placement. Apart from cognitive and social problems,
issues such as multiple previous complicated abdominal sur-
geries with likelihood of adhesions, the presence of bowel
or urinary ostomies, a convincing history of complicated
diverticular disease or recent abdominal aneurysm repair
are all relative, although not absolute, contraindications.
The abdominal wall needs to be assessed for defects or weak-
nesses and hernias, which may be contraindications or may at
least need to be repaired at the time of catheter insertion.
Insertion may be performed with the patient under general
or local anesthesia.
Catheter dysfunction is a relatively common and often
frustrating complication of PD that may manifest itself in sev-
eral ways, including complete two-way, or just one-way out-
flow obstruction; slow catheter drainage; or drainage that is
736
IX
Invasive Therapy of Renal Failure
Dialysis
solution
Liver
Omentum
Catheter
Abdominal Peritoneum
cavity Drain
Bladder bag
Peritoneal Dialysis
catheter is in an appropriate position in the pelvis. Catheters
with their tips in the upper portion or middle of the abdomen
are less likely to function. Usually, the obstruction in these
cases is outflow related. If the catheter appears to be in a good
position and does not improve with fibrinolytics or laxatives,
omental wrapping is presumed culpable. Sometimes a few
days of laxative therapy may resolve the issue. However, if
nonfunction persists, catheter manipulation is required. This
can be done in the radiologic suite using a guidewire or by a
physician or surgeon using a laparoscope, or even an open
procedure to reposition the catheter.
Peritoneal Dialysis
only through lymphatic flow. This does occur but not to a
degree that impairs the ability of icodextrin to induce ultrafil-
tration in a sustained manner during long dwells. Accord-
ingly, the solution is most useful for the long nocturnal
dwell of CAPD and the long diurnal dwell of automated peri-
toneal dialysis (APD), where it will typically remove between
300 and 600 mL of fluid. Side effects include skin rashes and
occasional aseptic peritonitis, which has been related to con-
tamination in the manufacturing process.
Buffers
When considering PD solutions, it is important to distinguish
between the pH of the solution and the buffer used. The buffer
has traditionally been lactate, which is then converted
in the liver to bicarbonate. Lactate is generally an effective
buffer, and most PD patients have well-controlled acid-base
status, mainly because of the continuous nature of the modal-
ity. However, concerns have been raised about the biocompat-
ibility of lactate, and there is some bench science data to
support the notion that lactate may be harmful to the perito-
neal membrane and host defenses. The use of bicarbonate
has been limited by concerns about precipitation of calcium
and bicarbonate if both are constituents of the same solution.
However, multipouch technology can be used to solve this
problem. Thus, the calcium and magnesium can be stored in
the same low-pH pouch as the glucose, while the bicarbonate
buffer can be in the high-pH pouch with the other constituents
of the solution. When mixing occurs before infusion, it results
in a normal-pH, bicarbonate-buffered solution.
Calcium
Traditionally, the calcium content of PD solutions was
1.75 mmol/L (3.5 mEq/L), which is notably higher than the
typical serum ionic calcium level of 1.1 to 1.3 mmol/L in
patients with renal failure. This results in diffusion of calcium
into the patient, resulting in positive calcium balance.
Although this was previously considered desirable in that it
helped suppress hyperparathyroidism, it became less attrac-
tive with the widespread use of calcium-based phosphate
740 binders and 1-hydroxylated vitamin D products. Hypercalce-
mia, excessive parathyroid suppression, and adynamic bone
diseases became increasing concerns, and there was a switch
to lower calcium dialysis solutions in both PD and hemodial-
IX ysis. The most common calcium concentration now used is
1.25 mmol/L (2.5 mEq/L), and this may lead to neutral or even
Invasive Therapy of Renal Failure
Peritoneal Dialysis
An analogous trial in hemodialysis was also negative, and so
there has been a move to de-emphasize high clearance targets
and to return to recommendations more easily achieved with
standard prescriptions.
Measurement of Clearance
Clearance on PD is a combination of peritoneal clearance and
that due to residual renal function. The latter is especially
important in PD because it is maintained for longer and is a
larger proportion of the total clearance than in hemodialysis.
It is typically measured using either or both of two indices—
fractional urea clearance, imported from hemodialysis and
best known as Kt/V, and creatinine clearance normalized for
body surface area (CrCl). The calculation of these two indices
requires 24-hour collections of PD effluent and urine with
measurements of urea and creatinine content, a simultaneous
blood sample to measure serum urea and creatinine, and then
a simple standard calculation of clearance. For the calculation
of the residual component of CrCl, a mean of renal urea and
creatinine clearance is used because residual renal creatinine
clearance is known to substantially overestimate the true glo-
merular filtration rate. The clearance is then normalized to a
measure of body size, which for urea is, by convention, the
total body water or “V” to give Kt/V and for creatinine is the
body surface area (BSA) to give CrCl.
Clearance Targets
The weekly Kt/V target advised by the Kidney Disease Out-
comes Quality Initiative (K/DOQI) is 1.7, with the same target
for both APD and CAPD and for all transport types. CrCl was
not considered to add extra useful information, although some
groups still support its use in high transporters. It is still rea-
sonable practice if a patient is doing poorly and is suspected
of being uremic to give a trial of increasing dialysis dose, even
if Kt/V already exceeds 1.7 weekly. Conversely, if a patient
cannot tolerate the prescriptions required to reach 1.7 weekly
but is clinically well or has a limited prognosis for other rea-
sons, a clinical judgment to continue PD may be appropriate.
There is also some concern that the populations studied in
742 the important trials had relatively low rates of cardiovascular
disease and so again a trial of higher-dose dialysis might be
appropriate if such patients appeared uremic.
Residual renal clearance and body size are two of the three
major determinants of Kt/V and CrCl. The third is, of course,
the peritoneal dialysis prescription, the only parameter that
can be adjusted to alter the achieved clearance (Table 35-4).
The membrane transport characteristics influence the deliv-
ered clearance for a given prescription. This is particularly
so for CrCl because, as can be seen in the standard PET curves,
creatinine transport exhibits a wider range of variation than
urea transport (see Fig. 35-1). Similarly, membrane transport
has bigger effect in APD than CAPD because the short cycles
used in the APD are associated with greater variations in
equilibration than the longer duration dwells of the CAPD.
CAPD prescription is essentially simple, and clearance can
be increased either by raising the dwell volume from 1.5 or 2 L
to 2.5 or 3 L or by going from three or four exchanges daily to
four or five. Both are effective, but increasing dwell volume is
usually preferred because it allows better spacing of dwells,
is less intrusive on patient time, is associated with better
adherence, and is less expensive. However, increasing dwell
volume may be limited by patient tolerance related to mechan-
ical symptoms such as bloating and back pain, and to histories
of hernias and leaks. Clearances can also be raised modestly
by increasing ultrafiltration, but this is generally not favored
because it entails greater exposure to hypertonic glucose with
consequent metabolic and other side effects.
Peritoneal Dialysis
cycles over 9 hours at night with a single day dwell; if residual
function is substantial, it may be possible to forego the day
dwell, at least initially. If this single-day-dwell approach does
not achieve the clearance target, either from the start or subse-
quently as residual function declines, then there are two com-
mon approaches. Either the number of cycles can be increased
to six or seven nightly or a second day dwell can be added. Add-
ing a second day dwell is less expensive but adds an additional
procedure and so is a little more onerous for the patient or care-
giver. Increasing the number of cycles may raise clearance a lit-
tle less but is generally well tolerated. The choice should, if
possible, take into account the patient’s lifestyle circumstances.
Volume Status
Strategies to control volume status should always include con-
sideration of salt intake. Although PD has been considered to
allow liberal salt and water intake, this is emphatically not
the case when high blood pressure or other signs of volume
overload are present. Salt removal through the urine should
also be promoted using high-dose loop diuretics as required
and either angiotensin-converting enzyme (ACE) inhibitors
or angiotensin receptor blockers (ARBs), as well as other vali-
dated strategies to preserve residual renal function. Peritoneal
strategies should include a focus on the long-duration noctur-
nal dwell in CAPD and day dwell in APD. If fluid resorption
or minimal ultrafiltration is being achieved in these settings
and if there is evidence of volume overload, a switch from
glucose to icodextrin should be considered. Alternatively,
the dwell can be shortened by doing an early drain, followed
by either a dry period or an additional dwell. Ultimately, more
hypertonic glucose will often be required to normalize volume
and should be used, if necessary. However, other strategies
should be used first in the light of real concerns about the
toxic effects of excess glucose absorption on the metabolic
and cardiovascular risk profile and on membrane longevity.
Ultrafiltration Failure
Ultrafiltration failure is defined as clinical evidence of fluid
overload occurring in association with less than 400 mL of
ultrafiltrate after a standardized 4-hour duration dwell with
744 a 4.25% glucose 2-L dwell. True ultrafiltration failure is rare
in the first 1 to 2 years on PD but becomes progressively more
common after that, owing, as already mentioned, to increases
in peritoneal transport characteristics. Management of all
IX cases of ultrafiltration failure include general measures such
as review of salt and water intake and restriction of these as
Invasive Therapy of Renal Failure
PERITONITIS
Peritonitis remains a leading complication of PD. It contri-
butes to patient morbidity, technique failure, hospitalizations,
and, occasionally, death. In most major centers, over the past
2 decades, peritonitis rates have fallen from 1 every 12 months
to 1 every 2 to 4 years.
Diagnosis of Peritonitis
Peritoneal Dialysis
Coagulase-negative staphylococci 39.9%
Staphylococcus aureus 21.6%
Streptococcus species 7.9%
Enterococcus species 1.9%
Gram-negative organisms 23.3%
Escherichia coli 8.6%
Pseudomonas aeruginosa 4.6%
Other Pseudomonas species 0.7%
Acinetobacter species 2.6%
Klebsiella species 1.9%
Serratia species 1.3%
Enterobacter 1.1%
Other gram-negative organisms 5.4%
Multiorganism 1.9%
Fungi 3.4%
Mycobacteria 0.1%
Adapted from Kim DK, Yoo TH, Ryu DR, et al: Changes in causative organisms and
their antimicrobial susceptibilities in CAPD peritonitis: A single center’s
experience over one decade. Perit Dial Int 24:424–432, 2004.
Management of Peritonitis
Initial Empiric Therapy
Initial antimicrobial therapy must account for all the common
causes of peritonitis. The 2005 International Society for Perito-
neal Dialysis (ISPD) guidelines recommended that gram-
positive organisms be covered by either a cephalosporin or
vancomycin and gram-negative organisms by a third-generation
cephalosporin or an aminoglycoside (Table 35-6). Aminogly-
cosides are effective and inexpensive, but there are concerns
about nephrotoxicity in patients with residual renal function,
although this may have been overstated, and short-duration,
once-daily courses appear safe. For cephalosporin-allergic
patients, aztreonam is an alternative to ceftazidime or cefepime
for gram-negative coverage, if aminoglycosides are not used.
Coagulase-Negative Staphylococcus
First-generation cephalosporins are preferable for 2 weeks of
therapy. Units with a high rate of methicillin resistance may
prefer to use vancomycin. Most peritonitis episodes due to a
coagulase-negative staphylococcus respond rapidly to therapy.
747
Intraperitoneal Antibiotic Dosing
Table 35-6
Recommendations for Patients on CAPD*
Antibiotic Intermittent (Once Continuous (mg/L,
Agent Daily) All Exchanges) CH 35
Aminoglycosides
Peritoneal Dialysis
Amikacin 2 mg/kg LD 25, MD 12
Gentamicin 0.6 mg/kg LD 8, MD 4
Netilmicin 0.6 mg/kg LD 8, MD 4
Tobramycin 0.6 mg/kg LD 8, MD 4
Cephalosporins
Cefazolin 15 mg/kg LD 500, MD 125
Cefepime 1000 mg LD 500, MD 125
Cephalothin 15 mg/kg LD 500, MD 125
Ceftazidine 1000–1500 mg LD 500, MD 125
Penicillins
Ampicillin No data MD 125
Amoxicillin No data LD 250–500, MD 50
Penicillin G No data LD 50,000 units, MD
25,000 units
Others
Ciprofloxacin No data LD 50, MD 25
Vancomycin 15–30 mg/kg every LD 1000, MD 25
5–7days
Aztreonam No data LD 1000, MD 250
Amphotericin Not applicable 1.5
Impenem/ 1000 mg bid LD 500, MD 200
cilistatin
*In patients with >100 mL/day urine output, dose should be empirically increased
by 25%.
CAPD, continuous ambulatory peritoneal dialysis; LD, loading dose; MD,
maintenance dose.
Adapted from Piraino B, Bailie GR, Bernardini J, et al: ISPD guidelines/
recommendations. Peritoneal dialysis–related infections recommendations:
2005 update. Perit Dial Int 25:107–131, 2005.
Polymicrobial Peritonitis
With multiple enteric organisms, intra-abdominal disease
such as ischemic bowel or diverticular disease should be
considered, and a surgical consultation should be obtained
and laparotomy performed if response to treatment is not
rapid.
Culture-Negative Peritonitis
With culture-negative peritonitis, repeat cell and differential
counts, along with culture, should be obtained after day 3.
If the repeat cell count points toward an unresolved infection,
special culture techniques should be used to isolate unusual
causes of peritonitis, such as fungi and mycobacteria, and
catheter removal should be considered.
Fungal Peritonitis
Fungal peritonitis is difficult to eradicate and generally
requires early catheter removal. Prolonged treatment with anti-
fungal agents to attempt clearance is not encouraged. Fungal
peritonitis is serious, leading to death in approximately 25%
of episodes. Evidence suggests that prompt catheter removal
may lessen the risk of death.
Initial therapy may be a combination of amphotericin B and
flucytosine until the culture results are available with suscept-
ibilities. Caspofungin, fluconazole, or voriconazole may
replace amphotericin B, based on culture and sensitivity.
Peritoneal Dialysis
• Refractory catheter infections (exit site and tunnel
infections)
• Fungal peritonitis
• Fecal peritonitis or other causes of significant intra-
abdominal infection
• Peritonitis occurring in association with intra-abdominal
infection
Simultaneous catheter removal and new catheter replace-
ment can be performed for refractory exit site and tunnel
infection and in relapsing peritonitis, provided there has been
temporary clearance of florid peritoneal infection.
NONINFECTIOUS COMPLICATIONS
Mechanical
Mechanical complications of PD are relatively common, as a
consequence of the raised pressure inside the peritoneal cav-
ity. Most frequent is the problem of hernias, which occur in
10% to 20% of patients during their time on PD. If hernias
are painful or large enough to cause discomfort, they should
be surgically repaired. With asymptomatic hernias, a judg-
ment must be made as to whether the risks of bowel incarcer-
ation are sufficient to justify the inconvenience and associated
risks of surgery. Repair does not require a routine switch to
hemodialysis, and patients can be managed with a 24- to 48-
hour break from PD, followed by 2- to 3-week period of day
dry APD or low-volume CAPD.
Pericatheter leaks are also common, especially in the early
weeks after initiation of PD. They usually occur around the
exit site and present as frank dialysate leakage, or as abdomi-
nal wall swelling or dependent genital edema. Again, the
management is to either discontinue PD for a number of weeks
or to switch to day dry APD: these options are often feasible
because the leaks usually occur at a time when residual renal
function is still good. All hernias and leaks can be imaged by
instilling contrast dye or radioactive isotope into the PD solu-
tion before infusion and then by performing computed tomog-
raphy, magnetic resonance imaging, or nuclear scanning. This
is most useful with genital swelling when it is often unclear
whether the problem is a patent processus vaginalis or a peri-
catheter leak.
750 Encapsulating Peritoneal Sclerosis
Metabolic Complications
Peritoneal Dialysis
mobility and increase cardiovascular risk.
Hypoalbuminemia is common in PD patients with an aver-
age value of 32 to 34 g/L. It is predominantly related to two
factors: dialysate protein losses and systemic inflammation.
Dialysate protein losses are mainly albumin and are typically
6 to 8 g/day. They are greater in high transporters and in
patients with peritonitis. High serum C-reactive protein levels
are also associated with low serum albumin, related to the
altered pattern of protein synthesis seen in inflammation.
Dietary protein intake has, contrary to common opinion, little
influence on serum albumin.
Serum sodium in PD tends to be a little lower than in
normal individuals, owing to fluid intake against a back-
ground of renal failure and due to the dialysate sodium of
132 mmol/L. Marked hyponatremia usually reflects hypergly-
cemia or very high water intake. Icodextrin causes a modest,
clinically unimportant fall in serum sodium related to serum
levels of maltose and other metabolites. Hypernatremia is rare
but can occur in the context of rapid cycling when dwell times
are short and the dominant factor is removal of a low sodium
ultrafiltrate due to sodium sieving with consequent rise in the
serum sodium, especially if the patient does not sense thirst or
have access to water.
753
754 every time the patient generates a negative inspiratory force,
or at a set rate, whichever is the higher frequency. CMV
minimizes the work of breathing done by the patient, and
therefore should be used in the setting of myocardial ische-
IX mia or profound hypoxemia. CMV can lead to dynamic
hyperinflation (breath stacking or “auto-PEEP” [positive
Invasive Therapy of Renal Failure
Clinical Features
Near drowning
Nonpulmonary Causes
Sepsis
Systemic inflammatory response syndrome
Shock
Trauma
Multiple blood transfusions
Pancreatitis
Burns
Coronary artery bypass grafting
Disseminated intravascular coagulation
Treatment
Supportive mechanical ventilation is the primary treatment of
ARDS. The goal should be to provide adequate oxygenation
while avoiding further barotrauma to the lung that can worsen
existing injury. Traditionally, tidal volumes used during
mechanical ventilation were in the range of 12 to 15 mL/min;
however, it is now felt that the resulting barotrauma may exac-
erbate pulmonary dysfunction. In the ARDS Network (ARDS-
NET) trial, conventional mechanical ventilation (12 mL/kg
ideal body weight [IBW]) was compared with a lower tidal vol-
ume goal starting at 6 mL/kg IBW. In each group, the tidal vol-
ume was decreased in increments of 1 mL/kg to maintain the
plateau pressure below 50 mm Hg for the traditional ventilation
group, and below 30 mm Hg for the lower tidal volume group.
The mortality rate was significantly better in the lower tidal vol-
ume group, albeit at the expense of a higher PaCO2 (“permissive
hypercapnia”) and a lower arterial pH. Other methods of
mechanical ventilation evaluated in the treatment of ARDS
include high-frequency oscillatory ventilation (HFOV), which
uses very low tidal volumes at 4 to 250 times the usual respira-
tory rate. This mode has been studied more extensively in
neonates with respiratory distress syndrome; studies in adults
have been less compelling, and there is currently insufficient
evidence to support its routine use. Permissive hypercapnia
may result in significant acidosis in a patient with renal failure
and may require a higher bicarbonate bath during hemodialysis
or continuous renal replacement therapy (RRT), as increasing 757
the minute volume to improve acid-base control is often not
an option. In patients with severe ARDS not yet on RRT, large
infusions of bicarbonate may not improve acidosis, as the
injured lung may not be able to expel the CO2 produced. Tris- CH 36
hydroxymethyl aminomethane (THAM) is a buffer that accepts
one proton per molecule, generating HCO3 but not CO2. It has
HYPOVOLEMIC SHOCK
Massive hematuria
Internal
Aortic dissection/rupture abdominal aortic aneurysm
Trauma: laceration/rupture of liver or spleen, fracture of pelvis/
long bones
Ruptured ectopic pregnancy
Fluid Loss
Diabetic ketoacidosis
Adrenal crisis
Burns
Diarrhea
Vomiting
Lack of Volume Replacement
Debilitated
Comatose/found down
Pathogenesis
Once 10% of circulating volume has been lost, compensatory
mechanisms are activated to maintain cardiac output, including
adrenal catecholamine release, activation of the sympathetic ner-
vous system, generation of angiotensin II via activation of the
renin-angiotensin-aldosterone system (RAAS), and vasopressin
released by the pituitary gland. Once the loss of volume exceeds
approximately 40%, these compensatory mechanisms are over-
whelmed and overt hypotension and shock ensue. In the early
stages this process is reversible, but if left untreated, irreversible
shock ensues. This state is characterized by capillary pooling of
blood and volume- and pressor-resistant hypotension. Although
restoration of flow to an ischemic organ is critical to restore func-
tion, reperfusion itself may contribute to organ damage via forma-
tion of reactive oxygen species and activation of complement.
