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Acute renal failure (acute kidney injury) is a rapid decrease in renal function over days to weeks, causing an accumulation of nitrogenous products in the blood (azotemia). It often results from major trauma, illness, or surgery but is sometimes caused by a rapidly progressive, intrinsic renal disease. Symptoms include anorexia, nausea, and vomiting. Seizures and coma may occur if the condition is untreated. Fluid, electrolyte, and acid-base disorders develop quickly. Diagnosis is based on laboratory tests of renal function, including serum creatinine. Urinary indexes, urinary sediment examination, and often imaging and other tests are needed to determine the cause. Treatment is directed at the cause but also includes fluid and electrolyte management and sometimes dialysis.

In all cases of acute renal failure (ARF), creatinine and urea build up in the blood over several days, and fluid and electrolyte disorders develop. The most serious of these disorders are hyperkalemia and fluid overload (possibly causing pulmonary edema). Phosphate retention leads to hyperphosphatemia. Hypocalcemia is thought to occur because the impaired kidney no longer produces calcitriol and because hyperphosphatemia causes Ca phosphate precipitation in the tissues. Acidosis develops because hydrogen ions cannot be excreted. With significant uremia, coagulation may be impaired, and pericarditis may develop. Urine output varies with the type and cause of ARF.

Etiology

Causes of ARF can be classified as prerenal, renal, or postrenal (see Table 1: Renal Failure: Major Causes of Acute Renal Failure).

Table 1
Major Causes of Acute Renal Failure Cause Examples Prerenal ECF volume depletion Excessive diuresis, hemorrhage, GI losses, loss of intravascular fluid into the extravascular space (due to ascites, peritonitis, pancreatitis, or burns), loss of skin and mucus membranes, renal salt- and water-wasting states Low cardiac output Cardiomyopathy, MI, cardiac tamponade, pulmonary embolism, pulmonary hypertension, positive-pressure mechanical ventilation Low systemic vascular resistance Septic shock, liver failure, antihypertensive drugs Increased renal vascular resistance NSAIDs, cyclosporine Some Trade Names NEORAL SANDIMMUNE Click for Drug Monograph , tacrolimus Some Trade Names PROGRAF Click for Drug Monograph , hypercalcemia, anaphylaxis, anesthetics, renal artery obstruction, renal vein thrombosis, sepsis, hepatorenal syndrome Decreased efferent arteriolar tone (leading to decreased GFR from reduced glomerular transcapillary pressure, especially in patients with bilateral renal artery stenosis) ACE inhibitors or angiotensin II receptor blockers Renal Acute tubular injury Ischemia (prolonged or severe prerenal state): Surgery, hemorrhage, arterial or venous obstruction, NSAIDs, cyclosporine Some Trade Names NEORAL SANDIMMUNE Click for Drug Monograph , tacrolimus Some Trade Names PROGRAF Click for Drug Monograph , amphotericin B Some Trade Names ABELCET AMBISOME AMPHOCIN AMPHOTEC Click for Drug Monograph Toxins: Aminoglycosides, amphotericin B Some Trade Names ABELCET AMBISOME AMPHOCIN AMPHOTEC Click for Drug Monograph , foscarnet Some Trade Names FOSCAVIR Click for Drug Monograph , ethylene glycol, hemoglobin (as in hemoglobinuria), myoglobin (as in myoglobinuria), ifosfamide Some Trade Names IFEX MITOXANA Click for Drug Monograph , heavy metals, methotrexate Some Trade Names RHEUMATREX Click for Drug Monograph , radiopaque contrast agents, streptozotocin Acute glomerulonephritis ANCA-associated: Crescentic glomerulonephritis, polyarteritis nodosa, Wegener's granulomatosis Anti-GBM glomerulonephritis: Goodpasture's syndrome Immune-complex: Lupus glomerulonephritis, postinfectious glomerulonephritis, cryoglobulinemic glomerulonephritis Acute tubulointerstitial nephritis Drug reaction (eg, β-lactams, NSAIDs, sulfonamides, ciprofloxacin Some Trade Names CILOXAN CIPRO Click for Drug Monograph , thiazide diuretics, furosemide Some Trade Names LASIX Click for Drug Monograph , cimetidine Some Trade Names TAGAMET Click for Drug Monograph , phenytoin Some Trade Names DILANTIN Click for Drug Monograph , allopurinol Some Trade Names ZYLOPRIM Click for Drug Monograph ), pyelonephritis, papillary necrosis Acute vascular nephropathy Vasculitis, malignant hypertension, thrombotic microangiopathies, scleroderma, atheroembolism Infiltrative diseases Lymphoma, sarcoidosis, leukemia Postrenal   Tubular precipitation Uric acid (tumor lysis), sulfonamides, triamterene Some Trade Names DYRENIUM Click for Drug Monograph , acyclovir Some Trade Names ZOVIRAX Click for Drug Monograph , indinavir Some Trade Names CRIXIVAN Click for Drug Monograph , methotrexate Some Trade Names RHEUMATREX Click for Drug Monograph , Ca oxalate (ethylene glycol ingestion), myeloma protein, myoglobin* Ureteral obstruction Intrinsic: Calculi, clots, sloughed renal tissue, fungus ball, edema, malignancy, congenital defects Extrinsic: Malignancy, retroperitoneal fibrosis, ureteral trauma during surgery or high impact injury Bladder obstruction Mechanical: Benign prostatic hyperplasia, prostate cancer, bladder cancer, urethral strictures, phimosis, paraphimosis, urethral valves, obstructed indwelling urinary catheter Neurogenic: Anticholinergic drugs, upper or lower motor neuron lesion ANCA = antineutrophil cytoplasmic antibody; GBM = glomerular basement membrane. *Myoglobin also has toxic effects on the kidneys.

