Acute Renal Failure

Background: Acute renal failure (ARF) is defined as an abrupt or rapid decline in renal function. A rise in serum blood urea nitrogen (BUN) or serum creatinine concentrations, with or without a decrement in urine output, usually is evidence of ARF. The condition often is transient and completely reversible.

Pathophysiology: ARF may occur in 3 clinical settings, including (1) as an adaptive response to severe volume depletion and hypotension, with structurally and functionally intact nephrons; (2) in response to cytotoxic insults to the kidney, with structural and functional damage; and (3) with obstruction to the passage of urine. Therefore, ARF may be classified as prerenal, intrinsic, and postrenal. While these classifications are useful in establishing a differential diagnosis, many pathophysiologic features are shared among the different categories.

The intrinsic form of the syndrome may be accompanied by a well-defined sequence of events. The first is an initiation phase, characterized by daily increases in serum creatinine and reduced urinary volume; the second is a maintenance phase, during which the glomerular filtration rate (GFR) is relatively stable and urine volume may be increased; and the third is a recovery phase, in which serum creatinine levels fall and tubule function is restored. This sequence of events is not always apparent, and oliguria may not be present.

The reason for this lack of a uniform clinical presentation is a reflection of the variable nature of the injury. Classifying ARF as oliguric or nonoliguric based on daily urine excretion may be useful. Oliguria is defined as a daily urine volume of less than 400 mL/d. Anuria is defined as a urine output of less than 50 mL/d and, if abrupt in onset, is suggestive of obstruction. Stratification of renal failure along these lines helps in decision-making (eg, timing of dialysis) and seems to be an important criterion for patient response to therapy.

Intrinsic renal failure

Various cellular fates are identified in ARF. Cells may die either by frank necrosis or in apoptosis. The cells may replicate and divide. The cells may appear indifferent to the stress.

Frank necrosis is not prominent in most human cases of ARF. It tends to be patchy, involving individual cells or small clusters of cells, sometimes denuding small areas of the basement membrane. Less obvious injury includes loss of brush borders, flattening of the epithelium, detachment of cells, formation of intratubular casts, and dilatation of the lumen. Although these changes are observed predominantly in proximal tubules, injury to the distal nephron can also be demonstrated. The distal nephron may also be subjected to obstruction by desquamated cells and cellular debris.

Apoptosis differs from necrosis because it requires the activation of a regulated program that leads to DNA fragmentation, cytoplasmic condensation, and cell loss, without precipitating an inflammatory response. In contrast to necrosis, the principal site of apoptotic cell death is the distal nephron. During the initial phase of ischemic injury, loss of integrity of the actin cytoskeleton leads to flattening of the epithelium, with loss of the brush border, loss of focal cell contacts, and subsequent disengagement of the cell from the underlying substratum.

Many endogenous growth factors that participate in the process of regeneration have not been identified; however, administration of growth factors exogenously has been shown to ameliorate and hasten recovery from ARF. Depletion of neutrophils and blockage of neutrophil adhesion reduce renal injury following ischemia, indicating that the inflammatory response is responsible, in part, for some features of ARF, especially in posttransplant ARF.

Intrarenal vasoconstriction is the dominant mechanism for the reduced GFR in patients with ARF. The mediators of this vasoconstriction are unknown, but tubule injury seems to be an important concomitant finding. While obstruction of urine outflow into the collecting system is an obvious cause of reduced net ultrafiltration, the intratubular obstruction that results from sloughed cells and cellular debris that evolves in the course of renal failure is a less obvious cause. The importance of this mechanism is highlighted by the improvement in renal function that follows relief of such intratubular obstruction. In addition, when obstruction is prolonged, intrarenal vasoconstriction is prominent.

Apart from the increase in basal renal vascular tone, the stressed renal microvasculature is more sensitive to potentially vasoconstrictive drugs and otherwise-tolerated changes in systemic blood pressure. Prolonged vasoconstriction may evolve into intrinsic ARF, especially when concomitant large vessel arterial disease occurs. Renal failure caused by prolonged vasoconstriction (especially with concomitant large vessel arterial disease) often is induced by the use of angiotensin-converting enzyme (ACE) inhibitors and/or diuretics. The vasculature of the injured kidney has an impaired vasodilatory response and loses its autoregulatory behavior. This latter phenomenon has important clinical relevance because the frequent reduction in systemic pressure during intermittent hemodialysis may provoke additional damage that can delay recovery from ARF.

