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Table of Contents

Reviewed July 14, 2004

Joseph V.
Nally, Jr., MD

Department of
Nephrology and
Hypertension

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Definition

Prevalence

Pathophysiology

Special
Risk Groups

Diagnosis

Therapy

Outcomes

Preventing ARF

References

Acute renal failure (ARF) is characterized by azotemia that progresses rapidly over several hours or days. It may or may not be accompanied by oliguria.

Early recognition of ARF is critical. Because renal failure is often asymptomatic, it must be detected by carefully tracking the serum creatinine level. Serum creatinine measurement is more specific than measurement of blood urea nitrogen, which may become elevated for a variety of reasons, including catabolic states, fever, and medications.

The earliest manifestations of ARF may be subtle. Losing the function of one half of the nephron mass (1 million glomeruli) will cause creatinine levels to rise from about 0.7 mg/dL up to only about 1.4 mg/dL. In general, the threshold used to identify ARF is a rise of serum creatinine level more than or equal to 1.0 mg/dL, but smaller elevations should be taken as early signs of trouble.

ARF is common, with a reported incidence of 2% to 5% of all patients admitted to general medical-surgical hospitals. Furthermore, approximately half of patients who develop ARF die; survivors face marked increases in morbidity and prolonged hospitalization.

The high frequency of occurrence and substantial morbidity and mortality of ARF demand a logical approach to its prevention and early diagnosis as well as prompt recognition and management of its complications.

Once ARF is discovered, it is important to determine the type—prerenal, postrenal, or intrinsic (Table 1)—because initial evaluation and management are tailored to the particular cause.

Prerenal ARF
Prerenal ARF is due to underperfusion of an otherwise normal kidney. In a multicenter study in Madrid, this type accounted for 21% of ARF cases.¹ The hallmark of prerenal failure is that it is quickly reversible with appropriate therapy. Thus, it can be thought of as "a good kidney looking at a bad world."

Prerenal kidney failure may be a result of volume depletion from renal or extrarenal losses, fluid sequestration in liver failure or other edematous states, or inadequate perfusion pressure due to heart failure. The urinalysis is bland, the urinary sodium level is low, but urine osmolality is high.

Treatment is imperative because continued renal hypoperfusion can progress to intrinsic renal failure. Renal perfusion and volume status must be optimized by giving isotonic fluids. Underlying diseases such as heart failure should be treated.

Postrenal ARF
Postrenal ARF is caused by obstruction of the urinary tract. This type of ARF accounted for 10% of cases in the Madrid study.¹ Urinary tract obstructions may be within the urinary tract (eg, blood clots, stones, sloughed papillae, or fungus balls) or extrinsic (eg, tumors, retroperitoneal fibrosis, or even inadvertent ligation).

Renal ultrasonography has a sensitivity and specificity of 90% to 95% when used to detect obstructions. Because it is highly operator-dependent, it should be performed by a highly experienced radiologist. Ultrasonography can give false-negative results if the obstruction is caused by retroperitoneal fibrosis or by certain malignancies that encase the entire system. It also might fail to detect an obstruction in very volume-depleted patients who do not have enough fluid buildup to show the obstruction.

Treatment should focus on removing the obstruction. Techniques vary depending on the type of obstruction.

Intrinsic ARF
Once prerenal and postrenal causes are ruled out, intrinsic renal failure is likely. Intrinsic ARF is due to disease of the renal parenchyma. In the Madrid study, intrinsic ARF accounted for 69% of cases. Of all cases of ARF, acute tubular necrosis (ATN) accounted for 45%.¹ Most of the following discussion therefore focuses on ATN, the most common type of intrinsic ARF; other types of intrinsic ARF are reviewed in detail in Lake and Humes.²

ATN is most often caused by renal hypoperfusion and renal ischemia. Other causes include various endogenous nephrotoxic substances (eg, myoglobin and hemoglobin after trauma, cellular products in tumor lysis syndrome, and crystals of uric acid, calcium, and oxalate) and a host of exogenous substances (Table 2). If a patient develops ATN while receiving medications, one must review each medication for the possibility of nephrotoxicity.

In oliguric ATN, renal plasma flow declines, but the glomerular filtration rate declines even more. This dichotomy suggests that constriction of the afferent arterioles contributes to the pathophysiologic process. Ischemic injury to epithelial cells can lead to tubular obstruction and to tubular backleak, which allows filtrate back into the bloodstream.