Prerenal azotemia is due to inadequate renal perfusion. The main causes are ECF volume depletion and cardiovascular disease. Prerenal conditions cause about 50 to 80% of ARF but do not cause permanent renal damage (and hence are potentially reversible) unless hypoperfusion is severe enough to produce tubular ischemia. Hypoperfusion of an otherwise functioning kidney leads to enhanced reabsorption of Na and water, resulting in oliguria with high urine osmolality and low urine Na.

Renal causes of ARF involve intrinsic renal disease or damage. Renal causes are responsible for about 10 to 40% of cases. Overall, the most common causes are prolonged renal ischemia and nephrotoxins (including IV use of iodinated radiopaque contrast agents—see Tubulointerstitial Diseases: Contrast Nephropathy). Disorders may involve the glomeruli, tubules, or interstitium. Glomerular disease reduces GFR and increases glomerular capillary permeability to proteins; it may be inflammatory (glomerulonephritis) or the result of vascular damage from ischemia or vasculitis. Tubules also may be damaged by ischemia and may become obstructed by cellular debris, protein or crystal deposition, and cellular or interstitial edema. Tubular damage impairs reabsorption of Na, so urinary Na tends to be elevated, which is helpful diagnostically. Interstitial inflammation (nephritis) usually involves an immunologic or allergic phenomenon. These mechanisms of tubular damage are complex and interdependent, rendering the previously popular term acute tubular necrosis an inadequate description.

Postrenal azotemia (obstructive nephropathy—see also Obstructive Uropathy) is due to various types of obstruction in the voiding and collecting parts of the urinary system and is responsible for about 5 to 10% of cases. Obstruction can also occur within the tubules when crystalline or proteinaceous material precipitates. This form of renal failure is often grouped with postrenal failure because the mechanism is obstructive. Obstructed ultrafiltrate flow in tubules or more distally increases pressure in the urinary space of the glomerulus, reducing GFR. Obstruction also affects renal blood flow, initially increasing the flow and pressure in the glomerular capillary by reducing afferent arteriolar resistance. However, within 3 to 4 h, the renal blood flow is reduced, and by 24 h, it has fallen to < 50% of normal because of increased resistance of renal vasculature. Renovascular resistance may take up to a week to return to normal after relief of a 24-h obstruction. To produce significant azotemia, obstruction at the level of the ureter requires involvement of both ureters unless the patient has only a single functioning kidney. Bladder outlet obstruction is probably the most common cause of sudden, and often total, cessation of urinary output in men.

Urine output: Prerenal causes typically present with oliguria, not anuria. Anuria usually occurs only in obstructive uropathy or, less commonly, in bilateral renal artery occlusion, acute cortical necrosis, or rapidly progressive glomerulonephritis.

