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RENAL FAILURE

317

such as furosemide. A markedly diminished FE

urea

cannot

distinguish between a rapidly reversible prerenal azotemia

and more definitive ischemic damage, such as occurs in acute

tubular necrosis. Nonetheless, values below 35% are very

useful in identifying renal hypoperfusion in patients taking

diuretics, as is most often the case in decompensated conges-

tive heart failure. Osmotic diuresis resulting from adminis-

tration of mannitol or acetazolamide or from diabetic

ketoacidosis increases the fractional excretion of urea despite

the existence of volume depletion.

Twenty-four hour urine collections for determinations of

creatinine, urea, and protein are the most reliable means of

assessing renal function and determining nitrogen balance.

Creatinine or urea clearance can be calculated as follows:

Creatinine clearance (mL/min)

Urea clearance (mL/min)

When serum levels of creatinine or urea are increasing

rapidly, the mean of the pre- and postcollection values is

used in the denominator. Timed collections less than 24 hours

are reasonably accurate for creatinine but are less useful for

assessing proteinuria or urea production.

Modest amounts of proteinuria (<1 g/day) are common in

many forms of acute renal failure, but proteinuria in the

nephrotic range (>3.5 g/day) is most often related to glomeru-

lar disease, except when associated with low-molecular-weight

proteins such as Bence Jones protein in multiple myeloma.

Urine protein electrophoresis performed on a 24-hour urine

collection will distinguish between these two disorders.

6. Urinalysis—Routine urinalysis consists of rapid dipstick

tests and microscopic examination. Dipstick determinations

measure pH and can reveal the presence of hemoglobin

(positive for intact red blood cells, free hemoglobin, and

myoglobin), protein, glucose, and ketones. Microscopic

analysis can suggest infection (white blood cells, white blood

cell casts, and bacteria), nephritis (red and white blood cells,

with or without cellular casts), or nephrosis (granular casts

or oval fat bodies). Red blood cell casts are associated most

commonly with glomerulonephritis but may be seen occa-

sionally with other types of acute glomerular injury such as

cholesterol emboli or with malignant hypertension. White

blood cell casts are seen most often with infectious

pyelonephritis, but when associated with sterile urine, they

may be a sign of immunologically mediated interstitial

nephritis. Tubular epithelial cells can be found with intersti-

tial nephritis or acute tubular necrosis. When associated with

muddy-brown casts, acute tubular necrosis is a more likely

diagnosis. Eosinophiluria, demonstrable on smears of urine

sediment stained with Wright’s or Hansel’s stain, can occur

in drug-induced allergic interstitial nephritis.

The urine dipstick test for protein is most sensitive for

albumin, whereas sulfosalicylic acid added to the urine

causes precipitation of all proteins. When the urine dipstick

is negative or only modestly positive for protein and the sul-

fosalicylic acid precipitation is markedly positive, Bence

Jones proteinuria should be suspected.

Urine culture and Gram staining should be performed on

any urine containing white blood cells. Sterile pyuria is often

a sign of drug-induced interstitial nephritis, but renal tuber-

culosis also should be considered.

7. Assessment of intravascular volume—Central

venous pressure monitoring can be accomplished with sub-

clavian, internal jugular, or femoral catheterization. A low

central venous pressure is most compatible with decreased

intravascular volume; elevated central venous pressure may

be secondary to intravascular expansion or pulmonary

hypertension. When the volume status is unclear in the con-

text of dyspnea, elevated levels of B-type natriuretic peptide

(BNP) may help to identify an element of heart failure that

would support a diagnosis of intravascular volume overload.

Pulmonary artery catheterization is the most reliable means

of assessing optimal fluid status by determination of cardiac

output and left ventricular filling pressure but usually is not

necessary.

8. Renal biopsy—Renal biopsy is most often helpful when

inflammatory nephritis (ie, glomerulonephritis, allergic

interstitial nephritis, etc.) is suspected. However, in patients

suspected of having acute tubular necrosis in whom renal

failure fails to resolve in 6–8 weeks, renal biopsy may be indi-

cated to diagnose irreversible causes of renal failure (eg, cho-

lesterol emboli, cortical necrosis, etc.).

D. Imaging Studies—Renal ultrasound provides an accurate

means of measuring renal size (small kidneys are evidence of

chronic renal disease) and determining the existence of

hydronephrosis. Because potentially nephrotoxic contrast

agents are not required, ultrasound has become the first

choice in the evaluation of ureteral obstruction. In rare

cases, tumor infiltration or retroperitoneal or perirenal

fibrosis may inhibit the expansion of the renal pelvis, thus

yielding a falsely negative result.

The plain abdominal x-ray can demonstrate the presence

of radiopaque kidney stones but is often more valuable in

evaluation of associated disease processes. Intravenous pyel-

ography (IVP) most reliably identifies the site of renal

obstruction, provided that creatinine levels are not exces-

sively elevated (≤4 mg/dL). Retrograde pyelography can image

both the ureters and the bladder. Percutaneous pyelography

can determine the site of renal obstruction when retrograde

pyelography is unsuccessful. CT scanning can evaluate the

site of obstruction (extrinsic versus intrinsic obstruction)

and assess for associated morbidity. Selective renal angiogra-

phy with digital subtraction is the best way to assess the renal

vasculature for stenosis or hemorrhagic leak.

×urine Urea (mg/dL) urine volume (mL/min)

rrum Urea (mg/dL)

×urine Cr (mg/dL) urine volume (mL/min)

seru

mmCr(mg/dL)

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CHAPTER 13

318

The potential for radiocontrast nephrotoxicity always

should be considered. Risk factors include volume deple-

tion, low cardiac output, preexisting renal disease, large

contrast load or multiple exposures to contrast agents, a

history of contrast-induced acute renal failure, multiple

myeloma, and most significantly, advanced diabetic

nephropathy. Patients with diabetic nephropathy and crea-

tinine levels above 4 mg/dL have a 90% probability of

developing some degree of renal dysfunction. In some of

these patients, renal failure may be irreversible. Patients at

increased risk should be well hydrated prior to and imme-

diately after exposure to radiocontrast dyes, and every

effort should be made to limit the amount of contrast

material administered. The newer low-osmolality agents

may be preferable. Other means of minimizing the risk of

contrast-induced renal damage include oral administration

of the antioxidant acetylcysteine and infusion of sodium

bicarbonate.

