Published: August 2010
Acute renal failure (ARF) is characterized by azotmeia that progresses over several hours or days, with or without oliguria. Recently, the term acute kidney injury (AKI) has been popularized to increase awareness of milder degrees of renal impairment and to better describe the underlying pathobiology. Azotemia, on the other hand, signifies the accumulation of nitrogenous waste (urea) and other solutes.
A consensus classification for acute renal failure has been proposed by the the Acute Dialysis Quality Initiative (ADQI) group to standardize the definition and severity categories of AKI. The entry criteria for RIFLE (risk of renal dysfunction, injury to the kidney, failure of kidney function, loss of kidney function, and end-stage kidney disease) are based on changes in serum creatinine or urine output (Table 1).1
|Category||GFR Criteria||Urine Output Criteria|
|Risk||Increased creatinine ×1.5GFR decrease >25%||UO < 0.5 mL/kg/h × 6 hr|
|Injury||Increased creatinine ×2GFR decrease >50%||UO < 0.5 mL/kg/h × 12 hr|
|Failure||Increase creatinine ×3GFR decrease >75%||UO < 0.3 mL/kg/h × 24 hrAnuria × 12 hr|
|Loss||Persistent ARF = complete loss of kidney function >4 weeks|
|ESKD||End-stage kidney disease (>3 months)|
ARF, acute renal failure; GFR, glomerular filtration rate; RIFLE, risk of renal dysfunction, injury to the kidney, failure of kidney function, loss of kidney function, and end-stage kidney disease; UO, urine output;
Acute renal failure is common, with a reported incidence of 2% to 5% of all patients admitted to general medical-surgical hospitals. Up to 50% of patients who develop ARF die; survivors face marked increases in morbidity and prolonged hospitalization. The high incidence and substantial morbidity and mortality of ARF demand a logical approach to its prevention and early diagnosis, prompt recognition, and management of its complications.
Once ARF is discovered, it is important to determine the cause—prerenal, postrenal, or intrinsic—because the initial evaluation and management are tailored to the particular cause (Figure 1).
Prerenal ARF, caused by underperfusion of an otherwise normal kidney, accounted for 21% of cases of ARF in a multicenter study in Madrid.2 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 can be a result of volume depletion from renal or extrarenal losses, fluid sequestration in liver failure or other edematous states, or inadequate perfusion pressure caused by heart failure. The urinalysis is bland and 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, caused by obstruction of the urinary tract, accounted for 10% of cases in the Madrid study.2 Urinary tract obstructions may be within the urinary tract (e.g., blood clots, stones, sloughed papillae, fungus balls), or extrinsic (e.g., tumors, retroperitoneal fibrosis, even inadvertent ligation).
Renal ultrasonography, when used to detect obstructions, has a sensitivity and specificity of 90% to 95%. Unfortunately, it is also highly operator-dependent, so it should be performed by a highly experienced radiologist. Ultrasonography can yield false-negative results if the obstruction is caused by retroperitoneal fibrosis or certain malignancies that encase the entire system. It might also fail to detect an obstruction in extremely volume-depleted patients who do not have enough fluid buildup to reveal the obstruction.
Treatment should focus on removing the obstruction. Techniques vary with the type of obstruction.
Once prerenal and postrenal causes are ruled out, intrinsic renal failure is likely. Intrinsic ARF, caused by disease of the renal parenchyma, accounted for 69% of cases in the Madrid study.2 Acute tubular necrosis (ATN), the most common type of intrinsic ARF, accounted for 45% of all cases of ARF. Most of the following discussion is therefore focused on ATN; other types of intrinsic ARF have been reviewed in detail in studies by Glassock and colleagues.3
ATN is most often caused by renal hypoperfusion and renal ischemia. Other causes include various endogenous nephrotoxic substances (e.g., myoglobin and hemoglobin after trauma; cellular products in tumor lysis syndrome; crystals of uric acid, calcium, or oxalate) and a host of exogenous substances (Box 1). If a patient develops ATN while receiving medications, each medication must be reviewed for the possibility of nephrotoxicity.
|Box 1: Drugs and Other Exogenous Causes of Acute Renal Failure|
|Angiotensin-Converting Enzyme Inhibitors|
|Chemotherapy agents and immunosuppressants
|HIV protease inhibitors
|Snake or insect venom|
Adapted from Nally JV Jr: Acute renal failure. In Stoller JK, Michota, Mandell BF (eds): The Cleveland Clinic Intensive Review of Internal Medicine, 4th ed. Philadelphia, Lippincott, Williams & Wilkins, 2005, pp 577-584.
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 back leak, which allows filtrate back into the bloodstream, and tubular obstruction.
The distribution of tubular necrosis in the kidneys is patchy, and the degree of necrosis does not correlate with the level of renal dysfunction. This is because the medulla of the kidneys, containing the thick ascending limbs 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 are at increased risk of ARF and have a poor prognosis. Perioperative ATN can result from tumor lysis, sepsis, and nephrotoxins, including antibiotics and contrast agents. If ARF develops 10 to 16 days after transplantation, 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 caused by hemolytic uremic syndrome, perhaps related to cyclosporine or radiation therapy.
HIV patients are also 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.
The diagnosis of AKI traditionally has been based on functional parameters; an increase in serum creatinine is most commonly used as surrogate for impaired glomerular filtration rate (GFR). However, estimation of GFR with creatinine in the setting of AKI is inaccurate due to lag time to steady state, as well as other changing determinants of serum creatinine such as volume and nutrition. In addition, significant renal impairment can occur with only subtle variation in serum creatinine due to renal reserve or increased secretion (or both).