A relatively preserved urine output of 1 to 2.4 L/day is initially present in most renal causes. In acute tubular injury, output may have 3 phases.

• The prodromal phase,with usually normal urine output, varies in duration depending on causative factors (eg, the amount of toxin ingested, the duration and severity of hypotension).
• The oliguric phase, with output typically between 50 and 400 mL/day, lasts an average of 10 to 14 days but varies from 1 day to 8 wk. However, many patients are never oliguric. Nonoliguric patients have lower mortality and morbidity and less need for dialysis.
• In the postoliguric phase, urine output gradually returns to normal, but serum creatinine and urea levels may not fall for several more days. Tubular dysfunction may persist and is manifested by Na wasting, polyuria (possibly massive) unresponsive to vasopressin, or hyperchloremic metabolic acidosis.

Symptoms and Signs

Initially, weight gain and peripheral edema may be the only findings. Often, predominant symptoms are those of the underlying illness or those caused by the surgical complication that precipitated renal deterioration. Later, as nitrogenous products accumulate, symptoms of uremia may develop, including anorexia, nausea and vomiting, weakness, myoclonic jerks, seizures, confusion, and coma; asterixis and hyperreflexia may be present on examination. Chest pain (typically worse with inspiration or when recumbent), a pericardial friction rub, and findings of pericardial tamponade may occur if uremic pericarditis is present. Fluid accumulation in the lungs may cause dyspnea and crackles on auscultation.

Other findings depend on the cause. Urine may be cola-colored in glomerulonephritis or myoglobinuria. A palpable bladder may be present with outlet obstruction.

Diagnosis

• Serum creatinine
• Urinary sediment
• Urinary diagnostic indices
• Postvoid residual bladder volume if postrenal cause suspected

ARF is suspected when urine output falls or serum BUN and creatinine rise. Evaluation should determine the presence and type of ARF and seek a cause. Blood tests generally include CBC, BUN, creatinine, and electrolytes (including Ca and phosphate). Urine tests include Na and creatinine concentration and microscopic analysis of sediment. Early detection and treatment increase the chances of reversing renal failure.

A progressive daily rise in serum creatinine is diagnostic of ARF. Serum creatinine can increase by as much as 2 mg/dL/day (180 μmol/L) depending on the amount of creatinine produced (which varies with lean body mass) and total body water. A rise of > 2 mg/dL/day suggests overproduction due to rhabdomyolysis.

Urea nitrogen may increase by 10 to 20 mg/dL/day (3.6 to 7.1 mmol urea/L), but BUN may be misleading because it is frequently elevated in response to increased protein catabolism resulting from surgery, trauma, corticosteroids, burns, transfusion reactions, parenteral nutrition or GI or internal bleeding.

When creatinine is rising, 24-h urine collection for creatinine clearance and the various formulas used to calculate creatinine clearance from serum creatinine are inaccurate and should not be used in estimating GFR, because the rise in serum creatinine concentration is a delayed function of GFR decline.

Other laboratory findings are progressive acidosis, hyperkalemia, hyponatremia, and anemia. Acidosis is ordinarily moderate, with a plasma HCO₃ content of 15 to 20 mmol/L. Serum K concentration increases slowly, but when catabolism is markedly accelerated, it may rise by 1 to 2 mmol/L/day. Hyponatremia usually is moderate (serum Na, 125 to 135 mmol/L) and correlates with a surplus of water. Normochromic-normocytic anemia with an Hct of 25 to 30 % is typical.

Hypocalcemia is common and may be profound in patients with myoglobinuric ARF, apparently due to the combined effects of Ca deposition in necrotic muscle, reduced calcitriol production, and resistance of bone to parathyroid hormone (PTH). During recovery from ARF, hypercalcemia may supervene as renal calcitriol production increases, the bone becomes responsive to PTH, and Ca deposits are mobilized from damaged tissue.

Cause: Immediately reversible prerenal or postrenal causes must be excluded first. ECF volume depletion and obstruction are considered in all patients. The drug history must be accurately reviewed and all potentially renal toxic drugs stopped. Urinary diagnostic indexes (see Table 2: Renal Failure: Urinary Diagnostic Indices in Prerenal Azotemia and Acute Tubular Injury) are helpful in distinguishing prerenal azotemia from acute tubular injury, which are the most common causes of ARF in hospitalized patients.