Radionuclide scanning provides the only noninvasive

means of assessing the relative percentage of renal function

from each kidney (split function studies). Renal blood flow

can be assessed with diethylenetriamine pentaacetic acid

(DTPA), which is excreted by glomerular filtration and may

demonstrate renal vascular stenosis. Repeat examination

after administration of captopril increases this test’s sensitiv-

ity. Gallium scans can identify any type of renal inflamma-

tion and are most valuable in assessing unilateral lesions or

identifying a renal origin of pyuria. Gallium scans also may

be positive in patients with nephrosis. Technetium-99m mer-

captoacetyltriglycine (MAG3) is both filtered and secreted

and is the radionuclide imaging agent of choice for patients

with substantial renal failure.

MRI is not yet widely employed in the evaluation of acute

renal failure, but it may be of value in the diagnosis of renal

vein thrombosis. Gadolinium-enhanced magnetic resonance

angiography (MRA) is an accurate means for assessing renal

artery stenosis without the risks of catheterization or the

contrast material used for percutaneous angiography.

Complications

The complications of acute renal failure are listed in

Table 13–3. Cardiovascular problems are most often due to

fluid overload and electrolyte abnormalities. Pericarditis is

probably the result of retained uremic toxins. Insufficient

erythropoietin may cause decreased red blood cell produc-

tion and anemia, but this mechanism is seen more commonly

in patients with chronic renal failure. In contrast, platelet dys-

function, clinically diagnosed on the basis of prolonged

bleeding time, is a common consequence of acute renal fail-

ure. Infections represent an important cause of morbidity

and death in acute renal failure—especially urinary tract

infections, which are particularly difficult to eradicate

because of inadequate urine concentrations of antibiotics.

Electrolyte and acid-base abnormalities are common, the

most serious being hyperkalemia. Hypoglycemia may result

from decreased renal catabolism of exogenously adminis-

tered insulin. Neurologic abnormalities include somnolence,

coma, and convulsions and are often compelling indications

for initiation of dialysis. GI hemorrhage in acute renal failure

is due to the combination of uremic coagulopathy and gas-

tritis, but in chronic renal failure, arteriovenous malforma-

tions are the most common causes.

Briguori C, Marenzi G: Contrast-induced nephropathy:

Pharmacological prophylaxis. Kidney Int Suppl 2006;100:

S30–8. [PMID: 16612399]

Carvounis CP, Nisar S, Guro-Razuman S: Significance of the

fractional excretion of urea in the differential diagnosis of

acute renal failure. Kidney Int 2002;62:2223–9. [PMID:

12427149]

Goldenberg I, Matetsky S: Nephropathy induced by contrast

media: Pathogenesis, risk factors and preventive strategies. Can

Med Assoc J 2005;172:1461–71. [PMID 15911862]

Hilton R: Acute renal failure. Br Med J 2006;333:786–90. [PMID

17038736]

Lameire N et al: Acute renal failure. Lancet 2005;365:417–30.

[PMID 15680458]

Maisel AS et al : Rapid measurement of B-type natriuretic peptide

in the emergency diagnosis of heart failure. N Engl J Med

2002;347:161–7. [PMID: 12124404]

Merten GJ et al: Prevention of contrast-induced nephropathy with

sodium bicarbonate. JAMA 2004;291:2328–34. [PMID:

15150204]

O’Neill WC, Baumgarten DA: Imaging. Am J Kidney Dis

2003;42:601–4. [PMID: 12955693]

Venkataraman R, Kellum JA: Prevention of acute renal failure.

Chest 2007;131:300–8. [PMID: 17218591]

Fluid overload

Pulmonary edema

Anasarca

Pericarditis

Electrolyte disorders

Hyperkalemia

Hyperphosphatemia

Hypocalcemia (rarely, hypercalcemia)

Hypermagnesemia

Metabolic acidosis

Neurologic disorders

Altered sensorium

Peripheral neuropathy

Seizures

Others

Anorexia, nausea, vomiting

Platelet dysfunction

Anemia

Table 13-3. Acute renal failure—Common complications.

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RENAL FAILURE

319



Prerenal Renal Failure

ESSENTIALS OF DIAGNOSIS



BUN:creatinine ratio >20:1.



Decreased urine output (unless renal losses are primary).



<1% and/or FE

urea

<35%.



Urine sediment may show a few granular casts but

absence of inflammatory cells and red and white blood

cell casts.



No evidence of urinary tract obstruction.

General Considerations

Prerenal azotemia is defined as a state of renal hypoperfu-

sion that can be rapidly reversed with proper management.

All causes of renal hypoperfusion stimulate renal autoregu-

latory mechanisms that function to maintain glomerular

filtration despite decreasing renal blood flow. Central in

this response is the balance between vasoconstricting

angiotensin II and vasodilating renal prostaglandins.

Angiotensin II causes vasoconstriction of both the afferent

and the efferent glomerular arterioles, but resistance in the

efferent arteriole rises more. As a result, glomerular hydro-

static pressure increases, filtration fraction rises, and unfil-

trable serum proteins are concentrated. The resulting

increase in efferent arteriolar oncotic pressure stimulates

water and urea reabsorption from the proximal tubule, thus

decreasing the fractional excretion of urea and increasing

the BUN:creatinine ratio. Furthermore, angiotensin II acts

directly on the proximal tubule to stimulate sodium reab-

sorption, thus decreasing the fractional excretion of

sodium.

The causes of prerenal failure can be classified as shown

in Table 13–4. A decrease in cardiac output can be the result

of primary cardiac disease or insufficient end-diastolic fill-

ing pressures. Volume depletion can occur along obvious

routes such as the GI or urinary system, via surgical drains,

or via more occult mechanisms, including diaphoresis and

retroperitoneal hemorrhage. Redistribution of fluid out of

the intravascular space with insufficient circulating vol-

ume can occur with hypoalbuminemia, vasodilatory shock

with capillary leak (sepsis), or intraabdominal accumula-

tion (eg, peritonitis, ascites, and pancreatitis). Crush injury

with massive tissue damage can cause sufficient localized

edema to result in intravascular depletion. Rarely,

overzealous administration of vasodilators decreases effec-

tive circulating volume and can mimic endogenous causes

of vasodilatory shock.