Reperfusion injury can manifest as myocardial stunning, reperfu-
sion arrhythmias, breakdown of the gut mucosal barrier, AKI,
hepatic failure, or multiorgan dysfunction syndrome (MODS).
Clinical Manifestations
Diagnosis
In most cases of hypovolemic shock, it is readily apparent that
trauma or blood loss is the primary cause, but care must be
taken not to overlook septic, cardiogenic, or anaphylactic
shock. Initial resuscitation should begin during the evalua-
tion. In the case of external blood loss, cross-matching of
blood should be done while fluids are infused for resuscita-
tion. Gastrointestinal bleeding can be evaluated and poten-
tially treated with upper or lower endoscopy or angiography,
once the patient is stabilized. In the event of trauma, chest
radiography should be performed to rule out tension pneumo-
thorax or hemothorax. If abdominal trauma has occurred, peri-
toneal lavage can be performed to assess for hemorrhage, most
commonly from splenic or hepatic lacerations. If the patient is
stabilized, CT or ultrasound may be used to assess for intra-
abdominal hemorrhage as well as organ injury. Laboratory
tests should include a complete blood count; a chemistry
panel, including electrolytes, creatinine, glucose, and liver
function tests; arterial blood gas measurements; arterial lactate
level; blood type and cross-match; and urinalysis. In the event
of trauma or bleeding, coagulation studies should include a
platelet count, prothrombin time (PT), and partial thrombo-
plastin time (PTT). If the cause of shock is not readily appar-
ent, an electrocardiogram (ECG) should be performed to rule
out myocardial infarction (MI).
Management
Fluid Resuscitation
Fluid resuscitation is the initial therapy in hypovolemic shock,
as this helps restore circulating volume and oxygen delivery.
The types of fluids used are quite varied (Table 36-3), and
controversy exists as to which agent is the most efficacious. Iso-
tonic crystalloid solutions have traditionally been used as the
primary fluid for volume expansion. Normal saline (0.9%) and
lactated Ringer’s solution are both commonly used, although
large volumes of lactated Ringer’s solution should be avoided
in the setting of renal failure, as they can result in hyperkalemia.
Approximately 75% of the crystalloid volume infused enters the
interstitial space, while 25% remains intravascular. Colloid solu-
tions, including albumin, dextran, and hydroxyethyl starch, are
retained in the intravascular space to a much greater extent than
isotonic crystalloids, and are widely used. Administration of
hydroxyethyl starch (hetastarch) has, however, been associated
with increased incidence of AKI and need for renal replacement
therapy in sepsis; its use should therefore be avoided.
Vasopressors
The use of vasopressors in hypovolemic shock should be
reserved for the patient in whom adequate fluid infusion has
not improved hypotension. In this setting, a pulmonary artery
catheter can help guide therapy, as persistent shock can be
caused by either peripheral vasodilation or myocardial dysfunc-
tion. A wedge pressure of 12 to 16 mm Hg is indicative of ade-
quate volume expansion. Choice of vasopressor agent depends
on the clinical circumstances. Vasopressin has often been used
as an adjunct to treatment in those refractory to fluid and cate-
cholamines, although a recently published randomized trial
comparing the use of vasopressin to norepinephrine failed to
demonstrate 28-day mortality rate benefit in those with severe
septic shock treated with vasopressin.
Treatment of Acidosis
In cases of intractable shock, metabolic acidosis may persist
despite volume expansion and improved oxygen delivery. Intra-
venous bicarbonate is often used in this setting in an attempt to
improve cardiac function. However, decreased cardiac contrac-
tility in the setting of lactic acidosis may be partially due to hyp-
oxemia, hypoperfusion, or sepsis, and establishing the direct
effects of the low pH is difficult. Many patients treated with
permissive hypercapnia/low tidal volume ventilation develop
acidosis that is well tolerated, with minimal change in the
cardiac output. Furthermore, bicarbonate infusion has been
theorized to cause worsening intracellular acidosis, as the CO2,
produced when bicarbonate reacts with acids can diffuse rapidly
across the cell membrane, whereas bicarbonate cannot. As the
treatment of lactic acidosis with sodium bicarbonate has not
been shown to be beneficial in clinical studies, and the potential
for adverse effects appears real, the routine administration of
sodium bicarbonate in this setting should be discouraged unless
further compelling evidence becomes available.
SEPSIS CH 36
Definition
The American College of Chest Physicians/Society of Critical
Care Medicine Consensus Conference in 1991 led to a uniform
definition of the systemic inflammatory response syndrome
(SIRS), sepsis, severe sepsis, and septic shock (Table 36-4).
The mortality rate for patients with SIRS increases as patients
fulfill more criteria and advance along the spectrum. Approx-
imate mortality rates for patients with two SIRS criteria are
7%; three SIRS criteria, 10%; four SIRS criteria, 17%; sepsis,
16%; severe sepsis, 20%; and septic shock, 46%.
Clinical Features
Management
The management of sepsis is primarily based on eradication of
the infection and support of the patient’s hemodynamics and
other organ systems.
Antibiotics
Identifying and treating the source of sepsis should be one of
the primary goals in the management of sepsis. The initial
choice of antibiotic often depends on the suspected site of
infection, and usually consists of broad-spectrum coverage,
progressing to focused therapy upon identification of a source.
Close consultation with local microbiologic departments is
essential. If no organism is isolated, initial broad-spectrum
antibiotics can be continued so long as the patient is improv-
ing. Immediate institution of antibiotic therapy is critical, as
there is a 10% to 15% higher mortality rate in patients not
treated promptly.
Hemodynamic Support
Intravascular volume depletion, peripheral vasodilation, and
increased microvascular permeability all contribute to the
hypotension seen in severe sepsis and septic shock, and
aggressive volume resuscitation should be the primary initial
therapy. The fluid requirements for resuscitation are very
large, and up to 10 L of crystalloid are often required in the
first 24 hours. Boluses of fluid should be given until blood
pressure, heart rate, or evidence of end-organ perfusion such
as urine output have improved. Prompt treatment is crucial;
early, goal-directed therapy, using central venous pressure,
mean arterial pressure, hematocrit, and central venous oxygen
saturation as end points, has been shown to lower the risk of
mortality (Fig. 36-1).
766
Supplemental oxygen ±
endotracheal intubation and
mechanical ventilation
IX
Invasive Therapy of Renal Failure
Sedation, paralysis
(if intubated),
or both
<8 mm Hg Crystalloid
CVP
Colloid
8–12 mm Hg
<65 mm Hg Vasoactive
MAP agents
>90 mm Hg
≥65 and
≤90 mm Hg
≥70%
<70% Transfusion of red cells
ScvO2 <70%
until hematocrit ≥ 30%
≥70%
Inotropic agents
Goals
No achieved
Yes
Hospital admission
Corticosteroids
Corticosteroids have long been the subject of studies in sepsis,
the rationale being that minimization of the inflammatory cas-
cade could improve outcome. There has been considerable
variability in the study outcomes, and while the use of low-
dose corticosteroids (200–300 mg/day in three to four divided
doses for 7 days) with the addition of fludrocortisone (50 mg
orally once daily) was advocated in patients who required
vasopressor therapy despite adequate fluid resuscitation, and
who failed to respond to a 250 mg ACTH stimulation test, more
recent evidence has failed to demonstrate any survival advan-
tage conferred by the use of corticosteroids.
Hemofiltration
The role of cytokines in sepsis and septic shock has led to the
theory that their removal by hemofiltration may improve out-
comes. The use of hemofiltration has been associated with
reduction in the hyperdynamic response, including improved
SVR, improvement in APACHE II scores, improvement in
vasopressor requirement, and beneficial hemostatic changes.
Despite this, no randomized, controlled trial has shown an
improvement in survival. Therefore, in the absence of AKI 769
requiring RRT, there is no evidence to support the routine
use of hemofiltration for sepsis.
CARDIOGENIC SHOCK CH 36
Pathophysiology
Cardiogenic shock may occur once 40% of the myocardium is
acutely lost. The resultant clinical sequelae of hypotension
and tachycardia can potentiate the myocardial damage. The
elevated wall stress resulting from left ventricular dilation
and pump failure increases myocardial oxygen requirements,
which also worsens ischemia.
Clinical Features
Hypotension is universal in cardiogenic shock. Tachycardia,
arrhythmias, jugular venous distention, pulmonary rales, and
a third heart sound may be observed. Signs of tissue hypoperfu-
sion include confusion, mottling of the skin, and oliguria. AKI
occurs in approximately one third of cases, with an associated
dramatic increase in mortality rate to as high as 90%. Multiple
organ failure and lactic acidosis develops in many patients,
primarily due to ischemia from decreased cardiac output.
Evaluation
MI with reduced left ventricular systolic function is the most
common cause; however, other causes of shock, such as sep-
sis, hypovolemia, and pulmonary embolism, must be consid-
ered. An ECG should be performed, and if an inferior MI is
770 suspected, a right-sided ECG should be performed to evaluate
for right-sided involvement. Routine blood tests, including car-
diac enzymes, should be performed, a Foley catheter should be
placed to monitor urine output, and a chest radiograph should
IX be obtained. Echocardiography is a valuable tool to confirm
the diagnosis of cardiogenic shock and can evaluate for
Invasive Therapy of Renal Failure
Management
General Measures
Airway management and maintenance of adequate oxygenation
should be of primary concern during resuscitation. Intubation
and mechanical ventilation may be required if supplemental
oxygen or noninvasive ventilation cannot maintain adequate
oxygenation with minimal work of breathing. b-Blockers, ACE
inhibitors, and nitrates should be discontinued as they may
worsen the clinical state. If there is no evidence of pulmonary
edema, an empirical fluid bolus (250 mL 0.9% NaCl) can
be administered. Significantly higher fluid requirements may
be seen in cases of right ventricular infarction in order to main-
tain left ventricular filling pressures.
Ionotropic Support
If hypotension persists despite optimization of filling pressures,
inotropic agents should be commenced. Dobutamine improves
myocardial contractility and cardiac output and is the drug of
first choice when the SBP exceeds 80 mm Hg. At lower SBP, its
vasodilatatory effects may worsen hypotension and it should
only be used in conjunction with another vasopressor. Dopamine
may be considered when the SBP falls below 80 mm Hg; at low
doses (<5 mg/kg/min), b1 effects predominate, with a effects more
prevalent at higher doses; peripheral ischemia, tachycardia, and
arrhythmias may occur. Norepinephrine is a pure a-agonist and
can be used when there is an inadequate response to dopamine.
Milrinone and amrinone are phosphodiesterase inhibitors
that increase inotropicity and cardiac output; however, they
cause peripheral vasodilation and should not be used in
patients with marginal blood pressures. Once the blood pres-
sure has been stabilized, the treatment of pulmonary edema
with diuretics, and the optimization of preload and afterload
with direct vasodilator therapy can be considered. Emerging
therapies include the use of recombinant human b-type
natriuretic peptide nesiritide, which can reduce pulmonary
capillary wedge pressure and systemic vascular resistance,
and improve the urine output in diuretic resistant patients.
Intra-Aortic Balloon Pumping 771
Intra-aortic balloon pumping (IABP) can improve diastolic
blood pressure and coronary perfusion, and increase cardiac
output in the setting of cardiogenic shock. Clinical studies
have suggested that IABP placement improves survival, par- CH 36
ticularly in patients who have received thrombolytic therapy,
Coronary Reperfusion
The outcome of cardiogenic shock in the setting of MI is
directly related to the patency of the involved coronary arteries.
Therefore, interventions to open occluded arteries are crucial.
Thrombolytics reduce the incidence of shock when adminis-
tered for acute MI, but once shock is established, the benefit
is less clear. Recent evidence suggests that a more aggressive
approach, involving early revascularization (percutaneous pro-
cedures/coronary artery bypass grafting), results in improved
outcomes in cardiogenic shock complicating acute MI. Ventric-
ular assist devices have been used in peri-infarction cardio-
genic shock, acute myocarditis, and postcardiotomy shock to
bridge patients to either recovery of adequate myocardial func-
tion or transplantation.
Ultrafiltration
Ultrafiltration by continuous renal replacement therapy
(CRRT) has also been proposed as a treatment for severe
refractory heart failure in patients who do not have uremia.
In patients who are diuretic-resistant, ultrafiltration, either
by continuous or intermittent methods, can improve systemic
hemodynamics and may result in improved diuresis and
reduced symptoms; however, compelling outcome data are
lacking. Although hemofiltration may improve CHF in some
patients, removal of intravascular volume may not be tolerated
by all and may lead to permanent renal dysfunction.
Clinical Features
FHF presents with a variety of symptoms including nausea,
vomiting, malaise, and jaundice. Hypoglycemia results from
impaired gluconeogenesis, high insulin levels, and inability to
utilize stored glycogen. Metabolic acidosis is a consequence of
poor tissue perfusion and inability to clear lactate. Hypokale-
mia and hyponatremia also occur frequently. Encephalopathy,
felt to be multifactorial in etiology, may develop quickly, and
IX Evaluation
Invasive Therapy of Renal Failure
Management
Acetaminophen toxicity should be treated with N-acetylcysteine
(NAC), which may improve outcome up to 36 hours after an over-
dose of acetaminophen. NAC should therefore be given when
acetaminophen overdose is suspected, even if levels are unde-
tectable. The oral dose is 140 mg/kg initially, followed by
70 mg/kg every 4 hours for 17 doses. When given intravenously,
the dose is 150 mg/kg bolus followed by 70 mg/kg intrave-
nously every 4 hours for 12 doses. Acyclovir should be used
for herpes simplex infection and lamivudine has been proved
to be of some benefit for hepatitis B infection. Acute fatty
liver of pregnancy and the HELLP (hemolysis, elevated liver
enzymes, and low platelets) syndrome require immediate
delivery of the fetus. Amanita poisoning should be treated with
high-dose penicillin (300,000 to 1 million U/kg/day), which has
an antagonistic effect on the mushroom toxin, amatoxin, and
sylibin (20–48 mg/kg/day), which blocks the hepatocellular
uptake of amatoxin.
In the majority of cases, therapy for FHF is supportive.
Fluid resuscitation is often required in the acute setting as
there is hypotension from decreased SVR, as well as redistrib-
utive losses. FFP continues to be used as a first-line agent for
volume resuscitation, although there are no studies to support 775
its use over normal saline. Once volume resuscitation is
complete, dextrose with 0.45% normal saline should be used
for maintenance fluids, with careful monitoring of serum elec-
trolytes. Hypotension that persists after fluid resuscitation is CH 36
adequate, as evidenced by a wedge pressure of 12 to 14
Plasmapheresis
The term plasmapheresis (PE) or therapeutic plasma exchange
(TPE) involves the therapeutic removal of macromolecules from
the plasma of patients with a variety of underlying medical
conditions. The plasmapheresis process involves the replace-
ment of plasma with albumin or other solutions (crystalloid
or colloid) to maintain a normovolemic state.
TECHNICAL CONSIDERATIONS
For most conditions, the aim of the procedure is the removal
of pathologic autoantibodies or toxins, and the initial treat-
ment goal is to exchange 1 to 1.5 times the plasma volume
per plasmapheresis procedure. A formula to estimate plasma
volume in an adult is as follows:
Venous Access
CH 37
Anticoagulation
Plasmapheresis
The plasmapheresis procedure requires anticoagulation to
prevent clotting of the extracorporeal circuit. For centrifuga-
tion procedures, the acid-citrate-dextrose (ACD) solution (1=9
volume of solute per volume of solution), given as a continu-
ous intravenous infusion, is the most commonly used agent.
Heparin, if not contraindicated, can be used alone or in combi-
nation with citrate when risk of catheter clotting is increased.
For membrane filtration procedures, the use of standard
unfractionated heparin is preferred, although approximately
twice the amount needed for hemodialysis is required, as a sig-
nificant amount of infused heparin is removed along with
plasma. Systemic anticoagulation may be potentiated, how-
ever, due to the additional effect of dilution of clotting factors
by nonplasma replacement solutions. The initial intravenous
loading dose of heparin (40 U/kg) is usually followed by a
continuous infusion (20 U/kg/hour), adjusted to maintain
adequate circuit anticoagulation. If patients are receiving stan-
dard oral anticoagulation, regional citrate or heparin should be
added to prevent circuit clotting. In critically ill patients with
coagulation abnormalities, regional citrate is recommended.
The use of citrate mandates careful monitoring of calcium
levels. Hirudin and lepirudin (thrombin inhibitors) are effec-
tive for patients with contraindications to heparin use.
Replacement Fluid
The choice of replacement fluids include 5% albumin, fresh-
frozen plasma (FFP) or other plasma derivatives such as cryo-
supernatant, and crystalloids (0.9% saline, Ringer’s lactate).
Albumin is the most commonly used solution and is generally
combined with saline on a 50:50 (volume %) basis. It lacks
calcium, potassium, coagulation factors, and immunoglobu-
lins. FFP contains complement and coagulation factors, and
is the replacement fluid of choice in patients with thrombotic
thrombocytopenic purpura (TTP), which is discussed in more
detail later. Plasma may also be preferable in patients at
increased risk of bleeding (e.g., liver disease, pulmonary-renal
syndromes with potential for pulmonary hemorrhage) or in
whom intensive therapy is required, as frequent albumin
replacement will result in post-plasmapheresis coagulopathy
780 and a net loss of immunoglobulins. Disadvantages of FFP use
include the risk of viral disease transmission and citrate
overload.
IX
Complications
Invasive Therapy of Renal Failure
Hypotension
Plasmapheresis can lead to a reduction in blood pressure, usu-
ally due to decreased plasma volume. Intermittent centrifugal
techniques use a greater volume of extracorporeal blood, with
higher incidence of hypotension. Hypotension can also occur
in response to complement-mediated reactions to the filter,
or sensitivity to ethylene oxide used as a sterilant. Anaphylac-
toid reactions have been reported with FFP use, although
cardiopulmonary collapse is rare.
Plasmapheresis
Hypokalemia
Replacement regimens using saline and albumin solutions
can result in a 25% reduction in the plasma potassium
concentration in the post-pheresis period. This can be mini-
mized by the addition of potassium 4 mEq/L to the replace-
ment solution.
Coagulation Abnormalities
Albumin replacement produces a predictable decrease in clot-
ting factors that may predispose to bleeding. A single plasma
volume exchange increases the prothrombin time by 30%
and the partial thromboplastin time by 100%. These changes
return to normal within several hours, but with repeated treat-
ments they may persist. Therefore, 3 to 4 units of FFP should
be included with the replacement fluid each week or sooner in
patients at risk for bleeding.
Infection
Repeated plasmapheresis with albumin replacement will
deplete a patient’s reserve of immunoglobulins for several
weeks, and this, combined with complement removal, could
result in an immunodeficient state. However, a study evaluat-
ing infection rates did not find increased likelihood of infec-
tion in patients treated with plasmapheresis. Should
infection occur, a single infusion of intravenous immunoglob-
ulin (100–400 mg/kg) will restore the plasma immunoglobulin
rates to normal. Although estimates for the risk of viral trans-
mission by the use of FFP are low, large volumes from multi-
ple donors increase the risk in patients undergoing long-term
treatment. Use of large-volume plasma from a single donor
and use of the hepatitis B vaccine may reduce the risk of viral
transmission.