Table 2
Urinary Diagnostic Indices in Prerenal Azotemia and Acute Tubular Injury Index Prerenal Tubular Injury U/P osmolality > 1.5 1–1.5 Urine Na (mmol/L) < 10 > 40 Fractional excretion of Na (FENa)* < 1 % > 1 % Renal failure index† < 1 > 2 BUN/creatinine ratio > 20 < 10 *U/P Na ÷ U/P creatinine. †Urine Na ÷ U/P creatinine ratio. AGN = acute glomerulonephritis; U/P = urine-to-plasma ratio. Adapted from Miller TR, et al: “Urinary diagnostic indices in acute renal failure.” Annals of Internal Medicine 89(1):47–50, 1978; used with permission of the American College of Physicians and the author.

Prerenal causes are often apparent clinically. If so, correction of an underlying hemodynamic abnormality (eg, with volume infusion) should be attempted. Abatement of ARF confirms a prerenal cause.

Postrenal causes should be sought in most cases of acute renal failure. Immediately after the patient voids, a urethral catheter is placed or bedside ultrasonography is used to determine the residual urine in the bladder. A postvoid residual urine volume > 200 mL suggests bladder outlet obstruction, although detrusor muscle weakness and neurogenic bladder may also cause residual volume of this amount. The catheter may be kept in for the first day to monitor hourly output but is removed once oliguria is confirmed (if bladder outlet obstruction is not present) to decrease risk of infection. Renal ultrasonography is then done to diagnose more proximal obstruction. However, sensitivity for obstruction is only 80 to 85% when ultrasonography is used because the collecting system is not always dilated, especially when the condition is acute, an intrarenal pelvis is present, the ureter is encased (eg, in retroperitoneal fibrosis or neoplasm), or the patient has concomitant hypovolemia. If obstruction is strongly suspected, CT can establish the site of obstruction and guide therapy.

The urinary sediment may provide etiologic clues. Granular casts and cells occur in prerenal azotemia and sometimes in obstructive uropathy. With renal tubular injury, the sediment characteristically contains tubular cells, tubular cell casts, and many brown-pigmented granular casts. Urinary eosinophils suggest allergic tubulointerstitial nephritis. RBC casts indicate glomerulonephritis or vasculitis.

Renal causes are sometimes suggested by clinical findings. Patients with glomerulonephritis (see Glomerular Diseases) often have edema, marked proteinuria (nephrotic syndrome), or signs of arteritis in the skin and retina, often without a history of intrinsic renal disease. Hemoptysis suggests Wegener's granulomatosis or Goodpasture's syndrome; certain rashes (eg, erythema nodosum, cutaneous vasculitis, discoid lupus) suggest polyarteritis, cryoglobulinemia, SLE, or Henoch-Schönlein purpura. Tubulointerstitial nephritis and drug allergy are suggested by a history of drug ingestion and a maculopapular or purpuric rash.

To further differentiate renal causes, antistreptolysin-O and complement titers, antinuclear antibodies, and antineutrophil cytoplasmic antibodies are determined. Renal biopsy may be done if the diagnosis remains elusive (see Table 3: Renal Failure: Causes of Acute Renal Failure Based on Laboratory Findings).

Table 3
Causes of Acute Renal Failure Based on Laboratory Findings Blood Test Finding Possible Diagnoses Anti–glomerular basement membrane antibodies Positive Goodpasture's syndrome Antineutrophil cytoplasmic antibodies Positive Small-vessel vasculitis (Wegener's granulomatosis or polyarteritis nodosa) Antinuclear antibodies or anti- antibodies to double-stranded DNA Positive SLE Antistreptolysin-O or antibodies to streptokinase Some Trade Names STREPTASE or hyaluronidase Positive Poststreptococcal glomerulonephritis CK or myoglobin level Markedly Elevated Rhabdomyolysis Complement titers Low Postinfectious glomerulonephritis, SLE, subacute bacterial endocarditis, cholesterol embolization Protein electrophoresis (serum) Monoclonal spike Multiple myeloma Uric acid level Elevated Cancer or tumor lysis syndrome (leading to uric acid crystals) Prerenal acute renal failure

Imaging: In addition to renal ultrasonography, other imaging tests are occasionally of use. In evaluating for ureteral obstruction, a noncontrast CT scan is preferred over antegrade and retrograde urography. In addition to its ability to delineate soft-tissue structures and Ca-containing calculi, CT can detect nonradiopaque calculi.