Intrarenal vasoconstriction can be mediated by several

mechanisms, including an imbalance between vasoconstric-

tive angiotensin II and vasodilating prostaglandins (most

often seen when prostaglandin synthetase inhibitors are

given to patients with nephrosis, cirrhosis, congestive heart

failure, preexisting renal disease, or volume depletion). Renal

artery stenosis, preeclampsia, malignant hypertension, scle-

roderma with severe hypertension and renal failure, and

intravenous cyclosporine may be associated with intrarenal

vasoconstriction mediated by angiotensin II or endothelin.

Finally, obstruction to blood flow to or from the kidney can

result from renal artery stenosis or emboli to the renal arter-

ies, related to valvular heart disease, or in patients with atrial

or ventricular mural thrombi; can occur from valvular heart

disease or arrhythmias; or can occur as a complication of

percutaneous renal angioplasty. Renal vein thrombosis in

adults is seen most often in the context of nephrotic syn-

drome and is considered to be the result of its associated

hypercoagulable state.

Table 13–4. Causes of prerenal renal failure.

Decreased cardiac output

Myocardial infarction

Cardiomyopathy

Pericarditis (constrictive or cardiac tamponade)

Arrhythmias

Valvular dysfunction

Pulmonary embolus

Pulmonary hypertension

Mechanical ventilation (especially with PEEP)

Trauma

Extracellular volume depletion

Dehydration

GI losses (vomiting, NG suction, diarrhea, ostomy output)

Renal losses (diuretics, osmotic diuresis, nonoliguric ATN, adrenal

insufficiency)

Peritoneal losses (surgical drains)

Skin losses (burns, diaphoresis)

Hemorrhage (gastrointestinal, intra- and retroperitoneal)

Redistribution of fluid

Hypoalbuminemia (nephrosis, cirrhosis, malnutrition)

Vasodilatory shock (sepsis, hepatic failure)

Peritonitis

Pancreatitis

Crush injury

Ascites

Vasodilators

Primary intrarenal vasoconstriction

NSAIDs (prostaglandin inhibition)

Hepatorenal syndrome

Preeclampsia

Malignant hypertension

Scleroderma

Cyclosporine

Renovascular obstruction

Renal artery (intravascular stenosis, embolus, laceration, thrombus)

Renal vein (intravascular thrombosis, tumor infiltration, extravascular

compression)

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CHAPTER 13

320

Clinical Features

A. Symptoms and Signs—Patients may present with a his-

tory of excessive fluid losses from diarrhea, high urine out-

put, or sweating, and this may be compounded by low fluid

intake. They may complain of lightheadedness or syncope

and may have tachycardia, hypotension, and diaphoresis.

Often, postural decrease in blood pressure and increase in

heart rate are present in patients with significant volume

depletion. Although prerenal azotemia is associated most

commonly with volume depletion, patients with congestive

heart failure, systemic vasodilation, or hypoalbuminemia

may have substantial peripheral edema yet still have insuffi-

cient cardiac output or intravascular volume to maintain

adequate renal perfusion. Conversely, a severely hypoalbu-

minemic patient who appears euvolemic is likely to be

intravascularly depleted.

Thromboembolic diseases, including renal artery

embolization and renal vein thrombosis, decrease renal per-

fusion but are distinct in their symptomatology and diagnos-

tic workup. Renal artery embolization is most often

associated with cardiac valvular disease and can present with

nausea, vomiting, flank pain, and hematuria.

Renal vein thrombosis in adults is most often associated

with nephrotic syndrome, but it also may result from extrin-

sic compression by tumor. Acute thrombosis can present

with flank pain, hematuria, and increased proteinuria and

may be misdiagnosed as a kidney stone. Chronic thrombosis

may be asymptomatic except for an ipsilateral varicocele

when the thrombosis is in the left renal vein.

B. Laboratory Findings—Considering these varying clini-

cal presentations, evaluation of serum and urine

chemistries is required to confirm the diagnosis. Although

both serum creatinine and urea nitrogen increase, low

tubular flow results in increased reabsorption of urea.

Therefore, the serum BUN:creatinine ratio increases usu-

ally to greater than 20:1, and the FE

urea

is less than 35%.

Because renal tubular function is normal in early prerenal

azotemia, avid sodium reabsorption in the face of volume

depletion causes FE

to be very low, usually less than 1%.

Urinary sediment is usually normal except for the finding

of a few granular casts; white blood cells and red and white

blood cell casts are absent.

C. Imaging Studies—The diagnosis of thromboembolic

disease may be suspected with the demonstration of

decreased function on IVP or absent flow on radionuclide

scan. The definitive diagnosis and a judgment about the

advisability of operation are best arrived at by renal

angiography (the presence of collateral circulation suggests

a better surgical outcome). Renal venography is the most

definitive diagnostic test for renal vein thrombosis but

risks dislodging the thrombus, with resulting pulmonary

embolization. Digital subtraction renal angiography with

evaluation of the venous phase, CT scan, and MRI are safer

alternatives.

Treatment

Prerenal azotemia caused by volume depletion should be

treated by correction of decreased extracellular fluid volume.

Most often, normal saline is given intravenously in an

amount sufficient to replete volume, but in some patients,

blood or colloid solutions are needed. The total volume of

replacement should be estimated in most cases as 10–25% of

extracellular fluid volume (ie, 2–4 L), but the amount actu-

ally given should be carefully titrated by monitoring urine

output, blood pressure, and heart rate. Elderly patients and

those with heart failure should be given fluid cautiously, usu-

ally with central venous pressure or pulmonary artery pres-

sure monitoring. Fluid replacement also should take into

account continued losses from the GI tract and other sources

of fluid loss.

Prerenal azotemia associated with cardiac failure usually

responds to standard drugs and procedures for improving

cardiac output, including loop diuretics, vasodilators,

inotropic agents, and oxygen. Low-dose dopamine (<5 μg/kg

per minute) has become a popular means of initiating diure-

sis in resistant cases. However, its use is unsupported by large

randomized studies. Potential secondary effects include

tachycardia and ischemia. Heart failure and prerenal

azotemia associated with substantial fluid overload also may

respond to infusions of nesiritide, with or without diuretics.

This approach has shown a remarkable success in allowing

for aggressive diuresis without worsening of renal perfusion.