There is great interest in biomarkers of kidney injury that are elevated with ischemia and within hours of the event. NGAL (neutrophil gelatinase-associated lipocalin) and KIM-1 (kidney injury molecule- ) are two of a dozen biomarkers that showed promising preliminary results but need further validation.4
A patient with ARF requires a complete evaluation by the physician (Box 2). The medical history should be reviewed for possible nephrotoxic insults, such as exposure to contrast materials, medications, or hypotension. 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.
|Box 2: Evaluation of Patients With Acute Renal Failure|
|1. Review records, perform history and physical examination
|2. Examine the urine sediment
|3. Calculate urinary indices
In addition, urine studies need to be performed, such as urinalysis and measurement of urine volume. Urine chemistry studies may provide additional information. Anuria is a clue that ARF has one of three causes: urinary tract obstruction, a severe type of ATN called cortical necrosis, or a blood vessel blockage by a clot or another obstruction. Urinalysis, especially examination of the sediment, is fundamental to the evaluation (see Box 2). Low fractional excretion of sodium in a patient with acute oliguria is a classic sign of prerenal failure, and it is also associated with hepatorenal syndrome and acute glomerulonephritis. However, some types of ATN 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.
With any patient with ARF, prescription and nonprescription medications should be reviewed immediately so that any potentially nephrotoxic drugs can be stopped. In addition to contrast media, other nephrotoxic agents include aminoglycosides and amphotericin (see Box 1). Outside the hospital, the main nephrotoxic agents are nonsteroidal anti-inflammatory drugs (NSAIDs). Patients can also be put at risk by angiotensin-converting enzyme (ACE) inhibitors, cisplatin, ifosfamide, and even Chinese herbal remedies.
If endogenous nephrotoxicity is diagnosed early enough, it can often be reversed with urinary alkalinization, which can prevent kidney failure and the need for dialysis. For example, pigment nephropathy from myoglobin, hemoglobin, or methemoglobin can be treated with urinary alkalinization. These types of nephrotoxicity often result from tumor-specific or plasma cell dyscrasias (e.g., myeloma kidney).3
Acute 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 suggests that increasing urine output should be attempted. Unfortunately, much of the literature on this subject is dated, the studies were poorly designed, and a beneficial effect on mortality is not clear.
Mannitol should be avoided in patients with established ARF because it is an osmotic agent that can induce hypervolemia.5 To increase urine output, hydrate the patient with saline and 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 normal subjects, dopamine increases renal blood flow by approximately 40% and the glomerular filtration rate by approximately 10%, resulting in increases in salt and water excretion. It is not clear whether these increases are caused by a direct effect on the kidneys or are the result of cardiac effects. Little information is available about how to apply these results to patients with ARF. Data are not available for routine clinical use, so a trial of dopamine should be for no longer than 24 to 48 hours, followed by a taper.5
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, and hepatocyte-type growth factor as therapy for ischemic ATN. Other researchers are investigating endothelium receptor blockers to address the ongoing vasoconstriction, and antiadhesion molecule antibodies to prevent vessel congestion by leukocytes.
The mortality rate in severe ARF is almost 50%, depending on the type of ARF and comorbidities of the patient. In the Madrid study, patients with ATN had a mortality rate of 60%, whereas those with prerenal or postrenal disease had a 35% mortality rate.2
Most deaths are not caused by the ARF itself but rather by the underlying disease or complications. In the Madrid data, 60% of deaths were caused by the primary disease and the remaining 40% were caused by cardiopulmonary failure or infection.2
ARF is not merely a marker of illness. In a follow-up report of 16,000 patients who were studied by 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 50% of people who survive ATN recover renal function completely and another 40% have an incomplete recovery. Only approximately 5% to 10% require maintenance hemodialysis.
Because few measures exist to treat ARF actively, 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 using contrast agents (Box 3).
|Box 3: Measures to Prevent Acute Renal Failure in Hospitalized Patients|
|• Prevent hypotension, and correct it rapidly when it does occur.|
|• Evaluate renal function before any surgery.|
|• Avoid prescribing nephrotoxic drugs.|
|• Correct volume deficits or electrolyte imbalances, especially before surgery.|
|• Replace traditional contrast agents with nonionic contrast, and use contrast sparingly.|
|• Treat infection quickly.|
|• Treat oliguria quickly.|
The incidence of contrast nephropathy can be reduced by adequately hydrating patients before the procedure, replacing traditional agents with nonionic contrast, and limiting the quantity of any contrast agent used.5
Using nonionic contrast agents can cut the overall risk of contrast nephropathy by 50%, from about 6% to 3%. In the study by Rudnick and colleagues, risk factors for contrast nephropathy were baseline chronic kidney disease (serum creatinine level higher than 1.5 mg/dL) and diabetes; the use of nonionic contrast agents reduced the incidence in the highest risk patients who had both risk factors from 24% to 12%.
The most effective strategy to hydrate patients is to give IV normal saline, 1 mL/kg/hour, before the procedure. No benefit is gained by adding mannitol or a loop diuretic. Pretreating with acetylcysteine can reduce the rise of creatinine levels slightly but might have minor clinical impact. One report has suggested a benefit of IV sodium bicarbonate hydration before contrast exposure.6