The distribution of tubular necrosis within the kidney is patchy, and the degree of necrosis does not correlate with the level of renal dysfunction. This is because the medulla of the kidney, containing the thick ascending loop of Henle, is less well vascularized and perfused than the cortex and, therefore, is disproportionately affected by ischemia. The ischemic insult in this region is worsened by reperfusion injury. Persistent vasoconstriction and congestion from white cells and cell debris lead to ongoing hypoxia and necrosis.

Bone Marrow Transplant Recipients
Marrow recipients are at increased risk of ARF and have a poor prognosis. Perioperative ATN may result from tumor lysis, sepsis, and nephrotoxins (including antibiotics and contrast agents).

If ARF develops 10 to 16 days after the transplant, the most likely immediate cause is hepatic veno-occlusive disease that mimics acute hepatorenal syndrome. ARF developing 4 to 12 months after bone marrow transplantation may be due to hemolytic uremic syndrome, perhaps related to cyclosporine or radiation therapy.

HIV Patients
These patients also are at risk of ARF, not only from the usual nephrotoxic insults but also from potential nephrotoxicity of protease inhibitors. Other agents with similar risks include acyclovir and foscarnet.

A patient with ARF requires the physician to play medical detective (Table 3). The medical history should be reviewed for possible nephrotoxic insults such as hypotension or exposure to contrast materials or medications.

The physical examination should focus on volume status. It is also prudent to screen for signs of systemic diseases that might affect kidney function, such as lupus erythematosus or Wegener's granulomatosis.

Renal ultrasonography should be performed to screen for urinary tract obstruction. Urinalysis, especially examination of the sediment, is fundamental to the evaluation (Table 3), and urine volume should be measured. Urine chemistry studies may provide additional information.

Anuria is a clue that ARF is caused by urinary tract obstruction, a severe type of ATN called cortical necrosis, or a blood vessel blockage by a clot or another obstruction. Low fractional excretion of sodium in a patient with acute oliguria is a classic sign of prerenal failure and is also associated with hepatorenal syndrome and acute glomerulonephritis. However, some types of ATN may also have low sodium excretion, specifically postcontrast ATN, rhabdomyolysis, and multisystem organ failure.

Treatment for intrinsic ARF is largely supportive, including adjusting medications, providing appropriate nutrition, and correcting volume status, hyperkalemia, and acidosis. The leading indications for dialysis are volume overload and hyperkalemia.

Stop Nephrotoxic Medications
Prescription and nonprescription medications should be reviewed immediately for any patient with ARF so that any potentially nephrotoxic drugs can be stopped. In addition to contrast media, other nephrotoxic agents include aminoglycosides and amphotericin B (Table 2). Outside the hospital, the leading nephrotoxic agents are nonsteroidal anti-inflammatory drugs. Patients can also be put at risk by angiotensin-converting enzyme inhibitors, cisplatin, ifosfamide, and even Chinese herbal remedies.

Manage Endogenous Nephrotoxic Insults
If endogenous nephrotoxicity is diagnosed early enough, it often can be reversed with urinary alkalization, which can prevent kidney failure and the need for dialysis. For example, pigment nephropathy from myoglobin, hemoglobin, or methemoglobin can be treated with urinary alkalization. In many cases, these types of nephrotoxicity result from tumor-Lysis syndromes or plasma cell dyscrasia, including myeloma kidney.²

Boost Urine Output
Renal failure patients who make urine tend to have lower morbidity and mortality rates. They are at less risk of hypervolemia, there is room for bicarbonate and nutrition, and there is less likelihood of hyperkalemia. This observation suggests that increasing urine output should be a priority. Unfortunately, much of the literature on this subject is dated, the studies had been poorly designed, and the effect on mortality is not clear.

Mannitol should be avoided in patients with established ARF because it is an osmotic agent that may induce hypervolemia.³ To increase urine output, hydrate the patient with saline; then start a loop diuretic.