If diuresis is associated with increasing BUN, ACE inhibitors

may be beneficial in decreasing renal resistance. When suc-

cessful, this approach yields an increase in the fractional

excretion of urea, which can be followed on a daily basis and

used as a guide to further treatment. The management of

pericarditis, arrhythmias, pulmonary emboli, and pul-

monary hypertension is discussed elsewhere. One should

note that positive end-expiratory pressure for treatment of

respiratory failure can spuriously elevate pulmonary wedge

pressure, thus making it a misleading measure of intravascu-

lar volume.

Volume repletion should be tailored to the patient’s car-

diopulmonary reserve. The hypoalbuminemic states associ-

ated with cirrhosis or malnutrition can be corrected with

intravenous albumin, but worsening of associated ascites

may occur in a third of patients. In contrast, albumin infu-

sions are futile in patients with ongoing nephrotic syndrome.

Treatment of vasodilatory shock often requires a combi-

nation of fluids and vasoconstrictors. Crush injury repre-

sents a particular case where intravascular volume depletion

combines with the potential nephrotoxicity of myoglobin to

yield a toxic acute tubular necrosis. Proper prevention of

myoglobin nephrotoxicity can be accomplished with aggres-

sive intravascular volume expansion (see below).

Primary intrarenal vasoconstriction by prostaglandin

synthetase inhibitors reverses spontaneously after cessation

of these drugs. Prevention of hepatorenal syndrome involves

restoration of intravascular volume despite increasing ascites



RENAL FAILURE

321

or edema (see below). Preeclamptic renal failure must be

treated by delivery or termination of pregnancy. Malignant

hypertension and renal crises associated with scleroderma

can be treated successfully with ACE inhibitors. Patients with

refractory hypertension may require nitroprusside, but pro-

longed use of this agent in renal failure may predispose to

thiocyanate toxicity. Intrarenal vasoconstriction resulting

from high doses of intravenous cyclosporine is reversed by

decreasing or discontinuing the drug.

Renal artery stenosis can be treated by percutaneous

angioplasty or surgery. Massive renal artery embolization

resulting from cardiac sources can be managed with anti-

coagulation and thrombolytic therapy but may require

operative management. Renal vein thrombosis is treated

with long-term anticoagulation with heparin and warfarin

but may respond to either intravenous or intraarterial

thrombolytic therapy.

Carvounis CP, Nisar S, Guro-Razuman S: Significance of the frac-

tional excretion of urea in the differential diagnosis of acute

renal failure. Kidney Int 2002;62:2223–9. [PMID: 12427149]

de Denus S, Pharand C, Williamson DR: Brain natriuretic peptide

in the management of heart failure: The versatile neurohor-

mone. Chest 2004;125:652–68. [PMID: 14769750]

Friedrich JO et al: Meta-analysis: Low-dose dopamine increases

urine output but does not prevent renal dysfunction or death.

Ann Intern Med 2005;142:510–24. [PMID 15809463]

Ichai C et al: Comparison of the renal effects of low to high doses

of dopamine and dobutamine in critically ill patients: A single-

blind, randomized study. Crit Care Med 2000;28:921–8. [PMID:

10809260]

Jones D, Bellomo R: Renal-dose dopamine: From hypothesis to

paradigm to dogma to myth and, finally, superstition? J

Intensive Care Med 2005;20:199–211. [PMID: 16061903]

Kaplan AA, Kohn OF: Fractional excretion of urea as a guide to

renal dysfunction. Am J Nephrol 1992;12:49–54. [PMID:

1415365]



Postrenal Renal Failure

ESSENTIALS OF DIAGNOSIS



Dilated renal pelvis on ultrasound.



Enlarged, palpable bladder (if obstruction to bladder

outflow).

General Considerations

Demonstrable changes in renal function occur only if both

kidneys are involved or if there is preexisting kidney disease

involving the contralateral kidney. It is important to keep in

mind that obstruction to urine flow decreases tubular sensi-

tivity to antidiuretic hormone, leading to nephrogenic dia-

betes insipidus. Thus the presence of a high urine volume

does not rule out the possibility of partial obstruction.

Obstruction to urine flow can occur anywhere along the

urinary tract and may be secondary to extrinsic compression

or intrinsic blockage (Table 13–5). Causes include tumors,

stones, blood clots, and sloughed renal papillae—the result

of papillary necrosis, a condition known to occur with anal-

gesic abuse, diabetes, recurrent infections, and sickle cell ane-

mia. Although sloughed renal papillae usually cause

unilateral obstruction, blockage of the bladder neck can

cause bilateral obstruction and acute-onset oliguria. In men,

the most common cause of postrenal renal failure is prosta-

tic hypertrophy.

Clinical Features

A. Symptoms and Signs—Obstruction to urine flow result-

ing in renal failure may be accompanied by symptoms and

signs related to unilateral ureteral obstruction or urethral or

bladder obstruction. Occasionally, obstruction is not associ-

ated with any symptoms or signs.

Acute ureteral obstruction may be painful, with the

patient complaining of severe flank and midback pain, espe-

cially when caused by renal stones or blood clots.

Examination may indicate localized tenderness, especially to

percussion. Urethral obstruction, especially in prostatic

hypertrophy, will cause bladder distention and inability to

urinate. Although urine output is very often low or absent,

partial obstruction may cause renal failure without oliguria

or anuria.

B. Laboratory Findings—Elevated serum creatinine and

BUN are indicative of renal insufficiency, and serum elec-

trolytes reflect the severity of renal failure. In patients with

renal stones or blood clots, hematuria without red blood cell

casts is a prominent feature, but ureteral or urethral obstruc-

tion from extrinsic compression such as tumors will not be

associated with abnormal urinary sediment.

Table 13-5. Causes of postrenal renal failure.

Ureteral obstruction (bilateral or unilateral single kidney)

Extrinsic

Tumors (endometrial, cervix, lymphoma, metastatic)

Retroperitoneal fibrosis or hemorrhage

Accidental surgical ligation

Intrinsic

Stones, blood clots, sloughed papillae (papillary necrosis), tumors

(transitional cell, etc.)