Contrast agents should be avoided if possible. However, renal arteriography or venography may sometimes be indicated if vascular causes are suggested clinically. Magnetic resonance angiography was increasingly being used for diagnosing renal artery stenosis as well as thrombosis of both arteries and veins because MRI used gadolinium, which was thought to be safer than the iodinated contrast agents used in angiography and contrast-enhanced CT. However, recent evidence suggests that gadolinium may be involved in the pathogenesis of nephrogenic systemic fibrosis, a serious complication that occurs only in patients with renal failure. Thus, many experts recommend avoiding gadolinium in patients with renal failure.

Kidney size, as determined with imaging tests, is helpful to know, because a normal or enlarged kidney favors reversibility, whereas a small kidney suggests chronic renal insufficiency.

Prognosis

Although many causes are reversible if diagnosed and treated early, the overall survival rate remains about 50% because many patients with ARF have significant underlying disorders (eg, sepsis, respiratory failure). Death is usually the result of these disorders rather than the renal failure itself. Most survivors have adequate kidney function. About 10% require dialysis or transplant—half right away and the others as renal function slowly deteriorates.

Treatment

• Immediate treatment of pulmonary edema and hyperkalemia
• Dialysis as needed to control hyperkalemia, pulmonary edema, metabolic acidosis, and uremic symptoms
• Adjustment of drug regimen
• Usually restriction of water, Na, and K intake, but provision of adequate protein
• Possibly phosphate binders and Na polystyrene sulfonate

Emergency treatment: Life-threatening complications are addressed, preferably in a critical care unit. Pulmonary edema (see Heart Failure: Pulmonary Edema) is treated with O₂, IV vasodilators (eg, nitroglycerin Some Trade Names
NITRO-BID
NITRO-DUR
NITROL
NITROQUICK
Click for Drug Monograph
), and diuretics (often ineffective in ARF). Hyperkalemia (see Fluid and Electrolyte Metabolism: Hyperkalemia) is treated as needed with IV infusion of 10% Ca gluconate, 10 mL; dextrose, 50 g; and insulin Some Trade Names
HUMULIN
NOVOLIN
Click for Drug Monograph
, 5 to 10 units. These drugs do not reduce total body K, so further (but slower acting) treatment with oral or rectal Na polystyrene sulfonate 30 g is begun. Although correction of an anion gap metabolic acidosis with NaHCO₃ is controversial, correction of the nonanion gap portion of severe metabolic acidosis (pH < 7.20) is less controversial. The nonanion gap portion may be treated with IV NaHCO₃ in the form of a slow infusion (≤ 150 mEq NaHCO₃ in 1 L of 5% D/W at a rate of 50 to 100 mL/h). The nonanion gap portion of metabolic acidosis is determined by calculating the increase in anion gap above normal and then subtracting this number from the decrease in HCO₃ from 24 mmol/L. HCO₃ is given to raise the serum HCO₃ by this difference. Because variations in body buffer systems and the rate of acid production are hard to predict, calculating the amount of HCO₃ needed to achieve a full correction is usually not recommended. Instead, HCO₃ is given via continuous infusion and the anion gap is monitored serially.

Hemodialysis or hemofiltration (see Renal Replacement Therapy: Hemodialysis; see Renal Replacement Therapy: Continuous Hemofiltration and Hemodialysis) is initiated when

• Severe electrolyte abnormalities cannot otherwise be controlled (for example K > 6.0)
• Pulmonary edema persists despite drug treatment
• Metabolic acidosis is unresponsive to drug treatment
• Uremic symptoms occur (eg, vomiting thought to be due to uremia, asterixis, encephalopathy, pericarditis, or seizures)

BUN and creatinine levels are probably not the best guides for initiating dialysis in ARF. In asymptomatic patients who are not seriously ill, particularly those in whom return of renal function is considered likely, dialysis can be deferred until symptoms occur, thus avoiding placement of a central venous catheter with its attendant complications.