Cryoglobulin
Complement products
ADAMTS-13
Lipoproteins
Protein-bound toxins
Cells—platelets or white blood cells (modified procedure ¼
cytapheresis)
ADAMTS-13, a disintegrin-like metalloprotease with thrombospondin type 1 repeats.
Plasmapheresis
and, often, glomerular crescent formation. There are
three major subgroups: (1) anti-GBM antibody disease, (2)
immune complex–mediated processes, including systemic
lupus erythematosus, postinfectious processes, and mixed
cryoglobulinemia, (3) pauci-immune diseases that are most
often associated with antineutrophil cytoplasmic antibodies
(ANCA), including Wegener granulomatosis and microscopic
polyangitis. These conditions are discussed in more detail in
Chapter 11, Primary Glomerular Disease. There is limited data
to support the use of plasmapheresis in immune complex–
mediated processes. The rationale for using plasmapheresis in
pauci-immune ANCA-associated disease was initially based
on the similarity of the renal pathology to anti-GBM antibody
disease. However, several studies performed in the 1990s failed
to demonstrate significant additional benefit in the absence of
dialysis dependence. Recently published results from the Euro-
pean Vasculitis Study Group (EUVAS), which evaluated
ANCA-associated glomerulonephritis with severe renal
involvement (creatinine > 5.7 mg/dL or >500 mmol/L), showed
a lower incidence of dialysis dependence at 12 months in
patients treated with plasmapheresis in addition to induction
and maintenance of immunosuppression. For patients present-
ing with severe ANCA-associated glomerulonephritis and
advanced renal involvement, there is therefore strong support
for the use of plasmapheresis, although less evidence for those
presenting without acute kidney injury. Plasmapheresis should
be initiated in any patient who co-presents with anti-GBM anti-
body disease, and in any patient with acute pulmonary alveolar
hemorrhage.
Lupus Nephritis
Lupus nephritis is a common and potentially serious compli-
cation of systemic lupus erythematosus and is discussed in
detail in Chapter 12, Secondary Glomerular Disease. Class
IV lupus nephritis is associated with poor renal outcomes
unless treated with immunosuppressive protocols utilizing
cytotoxic therapy, although there is little data to support
the use of plasmapheresis. A large randomized controlled
trial evaluated the use of plasmapheresis, in addition to a
standard therapy regimen of cyclophosphamide and prednis-
olone, in patients with lupus nephritis including histologic
784 subtypes III, IV, and V. Despite a significantly more rapid
reduction in serum concentrations of antibodies to double-
stranded DNA in the plasmapheresis-treated group, no addi-
tional clinical benefit was seen. It is thought that selected
IX patients with aggressive lupus nephritis may benefit, and it
has been used with some reported success in patients relaps-
Invasive Therapy of Renal Failure
Cryoglobulinemia
Cryoglobulinemia refers to the presence of serum proteins that
precipitate at temperatures below 37 C, and re-dissolve on
warming. The pathophysiology of cryoglobulinemia is dis-
cussed in more detail in Chapter 12, Secondary Glomerular
Disease. Hepatitis C virus (HCV)–related cryoglobulinemia
and glomerulonephritis is related to the glomerular deposition
of immune complexes. There are no randomized controlled
studies of plasmapheresis for the treatment of cryoglobuline-
mia. However, the goal of removing pathogenic cryoglobulins
is rational, and there are many case reports and uncontrolled
studies that suggest that severe, active disease (as manifested
by progressive renal failure, coalescing purpura, or advanced
neuropathy) may benefit from the addition of plasmapheresis.
Given the unique characteristics of cryoglobulins, modifica-
tion of the plasmapheresis technique has been made to
enhance their removal. Cryofiltration cools the plasma in an
extracorporeal circuit allowing for more efficient removal of
the pathogenic proteins, although this is best performed by a
continuous process, requiring a machine designed for the pur-
pose. Alternatively, a two-step procedure can be performed, in
which the patient’s own plasma can be reinfused after cold
incubation to precipitate out the abnormal proteins.
Plasmapheresis
platelets, thrombocytopenia, mechanical injury to erythro-
cytes, and end-organ injury. Although historically considered
to be the same disease, major advances have been made in
recent years in our understanding of the distinct pathophysi-
ology underlying each disease, and are discussed in more
detail in Chapter 13, Microvascular Diseases of the Kidney.
Genetic studies of congenital thrombotic thrombocytopenic
purpura (TTP) led to the identification of defects in a metallo-
proteinase called von Willebrand factor–cleaving protease,
now known as ADAMTS-13 (a disintegrin-like metalloprotease
with thrombospondin type 1 repeats). Deficiencies in
ADAMTS-13, now recognized to be due either to an inherited
or autoantibody-mediated defect, lead to the accumulation of
unusually large von Willebrand factor multimers in the circula-
tion, which subsequently initiate endothelial injury. Histori-
cally, this disease was nearly uniformly fatal; however, the
use of plasmapheresis has dramatically improved the progno-
sis, with response rates in adults of 60% to 80%. The use and
success of plasmapheresis are supported by our knowledge of
the underlying defect—in the case of inherited ADAMTS-13
deficiency, replacement of plasma with normal ADAMTS-13
activity, and in the case of an inhibitory autoantibody to
ADAMTS-13, its removal by plasmapheresis. It appears, how-
ever, that there is a wide range of normal ADAMTS-13 activity,
and deficiency alone may not be sufficient to cause disease in
the absence of additional causes of endothelial injury.
Hemolytic uremic syndrome (HUS) is classically associated
with a prodromal diarrheal illness, with endothelial injury
caused by verocytotoxin/shiga toxin–producing bacteria. Diar-
rhea-associated HUS is more common in children, and typically
has a high recovery rate, requiring only supportive therapy,
although therapy may include need for hemodialysis because
the incidence of renal failure is high. It is now clear, however,
that a significant proportion of cases of HUS are not associated
with a diarrheal illness, suggesting other mediators of endothe-
lial injury. Familial forms of HUS are described and have more
aggressive clinical courses, with high relapse rates. Inherited
complement disorders, including disorders of complement fac-
tor H (FH), factor I (FI), and membrane co-factor protein (MCP)
(CD46), have been shown to be associated with HUS. Approxi-
mately 20% of cases of familial HUS are due to FH mutations.
Inhibitory autoantibodies to FH have also been described. The
786 role of plasmapheresis in the treatment of HUS is less clear than
that for TTP, although the diseases are often clinically difficult to
distinguish, particularly in the absence of a diarrheal prodrome,
so that plasmapheresis may be commenced empirically. It is
IX often used for severe or persistent disease, particularly in adults.
The duration of plasmapheresis required is unknown, but it
Invasive Therapy of Renal Failure
Renal Transplantation
In addition to its role in the treatment of recurrent FSGS after
transplant, plasmapheresis has been utilized in several other
clinical settings involving transplantation, including ABO
blood group incompatibility, positive T-cell cross-match, and 787
acute humoral rejection.
Plasmapheresis
donor is blood group incompatible. The ABO blood group
consists of four common categories, A, B, AB, and O, with
types A and O the most frequently occurring in the U.S. pop-
ulation. The proteins comprising these antigens are on red
blood cells, lymphocytes, and platelets, in addition to epithe-
lial and endothelial cells. Historically, ABO incompatibility
was an exclusion criterion for transplantation, as blood group
antibodies arise against those antigens not native to the host,
and mismatched renal transplantation in this situation can lead
to acute humoral rejection. However, excellent reported out-
comes with ABO-incompatible transplants from Japan kindled
renewed interest in ABO-incompatible renal transplantation
with a variety of desensitization procedures.
Current desensitization protocols utilize intravenous
immune globulin (IVIG), with and without plasmapheresis,
to remove IgG and IgM antibodies against the ABO group of
the potential recipient. These treatments are performed in
addition to a variety of immunosuppression regimens includ-
ing tacrolimus, mycophenolate, and steroids.
CONCLUSION
The use of plasmapheresis to manage a variety of kidney dis-
eases has grown significantly in recent years. In some cases,
the rationale and benefit are supported by clinical studies, but
in others the evidence is not robust. Additional studies are
required to determine the potential benefits for plasmapheresis
in these conditions.
Chapter 38
Extracorporeal Treatment
of Poisoning
Poisoning may result from an unintentional toxic exposure,
an intentional misuse of a substance with or without self-
destructive intent, therapeutic error, or malicious activity.
The treating physician must have a working knowledge of
clinical pharmacokinetics and the relationship between a tox-
in’s characteristics and the ability to enhance its elimination
with extracorporeal therapy.
789
790 The osmolal gap indicates the presence of an unmeasured
solute and is considered elevated if the value is more than
10 to 12 mOsm/kg H2O. An elevated osmolal gap is most com-
monly seen with ethanol, ethylene glycol, isopropanol, and
IX methanol toxicity.
Invasive Therapy of Renal Failure
Drug-Related Factors
Molecular Weight
Toxin removal during hemodialysis occurs primarily by dif-
fusion into the toxin-free dialysate. As molecular weight
increases, the rate of diffusion across a given membrane pro-
gressively decreases. Low-molecular-weight solutes (<500 D)
diffuse easily through the pores of even low-flux dialysis
membranes, such that their clearance is primarily determined
by membrane surface area, blood-dialysate concentration gra-
dient, and blood and dialysate flow rates. Larger solutes have
limited membrane permeability and are removed through con-
vective clearance rather than diffusion; therefore, dialytic time
and membrane surface area determine their rate of removal.
Protein Binding
Drugs that are highly bound to plasma or tissue proteins have a
low proportion of drug available for removal by hemodialysis
or hemofiltration. Hemoperfusion may be more effective in these
cases as the adsorbent (e.g., activated carbon) competes with
plasma proteins for toxin binding and is dependent purely on
the adsorbent’s affinity for the toxin. The degree of protein bind-
ing can be influenced by many factors, including alterations in
plasma protein concentration and the presence of different path-
ologic states. For example, hypoalbuminemia results in less
protein available for binding, and uremic organic acid accumu-
lation leads to a reduction in binding sites for acidic drugs
(e.g., salicylates, phenytoin, warfarin). These actions increase
the fraction of unbound, biologically active drug relative to the
total drug concentration. It is possible that this may result in
therapeutic efficacy (or toxicity) occurring at a lower total drug
793
Protein Binding Characteristics of Common
Table 38-2
Drugs
Highly Protein Bound
Arsenic CH 38
Calcium channel blockers
Volume of Distribution
A drug’s volume of distribution (Vd) is the apparent vol-
ume into which the drug is distributed at equilibrium and
before metabolic clearance begins. Vd may be calculated by
the following formula:
Redistribution
Redistribution or rebound refers to the movement of a drug to
the plasma space from tissue/protein binding sites or from the
intracellular space. If this occurs slowly, total body clearance
of the substance is limited, especially if the Vd is large. The time
course and magnitude of the rebound varies dramatically by
drug, membrane characteristics, Vd, and degree of recirculation.
794 This phenomemon is seen in the elimination of drugs such as
lithium, methotrexate, and digoxin. For these toxins, a plasma
concentration obtained immediately after extracorporeal ther-
apy should therefore not be regarded as a nadir, and frequent
IX levels should be obtained in the redistribution period. Repeated
dialysis or continuous therapy may be required.
Invasive Therapy of Renal Failure
Dialysis-Related Factors
Hemoperfusion
Hemoperfusion refers to the circulation of anticoagulated
blood through an extracorporeal circuit with a disposable,
adsorbent-containing cartridge (typically activated charcoal
or an exchange resin). Drug elimination is dependent on the
affinity of the charcoal or resin to adsorb the toxin rather than
diffusion. Hemoperfusion is preferred when the toxin is lipid
soluble or highly protein bound. At present, the clinical use
of hemoperfusion occurs most commonly with theophylline
poisoning. Current hemoperfusion devices microencapsulate
the sorbent material with a thin, porous semipermeable mem-
brane, which serves to improve biocompatibility by mimi-
mizing direct contact between the adsorbent and the blood
constituents. Anticoagulation is performed with heparin infu-
sion at a rate of at least 2000 U/hour to avoid clotting of the
circuit. Requirements for resin hemoperfusion are slightly
higher. Blood flow rates should be maintained at 250 to
400 mL/min for efficient drug removal. Complications of hemo-
perfusion include (1) mild thrombocytopenia, platelet losses
at 30% or less, caused by adsorption of platelets by acti-
vated charcoal (recovery of platelet count within 24–48 hours),
796 (2) transient leukopenia (<10% decrease) due to complement
activation and margination of leukocytes, (3) reduction of
fibrinogen and fibronectin, (4) hypothermia, (5) hypocalcemia,
and (6) hypoglycemia. Although these problems were more
IX common with the earlier, uncoated charcoal devices, hemo-
perfusion still carries a higher complication rate than hemodi-
Invasive Therapy of Renal Failure
Hemodialysis-Hemoperfusion
Hemofiltration
Hemofiltration is a process in which solutes are removed by
convection. Drug elimination by hemofiltration depends on
the rate of ultrafiltration, the drug protein binding, and
the sieving coefficient of the membrane. The convective trans-
port of hemofiltration efficiently eliminates unbound high-
molecular-weight toxins (40,000 D) with small volumes of
distribution. Most poisons, however, are smaller, with a
molecular size of less than 1000 D, and as such, hemofiltration
does not offer much advantage over hemodialysis.
INTOXICATIONS RESPONSIVE TO
EXTRACORPOREAL THERAPY
Methanol
Pharmacology. Methanol is a clear, colorless liquid used
as a solvent (including glass cleaning solutions, paint remov-
ers), an intermediate of chemical synthesis during various
manufacturing processes, or as an octane booster in gasoline.
Methanol is rapidly absorbed and distributed with peak serum
concentrations reached within 30 to 60 minutes after inges-
tion, and an elimination half-life (untreated) of 12 to 20 hours.
802 Methanol is water-soluble, easily crosses the blood-brain bar-
rier, and has a low Vd. The estimated minimum lethal dose
is 10 mL, although this is highly variable.
Metabolism. Methanol is oxidized by alcohol dehydroge-
IX nase to formaldehyde, which is in turn rapidly metabolized
to formic acid, the primary substance responsible for the toxic-
Invasive Therapy of Renal Failure
Isopropanol
Pharmacology. Isopropanol (i.e., isopropyl alcohol) is a
clear, colorless, bitter liquid commonly found in “rubbing
alcohol,” skin lotion, hair tonics, aftershave lotion, denatured
804 alcohol, solvents, cements, cleaning products, and de-icers.
Intoxication may occur through ingestion or inhalation of
vapors, especially in infants. Isopropanol is rapidly absorbed
by the gastrointestinal system and reaches a peak serum con-
IX centration 15 to 30 minutes after ingestion with an elimination
half-life of 3 to 7 hours. Isopropanol is directly responsible for
Invasive Therapy of Renal Failure
Lithium
Pharmacology. Lithium is rapidly and completely absorbed
in the upper gastrointestinal tract, achieving peak serum CH 38
levels in 1 to 2 hours, although sustained-release preparations
Salicylates
Pharmacology. Salicylates are widely used as analgesics
and anti-inflammatory agents, and are found in many over-
the-counter medications and prescription drugs, the most
common of which is aspirin (i.e., acetylsalicylic acid). Salicy-
late is 90% protein bound at therapeutic levels and is primar-
ily distributed to the vascular space. Hepatic metabolism
predominates at therapeutic levels, being rapidly hydrolyzed
to salicylic acid and subsequently oxidized or conjugated to
glucuronic acid or glycine. Following intoxication, hepatic
pathways become saturated and protein binding decreases,
leading to a larger amount of circulating salicylic acid,
in which case the slow renal excretion of unmetabolized
salicylic acid becomes clinically more important. The elimina-
tion half-life can be extended from 2 to 4.5 hours to 18 to
36 hours.
Mechanism of Toxicity. The classic acid-base abnormality
that occurs with salicylate intoxication is mixed respiratory
alkalosis and a high anion gap metabolic acidosis. Salicylate
stimulates the medullary respiratory center independent of
the aortic and carotid chemoreceptors, leading to an early res-
piratory alkalosis. Several factors contribute to the metabolic
acidosis including salicylate-induced uncoupling of mitochon-
drial oxidative phosphorylation, and interruption of glucose
and fatty acid metabolism in the Krebs cycle, leading to an
increase in ketoacid, lactic acid, and tissue carbon dioxide pro-
duction. The salicylate anion itself has only a minor effect on
serum pH. An isolated metabolic acidosis is rare in adults but
is a common finding in the pediatric population.
Clinical Presentation. Two distinct syndromes of salicylate
intoxication may occur depending on whether the exposure
is acute or chronic. Following acute ingestion, nausea and
vomiting frequently occur, followed by tinnitus, tachypnea,
sweating, and lethargy. With severe intoxication, coma, sei-
zures, hypoglycemia, hyperthermia, oliguric AKI (thought sec-
ondary to prostaglandin synthesis inhibition), noncardiogenic
pulmonary edema, and death may occur. Victims of chronic 807
intoxication are usually young children, or the delirious/
demented elderly, who present with nonspecific symptoms
including confusion, dehydration, and metabolic acidosis.
Severe poisoning typically occurs at a lower plasma concen- CH 38
tration than that observed in acute intoxication, and morbidity
Theophylline
Pharmacology. Theophylline is extensively metabolized in
the liver by several hepatic cytochrome P-450 isoenzymes.
Knowledge of potential drug-drug interactions is therefore cru-
cial. The therapeutic index is very narrow (10–20 mg/L), with
some patients exhibiting symptoms of toxicity even within
the normal range. Interestingly, smoking significantly increases
the clearance of theophylline, so that abstinence from smoking,
even for a brief period, can result in supratherapeutic levels.
Clinical Presentation. Mild theophylline intoxication is
characterized by nervousness, tremors, tachycardia, abdominal
pain, vomiting, and diarrhea. In moderate toxicity, patients
are often lethargic and disoriented and exhibit cardiovascu-
lar tachyarrhythmias. Severe intoxication may manifest as
seizure activity (typically generalized, although focal signs
such as lip smacking and ocular deviation may occur), asso-
ciated with hyperthermia, hypotension, ventricular tachy-
cardia, rhabdomyolysis, and acute kidney injury. Seizures
and ventricular tachycardias generally do not occur until
plasma theophylline levels exceed 90 to 100 mg/L in acute over-
dose, although they may occur with levels of 40 to 60 mg/L in
chronic overdose.
Laboratory Data. The most common electrolyte abnor-
mality associated with acute toxicity is hypokalemia, due to
catecholamine-induced transcellular potassium shift. Total body
stores of potassium are preserved and return to normal with a
reduction in the theophylline concentration. Hyperglycemia,
hypomagnesemia, hypophosphatemia, metabolic acidosis, and
hypercalcemia are also observed.
Treatment. Multiple-dose activated charcoal accelerates 809
theophylline clearance and decreases the serum elimination
half-life from 7 to 20 hours to 1 to 3 hours. Activated charcoal
(50 g or 1 g/kg) should be administered every 4 hours until the
serum level is below 20 mg/L. b-Blockade is a useful adjunct CH 38
to control tachyarrhythmias. Seizures associated with the-
Valproic Acid
Pharmacology and Pathophysiology. Valproic acid (VPA)
is an anticonvulsant drug used in several neurologic condi-
tions such as seizures, bipolar affective disorder, and migraine
headaches. Acute VPA intoxication is usually self-limiting,
although serious toxicity and deaths have been reported. It is
typically highly protein-bound (90%) with a small Vd. The
elimination half-life normally ranges from 5 to 20 hours.