Bladder or urethral obstruction

Prostatic hypertrophy or tumor

Bladder carcinoma

Uterine prolapse

Stones, blood clots, sloughed papillae

Neurogenic bladder (functional or iatrogenic)

Obstructed Foley catheter

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322

C. Imaging Studies—The existence of postrenal obstruc-

tion, regardless of the site or cause, almost always can be

determined by renal ultrasound examination. In rare cases,

however, tumor infiltration of the renal parenchyma or

perirenal fibrosis may inhibit dilation of the renal pelvis and

yield a falsely negative ultrasound examination. Minimal or

absent caliceal dilation also may occur during the first few

hours after an acute obstruction. Radiologic procedures

requiring potentially nephrotoxic radiocontrast agents are

most helpful in determining the site and nature of the

obstruction. IVP is employed most often in the context of

suspected kidney stone, but imaging is poor if serum creati-

nine levels are elevated. Retrograde pyelography performed

through a cystoscope avoids intravenous contrast adminis-

tration and offers a direct view of the bladder and the possi-

bility of a corrective urologic procedure. Percutaneous

pyelography demonstrates the site of obstruction and offers

rapid relief of obstruction if the catheter is left in situ. CT

scans and MRI are most helpful for determining the extrin-

sic or intrinsic nature of the obstruction. Radionuclide scan-

ning can be valuable in cases of suspected obstruction when

dilation of the renal pelvis can be identified, but the severity

of the blockage is in doubt.

Treatment

Acute ureteral obstruction with a kidney stone or sloughed

papillae is most often managed with aggressive hydration

and control of pain. Treatment of other causes of ureteral

obstruction, such as tumors, depends on the location and

extent of obstruction and may require surgical relief of the

obstruction. Percutaneous nephrostomy is a reasonable

alternative for short-term correction of obstruction of the

kidney. Bladder obstruction or dysfunction can be treated

initially with insertion of a Foley catheter, but in some

patients this may be difficult to perform without special

urologic instruments. An infected, obstructed kidney is a

medical emergency that cannot be managed adequately

with antibiotic therapy alone. Rapid relief of obstruction is

essential.

Klahr S: Urinary tract obstruction. Semin Nephrol 2001;21:

133–45. [PMID: 11245776]

O’Neill WC: B-mode sonography in acute renal failure. Nephron

Clin Pract 2006;103:C19–23. [PMID: 16543751]



Intrinsic Renal Failure

Intrinsic renal failure is often a diagnosis of exclusion after

prerenal and postrenal causes have been eliminated or

treated. Cases of intrinsic acute renal failure can be catego-

rized as follows (Table 13–6): (1) those involving the

glomeruli (glomerulonephritis), (2) those involving the

interstitium (interstitial nephritis), (3) those leading to

microcapillary or glomerular occlusion, (4) acute tubular

necrosis, and (5) cortical necrosis.

1. Glomerulonephritis

ESSENTIALS OF DIAGNOSIS



Nephritic urine sediment with red blood cells, white

blood cells, and red blood cell casts.



Proteinuria (variable, sometimes in nephrotic range:

≥ 3.5 g/day).



Kidney size normal or increased; no evidence of

obstruction.



Hypertension (variable).



Evidence for immunologic disease: antinuclear anti-

bodies, antistreptolysin O, cryoglobulins, antineutrophil

cytoplasmic antibodies (ANCAs), anti–glomerular base-

ment membrane (anti-GBM) antibodies, IgA levels,

hepatitis B antigen, hepatitis C antibody, HIV, decreased

C3 and C4.



Renal biopsy to confirm diagnosis.

Table 13–6. Causes of intrinsic acute renal failure.

Acute glomerulonephritis

Postinfectious: streptococcal, bacteria, hepatitis B, HIV, visceral

abscess

Systemic vasculitides: systemic lupus erythematosus,

Wegener’s granulomatosis, polyarteritis nodosa, Henoch-Schönlein

purpura, IgA nephritis, Goodpasture’s syndrome

Membranoproliferative glomerulonephritis

Idiopathic

Acute interstitial nephritis

Drugs: penicillins, NSAIDs, ACE inhibitors, allopurinol, cimetidine, H

blockers, proton pump inhibitors

Infectious: streptococcal infections, diphtheria, leptospirosis

Metabolic: hyperuricemia, nephrocalcinosis

Poisons: ethylene glycol (calcium oxalate)

Autoimmune disease: systemic lupus erythematosus, cryoglobulinemia

Microcapillary/glomerular occlusion

Thrombotic thrombocytopenic purpura, hemolytic uremic syndrome,

disseminated intravascular coagulation, cryoglobulinemia,

cholesterol emboli

Acute tubular necrosis

Drugs: aminoglycosides, cisplatin, amphotericin B

Ischemia

Septic shock

Intratubular obstruction: rhabdomyolysis, hemolysis, multiple

myeloma, uric acid, calcium oxalate

Poisons: radiopaque contrast media, carbon tetrachloride,

ethylene glycol, heavy metals

Cortical necrosis

Key: ACE = angiotensin-converting enzyme; NSAID = nonsteroidal

anti-inflammatory drug



RENAL FAILURE

323

General Considerations

Table 13–6 lists several glomerulonephritides that are most

commonly associated with acute renal failure. Most—

perhaps all—are immunologically mediated as a result of

recent or ongoing infections, systemic vasculitis, or idiosyn-

cratic autoimmune reactions. Histologic evaluation is most

often positive for immune deposits in varying locations

within the glomerular structures. In pauci-immune

glomerulonephritis, such as is found with Wegener’s granu-

lomatosis or polyarteritis, no immune deposits are found,

but the presence of antineutrophil cytoplasmic antibodies

(ANCAs) may stimulate leukocytes to release their enzymes,

thus mediating an intraglomerular inflammatory reaction.

Clinical Features

A. Symptoms and Signs—Patients with acute glomeru-

lonephritis may present with edema (especially in periorbital

distribution), hypertension, fatigue, and possibly pulmonary

congestion. They may note smoky, rust-colored, or grossly

bloody urine. These findings are common to glomerulonephri-

tis owing to any cause. Other clinical features reflect the under-

lying disease causing glomerulonephritis. Postinfectious

glomerulonephritis presents about 10 days after acute infec-

tion, usually a streptococcal pharyngitis or skin infection.