A physiologic hallmark of intrinsic ARF is a failure to maximally concentrate urine. This defect is not responsive to pharmacologic doses of vasopressin. The injured kidney fails to generate and maintain a high medullary solute gradient. Because the accumulation of solute in the medulla depends on normal distal nephron function, this is yet another example of the role of the distal nephron in the pathophysiology of ARF. Failure to excrete concentrated urine, even in the presence of oliguria, is a helpful diagnostic clue to distinguish prerenal from intrinsic renal disease, in which urine osmolality is less than 300 mOsm/kg. In prerenal azotemia, urine osmolality is typically more than 500 mOsm/kg.

Frequency:
 

• In the US: Approximately 1% of patients admitted to hospitals have ARF at the time of admission, and the estimated incidence rate of ARF is 2-5% during hospitalization. Approximately 95% of consultations with nephrologists are related to ARF. Feest and colleagues calculated in their report that the appropriate nephrologist referral rate is approximately 70 cases per million population.

Mortality/Morbidity: The mortality rate estimates vary from 25-90%. The mortality rate is 40-50% in general and 70-80% in intensive care settings.

CLINICAL

WORKUP

Lab Studies:
 

• Several laboratory tests are useful for assessing the etiology of ARF, and the findings can aid in proper management. These tests include complete blood cell count, serum biochemistries, urine analysis with microscopy, and urine electrolytes.

• Blood urea nitrogen and serum creatinine

• Although increased levels of BUN and creatinine are the hallmarks of renal failure, the rates of BUN and creatinine increases are also very important.

• BUN test findings showing an increase that is disproportionately larger than that of creatine suggest prerenal ischemia. Typically, the serum creatine increases 1-2 mg/dL/d; however, a rate of increase greater than 5 mg/dL/d also can be observed in patients with rhabdomyolysis because muscle is a major source of creatine, which is the precursor of creatinine.

• The ratio of BUN to creatinine also is an important finding because the ratio can exceed 20:1 in conditions in which enhanced reabsorption of urea is favored (eg, in volume contractions). In conditions such as upper gastrointestinal bleeding and in some cases of obstructive uropathy, test findings may show a further increase in the ratio. Other conditions causing a BUN-to-creatinine ratio of greater than 20:1 are increased enteral or parenteral protein load, corticosteroid therapy, and a hypercatabolic state.

• Complete blood cell count and peripheral smear

• These tests may be useful, and the peripheral smear results may show schistocytes in conditions such as hemolytic uremic syndrome or thrombotic thrombocytopenic purpura.

• A finding of increased rouleau formation suggests multiple myeloma, and the workup should be directed toward protein electrophoresis of serum and urine.

• The presence of schistocytes, myoglobin or hemoglobin, increased serum uric acid level, and other related findings may help further define the etiology of ARF.

• Findings from serology tests for ANCA indicate intrinsic renal disease due to vasculitis.

• Urinalysis

• Urinalysis remains the most important test in the initial evaluation of ARF.

• Findings of granular muddy-brown casts are suggestive of tubular necrosis. The presence of tubular cells or tubular cell casts also supports the diagnosis of acute tubular necrosis (ATN).

• Reddish brown or cola-colored urine is present in patients with acute glomerular nephritis or in the presence of myoglobin or hemoglobin. Dipstick assay findings may show the presence of significant proteinuria such as occurs in intrinsic renal diseases, including glomerulonephritis, acute interstitial nephritis, tubular necrosis, and vascular diseases.

• When RBCs are present in the urine, they can aid in establishing a diagnosis. RBC casts are pathognomonic for glomerular disease. Dysmorphic RBCs also support a glomerular cause such as lupus nephritis. The presence of WBCs or WBC casts may denote pyelonephritis or acute interstitial nephritis.

• Eosinophils visualized with Wright stain or Hansel stain suggest urinary tract infections, glomerulonephritis, actual embolic disease, or drug-induced interstitial nephritis. One must use clinical judgment when ordering this test. The author suggests ordering this test only when the clinical suspicion for interstitial nephritis is high, especially due to atheroembolic disease or allergic interstitial disease. If the patient does not have leukocyturia, the results of this test carry little meaning.

• The presence of uric acid crystals may represent ATN associated with uric acid nephropathy, while calcium oxidate crystals may be present in ARF due to ethylene glycol poisoning. Also, urine and serum uric acid values may be a useful indicator for tumor lysis syndrome, an important cause of ARF.