Clinical Presentation. Acute intoxication commonly causes
gastrointestinal disturbance, CNS abnormalities (confusion,
obtundation, and coma with respiratory failure), hypoten-
sion, tachycardia, and death. Associated metabolic disturbances
include hypernatremia, hyperosmolality, hypocalcemia, high
anion gap metabolic acidosis, elevated serum aminotrans-
ferases, and hyperammonemia. Plasma concentrations correlate
poorly with severity of toxicity, but most patients with levels
higher than 180 mg/mL develop some degree of CNS depression.
Delayed complications include pancreatitis, optic nerve atro-
phy, cerebral edema, bone marrow suppression, and acute
kidney injury.
810 Diagnosis and Treatment. Diagnosis is based on history
of exposure, CNS depression, and typical metabolic distur-
bances, and confirmed with a serum valproate level, although
absolute levels correlate poorly with outcome. Initial treat-
IX ment consists of respiratory and cardiovascular stabiliza-
tion. Subsequent treatment includes gastrointestinal tract
Invasive Therapy of Renal Failure
Age
Most agree that older age per se should not be an absolute con-
traindication to transplantation, but an elderly patient’s over-
all physical condition, life expectancy, and chance for
improvement in quality of life should be carefully considered.
A living donor transplant is often the best option for an older
patient, and a healthy relative, friend, or spouse of a similar
age as the recipient may be a suitable donor. If living donation
is not an option, and the patient is placed on the transplant
waiting list, frequent reassessment of their condition and suit-
ability for transplantation is mandatory.
Infections
An active infection that is potentially life-threatening in an
immunosuppressed patient is a contraindication to transplanta-
tion. Transplant candidates should be screened for potentially
life-threatening infections, and vaccinations should be up to
date. A number of infections should be considered (Table 39-1).
Patients should be immunized against childhood infections,
influenza, pneumococcal infection, and hepatitis B. Asplenic
patients should also be immunized against Haemophilus influ-
enzae and Meningococcus sp. Patients seronegative for vari-
cella-zoster virus (VZV) infection should be immunized prior
to transplantation.
Patients with HIV infection may be transplant candidates if
they (1) are adherent to a highly active antiretroviral therapy
regimen, (2) have an undetectable virus load, (3) have a sus-
tained CD4 lymphocyte count greater than 200/mL, (4) have
no opportunistic infections, and (5) have no life-threatening
malignancies.
815
Table 39-1 Transplant Candidate Evaluation to
Minimize Infection Risk
Infection Screening Action
HIV HIV antibody Transplant only if CH 39
stringent conditions are
Malignancies
Obesity
Obesity, that is, body mass index (BMI) of 30 kg/m2 or greater,
is associated with a small, albeit statistically significant
increase in the relative risks of death and graft failure. In addi-
tion, obese patients are at increased risk for wound dehis-
cence, wound infections, and other surgical complications.
It seems prudent to recommend weight loss for patients with
BMI of 30 kg/m2 or higher and to insist on weight reduction
for patients with BMI of 35 kg/m2 or higher. If diet is unsuc-
cessful, bariatric surgery should be considered for patients
with BMI of 40 kg/m2 or higher.
Pulmonary Disease
Patients should be strongly encouraged to quit smoking prior
to transplantation. Patients who have a history of cigarette
smoking or shortness of breath may benefit from pulmonary
818 function testing and a chest x-ray. Rarely, patients with
chronic lung disease may be at risk for postoperative pneumo-
nia and ventilator dependence after transplant surgery.
Genitourinary Disorders
Patients who are asymptomatic and have no history of bladder
dysfunction do not usually require further evaluation. Trans-
plant candidates with a history of infections, bladder dysfunc-
tion, or analgesic nephropathy may benefit from a urologic
evaluation to rule out cancer, obstruction, reflux, bladder
stones, and chronic cystitis. It is important to have adequate
urinary drainage established at the time of transplantation.
This can usually be best accomplished with the patient’s
own bladder. A urinary diversion procedure is only occasion- 819
ally necessary. When there is doubt, it may be best to proceed
with transplantation and assume that the bladder will func-
tion adequately until proved otherwise.
CH 39
Thrombophilias
Immunologic Evaluation
Preformed antibodies to a donor kidney can be a major obsta-
cle to transplantation. Patients acquire preformed antibodies
to human tissues through (1) prior transplantations, (2) preg-
nancies, and (3) blood transfusions. The number of antibodies
against potential donor antigens can be tested by measuring
antibody-induced (complement-dependent) lysis of a panel
of lymphocytes from different individuals in the popula-
tion. The higher the panel reactive antibody (PRA; range
0–100%) titer, the more difficult it will be to find a donor that
the potential recipient will not reject with an antibody-
mediated rejection.
The PRA is generally measured at the time of transplant
evaluation and then periodically (usually quarterly) thereafter
until transplantation. Often, the PRA will decline with time,
820 especially if blood transfusions are avoided (through the use
of iron and erythropoietin treatment of anemia). Nevertheless,
a patient may also have an anamnestic antibody response if re-
exposed to an antigen, and it may be wise to avoid, if possible,
X transplantation with a donor antigen to which the recipient
once had an antibody.
Renal Transplantation
LIVING DONORS
Medical Evaluation of the Kidney Donor
Evaluation of the living kidney donor usually begins with
education about the process and a screening history by the
live donor coordinator, who is typically a registered nurse.
Prospective donors are then asked for a copy of their medical
records, if available. Evaluating the donor’s blood type is a
first step because it determines compatibility with the recipi-
ent. If the initial information does not disclose an immediate
contraindication to donation and the blood type is compatible,
the donor is usually asked to undergo an initial evaluation as
outlined in Table 39-3.
Obesity
There is evidence that obesity, in addition to its cosegregation
with other known risk factors for the development of kidney
disease, namely hypertension and diabetes, may lead to the
development of ESRD, and while the surgical aspects of obese
donors may have become more acceptable, most centers con-
tinue to exclude kidney donors with BMI greater than 35 kg/m2
until they have actually lost the weight.
Hypertension 823
Hypertension is an independent risk factor for ESRD. This
observation has generally excluded hypertensive subjects
from becoming kidney donors, although some programs will
allow a hypertensive donor whose blood pressure is well CH 39
controlled. The physician is not uncommonly faced with a sit-
Nephrolithiasis
It is generally accepted that subjects with nephrocalcinosis on a
plain x-ray of the abdomen, especially when bilateral in nature;
those with kidney stones that are known to have high recurrence
rates such as cystine stones, infection stones, and primary hyper-
oxaluria; and those with renal tubular acidosis or inflammatory
bowel disease should be excluded from donation. Whether one
should accept those with a history of a single kidney stone
remains debatable, but those with a favorable urine profile,
namely the absence of hypercalciuria, oxaluria, or recurrent uri-
nary tract infections, should probably be allowed to donate.
Malignancy
As part of the thorough living donor medical evaluation, basic
screening for malignancy should be performed. This includes
chest x-ray and flexible sigmoidoscopy plus hemoccult
screening or colonoscopy for those older than 50. A mammo-
gram (>35 years) and a pelvic examination for females
above the age of 20 should also be done.
Potential donors who have a history of renal cell carcinoma,
choriocarcinoma, lymphomas and leukemias, lung and breast
cancer, testicular cancer, and monoclonal gammopathy
should be excluded from donation. In regard to those with
824 remote history of malignancy, the Amsterdam Forum consid-
ers them acceptable candidates if prior treatment or the malig-
nancy itself do not decrease renal mass or put the donor at
increased risk for ESRD, and if the prior treatment does not
X increase the operative risk for nephrectomy.
Renal Transplantation
Infectious Diseases
Donors should be screened carefully for active infections by a
careful history, physical examination, chest x-ray, and com-
plete blood count. A more detailed and targeted approach
should be employed for the potential donor with a suspicion
for a certain infection (Table 39-4).
cystitis is not.
Potential donors with recurrent infection may
require a VCUG.
CMV, cytomegalovirus; EBV, Epstein-Barr virus; ELISA, enzyme-linked
immunosorbent assay; FTA, fluorescein treponemal antibody; HBsAg, hepatitis
B surface antigen; HCV, hepatitis C virus; HSV, herpes simplex virus; HTLV,
human T-cell lymphotropic virus; IgM, immunoglobulin M; PCR, polymerase
chain reaction; PPD, purified protein derivative; PTLD, post-transplantation
lymphoproliferative disorder; RPR, rapid plasma reagin test; TB, tuberculosis;
VCUG, voiding cystourethrogram; VDRL, Venereal Disease Research Laboratory.
Adapted from Delmonico F: Council of the Transplatation Society. A report of the
Amsterdam Forum on the Care of the Live Kidney Donor: Data and medical
guidelines. Transplantation 79:S53–S66, 2005.
Hematuria
The evaluation of microscopic hematuria in a potential donor
should be similar to that used in the general population.
Persistent microscopic hematuria (defined as longer than 3
months’ duration) is seen in up to 3% of the general population
and is more likely to be associated with pathologic findings
that warrant further investigation.
CONCLUSION
Living kidney donation constitutes the best renal replacement
therapy option for most patients with ESRD. Every effort should
be made to protect kidney donors and ensure that their motive for
donation is truly altruistic. The establishment of national donor
registries is greatly needed to answer many remaining questions
regarding the long-term renal and nonrenal consequences of
reduced renal mass.
Chapter 40
Overview
The T-lymphocyte is the primary target of most immunosuppres-
sive strategies. Currently used agents are classified as follows:
• Mono- or polyclonal anti–T-cell antibodies
• Calcineurin inhibitors (CNIs)—cylosporin, tacrolimus/FK506
• Glucocorticoids
827
828 • Inhibitors of purine synthesis—azathioprine and mycophe-
nolate mofetil
• Target of rapamycin (TOR) inhibitors—rapamycin/
sirolimus
X The risk of rejection is greatest in the early post-transplant
period, hence maximal immunosuppression is given at
Renal Transplantation
Nondepleting Antibodies
Tacrolimus (FK-506)
Tacrolimus is structurally distinct from cyclosporine, how-
ever, its mechanism of action is similar and both agents have
equivalent nephrotoxicity. Clinically relevant advantages over
cyclosporine include lower rates of acute rejection, better
lipid and blood pressure control, and less hirsutism. Neuro-
toxicity, alopecia, diarrhea (especially in combination with
mycophenolate mofetil [MMF]), and post-transplant diabetes
Azathioprine
Mycophenolate Mofetil
Glucocorticoids
Glucocorticoids are widely used in the induction and mainte-
nance of immunosuppression. Their dosage is progressively
decreased after transplantation to a maintenance regimen of
prednisone 5 to 10 mg/day. Adverse sequelae include hyper-
lipidemia, hypertension, glucose intolerance, and osteoporo-
sis. Glucocorticoid withdrawal has been associated with
increases in the risk of short-term and long-term graft dysfunc-
tion. Newer “steroid minimization” protocols incorporating
various combinations of thymoglobulin, tacrolimus, MMF,
and sirolimus are encouraging, but adequate long-term data
are not yet available.
Sirolimus 831
Medical Status
The potential recipient of a renal transplant should be evaluated
to ensure that there are no new contraindications to transplanta-
tion or general anesthesia. A key decision is whether or not hemo-
dialysis, with the attendant delay of surgery and prolongation of
cold ischemia time, is required. Preoperative hemodialysis is
advisable if either a plasma Kþ level higher than 5.5 mmol/L or
severe volume overload is present. Patients on peritoneal dialysis
need only drain out instilled fluid prior to surgery; if the patient is
hyperkalemic, several rapid exchanges can be performed.
Immunologic Status
A pretransplant cross-match of a recent recipient serum sample
against donor lymphocytes must always be performed to detect
preformed antibodies against donor human leukocyte antigens
(HLA). The presence of cytotoxic donor IgG antibodies is a
contraindication to transplantation. For immunologically
“high-risk” patients (Table 40-2), flow cytometry cross-matching
No Rejection No
rejection rejection
Rebiopsy in Rebiopsy in
5–10 days 7–10 days
if DGF if DGF
persists persists
Cr still elevated
CsA/tacrolimus
trough blood
concentration
Empirical
Reduce CsA/tacrolimus steroid pulse
No response
No improvement
in 3–5 days
in 1–2 days
Biopsy
Specific intervention
Thrombotic Microangiopathy
Thrombotic microangiopathy (TMA) after renal transplanta-
tion is a rare but serious complication. Laboratory findings
include rising plasma creatinine, thrombocytopenia, anemia,
and the presence of schistocytes on the blood film. CNIs
and, to a lesser extent, other factors (OKT3, viral infection,
antiphospholipid syndrome) are associated with development
of this syndrome. Onset is usually in the early post-transplant
period. The long-term prognosis for graft function is often
poor, and early diagnosis and intervention are essential. There
are no prospective controlled trials of therapy in post-
transplant TMA. Suggested measures include cessation of CNI
therapy and tight control of blood pressure. There is no evidence
to support the use of plasma exchange. Combination therapy
838 with MMF, corticosteroids, and sirolimus would appear to be
the most prudent immunosuppresive regimen in such cases.
Acute Pyelonephritis
X Urinary tract infections (UTIs) may occur at any period but are
most frequent shortly after transplantation. Risk factors for
Renal Transplantation
Urine Leaks
Urine leaks usually occur within weeks of transplantation.
Causes include ureteric infarction due to perioperative dis-
ruption of its blood supply and breakdown of the ureterove-
sical anastomosis. The clinical features include abdominal
pain and swelling with rising plasma creatinine levels
secondary to reabsorption of solutes across the peritoneal
membrane. If a perirenal drain is being used, a urine leak
may present with high-volume drainage. Ultrasound often
demonstrates a fluid collection (urinoma). Antegrade pyelo-
graphy allows precise diagnosis and localization of proximal
urinary leaks. Whenever urine leakage is suspected, a blad-
der catheter should be immediately inserted to decompress
the urinary tract and most cases require urgent surgical
exploration and repair.
X Polyomavirus Infection
Reactivation of polyomavirus infection with shedding of
Renal Transplantation
MEDICAL MANAGEMENT OF
THE TRANSPLANT RECIPIENT
With the current low acute rejection rates and improvements
in long-term graft survival, more emphasis is being placed
on the general medical management of transplant patients.
The management of common electrolyte, endocrine, and
cardiovascular complications after transplant is discussed in 843
the following sections.
Electrolyte Disorders
CH 40
Hypophosphatemia
Hyperkalemia
Mild hyperkalemia due to CNI-mediated impairment of tubule
potassium secretion is common after renal transplant and may
be exacerbated by poor allograft function, dietary indiscretion,
and medications such as ACEIs or b-blockers. The hyperkale-
mia is usually not severe and improves with reduction in
CNI dosage; treatment is often not required; exacerbating
factors should be minimized.
Metabolic Acidosis
A mild distal (hyperchloremic) renal tubular acidosis (RTA) is
common after transplantation. This reflects tubule dysfunc-
tion caused by CNIs, rejection, or residual hyperparathyroid-
ism. Oral bicarbonate replacement is given in severe cases.
Osteoporosis
X Osteoporosis, defined as bone density more than 2.5 standard
deviations below the mean of sex-matched, young adults, is
Renal Transplantation
Osteonecrosis
Osteonecrosis (avascular necrosis), the most serious bone com-
plication of renal transplantation, is seen 5% to 10% of renal
transplant recipients. The most commonly affected site is the
femoral head, and high-dose corticosteroid use is a risk factor.
The principal symptom is pain and MR imaging is diagnostic.
Treatment options include rest, core decompression, osteotomy,
or joint replacement.
Gout
The majority of cyclosporine-treated renal transplant recipi-
ents develop hyperuricemia, with less than 10% developing
clinical symptoms. Acute attacks are treated with colchicine
or an oral corticosteroid pulse. NSAIDs should be avoided.
The use of azathioprine and allopurinol in combination
for the treatment of hyperuricemia can result in severe bone
marrow suppression and is best avoided.
Hypertension
Hyperlipidemia
Hyperlipidemia is seen in 60% to 70% of kidney transplant
recipients and may contribute not only to the high cardiovas-
cular mortality rate observed but also to the development of
CAN. The target low-density lipoprotein cholesterol should
to be lower than 100 mg/dL and pharmacologic therapy is
required to achieve this in the majority of patients. Other treat-
ment options include steroid minimization and switching
cyclosporine to tacrolimus. Statins are the cholesterol-lowering
drug of choice despite concerns regarding rhabdomyolysis (see
earlier). Bile acid sequestrants bind CNIs and should be taken
separately.
Post-Transplant Malignancy
The overall incidence of cancer in renal transplant recipients
is greater than that in dialysis patients and the general popula-
tion; for specific “transplant-associated” malignancies the risk
is dramatically higher, but for the common malignancies
(lung, breast, and prostate) the risk is similar. The cumulative
amount of immunosuppression is the most important factor in
increasing the risk of malignancy, and the long-term impact of
more powerful immunosuppression regimens on cancer inci-
dence is an emerging concern. The common post-tranplant
malignancies are discussed here.
Cytomegalovirus
CMV is one of the most important post-transplant pathogens
and disease is typically observed 1 to 6 months after trans-
plant. CMV infection is seen in 50% to 80% of patients; how-
ever, CMV disease implies both laboratory evidence of viral
exposure (rising IgG titer or CMV antigen in body fluids)
and symptoms of tissue invasion. The risk of CMV infection
or disease is highest in the CMV-negative recipient of a
CMV-positive kidney. OKT3/polyclonal therapy, particularly
when prescribed for treatment of rejection, significantly
increases the risk of subsequent CMV disease. Typical clini-
cal features include fever, malaise, leukopenia, pneumonitis,
hepatitis, and ulcerating lesions of the gastrointestinal tract.
The gold standard diagnostic test is detection of CMV antige-
nemia by quantitative serum DNA PCR. Less sensitive alter-
natives include the centrifuged shell viral technique.
Demonstration of shed virus in the urine or sputum corre-
lates poorly with clinical outcomes and biopsy interpretation
is complicated by the focal nature of the infection in many
organs. CMV disease should be treated with reduction in
immunosuppression and intravenous ganciclovir therapy
for 2 to 4 weeks. Valganciclovir has greatly improved oral
bioavailability compared to oral ganciclovir and is emerging
as a possible replacement for intravenous ganciclovir in
some situations. Foscarnet is reserved for CMV-resistant
cases. Prevention of CMV disease is of great clinical impor-
tance and patients at highest risk of CMV should routinely
receive CMV prophylaxis for up to 6 months; whether
all low-risk patients need to receive prophylaxis is
controversial.
Pneumocystosis
The incidence of post-transplant Pneumocystis carinii infec-
tion has declined with the widespread use of SMX-TMP
848 prophylaxis. Alternative agents in sulfa-allergic patients
include dapsone and pyrimethamine, atovaquone, and aeroso-
lized pentamidine.