General measures: Nephrotoxic drugs are stopped, and all drugs excreted by the kidneys (eg, digoxin Some Trade Names
DIGITEK
LANOXIN
Click for Drug Monograph
, some antibiotics) are adjusted; serum levels are useful.

Daily water intake is restricted to a volume equal to the previous day's urine output plus measured extrarenal losses (eg, vomitus) plus 500 to 1000 mL/day for insensible loss. Water intake can be further restricted for hyponatremia or increased for hypernatremia. Although weight gain indicates excess fluid, water intake is not decreased if serum Na remains normal; instead, dietary Na is restricted.

Na and K intake is minimized except in patients with prior deficiencies or GI losses. An adequate diet should be provided, including daily protein intake of about 0.8 to 1 g/kg. If oral or enteral nutrition is impossible, parenteral nutrition is used, but in ARF, risks of fluid overload, hyperosmolality, and infection are increased by IV nutrition. Ca salts (carbonate, acetate) or synthetic non-Ca—containing phosphate binders before meals help maintain serum phosphate at < 5 mg/dL (< 1.78 mmol/L). To help maintain serum K at < 6 mmol/L in the absence of dialysis, a cation-exchange resin, Na polystyrene sulfonate, is given 15 to 60 g po or rectally 1 to 4 times/day as a suspension in water or in a syrup (eg, 70% sorbitol). An indwelling bladder catheter is rarely needed and should be used only when necessary because of an increased risk of UTI and urosepsis.

In many patients, a brisk and even dramatic diuresis after relief of obstruction is a physiologic response to the expansion of ECF during obstruction and does not compromise volume status. However, polyuria accompanied by the excretion of large amounts of Na, K, Mg, and other solutes may cause hypokalemia, hyponatremia, hypernatremia, hypomagnesemia, or marked contraction of ECF volume with peripheral vascular collapse. In this postoliguric phase, close attention to fluid and electrolyte balance is mandatory. Overzealous administration of salt and water after relief of obstruction can prolong diuresis. When postoliguric diuresis occurs, replacement of urine output with 0.45% saline at about 75% of urine output prevents volume depletion and the tendency for excessive free water loss while allowing the body to eliminate excessive volume if this is the cause of the polyuria.

Prevention

ARF can often be prevented by maintaining normal fluid balance, blood volume, and BP in patients with trauma, burns, or major hemorrhage and in those undergoing major surgery. Infusion of isotonic saline and blood may be helpful. If additional BP support is required, at-risk groups (eg, the elderly and those with preexisting renal insufficiency, volume depletion, diabetes, or heart failure). If contrast agents are necessary, risk can be lowered by minimizing volume of IV contrast agent, using nonionic and low osmolal or iso-osmolal contrast agents, avoiding NSAIDs, and pretreating with normal saline at 1 mL/kg/h IV for 12 h before the test. Isotonic NaHCO₃ has been used successfully instead of normal saline in some patients. However, further study is needed to confirm this finding. N- acetylcysteine Some Trade Names
MUCOMYST
Click for Drug Monograph
(600 mg po bid the day before and the day of IV contrast administration) has been used to prevent contrast nephropathy, but reports are conflicting as to its efficacy.

Before cytolytic therapy is initiated in patients with certain neoplastic diseases (eg, lymphoma, leukemia), treatment with allopurinol Some Trade Names
ZYLOPRIM
Click for Drug Monograph
should be considered along with increasing urine flow by increasing oral or IV fluids to reduce urate crystalluria. Making the urine more alkaline (by giving oral or IV NaHCO₃ or acetazolamide Some Trade Names
DIAMOX
Click for Drug Monograph
) has been recommended by some but is controversial since it may also induce urinary Ca phosphate precipitation and crystalluria, which may cause ARF.

The renal vasculature is very sensitive to endothelin, a potent vasoconstrictor that reduces renal blood flow and GFR. Endothelin is implicated in progressive renal damage, and endothelin receptor antagonists have successfully slowed or even halted experimental renal disease. Antiendothelin antibodies and endothelin-receptor antagonists are being studied to protect the kidney against ischemic ARF.

Last full review/revision December 2007 by James I. McMillan, MD

Content last modified December 2007