Symptoms and signs of systemic vasculitis are highly variable

and depend on the distribution of involvement and the size of

the vessels involved. They may include arthralgias and arthritis,

fever, rash, myalgias and muscle tenderness, hypertension,

abdominal pain, nausea, vomiting, diarrhea, headache, and

other features that are manifestations of organ system involve-

ment, including the heart, GI tract, kidneys, CNS, peripheral

nerves, lungs, pleura, and pericardium. In some situations, the

clinical presentation may strongly suggest a given diagnosis,

such as one of the pulmonary-renal syndromes.

B. Laboratory Findings—The most compelling finding sug-

gestive of acute glomerulonephritis is the presence of red

blood cell casts in the urine. These casts are the result of leak-

age of red blood cells past damaged glomeruli into the tubu-

lar lumen, and they must be carefully distinguished from

granular pigmented casts. The absence of red blood cell casts

does not rule out the diagnosis of glomerulonephritis, how-

ever, and they are found occasionally in other disorders such

as acute interstitial nephritis and cholesterol emboli. Other

urinary abnormalities include varying degrees of proteinuria

and pyuria in the absence of urinary infection. A history of

symptoms suggestive of systemic vasculitis can be confirmed

by serologic testing, including antinuclear antibodies, anti-

GBM antibodies, IgA levels, antistreptolysin O antibodies,

cryoglobulins, ANCAs, antibodies and markers for hepatitis

B, hepatitis C, and HIV, and decreased levels of the third and

fourth components of complement (C3 and C4).

Since therapy of glomerulonephritis often entails long-

term risk, renal biopsy usually should be performed to

confirm the diagnosis.

Treatment

Most cases of acute glomerulonephritis are treated with

aggressive immunosuppressive medications, including high-

dose corticosteroids and cyclophosphamide. Recent reports

suggest that mycophenolate mofetil may be an effective alter-

native to cyclophosphamide in some cases. Since therapy is

likely to be prolonged, with the possibility of substantial

morbidity, consultation with a nephrologist is strongly sug-

gested prior to initiation of treatment. On the other hand,

poststreptococcal glomerulonephritis is treated with sup-

portive therapy alone, including prevention of fluid overload

and control of hypertension.

Glomerulonephritis associated with infective endocardi-

tis responds to appropriate antibiotics. Goodpasture’s syn-

drome and cryoglobulinemia often require plasma exchange.

ANCA-positive glomerulonephritis commonly requires

treatment with cyclophosphamide. Patients presenting with

dialysis-requiring renal failure also may benefit from plasma

exchange.

Chadban SJ, Atkins RC: Glomerulonephritis. Lancet

2005;365:1797–806. [PMID 15910953]

Kaplan AA: The use of apheresis in immune renal disorders. Ther

Apher Dial 2003;7:165–72. [PMID: 12918939]

2. Acute Interstitial Nephritis

ESSENTIALS OF DIAGNOSIS

Interstitial nephritis:



History of drug sensitivity, infection, or toxin ingestion.



Flank pain (occasionally).



Kidney size normal or increased.

Allergic interstitial nephritis:



Fever, rash, peripheral blood eosinophilia.



Sterile pyuria, hematuria, white blood cell casts, tubular

epithelial cells, eosinophiluria.



Positive renal gallium scan with prolonged renal uptake.

General Considerations

Several drugs are capable of eliciting an autoimmune attack

on the renal interstitium, resulting in allergic interstitial

nephritis (see Table 13–2). Direct invasion by infection is less

common. Acute urate nephropathy results from the

intratubular precipitation of uric acid and is most often asso-

ciated with the chemotherapeutic treatment of large lym-

phomas or leukemias, with serum levels of uric acid often

above 20 mg/dL. The metabolism of ethylene glycol, ingested

accidentally or deliberately, results in calcium oxalate deposi-

tion within the interstitium and may result in irreversible



CHAPTER 13

324

renal damage. Autoimmune diseases such as systemic lupus

erythematosus or cryoglobulinemia may cause a “pure”

interstitial nephritis but more often present with concomi-

tant glomerular disease.

Clinical Features

A. Symptoms and Signs—Drug-induced allergic intersti-

tial nephritis is often associated with a history of drug hyper-

sensitivity and classically presents with a triad of fever, rash,

and peripheral blood eosinophilia. Unfortunately, the triad is

complete in only one-third of patients. The rash is usually

symmetric and widespread, appears suddenly, and is usually

not pruritic. In the case of NSAID toxicity, nephrotic syn-

drome with glomerular involvement may be present in addi-

tion to evidence of interstitial involvement.

B. Laboratory Findings—Further evidence for interstitial

nephritis includes sterile pyuria, white blood cell casts, and

occasionally, eosinophiluria. Hematuria and varying degrees

of proteinuria usually are present as well. Infectious causes of

interstitial nephritis can be identified by blood or urine cul-

tures. Acute urate nephropathy should be anticipated when-

ever aggressive chemotherapy is initiated in a patient with a

large lymphoma or acute leukemia. In these patients, serum

uric acid is often above 20 mg/dL, and urinalysis reveals flat,

rhomboid crystals of uric acid or needle-shaped crystals of

sodium urate. Autoimmune diseases are best identified by

finding serologic evidence of specific diseases.

C. Imaging Studies—A gallium scan positive for prolonged

renal uptake (>72 hours) supports the diagnosis of allergic

interstitial nephritis.

Treatment

Drug-induced acute interstitial nephritis usually reverses

spontaneously after cessation of the offending agent, but

patients may benefit from a course of corticosteroids if renal

failure is severe or prolonged. In anticipation of aggressive

chemotherapy for lymphomas or leukemias, the risks of

acute urate nephropathy can be greatly reduced by pretreat-

ment with allopurinol and forced alkaline diuresis designed

to keep urine pH ≥ 7.0. Alkalinization of the urine can be

accomplished by administration of 5% dextrose in water to

which approximately 100–150 meq/L of sodium bicarbonate

has been added. Acetazolamide may be added to stimulate

bicarbonate excretion.

Infectious causes of interstitial nephritis are treated with

antibiotics selected for urinary tract bacterial pathogens and

adjusted on the basis of urine and blood cultures. Ethylene

glycol-induced renal failure may require hemodialysis.