• Urine electrolytes

• Urine electrolyte findings also can serve as valuable indicators of functioning renal tubules.

   

• The fractional excretion of sodium (FENa) is the commonly used indicator. However, the interpretation of results from patients in nonoliguric states, those with glomerulonephritis, and those receiving or ingesting diuretics can lead to an erroneous diagnosis. FENa can be a valuable test for helping detect an extreme renal avidity for sodium in conditions such as hepatorenal syndrome. The formula for calculating the FENa is as follows:

   

  FENa = (U_Na/P_Na) X (U_Cr/P_Cr) X 100

• The FENa assay is useful in ARF only in the presence of oliguria.

   

• In patients with prerenal azotemia, the FENa is usually less than 1%. In ATN, the FENa is greater than 1%. Exceptions to this rule are ATN caused by radiocontrast nephropathy or severe burns.

   

• In the presence of liver disease, FENa can be less than 1% in the presence of ATN. On the other hand, because administration of diuretics may cause the FENa to be greater than 1%, these findings cannot be used as the sole indicators in ARF.

Imaging Studies:
 

• In some cases, renal imaging is very useful, especially if the cause of renal failure is secondary to obstruction.

• Ultrasound

• Renal ultrasonography is useful for evaluating obstruction of the urinary collecting system.

• This technique is readily available, and findings are quite accurate for indicating obstructive causes of renal failure. This test is also useful for detecting intrinsic renal disease, which enhances renal echogenicity; however, this finding is nonspecific.

• Ultrasonography also aids in performing a renal biopsy, which may be necessary in the diagnosis of cases of ARF due to vasculitis or interstitial renal diseases. Obtaining images of the kidneys can be technically difficult in patients who are obese or in those with abdominal distension due to ascites, gas, or retroperitoneal fluid collection.

• Ultrasound scans or other imaging studies showing small kidneys suggest chronic renal failure. The presence of the radiological and clinical features of hyperparathyroidism also supports the presence of chronic renal failure.

• Doppler scans

• Doppler scans are useful for detecting the presence and nature of renal blood flow.

• Because renal blood flow is reduced in prerenal or intrarenal ARF, test findings are of little use in the diagnosis of ARF.

• Doppler scans can be quite useful in the diagnosis of thromboembolic or renovascular disease.

• Nuclear scans

• Radionuclide imaging with a technetium Tc 99m diethylenetriamine pentaacetic acid (DTPA), 99m Tc-DTPA iodine I 131–hippuran scan can be used to assess renal blood flow and tubular functions.

• Because of a marked delay in tubular excretion of radionuclide in both prerenal and intrarenal diseases, the value of these scans is limited.

• Aortorenal angiography can be very helpful in the diagnosis of renal vascular diseases, including renal artery stenosis, renal atheroembolic disease, atherosclerosis with aortorenal occlusion, and in certain cases of necrotizing vasculitis (eg, polyarteritis nodosa

• Although serologic tests can be very informative, the costs can be prohibitive if not ordered judiciously. Tests such as antinuclear antibody, ANCA, cryoglobulins, and hepatitis serology markers are not warranted when investigating ARF due to an obvious cause (eg, ATN due to contrast toxicity). These tests may be best ordered when ARF is suggested to be due to a vasculitic process.

Procedures:
 

• Renal biopsy

• A renal biopsy can be very useful in the diagnosis of intrarenal causes of ARF. Performing a renal biopsy is comparatively easy, and the findings establish the diagnosis in most cases.

• In as many as 40% of cases, renal biopsy results reveal an unexpected diagnosis.

• A renal biopsy is especially useful in rapidly progressive glomerulonephritis due to crescentic glomerulonephritis when clinical differentiation between acute glomerulonephritis and interstitial nephritis becomes difficult. Acute cellular rejection in a renal transplant can be definitively diagnosed only by performing a renal biopsy.

TREATMEN

Medical Care: The mortality rate for patients in the intensive care unit (ICU) is lower in those who have ARF, especially when ARF is severe enough to require dialysis treatment. In addition, evidence suggests that the relative risk of death is 4.9 in patients in the ICU who have renal failure that is not severe enough to require dialysis. This reflects that the very high mortality rate in patients with ARF who require dialysis may not be related to the dialysis procedure or accompanying comorbidities and that ARF alone may be an independent indicator of mortality.

• Aggressive treatment should begin at the earliest indication of renal dysfunction. A large proportion of the renal mass is damaged before any biochemical evidence of renal dysfunction is appreciated because the relationship between the GFR and the serum creatinine level is exponential, not linear. The rise of serum creatinine may not be evident before 50% of the GFR is lost.