Dopamine in renal doses should probably be used sparingly, if at all, because data on its effectiveness and safety are scant. In normalpeople, dopamine increases renal blood flow by about 40% and the glomerular filtration rate by about 10%, resulting in increases in salt and water excretion. It is not clear whether these increases are due to a direct effect on the kidney or the result of cardiac effects. Very little information is available about how to apply these results to patients with ARF. Data are not available for routine clinical use, so a dopamine trial should last no longer than 24 to 48 hours, followed by a taper.^4,5

New Directions for Therapy
In cells that recover from an ischemic insult, growth factors play a role in recovery. This phenomenon has led to research with epidermal growth factor, insulin-like growth factor, or hepatocyte-type growth factor as therapy for ischemic ATN. Others are investigating endothelium receptor blockers to address the ongoing vasoconstriction as well as antiadhesion-molecule antibodies to prevent vessel congestion by leukocytes.

The mortality rate in ARF is nearly 50%, depending on the type of ARF and comorbidities of the patient. In the Madrid study,¹ patients with ATN had a mortality rate of 60%, whereas those with prerenal or postrenal disease had a 35% mortality rate.

Most deaths are not due to the ARF itself but rather to the underlying disease or complications. The Madrid data¹ showed that 60% of deaths were due to the primary disease and the remaining 40% were due to cardiopulmonary failure or infection.

ARF is not merely a marker of illness. In a follow-up study⁶ of 16,000 patients who underwent computed tomography with contrast, 183 developed ARF. The mortality rate among those with ARF was 34%, compared with only 7% in a matched cohort from the similarly exposed group.

About half of people who survive ATN recover renal function completely, and another 40% have an incomplete recovery. Only about 5% to 10% require maintenance hemodialysis.

Because few measures exist to actively treat ARF, clinicians should try to prevent it. Issues to consider are correcting volume status, avoiding exposure to nephrotoxins, and preparing for high-risk procedures such as those using contrast agents (Table 4).

Preventing Contrast Nephropathy
The incidence of contrast nephropathy can be reduced by replacing traditional agents with nonionic contrast, limiting the quantity of any contrast agent used, and adequately hydrating patients before the procedure.

Using nonionic contrast agents can cut the overall risk of contrast nephropathy by one half—from about 6% to 3%. In a study by Rudnik et al,⁷ risk factors for contrast nephropathy were baseline renal insufficiency (serum creatinine >1.5 mg/dL) and diabetes. In the highest-risk patients who had both risk factors, the use of nonionic contrast agents reduced the incidence of nephropathy from 24% to 12%.

The most effective strategy to hydrate patients is to give half-normal saline at 1 mL/kg/hour overnight before the procedure. No benefit is gained by adding mannitol or a loop diuretic.⁸ Pretreating with acetylcysteine reduces the rise of creatinine levels slightly but may have minor clinical impact.⁹

Return to Medicine Index

1. Liano F, Pascual J. Epidemiology of acute renal failure: a prospective, multicenter, community-based study. Madrid Acute Renal Failure Study Group. Kidney Int. 1996; 50:811-818.

2. Lake EW, Humes HD. Acute renal failure including cortical necrosis. In: Textbook of Nephrology (vol I), 3rd ed. Glassock RJ, Massry SG, eds. Baltimore: Williams & Wilkins;1995:984-1003.
   
   
3. Cosentino F. Drugs for the prevention and treatment of acute renal failure. Cleve Clin J Med. 1995;62:248-253.
   
   
4. Olsen NV, Hansen JM, Ladefoged SD, Fogh-Andersen N, Leyssac PP. Renal tubular reabsorption of sodium and water during infusion of low-dose dopamine in normal man. Clin Sci. (Lond) 1990;78:503-507.
   
   
5. Graziani G, Cantaluppi A, Casati S, et al. Dopamine and frusemide in oliguric acute renal failure. Nephron. 1984;37:39-42.
   
   
6. Levy EM, Viscoli CM, Horwitz RI. The effect of acute renal failure on mortality. A cohort analysis. JAMA. 1996;275:1489-1494.
   
   
7. Rudnick MR, Goldfarb S, Wexler L, et al. Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: a randomized trial. The Iohexol Cooperative Study. Kidney Int. 1995;47:254-261.
   
   
8. Solomon R, Werner C, Mann D, D'Elia J, Silva P. Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents. N Engl J Med. 1994;331:1416-1420.
   
   
9. Birck R, Krzossok S, Markowetz F, Schnulle P, van der Woude FJ, Braun C. Acetylcysteine for prevention of contrast nephropathy: Meta-analysis. Lancet. 2003;362:598-603.

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