CONCLUSION
851
852 Acute kidney injury (AKI) (Cont.) intrinsic renal azotemia and,
after cardiovascular surgery, 213–216
209 postrenal azotemia and, 220
after intravenous contrast prerenal azotemia and,
studies, 207 212–213
after organ or bone marrow neurologic disorder in, 605
transplantation, 208 outcome of, 220–221
Index
Index
Adrenergic antagonists Alcoholism, hypophosphatemia
a, peripheral, 529–530 in, 184–185
dose modification of, in Aldosterone
renal insufficiency, 544t potassium excretion and, 139
for hypertensive regulation of, 140
emergencies, 536, 537t Aldosterone receptor antagonists,
moderately selective, 531
528–529 dose modification of, in renal
b, 518–520, 537t insufficiency, 544t
class members of, 518, 519t for cardiac failure, 578
dose modification of, in Aldosterone-producing adenoma,
renal insufficiency, 544t 464
efficacy and safety of, Aldosterone-renin ratio, 460
518–520 Alfacalcidol, 631
for cardiac failure, 578–579 Aliskiren, 530
for hypertensive Alkaline urine, 27–28
emergencies, 537t, Alkalosis
540–541 metabolic, 127–128
for pheochromocytoma, 456 acute kidney injury and, 211
mechanism of action of, 518 causes of, 127t
renoprotective effects of, diuretic-related, 557
518, 657 in plasmapheresis, 780–781
side effects associated with, maintenance of, 128
520 treatment of, 134–135
Adrenergic receptor blockade, a respiratory, 129t, 130–131
dose modification of, in renal hypophosphatemia and, 184
insufficiency, 544t in pregnancy, 489
for pheochromocytoma, 456 treatment of, 135
African Americans, hypertension Allergic drug reactions, diuretic-
in, 465–466 related, 558
Age, of renal transplant recipient, Allergic granulomatosis. See
814 Churg-Strauss
Airway pressure release syndrome.
ventilation (APRV), 754 Allergic interstitial nephritis, in
Albumin early post-transplant
as nutritional status index, 640 period, 838
as replacement fluid, in Allogeneic transplantation, for
plasmapheresis, renal cell carcinoma, 386
779–780 Allograft dysfunction
Albumin excretion ratio (AER), clinical approach to, 832–842
urinary, 348 in early post-transplant period,
Albumin:creatinine ratio, 31–32 835–839, 835t
Albuminuria. See also Microal- acute calcineurin inhibitor
buminuria; Normo- nephrotoxicity, 835–836
albuminuria. acute pyelonephritis, 838
in diabetic nephropathy, 345 acute rejection, 837
Albuterol, for hyperkalemia, algorithm for management
161–162 of, 834f, 836
854 Allograft dysfunction (Cont.) Ambulatory peritoneal dialysis
allergic interstitial nephritis, (APD), 740, 742, 742t
838 Amikacin, for peritonitis, 747t
hypovolemia, 835 Amiloride-sensitive epithelial
thrombotic microangiopathy, sodium ion channel, 156
837–838 Amino acid transport disorder(s),
urinary tract obstruction, 399–402, 399t
Index
Index
in autosomal dominant 292–293
polycystic kidney hyperkalemia and, 156–157
disease, 423–424 mechanism of action of, 511,
Angina, in hemodialysis, 727 512t
Angioedema, ACE inhibitors renoprotective effects of,
causing, 514–515 511–514, 513t, 655–656
Angiography use of, causing inadequate
coronary, 577 response to rHuEPO,
in acute kidney injury, 13 597–598
Angioinfarction, for renal cell Anion gap, 117–118, 117t
carcinoma, 382 calculation of, 113–116
Angiokeratoma corporis drug intoxication and, 789
diffusum universale, high, 118t, 123–126
274–275 normal (hyperchloremic),
Angiomyolipoma, renal, imaging 118–123, 118t
of, 53 urine
Angioplasty calculation of, 123
for arteriovenous fistula, 62–63 in diagnosis of metabolic
for atherosclerotic renal artery acidosis, 123
stenosis, 484–485 Anogenital cancer, in transplant
for fibromuscular disease, recipient, 845–846
483–484 Antegrade pyelography, of
for graft stenosis, 60–61 urinary tract
Angiotensin antagonist, obstruction, 341
hyperkalemia and, Antenatal ultrasonography, of
156–157 urinary tract
Angiotensin receptor antagonists, obstruction, 339–340
515–517 Anthropometrics, 639–640
efficacy and safety of, 517 Antiarrhythmic agents, dosage of,
for cardiac failure, 578 668
for preeclampsia, 497t Antibiotics
mechanism of action of, 515 dosage of, 668–669
pharmacodynamic properties for pyelonephritis, 326
of, 516t for sepsis, 765
renoprotective effects of, for urease-producing struvite
515–517, 656 stones, 375–376
Angiotensin-converting enzyme Anticoagulants
(ACE) inhibitors, in hemodialysis, 711–712
511–515, 537t in hemoperfusion, 795–796
class members of, 511, 512t in plasmapheresis, 779
diabetic nephropathy and, 352 Anticonvulsants
blood pressure control with, dosage of, 668
351–352, 354 for ethylene glycol poisoning,
dosage of, 668 800
dose modification of, in renal Antidotes
insufficiency, 544t for ethylene glycol poisoning,
efficacy and safety of, 514–515 800
for cardiac failure, 578 for methanol poisoning, 802–803
856 Anti–glomerular basement Arginine vasopressin. See
membrane disease, Vasopressin.
244–246 Arrhythmias, 573–574
clinical features and natural in hemodialysis, 726–727
history of, 245 treatment of, 580
in transplant recipient, Arterial blood gas(es), assessment
840–842, 841t of, in acid-base
Index
Index
247–248 urinary nitrates affected by,
Autoimmune disease, 28–29
hypocalcemia and, 173 Bacterial infections
Autonomic nephropathy, in in glomerular disease,
diabetic patient, 349 276–278
Autosomal dominant infectious nephritis,
hypophosphatemic 276–277
rickets, 403–404 shunt nephritis, 277
Autosomal dominant nephrotic of urinary tract, 314. See also
syndrome, 274 Urinary tract infection.
Autosomal dominant polycystic Balkan endemic nephropathy,
kidney disease (ADPKD), 305t, 309–310
417–425. See also Bartter syndrome, 406–408
Polycystic disease, vs. Gitelman syndrome, 407t
autosomal dominant. Benazepril, dose and response of,
Autosomal dominant 512t
pseudohypoal- Bence Jones protein, 33
dosteronism, 413 Benign prostatic hyperplasia
Autosomal recessive nephrotic (BPH), in urinary tract
syndrome, 273–274 infection, 336–337
Autosomal recessive polycystic Benign tumors, diagnostic
kidney disease imaging of, 53
(ARPKD), 426–427 Beta-adrenergic agonists, for
Autosomal recessive hyperkalemia, 161–162
pseudohypoal- Beta-adrenergic antagonists,
dosteronism, 413 518–520, 537t
AVPR2 gene, loss-of-function class members of, 518, 519t
mutations of, 415–416 dose modification of, in renal
Azathioprine insufficiency, 544t
for lupus nephritis, 255 efficacy and safety of, 518–520
for pregnant transplant for cardiac failure, 578–579
recipient, 509t, 510 for hypertensive emergencies,
for renal transplant recipient, 830 537t, 540–541
Azotemia for pheochromocytoma, 456
diuretic-related, 555 mechanism of action of, 518
intrinsic renal, 203–206 renoprotective effects of,
acute tubular necrosis and, 518, 657
204–206, 205t side effects associated with, 520
management of, 213–216 Beta-lactam antibiotics, for
vascular and tubulointerstitial cystitis, 323–324
disorders and, 203–204 Bevacizumab, for renal cell
postrenal, 206–207 carcinoma, 385
management of, 220 Bicarbonate
prerenal, 11, 202–203, 203t in metabolic acidosis, 116
fractional excretion of distal renal tubular, 120
sodium in, 11 gastrointestinal loss of, 117
management of, 212–213 proximal renal tubular,
Aztreonam, for peritonitis, 747t 119–120
858 Bicarbonate (Cont.) extracellular fluid volume
in metabolic alkalosis, 127–128 depletion and, 77
in respiratory acidosis, 128–130 in diabetic nephropathy,
in respiratory alkalosis, control of, 351–352
130–131 intradialytic and interdialytic,
Bilirubin, in urine, 28 356
Biochemical markers management of, in
Index
Index
C Calcium gluconate
C1C Kb gene, mutations of, for ethylene glycol poisoning,
406–408 800
Cadaveric donor, in renal for hyperkalemia, 160–161
transplantation, 196 intravenous
Cadmium, exposure to, 309 for hypermagnesemia, 180
Calcification for hypocalcemia, 175
aortic valve, 574 Calcium homeostasis, 619
coronary artery, 577 Calcium magnesium ammonium
diagnostic imaging of, 48–49 pyrophosphate crystals,
metastatic, radiographic 38
features of, 628t Calcium oxalate crystals, 38
mitral valve, 574 in acute kidney injury, 9–10
Monckeberg, 624–625 Calcium phosphate crystals, 38
vascular, 624–626 Calcium stones, 361–362,
inhibitors of, 625–626 366–368
Calcimimetic agents, 632–633 epidemiology and natural
Calcineurin inhibitor(s), for renal history of, 366
transplant recipient, etiology of, 367–368
828–829, 829t idiopathic, 370–371
Calcineurin inhibitor Calcium supplements
nephrotoxicity for hypocalcemia, 175
acute, 835–836 prophylactic, for preeclampsia,
chronic, 840 496
Calciphylaxis, 626–627 Calcium-sensing receptor,
Calcitriol, 631 619–620
for hypercalcemia, 172 Calculi. See also Nephrolithiasis.
Calcium analysis of, 364–365
dietary, 643–644 calcium, 361–362, 366–368
disorder(s) of, 166–175 in medullary sponge kidney,
hypercalcemia as, 166–172. 430–431
See also Hyperkalemia. in urinary tract obstruction,
hypocalcemia as, 172–175. 335, 342
See also Hypocalcemia. recurrence of, therapy
for osteoporosis, 844 minimizing, 366
in hemodialysis, 714 renal, diagnostic imaging of,
in peritoneal dialysis, 48–49
739–740 struvite, 374–376
serum levels of, 618–620 uric acid, 361–362, 372–374
Calcium channel blockers, Cancer. See Malignancy; specific
520–525 neoplasm.
class members of, 521–522, Candesartan, doses and
521t responses of, 516t
dose modification of, in renal Candida, in urinary tract
insufficiency, 544t infection, treatment of,
drug interactions with, 330
524–525 Candida albicans, in peritonitis,
efficacy and safety of, 523–525 745
860 Capillary(ies), peritoneal ischemic heart disease as,
distribution of, 730–731 570–572, 571t
transport across, 730 treatment of, 579–580
Capillary glomerulonephritis, left ventricular hypertrophy
mesangial, 235–237 as, 568–569, 569t
classification of, 236t management of, 575–584
clinical features and natural pathology and
Index
Index
treatment of, 96–97, 97t renal osteodystrophy in, 17
Central vein stenosis, 64 urinalysis in, 17
Central venous catheter, for cardiovascular aspects of,
plasmapheresis, 565–584. See also
778–779 Cardiovascular disease,
Central venous pressure, 77 in chronic kidney
Centrifugation method, of plasma disease.
separation, 777–778 definition of, 19–20, 189
Cephalosporins, for peritonitis, diuretics for, 562–563
747t electroencephalography in, 604
Cephalothin, for peritonitis, 747t end-stage renal disease and,
Cerebral edema, in hepatic 14. See also End-stage
failure, 772–773, 775 renal disease (ESRD).
Cerebral salt wasting, 101 epidemiology of, 187–198
Chagas disease, screening for, in granulocytes and monocytes
kidney donor, 824t affected by, 599–600
Chemotherapy hemostasis disorder in,
for renal cell carcinoma, 384 598–599
for renal pelvic tumors, 387 therapeutic strategies for,
for Wilms tumor, 388–389 598–599
Children uremic bleeding and, 598
acute poststreptococcal hypertension in, 443
glomerulonephritis in, hyponatremia and, 102
237–239 in pregnancy, 505–510
minimal change incidence of, 190–191
glomerulopathy in, mineral bone disease in,
227–229 616–634. See also
treatment of, 228 Mineral bone disease.
urinary tract infection in, 323 neurologic disorder in, 604–605
treatment of, 328 nutritional therapy in,
Chinese herb–aristolochic 635–648. See also
nephropathy, 305t, 306 Nutrition.
Chlamydia trachomatis, in prevalence of, 191
urinary tract infection, psychologic testing in, 604–605
314 risk factors for, 18–19, 19t
Chlorambucil, for membranous screening for, 21
glomerulopathy, 234 staging of, 19–20, 20t
Chloride deficiency, in metabolic National Kidney Foundation
alkalosis, 128 guidelines in, 189–190,
Chlorpropamide, hyponatremia 190t
caused by, 105 transitioning to hemodialysis
CHOIR study, of target in, 703–704. See also
hemoglobin, 590 Hemodialysis.
Chronic kidney disease (CKD), vs. acute kidney injury, 3, 4t
14–20 Churg-Strauss syndrome, 259–261
anemia in, 585–588. See also clinical and laboratory features
Anemia, in chronic of, 260–261
kidney disease. prognosis and treatment of, 261
862 Chvostek sign, 172 Co-morbidity, reduction of, in
Cinacalcet hydrochloride, hemodialysis, 703–704
632–633 Computed tomographic
Cirrhosis angiography (CTA), of
diuretics for, 561 renal artery stenosis, 56
glomerular disease and, 282 Computed tomography (CT),
sodium retention and edema 43–44
Index
Index
hemofiltration (CVVH), CRISP study, 417–419
218–219 Critical illness, hypocalcemia
Contrast agents, iodinated, 43 and, 174
Contrast studies, intravenous, Crohn disease, in urinary tract
acute kidney injury obstruction, 337
after, 207 Cryoglobulinemia
Convection, in hemodialysis, 708 mixed, 269–271
Coronary artery clinical and laboratory
angiography of, 577 findings in, 270
calcification of, 577 course and treatment of,
Coronary artery bypass graft, 580 270–271
Coronary artery disease, choice of plasmapheresis for, 784
antihypertensive and, Cryoprecipitate infusion,
534 for uremic bleeding,
Coronary atherosclerotic plaque, 599
571–572 Cryotherapy, with cryoballoon,
Coronary reperfusion, for for severe stenosis,
cardiogenic shock, 771 63–64
Coronary revascularization, Crystal(s), urinary, 38. See also
579–580 specific crystals.
Corticosteroids Crystalloid(s), as replacement
for acute rejection, 837 fluid, in plasmapheresis,
for focal segmental 779–780
glomerulosclerosis, 231 Crystalloid resuscitation
alternatives to, 231 for sepsis, 765
for membranous vs. colloid resuscitation,
glomerulopathy, 760–762
233–234 CTNS gene, mutations of, 396
for sepsis, 768 Cutting balloon therapy, for
Cough, nonproductive, ACE severe stenosis, 63
inhibitors causing, Cyclooxygenase-2 (COX-2), 140
514–515 Cyclophosphamide
Cramps, in hemodialysis, 725 for anti–glomerular basement
CREATE study, of target membrane
hemoglobin, 590 glomerulonephritis,
Creatinine 245–246
glomerular filtration rate for lupus erythematosus, 255
and, 22 for lupus nephritis, 255
formulas for, 23–24, 23t for membranous
in acute kidney injury, 10, 201 glomerulopathy, 234
Creatinine clearance for pauci-immune crescentic
glomerular filtration rate and, glomerulonephritis, 248
22–23, 201–202 for polyarteritis nodosa, 259
in pregnancy, 487–488 Cyclosporine
Crescentic glomerulonephritis, for focal segmental
225–226 glomerulosclerosis, 231
immune complex–mediated, for membranous
243–244 glomerulopathy, 234
864 Cyclosporine (Cont.) Cytomegalovirus (CMV)
for pregnant transplant post-transplant, 847
recipient, 509t screening for, in kidney
for renal transplant recipient, donor, 824t
828–829, 829t Cytoreductive (debulking)
hyperkalemia caused by, nephrectomy, for renal
155–156 cell carcinoma, 382–383
Index
Index
Diabetic nephropathy, 345–359 calcium, 714, 739–740
bladder dysfunction in, 358 glucose, 715
clinical course and potassium, 714
pathophysiology of, sodium, 713–714
347–349, 347f flow rate of, 712–713
clinical features of, 348–349 peritoneal, 737–740, 738t
end-stage renal disease in, temperature of, 715
353–358, 353t ultrafiltration rate of, 711
advanced renal failure in, Dialysis. See also Hemodialysis;
management of, 354–355 Peritoneal dialysis.
hemodialysis for, 355–357 chronic, pregnancy during,
peritoneal dialysis for, 357 507–508
transplantation for, 357–358 complication(s) of
epidemiology of, 345–346 dementia as, 606–609, 607t
extrarenal complications of, aluminum and, 608–609
349, 350t clinical manifestations of,
in pregnancy, 506 607–608
incidence of, 345 differential diagnosis of,
microalbuminuria in, 345–346 610t
natural history of, 348–349 prevention and treatment
normoalbuminuria in, 347–348 of, 609
other disorders in, 359 dysequilibrium syndrome as,
prevention of, 345 605–606, 607t
prognosis of, 346 stroke as, 612–613
treatment of, 350–353 subdural hematoma as,
blood pressure control in, 611–612
351–352 drug removal by, 665–670, 797
dietary protein restriction estimation of clearance in,
in, 353 665–666
glycemic control in, 350–351 factors affecting, 792t, 794
lipid lowering in, 353 heparin-free, 712
urinary tract infection in, hypotension and, 572–573
358–359 in acute kidney injury,
Diabetic retinopathy, 349 216–220
Diagnostic imaging indications for, 216–217
modalities in, 42–45. See also vascular access for, 217
specific modalities. in end-stage renal disease, 194
of acute kidney injury, 45–47 autosomal dominant
of kidney infections, 49–51 polycystic kidney
of renal artery stenosis, 55–57 disease and, 423
of renal calcifications, 48–49 survival rates associated
of renal calculi, 48–49 with, 194–195
of renal masses, 51–55 in hyperkalemia, 163–164
benign, 53 in lupus nephritis, 253
cystic, 51–53 loss of efficiency of,
malignant, 53–55 recombinant
solid, 53 erythropoietin and, 594
of renal vein thrombosis, 57 sustained low-efficiency, 797
866 Dialysis disequilibrium post–acute tubular necrosis,
syndrome, 605–606, 204
607t, 725–726 postobstructive, 344
Dialysis errors, technical, 612 saline, for hypercalcemia, 171
Dialysis Outcomes and Practice water, 110
Patterns Study Diuretics, 546–564
(DOPPS), 597 adaptation to, 553–555
Index
Index
cadaver, 196 for cardiovascular agents, 668
living. See Living kidney for diuretics, 668
donor. for hypnotics, 670
Dopamine, 552 for hypoglycemic agents, 669
for cardiogenic shock, 770 for nonsteroidal anti-
for sepsis, 767 inflammatory agents, 669
Dopamine D1-like receptor for psychotropic agents, 670
antagonist, for for sedatives, 670
hypertensive for specific drug categories,
emergencies, 537t, 542 667–670
Doppler flow scanning, of acute in renal failure, 666–667, 671t
kidney injury, 12 initial patient assessment for,
Doppler ultrasonography, of 665
renal arteries, 478 Dry weight, definition of,
Dosing, drug. See Drug dosing. 715–716
Doxazocin, 529 Dyslipidemia
Drug(s). See also named drug or as cardiovascular risk factors,
drug group. 582–583
acidosis caused by, 125–126 as risk factor for renal failure,
acute interstitial nephritis 653–654
caused by, 297–299, 298t Dysplasia
affecting vasopressin fibromuscular, 56
secretion, 89t renal artery stenosis and,
dialysis removal of, 665–670, 55–56
797 renal, 432
estimation of clearance in, Dysuria, 317, 318f
665–666
factors affecting, 792t, 794
hemolytic-uremic syndrome E
caused by, 287, 288t Echocardiography (ECHO)
hypercalcemia caused by, 170 in heart disease, 576
hyperkalemia caused by, in hypertension, 441
155–157 Eclampsia, 491t, 493–494.
hypocalcemia caused by, 174 See also Preeclampsia.