Baker RJ, Pusey CD: The changing profile of acute tubulointersti-

tial nephritis. Nephrol Dial Transplant 2004;19:8–11. [PMID:

14671029]

Taber SS, Mueller BA: Drug-associated renal dysfunction. Crit

Care Clin 2006;22:357–74. [PMID 16678005]

3. Microcapillary & Glomerular Occlusion

ESSENTIALS OF DIAGNOSIS



Hematuria.



Proteinuria (variable).



Thrombotic thrombocytopenic purpura–hemolytic

uremic syndrome and disseminated intravascular

coagulation: thrombocytopenia and microangiopathic

hemolytic anemia.



Cryoglobulinemia: cryoglobulin present in serum, pur-

pura (variable), and hypertension (variable).



Cholesterol embolization: hypertension, signs of periph-

eral vascular occlusive disease (claudication), skin discol-

oration (livedo reticularis, purple toes), eosinophilia, and

a history of recent intraaortic catheterization.

General Considerations

These disorders have in common obstruction of the various

parts of the renal circulation or glomerular vascular pole.

Thrombotic thrombocytopenic purpura (TTP), hemolytic

uremic syndrome (HUS), and disseminated intravascular

coagulation (DIC) have the potential to deposit thrombi of

fibrin and platelets in the glomerular capillary lumen.

Cryoglobulins can precipitate in glomerular capillaries but

also may cause an immunologically mediated glomeru-

lonephritis. Microscopic cholesterol emboli may occur spon-

taneously in patients with severe atherosclerotic disease but

are seen most often after catheterization of the aorta for diag-

nostic purposes. Cholesterol emboli are of varying size and

may block intrarenal arteries, preglomerular arterioles, or

the vascular pole of the glomerulus.

Clinical Features

A. TTP and HUS—Thrombotic thrombocytopenic purpura

(TTP) and hemolytic uremic syndrome (HUS) can be sus-

pected when severe thrombocytopenia is associated with

microangiopathic hemolytic anemia in the presence of nor-

mal prothrombin time and partial thromboplastin time.

Symptoms include jaundice, renal disease, and varied neuro-

logic manifestations.

B. DIC—Disseminated intravascular coagulation (DIC) is

often associated with sepsis and is diagnosed by a combina-

tion of thrombocytopenia, increased fibrin split products,

elevated

-dimers, and elevated prothrombin time and par-

tial thromboplastin time. Owing to the ongoing coagulopa-

thy, renal biopsies are performed only rarely in these diseases.

C. Cryoglobulinemia—Cryoglobulinemia is often associ-

ated with purpura and hypertension and is confirmed by

identification of serum cryoglobulins. It has now been



RENAL FAILURE

325

established that many cases of cryoglobulinemia are associ-

ated with hepatitis C infection.

D. Cholesterol Embolization—A syndrome of microvascu-

lar embolization with livedo reticularis, purple toes, signs of

peripheral vascular disease, and occasionally eosinophilia

will lead to a suspicion of cholesterol embolization. Renal

biopsy, however, is the only confirmatory test.

Treatment

TTP requires aggressive plasma exchange with fresh-frozen

plasma. HUS may respond to intravenous immune globulin

or plasma exchange. DIC is best treated by management of

the inciting cause. Cryoglobulinemia may respond to

immunosuppressive therapy or plasma exchange. If there is

an associated hepatitis C infection, long-term management

may include interferon. Renal failure associated with choles-

terol embolization is irreversible. However, on occasion,

renal failure from cholesterol emboli may be associated with

an element of acute tubular necrosis owing to vascular occlu-

sion. In these patients, some improvement may occur. On

theoretical grounds, anticoagulation is contraindicated

because it may be a precipitating factor.

Fukumoto Y et al: The incidence and risk factors of cholesterol

embolization syndrome, a complication of cardiac catheteriza-

tion: A prospective study. J Am Coll Cardiol 2003;42:211–6.

[PMID: 12875753]

Gallosi A et al: Extrahepatic manifestations of chronic HCV infec-

tion. J Gastrointest Liver Dis 2007;16:65–73. [PMID: 17410291]

George JN: Clinical practice: Thrombotic thrombocytopenic pur-

pura. N Engl J Med 2006;354:1927–35. [PMID: 6672704]

Guillevin L, Pagnoux C: Indications of plasma exchanges for sys-

temic vasculitides. Ther Apher Dial 2003;7:155–60. [PMID:

12918937]

Kamar N et al: Treatment of hepatitis C-virus-related glomeru-

lonephritis. Kidney Int 2006;69:436–9. [PMID: 16514428]

Meyrier A: Cholesterol crystal embolism: Diagnosis and treatment.

Kidney Int 2006;69:1308–12. [PMID: 16614719]

Rock G: The management of thrombotic thrombocytopenic pur-

pura in 2005. Semin Thromb Hemost 2005;31:709–16. [PMID:

16388422]

4. Acute Tubular Necrosis

ESSENTIALS OF DIAGNOSIS



History of exposure to nephrotoxic drugs or hypotension.



Oliguria in ischemic ATN but absence of oliguria in toxic

ATN.



>1%.



Urinalysis: tubular epithelial cells, red blood cells, and

“muddy brown” casts.

General Considerations

The most common form of hospital-acquired intrinsic acute

renal failure is referred to as acute tubular necrosis (ATN).

This designation is somewhat misleading because in many

cases there is more tubular dysfunction than necrosis. In gen-

eral, the pathogenesis involves direct toxicity to the tubular

epithelium, resulting in inability to reabsorb glomerular fil-

trate properly and massive sodium wasting, intrarenal vaso-

constriction, and tubular blockage with necrotic cellular

debris and proteinaceous material. The most common

causes are ischemia, exogenous toxins including drugs (see

Table 13–2) and radiocontrast agents, and endogenous tox-

ins such as myoglobin, hemoglobin, light chains of

immunoglobulins, or crystals (see Table 13–6). Any cause of

prerenal azotemia (see Table 13–4), if sufficiently severe or

prolonged, can cause ischemic tubular damage and lead to

this disorder. Furthermore, all conditions of renal hypoper-

fusion increase the likelihood of toxicity from exogenous or

endogenous toxins. In many cases, a combination of noxious

stimuli can be identified.

Clinical Features

Ischemic ATN is encountered most often after an identifiable

episode of hemodynamic compromise or after prolonged

ischemia during aortic surgery. The presentation is that of

acute onset of oliguria with an FE

greater than 1% and a

urine rich with cellular and proteinaceous debris, including

red blood cells, white blood cells, tubular epithelial cells, and

“muddy brown” casts. In this setting, correction of identifi-

able prerenal factors and a renal ultrasound examination

excluding obstruction are often sufficient to make the diag-

nosis on clinical grounds, and renal biopsy usually is reserved

for patients in whom renal failure is abnormally prolonged

(6–8 weeks).

ATN from toxic causes is often nonoliguric, and the urine

sediment may be unremarkable. A history of toxin exposure

(eg, aminoglycosides, radiocontrast agents, etc.) and the

exclusion of prerenal and postrenal causes are often suffi-

cient for a clinical diagnosis. Urinalysis with dipstick positive

for blood in the absence of identifiable red blood cells is sug-

gestive of rhabdomyolysis or hemolysis.

Treatment

Although several experimental treatments have been

designed to enhance recovery (eg, antiendothelin antibodies,

ATP, MgCl

, thyroxine, growth factors, etc.), none are cur-

rently applied in clinical practice. Experimentally, infusions

of atrial natriuretic peptide have been shown to increase cre-

atinine clearance and decrease the need for dialysis, but cur-

rently available treatment strategies are limited to prevention

and management. Preventive measures include ensuring ade-

quate hydration when nephrotoxic agents are unavoidable

(eg, radiocontrast agents or necessary nephrotoxic antibi-

otics) and proper dosing of nephrotoxic drugs with special



CHAPTER 13

326

attention to changing renal function and daily measurements

of toxic drug levels. Recent evidence suggests that pretreat-

ment with acetylcysteine or infusions of sodium bicarbonate

may help to prevent contrast-induced nephropathy.

In the early stages of oliguric ATN, a short course of man-

nitol or furosemide may decrease the tendency toward tubu-

lar obstruction. Mannitol has the theoretical advantage of

stimulating an osmotic diuresis originating in the proximal

tubule, with the possibility of increasing tubular flow

throughout the nephron. Unfortunately, when mannitol is

given without resulting diuresis, it may precipitate intravas-

cular volume expansion, which may be poorly tolerated. If

diuresis is not established after 24 hours of treatment with

furosemide or mannitol, further attempts at diuretic therapy

will be futile and potentially harmful.

Birck R et al: Acetylcysteine for prevention of contrast nephropathy:

Meta-analysis. Lancet 2003;362:598–603. [PMID: 12944058]

Gill N et al: Renal failure secondary to acute tubular necrosis:

Epidemiology, diagnosis, and management. Chest

2005;128:2847–63. [PMID: 16236963]

Merten GJ et al: Prevention of contrast-induced nephropathy with

sodium bicarbonate. JAMA 2004;291:2328–34. [PMID:

15150204]

Weisbord SD, Palevsky PM: Radiocontrast-induced acute renal

failure. J Intensive Care Med 2005;20:63–75. [PMID: 15855219]

5. Cortical Necrosis

Cortical necrosis is the result of severe and prolonged renal

hypoperfusion and has been most often associated with the

hemodynamic catastrophes of pregnancy, including eclamp-

sia, abruptio placentae, and postpartum hemorrhage. The

diagnosis is usually suspected when an episode of acute renal

failure fails to resolve in 6–8 weeks. Renal biopsy is often

required for definitive diagnosis. Renal damage is irre-

versible.



Common Syndromes Associated with

Acute Renal Failure

1. Pigment Nephropathy: Rhabdomyolysis

& Hemolysis

ESSENTIALS OF DIAGNOSIS



Urine dipstick positive for heme in the absence of red

blood cells.



Rhabdomyolysis: elevated creatine kinase and aldolase;

decreased BUN:creatinine ratio.



Hemolysis: elevated serum-free hemoglobin, decreased

haptoglobin, elevated lactate dehydrogenase (LDH).

General Considerations

Rhabdomyolysis is commonly associated with acute renal

failure, especially in the context of traumatic crush injury.

Hemolysis is usually more insidious and less likely to cause

renal failure except when severe, such as with major transfu-

sion incompatibilities.

In the case of rhabdomyolysis, intravascular volume deple-

tion promotes intratubular precipitation of myoglobin and is

probably the most important comorbid factor in the initiation

of nephrotoxicity. Hemoglobin-related toxicity seems to be

enhanced by the presence of fragmented red blood cell mem-

branes. Several etiologic factors in the development of rhab-

domyolysis and hemolysis are listed in Table 13–7.

Clinical Features

A. Symptoms and Signs—Patients may note dark-colored

red or brown urine. Symptoms and signs in rhabdomyolysis

may be due to crush injury and other associated trauma and

may be focal or diffuse. However, patients with rhabdomyol-

ysis owing to inflammatory muscle disorders such as

polymyositis may complain of muscle pain, tenderness, and

weakness. Patients with hemolysis-induced renal failure will

have symptoms related to severe anemia. Other clinical find-

ings are due to renal failure and associated complications.

Table 13–7. Causes of pigment nephropathy: hemolysis

and rhabdomyolysis.

Rhabdomyolysis

Physical trauma: crush injury, heat stress, electrocution, exercise,

hypothermia, malignant hyperthermia, neuroleptic malignant syndrome

Anoxic injury: arterial occlusion, seizures, tetanus, compartment

syndrome

Metabolic: hypokalemia, hypophosphatemia, diabetic ketoacidosis,

myxedemia, carnitine deficiency, hereditary muscle enzyme

deficiency

Infections: influenza-like viral infections, gas gangrene, pyomyositis

Inflammation: polymyositis, dermatomyositis

Poisons and toxins: ethanol, amphetamine, cocaine, snake and

spider venom.

Hemolysis

Transfusion reactions

Drug toxicities: quinine sulfate, hydralazine, etc.

Poisons and toxins: benzene, aniline, fava beans, snake and spider

venom, etc.

Mechanical trauma: valvular prosthesis, extracorporeal circulation,

march hemoglobinuria

Enzyme deficiencies: glucose-6-phosphate dehydrogenase deficiency

Osmotic stress: intoxication with hypotonic fluids as seen in drowning,

transuretheral prostatectomy, incorrect priming of extracorporeal

circulation

Infections: malaria

Autoimmune: drugs, systemic lupus erythematosus