hypokalemia caused by, 144 magnesium for, 498–499
hyponatremia caused by, 105 Edema
hypophosphatemia caused capillary leak and, 85
by, 185 cerebral, in hepatic failure,
lupus nephritis caused by, 253 772–773, 775
overdose of, 789–810. See also diuretics for, 559–562
Poisoning. generalized, 79
refractory hypertension caused in cirrhosis with ascites, 81–82
by, 535 in congestive heart failure,
thrombotic thrombocytopenic 79–81
purpura caused by, in nephrotic syndrome, 82–84
287, 288t in poststreptococcal
uric acid stones caused by, 373 glomerulonephritis, 238
Drug allergy, diuretic-related, 558 in preeclampsia, 493
868 Edema (Cont.) hypertonic, 94–95
local mechanisms in, 78–79 in poststreptococcal
pathophysiology of, 78–85 glomerulonephritis, 238
Effector mechanisms, in uremic, 601–604
extracellular fluid diagnosis of, 603
volume regulation, 72–75 hepatic insufficiency and,
natriuretic peptides, 74 603–604
Index
Index
polycystic kidney 467f
disease, 423 Ethanol, intravenous, for
incidence of, 192 ethylene glycol
trends and determinants poisoning, 800–801
in, 192 Ethylene glycol, acidosis caused
variation in, 192–193 by, 126
lupus nephritis and, 253 Ethylene glycol poisoning,
prevention of 798–801
global comparisons in, clinical course of, 798–799
193–194 diagnosis and laboratory data
in U.S, 193 in, 799–800
scleroderma renal crisis– treatment of, 800–801
induced, 292–293 Euvolemic hypernatremia,
sickle cell disease and, 91–95
295–296 in central diabetes insipidus,
Energy requirements, in uremia, 92, 93t
641 in gestational diabetes
Energy-based tissue ablation, for insipidus, 94
renal cell carcinoma, 382 in nephrogenic diabetes
Eosinophilia, in acute kidney insipidus, 94, 93t
injury, 10–11 osmoreceptor dysfunction in,
Eosinophilic peritonitis, 746 92–94, 93t
Eosinophiluria, diseases treatment of, 96
associated with, 36, 36t Excitable tissue consequences
Epherenone, 531 of hyperkalemia, 142, 142t
Epithelial cells, in urine, 37 of hypokalemia, 141
Epithelial sodium ion channel, Exercise, strenuous,
amiloride-sensitive, 156 hyponatremia caused
Epoetin alfa, 588 by, 105
Epoetin beta, 588 Extended Criteria Donors (ECD),
Eprosartan, doses and responses UNOS establishment of,
of, 516t 196
Epstein-Barr virus (EBV), Extracellular fluid volume
screening for, in kidney control of, 71–75
donor, 824t effector mechanisms in,
Erythrocytosis, definition of, 72–75
377–378 natriuretic peptides in, 74
Erythropoiesis prostaglandins in, 74
negative regulation of, receptors in, 72
cytokine-induced, 597 renin-angiotensin-
normal, 585–586 aldosterone axis in,
Erythropoiesis-stimulating 72–73
agents, 587–588 sympathetic nervous system
Erythropoietin (EPO), 585 in, 73
interactions of, 585–586 tubuloglomerular feedback
recombinant. See Recombinant in, 74–75
erythropoietin vasopressin in, 73
(rHuEPO). depletion of, 75–78
870 Extracellular fluid volume for alcohol poisoning, 797–804
(Cont.) ethylene glycol, 798–801
clinical manifestations of, isopropanol, 801–803
76–77 methanol, 801–803
dermal losses causing, 76 for lithium poisoning, 805–806
diagnosis of, 77–78 for salicylate poisoning,
diuretic-related, 555 806–808
Index
Index
treatment of, 243 Focal segmental
Fibrin, deposition of, in glomerulosclerosis,
thrombotic 229–231, 230t
thrombocytopenic clinical features and natural
purpura, 289 history of, 229–230
Fibromuscular disease collapsing variant of, 229–230
angioplasty for, 483–484 in transplant recipient,
in renal artery stenosis, 840–842, 841t
471–472 laboratory findings in, 230
Fibromuscular dysplasia, 56 pathology of, 229
renal artery stenosis and, treatment of, 231
55–56 alternatives to corticosteroid
Fibrosis, retroperitoneal, in therapy in, 231
urinary tract Folic acid, for methanol
obstruction, 337 poisoning, 802–803
Filariasis, 279 Fomepizole, for ethylene glycol
Filters poisoning, 801
granular activated-carbon, Formed elements, in urine,
710 33–38
in water purification, 710 casts as, 37
First-use syndrome, in cells as, 37
hemodialysis, 728–729 crystals as, 38
Fish oil therapy, for IgA fat as, 37
nephropathy, 241–242 hematuria and, 34–36, 35t
Fistula, arteriovenous. See leukocyturia and, 36, 36t
Arteriovenous fistula. microorganisms as, 38
Fixed proteinuria, 222 microscopy of, 33–34
Fludrocortisone, for sepsis, 768 Fosinopril
Fluid(s) dose and response of, 512t
absorption of, in peritoneal prophylactic, for
dialysis, 733 hyperkalemia, 165
body, disorders of, 87 Fractional excretion of
extracellular. See Extracellular magnesium (FeMg2þ),
fluid entries. 175–176
interstitial, accumulation of, Fractional excretion of sodium
78–79 (FeNa), 78
replacement, in definition of, 11
plasmapheresis, in acute kidney injury, 11
779–780 Fresh frozen plasma (FFP), as
thirst and, 89–90 replacement fluid, in
Fluid abnormality(ies), diuretic- plasmapheresis,
related, 555–557 779–780
Fluid challenge, in acute kidney Fructose intolerance, hereditary,
injury, 12 398–399
Fluid resuscitation Fluconazole, for candidal urinary
for cystinuria, 401 tract infection, 330
for hepatic failure, Fungal infections, in hepatic
774–775 failure, 773–774
872 Fungal pathogens, in urinary Glomerular basement membrane
tract infection, 314 disease, thin, 272
Fungal peritonitis, 748 Glomerular disease
Furosemide, for hypercalcemia, primary, 222–249
563 crescentic
glomerulonephritis as,
225–226
Index
Index
deposition disease, 267 in pregnancy, 487–488
in multiple myeloma, inulin and, 25
268–269 metabolic acidosis and,
in parasitic disease, 278–279 120–121
filariasis, 279 plasma urea and, 24
leishmaniasis, 279 radionuclide and radiocontrast
malaria, 278 markers of, 25–27
schistosomiasis, 279 renoprotection and, 651–652,
trypanosomiasis, 279 658t
in polyarteritis nodosa, serum creatinine and, 22
258–259 formulas for, 23–24, 23t
in sarcoidosis, 264 serum cystatin C and, 24–25
in Sjögren’s syndrome, threshold, in living kidney
263–264 donor, 821
in Takayasu’s arteritis, Glomerular hematuria, 223–225
261–262 Glomerular hypertension
in temporal arteritis, 261 as risk factor for renal failure,
in viral infections, 279–280 651–652, 652f
HIV-associated in diabetic nephropathy,
nephropathy, 279–280 348–349
in Wegener’s Glomerulonephritis, 237–243
granulomatosis, 269 acute poststreptococcal,
myeloma kidney as, 268–269 237–239
podocyte protein mutations clinical features and natural
and, 273–274 history of, 238
systemic lupus laboratory findings in,
erythematosus as, 238–239
250–256, 251t. See also treatment of, 239
Lupus nephritis. algorithm for, 227f
thin glomerular basement cirrhotic, 282
membrane disease crescentic, 225–226
as, 272 fibrillary
Glomerular filtration rate (GFR) epidemiology and clinical
calculation of, 21–22 features of, 243
creatinine clearance and, nomenclature related to, 242
22–23 treatment of, 243
dietary calcium and membranoproliferative,
phosphorus affecting, 235–237
643–644 classification of, 236t
dietary protein affecting, 642 clinical features and natural
effect of ACE inhibitors on, history of, 235–236
513–514 in transplant recipient,
effect of calcium channel 840–842, 841t
blockers on, 513–514, laboratory findings in,
522–523 236–237
in acute kidney injury, treatment of, 237
201–202 mesangial capillary, 235–237
874 Glomerulonephritis (Cont.) Glucose transport disorder, 405
proliferative, malignancy Glucosuria
and, 283 in Fanconi syndrome, 393–395
rapidly progressive, 225–226 renal, 405
anti–glomerular basement Glycemic control
membrane, 244–246 in diabetic nephropathy,
clinical features and 350–351
Index
Index
Heart disease, 568–572 complication(s) of, 721–729
diagnosis of, 575–577 angina as, 727
ischemic, 570–572, 571t arrhythmias as, 726–727
treatment of, 579–580 blood-membrane interaction
valvular, 574 as, 728–729
treatment of, 580 cramps as, 725
Heart failure, 569–570 dialysis disequilibrium
congestive. See Congestive syndrome as, 725–726
heart disease. first-use syndrome as,
diuretics for, 559–560 728–729
hypertension in, 443 hemorrhage as, 727–728
symptomatic, 570 hypoglycemia as, 727
treatment of, 577–579 hypotension as, 721–724,
Heavy chain deposition disease 722t
(HCDD), 267 management of, 724
HELLP syndrome, 208, 287 conventional, 219
in pregnancy, 494, 503, 504t demographics of, 703
management of, 499 drug removal by, 665–670, 795
Hematoma estimation of clearance in,
perinephric, biopsy-related, 41 665–666
subdural, dialysis-related, for end-stage renal disease
611–612 in diabetic patient, 355–357
Hematuria, 29–30, 34–36, 35t, malnutrition and, 356–357
223–225 for ethylene glycol poisoning,
asymptomatic, 35–36 801
benign familial, 272 for hypercalcemia, 172
glomerular, 223–225 for isopropanol poisoning, 804
gross, 34 for lithium poisoning, 806
in autosomal dominant for methanol poisoning, 803
polycystic kidney for salicylate poisoning, 808
disease, 421–422 for theophylline poisoning,
in glomerular disease, 242 809
in IgA nephropathy, 240, 241 general principles of,
in living kidney donor, 826 707–710
in nephrolithiasis, 360–361 immunity and, 719–721
in poststreptococcal infection in, 719–721
glomerulonephritis, intermittent, 217–218
238–239 long, slow, 719
in renal cell carcinoma, maintenance of, patient
377–378 management in,
in renal pelvic tumors, 387 719–721
in simple cystic disease, 432 membranes in, 708–709
isolated, biopsy for, 39 morbidity and mortality of, 703
Heme pigment, 9–10 nocturnal, 719
Hemodialysis, 701–729. See also paralbumin and, 640–641
Dialysis; Peritoneal prescription for, 710–716
dialysis. alternative, 718–719
adequacy of, 716–718 anticoagulation in, 711–712
876 Hemodialysis (Cont.) renal involvement in, 286
blood and dialysate flow in, management of, 290
712–713 shiga-toxin–associated,
dialysate composition in, 285–287
713–715 management of, 289–290
dialysate temperature in, 715 Hemoperfusion, 795–796
dialysis time in, 713 for theophylline poisoning, 809
Index
Index
in transplant recipient, 818 nephropathy associated with,
Hepatitis B core antibody 279–280
(HBcAb), 818 screening for, in kidney donor,
Hepatitis B surface antibody 824t
(HBsAb), 818 Human T-cell lymphotrophic
Hepatitis B vaccine, for virus-1 (HTLV-1),
hemodialysis patients, screening for, in kidney
720–721 donor, 824t
Hepatitis C Humoral hypercalcemia of
in hemodialysis, 720 malignancy (HHM), 169
membranoproliferative Humoral rejection, acute, in renal
glomerulonephritis and, transplantation, 788
236–237 Hungry bone syndrome,
mixed cryoglobulinemia and, hypocalcemia of,
270–271 hypomagnesemia and,
screening for 177
in kidney donor, 824t Hyaline casts, 37
in transplant recipient, 818 Hydralazine, 526–527
Hepatorenal syndrome, 208, for hypertensive emergencies,
209–210 537t, 539
Hernia, in peritoneal dialysis, for preeclampsia, 497t
749 Hydronephrosis, 332
Herpes simplex virus-8 (HSV-8), ultrasonography of, 46, 48
screening for, in kidney 11b-Hydroxsteroid
donor, 824t dehydrogenase type 2,
High anion gap metabolic apparent
acidosis, 118t, 123–126 mineralocorticoid excess
drug- and toxin-induced, and, 411
125–126 11b-Hydroxylase deficiency,
ketoacidosis, 124–125 409–410
lactic acidosis, 123–124 glucocorticoid-remediable
D-lactic acidosis, 124 hyperaldosteronism
uremia and, 126 and, 412
High osmolar contrast media 17a-Hydroxylase deficiency, 410
(HOCM), 43 1a,25-Hydroxyvitamin D3
HIV-associated nephropathy deficiency of, 404
(HIVAN), 279–280 mineral bone disease and, 620
Hollow-fiber dialyzer, 708–709 resistance to, 404–405
Home blood pressure 25-Hydroxyvitamin D3, for
monitoring, 441 X-linked hypo-
Hormone(s). See also named phosphatemic rickets,
hormones. 403
affecting vasopressin secretion, Hyperacute rejection, post-
89t transplant, 833
Hospitalization, nontransplant- Hyperaldosteronism
related, 848 familial, 145
Host factors, influencing urinary type 1, 457
tract infection, 315–316 type 2, 458
878 Hyperaldosteronism (Cont.) proximal renal tubular,
glucocorticoid-remediable, 119–120, 122t
411t, 412–413, 457–458 treatment of, 133–134
potassium loss due to, 145 urine in diagnosis of, 117
primary, 457–458 Hyperglycemia
clinical characteristics of, diuretic-related, 557
459 in peritoneal dialysis, 750
Index
Index
definition of, 90 as risk factor for renal failure,
euvolemic, 91–95 651–652, 652f
treatment of, 96 in African Americans, 465–466
hypervolemic, 95 in autosomal dominant
treatment of, 98 polycystic kidney
hypovolemic, 91 disease, 419, 421
treatment of, 96 in autosomal recessive
in peritoneal dialysis, 751 polycystic kidney
management of patient with, disease, 426–427
91 in cardiovascular disease,
treatment of, 95–98 442–443
Hyperoxaluria, 371–372 in chronic kidney disease,
Hyperparathyroidism 443–444
calcium stones in, 367 in diabetic nephropathy, end-
hypercalcemia caused by, stage renal disease and,
167–168 354
in transplant recipient, in elderly, 466
843–844 in heart failure, 443
neonatal severe, 170 in living kidney donor, 823
secondary, causing inadequate in poststreptococcal
response to rHuEPO, glomerulonephritis, 238
597 in preeclampsia, 490–499,
treatment of, 168 491t. See also
Hyperphosphatemia, 181–182 Preeclampsia.
acute kidney injury and, 211 definition of, 493
clinical manifestations of, 182 in pregnancy, 490–505, 491t
etiology of, 181–182 chronic, 499
treatment of, 182, 215 gestational, 499–500
Hyperreninemic management of, 500–501
hypoaldosteronism, 154 secondary, 497
Hypertension, 437–467 in transplant recipient,
accelerated, 442 844–845
as cardiovascular risk factor, isolated systolic, 440
581–582 labile, 440
as risk factor for renal failure, malignant, 440
649–650 microalbuminuria and, 444
borderline, 440 nomenclature in, 439–442
complications of, 442–447 prevention of renal function
risk of, 442 loss in, 659
essential, 440 recombinant erythropoietin
treatment of, 464–465, 466t, causing, 594
467f refractory, 534–536
evaluation of renin-dependent forms of,
blood pressure monitoring 453–457
in, 441 renovascular. See
echocardiogram in, 441 Renovascular
electrocardiogram in, 441 hypertension.
general principles in, 447 secondary, 440, 441t
880 Hypertension (Cont.) in plasmapheresis, 780–781
stroke and, 443 treatment of, 175, 215
treatment of, benefits of, 445 Hypocalciuric hypercalcemia,
in specific clinical settings, familial, 169–170
445–447 Hypocitraturia, 370
urinary tract infection and, 317 Hypoglycemia
Hypertensive crisis, treatment of, in hemodialysis, 727
Index
Index
acute kidney injury and, 211 cause(s) of, 183–185
clinical manifestations of, 178, decreased intestinal
178t absorption as, 184
diagnosis of, 175–176 drug-related, 185
diuretic-related, 556 increased renal excretion as,
etiology of, 175–176 183
extrarenal causes of, 176–177 redistribution as, 184–185
hypocalcemia and, 173 clinical manifestations of,
in transplant recipient, 843 182–183
renal magnesium wasting and, diagnosis of, 183
177–178 in transplant recipient, 843
treatment of, 178–179 treatment of, 185
Hyponatremia, 98–109 Hypophosphatemic rickets
acute kidney injury and, autosomal dominant, 403–404
210–211 with hypercalciuria, 404
diuretic-related, 101, 555–556 X-linked recessive, 395–396,
drug-induced, 105 403
etiology of, 99–101, 100f Hypoproteinemia, in focal
exercise-induced, 105 segmental
extracellular fluid volume glomerulosclerosis, 230
depletion in, 101 Hyporeninemic
extracellular fluid volume hypoaldosteronism,
excess in, 102 154–155
factitious, 98–99 Hypotension
hypervolemic, treatment of, in dialysis, 572–573
108 in hemodialysis, 721–724,
hypovolemic, treatment of, 107 722t
in congestive heart management of, 724
failure, 102 in plasmapheresis, 780
in glucocorticoid deficiency, overt, 77
104 Hypothyroidism, hyponatremia
in hepatic failure, 102 and, 104
in hypothyroidism, 104 Hypovolemia, 76–77
in nephrotic syndrome, 102 in early post-transplant
in peritoneal dialysis, 751 period, 835
in renal failure, 102 Hypovolemic hypernatremia, 91
in syndrome of inappropriate treatment of, 96
antidiuretic hormone Hypovolemic hyponatremia,
secretion, 103–104, 103t treatment of, 107
normal extracellular fluid Hypovolemic shock, 757–763
volume in, 103–105, clinical manifestations of,
103t 758–759
normovolemic, treatment of, diagnosis of, 759
107–108 effects of, on renal function,
postoperative, 104 762–763
symptomatic, 106 etiology of, 758t
treatment of, 108–109 management of, 759–762, 761t
treatment of, 106–109 pathogenesis of, 758
882 I for pregnant transplant
recipient, 509t
Icodextrin, in peritoneal dialysis, for renal transplant recipient,
737–739 827–831, 829t
IgA nephropathy, 239–242 antilymphocyte antibodies
clinical features and natural in, 828
history of, 240–241 azathioprine in, 830
Index
Index
Intensive care, 753–776 in acute kidney injury, 210
for acute respiratory distress prerenal azotemia and,
syndrome, 755–757 212–213
for acute respiratory failure, renal azotemia and, 214–215
753–754 Intravenous urography (IVU),
for cardiogenic shock, 42–43
769–771 of medullary sponge
for hepatic failure, 771–776 kidney, 431
for hypovolemic shock, of renal infection, 50
757–763 of unilateral obstruction, 47
for sepsis, 763–769 of urinary tract
Interferon-a, for renal cell obstruction, 340
carcinoma, 384 Intrinsic renal azotemia, 203–206
Interleukin-2, for renal cell acute tubular necrosis and,
carcinoma, 384–385 204–206, 205t
Interstitial fluid, accumulation management of, 213–216
of, 78–79 specific therapies in, 214
Interstitial nephritis prevention of, 213–214
acute, 297–302 vascular and tubulointerstitial
clinical features of, 300–301 disorders and, 203–204
course and treatment of, Intubation, in salicylate
301–302 poisoning, 807–808
drug-induced, 297–299, 298t Inulin, glomerular filtration rate
etiology of, 297–299, 298t and, 25
idiopathic, 299 Ion metabolism, abnormal
infectious agents in, 298t, divalent, 584
299 Ionotropic agents, for cardiogenic
pathology of, 300 shock, 770
allergic, in early post- Irbesartan, doses and responses
transplant period, 838 of, 516t
chronic, 302–312 Iron deficiency, causing
analgesic nephropathy and, inadequate response to
302–304, 305t rHuEPO, 596
Balkan endemic Iron status, assessment of,
nephropathy and, 305t, 590–593
309–310 Iron therapy
cadmium exposure and, 309 adverse effects of, 593
Chinese herb–aristolochic intravenous, 592–593
nephropathy and, 305t, oral, 591–592
306 Ischemia, biochemical markers
common causes of, 303t of, 576
hypokalemia and, 310–311 Ischemic heart disease, 570–572,
lead exposure and, 308 571t
lithium exposure and, 307 treatment of, 579–580
sarcoidosis and, 311–312 Ischemic nephropathy
urate nephropathy and, 310 diagnosis of, 475–479, 476t
Interventional nephrology, management of, 479–486
59, 59t mechanisms of, 469–470
884 Ischemic stroke, antihypertensive Kt/V
therapy and, 446 in hemodialysis, 716
Islet cell transplantation, 358 clinical importance of,
Isolated proteinuria, 222 717–718
Isolated systolic hypertension, 440 in malnutrition, 646–647
Isopropanol poisoning, 801–803 in peritoneal dialysis, 741–742
Isotonic contrast media
Index
(IOCM), 43
Isradipine, doses and responses L
of, 521t Labetalol
doses and responses of, 519t
J for hypertensive emergencies,
537t, 541
Jugular venous pressure, 76–77
for hypertensive urgencies,
539t
K for preeclampsia, 497t
Kþ ion. See also Potassium Labile hypertension, 440
entries. Lactam, b, for cystitis, 323–324
acid-base disturbances Lactic acidosis, 123–124
affecting, 138 treatment of, 132–133
dietary intake of, 139 D-Lactic acidosis, 124
in potassium balance, 136–137 Laparoscopic nephrectomy, for
nonrenal loss of, 144 renal cell carcinoma,
Ketoacidosis, 124–125 382
alcoholic, 125 LCAT gene, 276
diabetic, 124 Lead, exposure to, 308
hypophosphatemia in, Leak(age)
184–185 capillary, edema and, 85
treatment of, 133 in peritoneal dialysis, 749
starvation, 125 urine, in early post-transplant
Ketones, in urine, 29 period, 838
Kidney(s). See also Glomerular; Lecithin-cholesterol
Glomerulo-; Nephr-; acryltransferase
Renal entries. deficiency, 275–276
adaptation of, to pregnancy, Left ventricular failure, 559
487–489 Left ventricular hypertrophy,
failing, in transplant recipient, 568–569, 569t, 573
849 antihypertensive therapy
hyperkalemia affecting, 142 and, 445
hypokalemia affecting, 141 electrocardiography in, 445
medullary sponge, 430–431 Leishmania donovani, 279
myeloma, 268–269 Leishmaniasis, 279
stones in. See Calculi; Leptospira infections, 278
Nephrolithiasis. Leukemia, uric acid stones in,
transplanted, biopsy of, 40 373
Kidney disease Leukocyte esterase, 28–29
in diabetic nephropathy, acute- Leukocytes
on-chronic, 355 chemotactic activity of, in
Kidney donor, living. See Living uremia, 599–600
kidney donor. in urine, 313–314
Kidney patients, risk factor Leukocyturia, 36, 36t
profile in, 657–658 Liddle syndrome, 410–411, 411t,
King’s College criteria, for liver 458
transplantation, in Light chain deposition disease
hepatic failure, 776, 776t (LCDD), 267
Lipid(s) potassium-sparing diuretics 885
dietary, 644–645 with, 555
reduction of, renoprotective thiazides combined with, 555
effect of, 654 Losartan, doses and responses of,
urinary, 37 516t
Lipid lowering therapy, in Low osmolar contrast media
diabetic nephropathy, (LOCM), 43
Index
353 Lowe oculocerebrorenal
Lisinopril, dose and response of, syndrome, 398
512t Lung(s). See Pulmonary;
Lithium, exposure to, 307 Respiratory entries.
Lithium poisoning, 805–806 Lupus nephritis, 250–256
Liver. See also Hepatic; classification of, 251t
Hepatitis; Hepato- clinical manifestations of,
entries. 250–252
biopsy of, 774 course and prognosis of,
cirrhosis of. See Cirrhosis. 253–254
fatty, in pregnancy, 501–502 dialysis in, 253
transplantation of, King’s drug-induced, 253
College criteria for, 776, in pregnancy, 506–507
776t monitoring of, 252
Liver disease pathology of, 250
acute kidney injury and, plasmapheresis for, 783–784
209–210 pregnancy and, 253
glomerular manifestations of, serologic tests for, 252
280–282 transplantation in, 253
in renal transplant recipient, treatment of, 254–256
818 for class I and II disease, 254
polycystic, 424–425 for class III disease, 254
Living kidney donor, 820–826 for class IV disease,
and consequences of living 254–255
with one kidney, 822 for class V disease, 256
assessment of renal function Lymphoma, hypercalcemia in,
in, 821 169
hematuria in, 826 Lymphoproliferative disorder,
hypertension in, 823 post-transplant, 846
infectious diseases in,
824–825, 824t
malignancy in, 823–824 M
medical evaluation of, 820, Magnesium
820t defective reabsorption of, in
nephrolithiasis in, 823 distal nephron, 177
obesity in, 822 deficiency of, 175–179.
postdonation diabetes in, 822 See also Hypomagne-
postdonation nephropathy in, semia.
822 clinical manifestations of,
Loin pain hematuria syndrome, 178, 178t
361 potassium loss due to, 146
Loop diuretics, 548–550. See also excessive intake of, 179–180.
Diuretics. See also Hypermagne-
for cardiac failure, 572 semia.
for hypercalcemia, 171, 563 for eclampsia, 498–499
mechanism of action of, for hypomagnesemia
548–549 intravenous, 178–179
pharmacokinetics of, 549–550 oral, 179
886 Magnesium (Cont.) in renal transplant recipient
fractional excretion of, disease-free intervals
175–176 recommended, 816, 816t
Magnesium wasting disorders, post-transplant, 845–846
renal, 177–178 screening for, 815–816
inherited, 178 uric acid stones in, 373
Magnetic resonance angiography Malignant hypertension, 440
Index
Index
840–842, 841t associated with, 117
laboratory findings in, 236–237 proximal renal tubular,
treatment of, 237 119–120, 122t
Membranous glomerulopathy, treatment of, 133–134
232–235 urine in diagnosis of, 117
clinical features and natural pH in, 116
history of, 232–233 renal azotemia and, 215
laboratory findings in, 233 treatment of, 131–132
pathology of, 232 Metabolic alkalosis, 127–128
treatment of, 233–235 acute kidney injury and, 211
corticosteroids in, 233–234 causes of, 127t
cyclophosphamide in, 234 diuretic-related, 557
immunosuppression in, in plasmapheresis, 780–781
234–235 maintenance of, 128
Membranous nephropathy treatment of, 134–135
diabetes and, 359 Metabolic disorder(s)
malignancy and, 283 diuretic-related, 557–558
Men, urinary tract infection in, peritoneal dialysis–related,
323 750–751
treatment of, 327 Metabolic neuropathy, 615, 615t
Menin gene, in MEN-I, 169 Metabolism, ion, abnormal
Mensuration, in chronic kidney divalent, 584
disease, 18 Metanephrines, free, plasma and
Mesangial capillary urinary, 454
glomerulonephritis, Metastasis, renal cell carcinoma,
235–237 resection of, 383
clinical features and natural Methanol, acidosis caused by,
history of, 235–236 126
laboratory findings in, 236–237 Methanol poisoning, 801–803
treatment of, 237 treatment of, 802–803
Metabolic acidosis, 114t, 115f, Methenamine mandelate, for
116–126 urinary tract infection,
acute kidney injury and, 211 in children, 328
anion gap in, 117–118, 117t Methyldopa, 525
high anion gap in, 118t, for hypertensive emergencies,
123–126 537t
drug- and toxin-induced, for preeclampsia, 497t
125–126 Methylprednisolone
ketoacidosis, 124–125 for acute rejection, 837
lactic acidosis, 123–124 for IgA nephropathy, 241
D-lactic acidosis, 124 for lupus erythematosus, 255
uremia and, 126 for membranous
in hypovolemic shock, glomerulopathy, 234
treatment of, 762 for pauci-immune crescentic
in transplant recipient, 843 glomerulonephritis, 248
normal anion gap Metoprolol
(hyperchloremic) in, doses and responses of, 519t
118–123, 118t for preeclampsia, 497t
888 Metyrosine, 531–532 vitamin D sterols in,
Microalbuminuria, for 630–632
hypotension parathyroid hormone and,
definition of, 32, 345 621–622
hypertension and, 444 pathogenesis of, 616, 617t
in diabetic nephropathy, phosphorus levels in,
345–346 616–618
Index
Index
in anemia, 587 extracellular fluid
in end-stage renal disease, volume regulation, 74
195 Nebivolol, doses and responses
modality-specific, 195 of, 519t
in preeclampsia, maternal and Necrosis
neonatal, 494 acute tubular. See Acute
of hemodialysis patient, 703 tubular necrosis
Moxonidine, 525, 526 (ATN).
Mucous membranes, in tissue, hyperkalemia and,
extracellular fluid 153
volume depletion, 76 Neonatal injury, ACE inhibitors
Multiple endocrine neoplasia causing, 514–515
(MEN), hypercalcemia Neonatal severe
and, 169 hyperparathyroidism,
Multiple myeloma, 268–269 170
renal failure associated with, Nephrectomy
plasmapheresis for, 784 allograft, 848
Muscle for renal cell carcinoma,
hyperkalemia affecting, 142 380–381
hypokalemia affecting, 141 cytoreductive (debulking),
Muscle cramps, in hemodialysis, 382–383
725 laparoscopic, 382
Mutations. See also specific gene palliative, 383
mutations. Nephritic syndrome, 225
inherited, of podocyte Nephritis
proteins, 273–274 5-aminosalicylic acid,
Mycobacterium tuberculosis, 304–306, 305t
278 hereditary, 271–272
Mycophenolate mofetil infectious, 276–277
for lupus nephritis, 255 interstitial. See also Interstitial
for pregnant transplant nephritis.
recipient, 509t acute, 297–302
for renal transplant recipient, chronic, 302–312
830 lupus, 250–256. See also
Myeloma, glomerular disease in, Lupus nephritis.
268–269 shunt, 277
Myeloma kidney, 268–269 Nephrocalcinosis, 48
Myoglobin, in urine, 29–30 Nephrogenic diabetes insipidus,
93t, 94
treatment of, 98
N Nephrolithiasis, 360–376
N-Acetylcysteine, for asymptomatic, 361
acetaminophen calcium stones and, 361–362,
overdose, 774 366–368
Nadolol, doses and responses of, clinical presentation of,
519t 360–362
Naþ/Kþ-ATPase, potassium diet and, 368–369
transport and, 136–137 diuretics for, 563
890 Nephrolithiasis (Cont.) Clq, 232
hematuria in, 360–361 diabetic. See Diabetic
hyperoxaluria and, 371–372 nephropathy.
hyperuricosuria and, 369 HIV-associated, 279–280
hypocitraturia and, 370 hypokalemic, 310–311
idiopathic, 370–371 IgA, 239–242
in autosomal dominant clinical features and
Index
Index
exposure to, acute kidney 537t, 539–540
injury and, 5–6, 5t for preeclampsia, 497t
tubular, hypomagnesemia and, NKCC2 gene, mutations of,
177 406–408
Nervous system Nocturnal hemodialysis, 719
in hypermagnesemia, 180 Nonatheromatous ischemic heart
sympathetic disease, 572
in extracellular fluid volume Noncompliance issues, in renal
regulation, 73 transplant recipient, 819
potassium balance and, 138 Nondepleteing antibodies, for
Netilmicin, for peritonitis, 747t renal transplant
Neurologic disorder(s), 601–615 recipient, 828
in acute kidney injury, 605 Nonedematous conditions,
in chronic kidney disease, diuretics for, 562–564
604–605 Non-nephrotic proteinuria,
in end-stage renal disease, biopsy in, 39
605–611. See also End- Nonoliguric output, 12
stage renal disease Nonparathyroid endocrinopathy,
(ESRD), neurologic hypercalcemia caused
complication(s) of. by, 171
restless leg syndrome as, 604 Nonsteroidal anti-inflammatory
sexual dysfunction as, drugs (NSAIDs)
613–614 dosage of, 669
uremic brain as, 611 hyperkalemia caused by, 155
uremic encephalopathy as, interstitial nephritis and, 298t,
601–604, 602t 304
diagnosis of, 603 Nontransplant-related surgery/
hepatic insufficiency and, hospitalization, of
603–604 transplant recipient, 848
uremic neuropathy as, Norepinephrine, for sepsis, 767
614–615, 615t Normal anion gap metabolic
Neurologic examination, in acidosis, 118–123, 118t
hypertensive patient, gastrointestinal bicarbonate
451 loss in, 117
Neuropathy hyperkalemic distal renal
metabolic, 615, 615t tubular, 119t, 121, 122t
uremic, 614–615, 615t hypokalemic distal renal
Neuropsychiatric disorders, 8 tubular, 120–121, 122t
Nicardipine progressive kidney disease
doses and responses of, 521t associated with, 117
for hypertensive emergencies, proximal renal tubular,
537t, 542 119–120, 122t
for preeclampsia, 497t treatment of, 133–134
Nifedipine urine in diagnosis of, 117
doses and responses of, 521t Normoalbuminuria, in diabetic
for preeclampsia, 497t nephropathy, 347–348
Nitrates, urinary, 28–29 Normovolemic hyponatremia,
Nitrites, urinary, 28–29 treatment of, 107–108
892 NPHP gene, 429 OKT3, 837
NPHS1 gene, 273 Oliguria, 12
NPHS2 gene, 273–274 Olmesartan, doses and responses
Nuclear imaging. See of, 516t
Scintigraphy. Opioid agonists, hyponatremia
Nutrition, 635–648 caused by, 105
calcium and, 643–644 Optic fundus, examination of, 450
Index
Index
measurement of, in renal Peripheral nerves, restless leg
transplant recipient, syndrome and, 615
819–820 Peritoneal dialysis, 730–752.
Paraneoplastic syndromes, See also Dialysis;
associated with renal Hemodialysis.
cell carcinoma, 377–378, adequacy of, 741
378t arrhythmias and, 573–574
Parasitic disease, 278–279 catheters for, 66–67, 735–737,
filariasis, 279 736f
leishmaniasis, 279 insertion of, 735–737
malaria, 278 removal of, indications for,
schistosomiasis, 279 748–749
trypanosomiasis, 279 choice of modality for, 740
Parathyroid carcinoma, clearance in
hypercalcemia in, 169 factors affecting, 742–743,
Parathyroid hormone (PTH), 742t
621–622 measurement of, 741
dysfunction of, genetic clearance targets in, 741–742
disorders of, 175 complication(s) of
hypercalcemia and, 167, 170 catheter dysfunction as,
hypocalcemia and, 173 735–737
plasma levels of, 622 encapsulating sclerosis as,
primary function of, 621–622 750
Parathyroid hormone–related hernias as, 749
protein (PTHrP), hyperglycemia as, 750
hypercalcemia and, 167, hyperlipidemia as, 750
169 hypernatremia as, 751
Parathyroidectomy, for hypoalbuminemia as, 751
hyperparathyroidism, hyponatremia as, 751
168, 633–634 infectious, 744–749, 745t.
Pauci-immune crescentic See also Peritonitis.
glomerulonephritis, leakage as, 749
246–249 mechanical, 749
Pelvic inflammatory disease, in metabolic, 750–751
urinary tract noninfectious, 749–751
obstruction, 336 weight gain in, 751
Pelvic tumors drug removal by, 666
in urinary tract obstruction, equilibration test in, 734,
336 736f
renal, 386–387 for end-stage renal disease, in
D-Penicillamine, for cystinuria, diabetic patient, 357
401 in poisoning, 797
Penicillin(s) patient outcomes with,
for Amanita poisoning, 774 751–752
for peritonitis, 747t prescription for, 740–744
Percutaneous nephrolithotomy, solutions for, 737–740, 738t
for struvite stones, buffers, 739
375 calcium, 739–740
894 Peritoneal dialysis (Cont.) Phosphate disorder(s)
transport process in, 730–734 hyperphosphatemia as,
changes with time of, 734 181–182. See also
diffusion, 731, 731t Hyperphosphatemia.
fluid absorption, 733 hypophosphatemia as,
fluid removal 182–185. See also
(ultrafiltration), Hypophosphatemia.
Index
Index
hypokalemia as, 781 ethylene glycol, 798–801
hypotension as, 780 extracorporeal techniques for,
infection as, 781 794–797
for anti–glomerular basement intoxications response to,
membrane disease, 782 797–810
for anti–glomerular basement principles of, 790–791, 792t,
membrane 793t
glomerulonephritis, general management of,
245–246 789–790
for cryoglobulinemia, 784 isopropanol, 801–803
for focal segmental lithium, 805–806
glomerulosclerosis, 786 methanol, 801–803
for hemolytic-uremic salicylate, 806–808
syndrome, 785–786 theophylline, 808–809
for HUS/TTP, 290 valproic acid, 809–810
for lupus nephritis, 783–784 Polyarteritis nodosa, 258–259
for pauci-immune crescentic prognosis and treatment
glomerulonephritis, 248 of, 259
for polyarteritis nodosa, 259 renal features of, 258–259
for rapidly progressive Polycystic kidney disease (PKD),
glomerulonephritis, 783 417–427
for renal failure associated autosomal dominant, 417–425
with multiple myeloma, cyst development and
784 growth in, 420
for thrombotic diagnosis of, 420
thrombocytopenic end-stage renal disease in,
purpura, 785–786 423
in poisoning, 797 hematuria in, 421–422
in renal disease, 781–788, 782t hypertension in, 421
in renal transplantation, in pregnancy, 425
786–788 nephrolithiasis in, 423
plasma separation techniques pain in, 421–422
in, 777–778 polycystic liver disease and,
technical considerations in, 424–425
777–781 renal failure in, pathogenesis
venous access in, 778–779 of, 419
Plasmodium falciparum, 278 renal function abnormalities
Plasmodium malariae, 278 in, 420–421
Pneumococcal vaccine, for renal infection in, 422–423
hemodialysis patients, treatment of, novel therapies
720–721 in, 425
Pneumocystosis, post-transplant, vascular manifestations in,
847–848 423–424
Podocyte protein mutations, autosomal recessive, 426–427
273–274 Polycystic liver disease, 424–425
Podocytes, in urine, 37 Polydipsia
Poison(s) primary, 93t, 110–111
acidosis caused by, 125–126 psychogenic, 110–111
896 Polymicrobial peritonitis, 748 urinary indices of, 140–141
Polyomavirus infection, in renal renal loss of, 144–146
transplant recipient, 842 Potassium balance, normal,
Polytetrafluoroethylene (PTFE) 136–138
graft, in hemodialysis, acid-base status and, 137t, 138
705 factors affecting, 137–138, 137t
Polyuria, 109–110 insulin and, 137–138, 137t
Index
Index
treatment of, 496–499 Pressure support ventilation
blood pressure management (PSV), 754
in, 496–497, 497t Proliferative
magnesium and seizure glomerulonephritides,
prophylaxis in, 498–499 malignancy and, 283
novel therapies in, 499 Propranolol, doses and responses
timing of delivery in, 496 of, 519t
Pregnancy Prostaglandins, in extracellular
acute fatty liver of, 501–502 fluid volume regulation,
acute kidney injury in, 208, 74
502–505 Protein(s)
autosomal dominant polycystic amyloid A, 265–266
kidney disease in, 425 Bence Jones, 33
chronic dialysis and, 507–508 dietary, 642
chronic kidney disease in, in chronic kidney disease,
505–510 638t
diabetic nephropathy in, 506 restriction of
diuretics and, 558 in diabetic nephropathy,
hemodynamic and vascular 353
changes of, 487 in optimizing
hemolytic-uremic syndrome renoprotective
in, 503 interventions,
hypertension in, 490–505, 491t 661–662
chronic, 499 in urine. See also Proteinuria.
gestational, 499–500 measurement of, 30–33
management of, 500–501 applications of, 32–33
secondary, 497 techniques of, 30–32
in renal transplant recipient, Tamm-Horsfall, 30–31,
508–510, 509t, 849–850 268–269
management of rejection Protein binding, of drugs,
and, 510 792–793, 792t, 793t
lupus nephritis in, 253, Protein C, activated, 767–768
506–507 Protein stores, assessment of,
mechanism of vasodilation in, 639–641
489–490 Protein:creatinine ratio, 31–32
nephrolithiasis in, 361, Protein-energy malnutrition,
504–505 637–639
obstructive uropathy in, 504–505 Proteinuria, 222–223
physiologic changes of, as risk factor for cardiovascular
487–490 mortality, 658
preeclampsia in, 490–499. as risk factor for renal failure,
See also Preeclampsia. 653
treatment of, 496–499 dose titration for, 662–663
renal adaptation to, 487–489 fixed, 222
respiratory alkalosis of, 489 glomerular, 30, 33
thrombotic thrombocytopenic in acute interstitial nephritis,
purpura in, 503 301
urinary tract infection in, 505 in acute kidney injury, 9–10
898 Proteinuria (Cont.) Pulmonary disease
in autosomal dominant acute kidney injury
polycystic kidney and, 209
disease, 420 in renal transplant recipient,
in diabetes, 359 817–818
in Fanconi syndrome, 393–395 Pure red blood cell aplasia,
in focal segmental recombinant
Index
Index
crescentic, 243–244 Renal. See also Kidney(s).
pauci-immune crescentic, Renal artery(ies), Doppler
246–249 ultrasonography of, 478
plasmapheresis for, 783 Renal artery stenosis
Recirculation atherosclerotic
fractional, calculation of, 712 angioplasty and stent
in dialysate flow, 712 placement for, 484–485
Recombinant erythropoietin progressive, 475
(rHuEPO), 586 renovascular hypertension
adverse effects of, 593–595 and, 472
for anemia, 588–590 clinical presentation of,
initiating doses of, 589 473–475, 473t
for uremic platelet diagnostic imaging of, 55–57
dysfunction, 599 epidemiology of, 471–472
forms of, 588 fibromuscular disease in,
inadequate response to, 471–472
595–598, 596t management of, 479–486
ACE inhibitor use and, progressive, 482–483
597–598 transplant, 833–834, 840
aluminum overload as, 596 unilateral, 480–482
carnitine deficiency as, 597 vs. renovascular hypertension,
infection, inflammation, and 468–469, 470f
malignancy as, 597 Renal azotemia, intrinsic,
iron deficiency as, 596 203–206
secondary acute tubular necrosis and,
hyperparathyroidism as, 204–206, 205t
597 management of, 213–216
intravenous iron therapy with, vascular and tubulointerstitial
592–593 disorders and, 203–204
Recurrent disease, in transplant Renal biopsy. See Biopsy, renal.
recipient, 840–842, 841t Renal cell carcinoma, 377–386
Red blood cell(s) allogeneic transplantation for,
hypochromic, percentage of, 591 386
life span of, in chronic kidney chemotherapy for, 384
disease, 586 clinical and laboratory features
Red blood cell aplasia, pure, of, 377–378
recombinant epidemiology of, 377
erythropoietin causing, FDG-PET scan of, 55
595 immunotherapy for, 384–385
Red blood cell casts, in urine, 37 in acquired cystic disease,
Redistribution (rebound), of 427–428
drugs, 792t, 793–794 in autosomal dominant
Refeeding syndrome, polycystic kidney
hypophosphatemia and, disease, 422
184 in tuberous sclerosis complex,
Referral, for renal 433
transplantation, timing in von Hippel–Lindau
of, 813–814 syndrome, 434
900 Renal cell carcinoma (Cont.) presentations in, 3, 4t
MR imaging of, 54–55 progressive, acidosis of, 117
paraneoplastic syndromes screening for, 32
associated with, Renal dysplasia, 432
377–378, 378t Renal elimination, of toxins,
prognosis of, 379–380 principles and
radiation therapy for, 383 techniques for,
Index
Index
Renal transplantation. See for glomerular hypertension,
Transplantation, renal. 651–652, 652f
Renal tubular acidosis. See for hyperlipidemia, 653–654
Tubular acidosis, renal. for hypertension, 649–650
Renal tubule(s). See Tubule(s), for lipid reduction, 654
renal. for obesity, 654–655
Renal vein thrombosis for proteinuria, 653
diagnostic imaging of, 57 reduction of, 653
transplant, 833–834 for targeted blood pressure,
Renin, regulation of, 140 651
Renin activity, plasma, Renovascular hypertension
459–460 changing demographics and,
Renin inhibitors, 530–531 472–473
Renin-angiotensin system (RAS), clinical features of, 469t,
physiologic and 472–475
functional studies of, clinical manifestations of,
476–477 468
Renin-angiotensin-aldosterone diagnosis of, 475–479
system (RAAS) goals of evaluation in,
ACE inhibitors and, 514 475–476, 476t
blockade of, 662t, 663 noninvasive imaging in,
in extracellular fluid volume 477–479
regulation, 72–73 renal function studies in,
in potassium homeostasis, 477
140 renin-angiotensin system
Renin-dependent hypertension, studies in, 476–477
453–457 management of, 479–486, 480f
Renography endovascular procedures in,
captopril, in renovascular 483–485
hypertension, 478 predictors of benefit
isotopic, in urinary tract regarding, 485–486
obstruction, 340 progressive renal artery
Renoprotection, 649–664 stenosis and, 482–483
clinical management of, surgical, 483
658–664 unilateral renal artery
framework for, 658–659, 658t stenosis and, 480–482
monitoring in, 661–664, 662t pathophysiology of, 468–470,
optimizing response in, 469t
660–661 vs. renal artery stenosis,
primary prevention in, 468–469, 470f
659–660 Replacement fluids, choice of, in
secondary prevention in, plasmapheresis,
660 779–780
pharmacologic approaches to, Respiratory acidosis, 128–130,
655–657 129t
antihypertensive, 655–657 hyperphosphatemia and, 181
diuretic, 657 treatment of, 135
902 Respiratory alkalosis, 129t, Saline diuresis, for
130–131 hypercalcemia, 171
hypophosphatemia and, 184 Salt-losing nephropathy, 101
of pregnancy, 489 Salt-wasting syndrome, 220
treatment of, 135 cerebral, 101
Respiratory disorders, acid-base, Salvage, of immature AV fistulas,
128–131 62
Index
Index
glycemic control in, 768 extracellular fluid volume
hemodynamic support in, depletion and, 76
765–767, 766f in acute kidney injury, 7
hemofiltration in, in chronic kidney disease, 16
768–769 magnesemia loss via, 176
nutritional support in, Skin cancer, in transplant
768 recipient, 845–846
source of infection in, Skin turgor, extracellular fluid
763–764 volume depletion and,
Septic abortion, 502–503 76
Sequestration, extracellular fluid Skinfold thickness, in triceps,
volume depletion and, 639–640
76 SLC3A1 gene, mutations of, 400
Serum amyloid P (SAP), SLC7A9 gene, mutations of, 400
265–266 SLC12A3 gene, mutations
Serum indices, of extracellular of, 408
fluid volume depletion, Slow continuous ultrafiltration
77–78 (SCUF), 218
Sexual dysfunction, in uremia Slow low-efficiency daily
pathogenesis of, 613 dialysis (SLEDD),
treatment of, 614 217–218
Shock Smoking
cardiogenic, 769–771 as cardiovascular risk factor,
clinical features of, 769 583
evaluation of, 769–770 hypertension and, 449
management of, 770–771 Sodium
pathophysiology of, 769 dietary, 642
hypovolemic, 757–763 in chronic kidney disease,
clinical manifestations of, 638t
758–759 fractional excretion of, 78
diagnosis of, 759 definition of, 11
effects of, on renal function, in acute kidney injury, 11
762–763 in hemodialysis, 713–714
etiology of, 758t renal retention of
management of, 759–762, in cirrhosis with ascites,
761t 81–82
pathogenesis of, 758 in congestive heart failure,
septic. See also Sepsis. 79–81
definition of, 763t in nephrotic syndrome,
Shunt nephritis, 277 82–84
Sickle cell anemia, 294–295 Sodium bicarbonate
Sickle cell crisis, 295–296 for hyperkalemia, 162
Sickle cell disease intravenous, for salicylate
clinical manifestations of, poisoning, 807–808
294–295 Sodium deficit, estimation of,
pathogenesis of, 295 107
treatment of, 295–296 Sodium ion channel, epithelial,
Simple cystic disease, 431–432 amiloride-sensitive, 156
904 Sodium status, in optimizing Steroids. See also specific agents.
renoprotective minimal change
interventions, 661 glomerulopathy
Sodium wasting, extracellular resistant to, 229
fluid volume depletion Stones. See Calculi; specific
and, 75 types of stone.
Sodium-loading maneuvers, Strenuous exercise,
Index
Index
Syphilis, 277–278 loop diuretics with, 555
screening for, in kidney donor, mechanism of action of, 550
824t nephrolithiasis and, 369–372
Systemic inflammatory response pharmacokinetics of, 550
syndrome, definition of, potassium-sparing diuretics
763, 763t with, 555
Systemic lupus erythematosus, Thirst
250–256, 251t. See also hyperosmolar-induced, 90–91
Lupus nephritis. plasma osmolality and, 89–90
Systemic sclerosis Thirst threshold, osmotic, 89–90
clinical features of, 288 Thrills, in hypertensive patient,
laboratory findings in, 288 451
pathogenesis of, 288 Thrombectomy
renal involvement in, 288 of arteriovenous fistula, 63
management of, 288 of grafts, 61
Systemic therapy, for renal cell Thrombolysis, for arteriovenous
carcinoma, 384–385 fistula, 63
Systemic vascular resistance Thrombophilia, in renal
(SVR), in pregnancy, transplant recipient, 819
489–490 Thrombosis
Systolic dysfunction, 570 graft, 61
Systolic hypertension, isolated, in thrombotic
440 thrombocytopenic
purpura, 289
recombinant erythropoietin
causing, 594
T renal vein
Tacrolimus diagnostic imaging of, 57
for pregnant transplant transplant, 833–834
recipient, 509t Thrombotic microangiopathy
for renal transplant recipient, in early post-transplant period,
829–830, 829t 837–838
hyperkalemia caused by, malignancy and, 284
155–156 pregnancy and, 503
Takayasu’s arteritis, 261–262 Thrombotic thrombocytopenic
Tamm-Horsfall protein, 30–31, purpura (TTP), 207–208
268–269 clinical features of, 285–286
Targeted agents, for renal cell etiology of, 287–289, 288t
carcinoma, 384 in pregnancy, 503, 504t
T-cell cross-match, positive, in in transplant recipient,
renal transplantation, 840–842, 841t
787–788 laboratory findings in, 286
Telmisartan, doses and responses plasmapheresis for, 785–786
of, 516t postpartum, 208
Temperature, dialysate, 715 prognosis and treatment of,
Temporal arteritis, 261 289–290
Temsirolimus, for renal cell renal involvement in, 286
carcinoma, 386 management of, 290
906 Thrombotic thrombocytopenic malignancies in, 815–816,
purpura (TTP) (Cont.) 816t
shiga-toxin-associated, noncompliance in, 819
285–286 obesity in, 817
management of, 289–290 pulmonary disease in,
thrombosis and fibrin 817–818
deposition in, 289 thrombophilia in, 819
Index
Index
831–832, 831t Trimethaphan, for hypertensive
for autosomal dominant emergencies,
polycystic kidney 537t, 541
disease, 423 Trimethoprim-sulfamethoxazole
for autosomal recessive for cystitis, 324
polycystic kidney for pyelonephritis, 326
disease, 427 for urinary tract infection
for hemolytic-uremic in children, 328
syndrome, 290 recurrent, 324
for lupus nephritis, 253 Trousseau sign, 172
for sickle cell disease and, Trypanosoma brucei, 279
295–296 Trypanosoma gambiense, 279
hypophosphatemia and, 184 Trypanosoma rhodesiense, 279
immunosuppressive agents Trypanosomiasis, 279
used in, 827–831, 829t TSC1 gene, 432–433
in diabetic patient, 357 TSC2 gene, 432–433
living donor issues in, Tuberculosis
820–826. See also Living in renal transplant recipient,
kidney donor. 815
outcomes of, 196–197 screening for, in kidney donor,
plasmapheresis in, 786–788 824t
positive T-cell cross-match Tuberous sclerosis complex,
and, 787–788 432–434
pregnancy after, 508–510, Tubular acidosis, renal
509t, 849–850 distal
management of rejection hyperkalemic, 119t, 121,
and, 510 122t
procedure for, 827 hypokalemic, 120–121, 122t
recipient issues in, nephrolithiasis and, 370
evaluation of, 813–820. potassium excretion and, 155
See also Transplant proximal, 119–120, 122t
recipient. Tubule(s), renal
timing of referral for, hypomagnesemia and, 177
813–814 inherited disorder(s) of,
Transport 391–416. See also
peritoneal, 730–734 specific disorders.
changes with time of, 734 diabetes insipidus, 415–416
diffusion, 731, 731t Fanconi syndrome, 393–399.
fluid absorption, 733 See also Fanconi
fluid removal syndrome.
(ultrafiltration), hyperkalemic hypertensive,
732–733, 732t 414
potassium, mechanisms of, hyperkalemic hypotensive,
136–137 413
Transport disorder(s) hypokalemic hypertensive,
amino acid, 399–402, 399t 409–413, 411t
glucose, 405 hypokalemic hypotensive,
phosphate, 402–405 406–409, 407t
908 Tubule(s), renal (Cont.) in hydronephrosis, 46, 48
in amino acid transport, in renal cancer, 54
399–402, 399t in renal infection, 50
in glucose transport, 405 of renal cysts, 51–52
in phosphate transport, of renal vein thrombosis, 57
402–405 of urinary tract obstruction,
Tubuloglomerular feedback, 339
Index
Index
idiopathic, 372–373 diagnosis of, 321–323
natural history of, 372 history and physical
treatment of, 374 examination in, 321–322
Urinalysis, 27–38 radiologic and urologic,
bilirubin and, 28 322–323
color in, 27 urine tests in, 322
formed elements in, 33–38 epidemiology of, 317, 318f
casts as, 37 frequency of, 317
cells as, 37 host factors influencing,
crystals as, 38 315–316
fats as, 37 in autosomal dominant
hematuria and, 34–36, 35t polycystic kidney
leukocyturia and, 36, 36t disease, 422–423
microorganisms as, 38 in diabetic nephropathy,
microscopy of, 33–34 358–359
glucose in, 29 in pregnancy, 505
hemoglobin in, 29–30 pathogenesis of, 315
in acute kidney injury, pyelonephritis and. See also
9–10, 9t Pyelonephritis.
in chronic kidney disease, 17 acute, 320
in urinary tract infection, chronic, 320–321
313–314 recurrent
ketones in, 29 in young women, 324–325
leukocyte esterase and, 28–29 treatment of, 324–325
myoglobin in, 29–30 screening for, in kidney donor,
nitrites and, 28–29 824t
protein measurement in, treatment of, 323–330
30–33 in catheter-associated
applications of, 32–33 infection, 329–330
techniques of, 30–32 in children, 328
urobilinogen and, 28 in complicated infection,
Urinary dipstick test, 27, 30–31 328–329
for urinary tract infection, 322 in men, 327
Urinary free metanephrines, 454 in recurrent infection,
Urinary indices 324–325
of extracellular fluid volume in uncomplicated cystitis
depletion, 78 in older women, 325–326
of potassium excretion, 140–141 in young women, 323–324
Urinary pH, 27–28 in uncomplicated
manipulation of, in renal pyelonephritis, 326
elimination of toxins, urinalysis in, 313–314
790–791 urine culture in, 313
Urinary tract infection Urinary tract obstruction,
acute, 319–320 332–344
bacteriology of, 313–317 acquired causes of, 333–337,
etiologic agents in, 314 334t
candidal, treatment of, 330 extrinsic, 334t, 336–337
chronic, 320–321 intrinsic, 334t, 335–336
910 Urinary tract obstruction (Cont.) Urobilinogen, in urine, 28
clinical aspects of, 337–338 Uroepithelial tumors, 386
congenital causes of, 332–333, Urography
333t CT, 43–44
diagnosis of, 338–341 intravenous. See Intravenous
history and physical urography (IVU).
examination in, 338 MR, of renal calculi, 49
Index
Index
Vasopressors, for hypovolemic drugs, 792t, 793
shock, 762 Volume overload, in refractory
Vena caval involvement, in renal hypertension, 535
cell carcinoma, Volume receptors, in
nephrectomy and, 383 extracellular fluid
Venous catheters, for volume control, 72
hemodialysis, 706–707 Volume status
Ventilation, mechanical, modes in acute kidney injury, 7–8
of, 753–754 in chronic kidney disease, 16
Ventricular failure, diuretics for, in peritoneal dialysis, 743
559, 560 Von Hippel–Lindau syndrome,
Ventricular hypertrophy, left, 434–435
568–569, 569t, 573
antihypertensive therapy and,
445
electrocardiography in, 445 W
Verapamil WAGR syndrome, 388
doses and responses of, Wasting disorders
521t magnesium, renal, 177–178
for preeclampsia, 497t inherited, 178
renal effects of, 523t sodium, extracellular fluid
Vesicoureteral reflux, volume depletion and,
315–316 75
Vincristine, hyponatremia Water diuresis, 110
caused by, 105 Water metabolism, 87–111
Viral infections hypernatremia and, 90–98.
glomerular disease in, See also Hypernatremia.
279–280 hypo-osmolar disorders in,
in hemodialysis, 720 98–109. See also
Vitamin(s), 645–646 Hyponatremia.
dietary, in chronic kidney polydipsia in, 110–111
disease, 638t polyuria in, 109–110
Vitamin A intoxication, Water purification, in
hypercalcemia caused hemodialysis, 710
by, 170 Water softeners, 710
Vitamin B deficiency, diuretic- Water treatment systems, for
related, 558–559 hemodialysis, 710
Vitamin D, 620–621 Waxy casts, 37
for osteoporosis, 844 Wegener’s granulomatosis,
Vitamin D deficiency 209, 269
hypocalcemia and, 173–174 in transplant recipient,
hypophosphatemia and, 841t
184 Weight
nutritional, 621 body, in extracellular fluid
Vitamin D intoxication, volume depletion,
hypercalcemia caused 76
by, 171 dry, definition of, 715–716
912 Weight gain, in peritoneal X
dialysis, 751 Xanthogranulomatous
White coat hypertension, pyelonephritis, 330–331
535 X-linked recessive
Wilms tumor, 388–389 hypophosphatemic
WNK1 gene, 414 rickets, 395–396, 403
WNK4 gene, 414 X-linked recessive
Index