• At this point, recognizing the presence of ARF and promptly initiating therapy aimed at minimizing the damage to the remaining functional renal mass are important considerations. This may also aid in reversing the renal damage that has already occurred. Reversing renal damage can be accomplished only by identifying the underlying cause and directing the appropriate therapy.

• Maintenance of volume homeostasis and correcting biochemical abnormalities remain the primary goals of treatment. At this stage, the kidneys remain vulnerable to the toxic effects of various chemicals. All nephrotoxic agents (eg, radiocontrast agents, antibiotics with nephrotoxic potential, heavy metal preparations, cancer chemotherapeutic agents, NSAIDs) are either avoided or used with extreme caution. Similarly, all medications cleared by renal excretion should be avoided or their doses should be adjusted appropriately.

• Correcting acidosis with bicarbonate administration is important. It cannot be overstated that the current treatment of ARF is mainly supportive in nature and no therapeutic modalities to date have shown efficacy in treating the condition. Although therapeutic agents such as dopamine, Lasix, fenoldopam, and mannitol are still being used, the efficacy of this treatment remains controversial.

MEDICATION

Pharmacologic treatment of ARF has been attempted on an empiric basis, with varying success rates. Several promising experimental therapies in animal models are awaiting human trials. Experimental therapies include growth factors, vasoactive peptides, adhesion molecules, endothelin inhibitors, and bioartificial kidneys. Aminophylline has also been used experimentally for prophylaxis against renal failure.

One therapeutic agent used successfully as a prophylactic agent for the prevention of ARF, by preventing contrast-induced renal injury, is N-acetylcysteine at a dose of 600 mg PO q12h. This is administered to high-risk patients the day before a contrast study is performed and is continued the day after the procedure.
 

Drug Category: Diuretics -- Although diuretics seem to have no effect on the outcome of established ARF, they appear useful in fluid homeostasis and are used extensively. The use of isotonic sodium chloride solution in conjunction with diuretics is debatable. The only therapeutic or preventive intervention that has an established beneficial effect in the management of ARF is administration of isotonic sodium chloride solution to keep the patient euvolemic or even hypervolemic.

Drug Category: Vasodilators -- Dopamine in small doses (eg, 1-5 mcg/kg/min) causes selective dilatation of the renal vasculature, enhancing renal perfusion. Dopamine also reduces sodium absorption, thereby decreasing the energy requirement of the damaged tubules. This enhances urine flow, which, in turn, helps prevent tubular cast obstruction. Most clinical studies have failed to establish this beneficial role of renal-dose dopamine infusion.

Drug Category: Calcium channel blockers -- Effective in animal models but efficacy not proven in humans. Effects are believed to be mediated through vasodilation, and calcium channel blockers increasingly are used to enhance the function of transplanted kidneys.

Drug Category: N-acetylcysteine -- Used for prevention of contrast toxicity in susceptible individuals such as those with diabetes mellitus.

 Outpatient Care:
 

• Always keep in mind that renal recovery in most cases is not complete and the kidneys remain vulnerable to nephrotoxic effects of all therapeutic agents. Therefore, agents with nephrotoxic potential are best avoided.

Prognosis:
 

• The prognosis of patients with ARF is directly related to the cause of renal failure and, to a great extent, to the duration of renal failure prior to therapeutic intervention. If ARF is defined by a sudden increment of serum creatinine of 0.5-1 mg/dL and is associated with a mild-to-moderate rise in creatinine, the prognosis tends to be worse. However, even if renal failure is mild, the mortality rate is 30-60%. If these patients need dialytic therapy, the mortality rate is 50-90%.

• The mortality rate is 31% in patients with normal urine sediment test results and is 74% in patients with abnormal urine sediment test results.

• If using Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, the survival rate is nearly 0% among patients with ARF who have a score higher than 40 and is 40% in patients with APACHE II scores of 10-19.

• Other prognostic factors include the following:

   

  • Older age

     

  • Multiorgan failure (ie, the more organs that fail, the worse the prognosis)

     

  • Oliguria

     

  • Hypotension

     

  • Vasopressor support

     

  • Number of transfusions

     

  • Noncavitary surgery

• Prerenal renal azotemia due to volume contraction is treated with volume expansion; however, if left untreated for a prolonged duration, tubular necrosis may result and may not be reversible.

• Postrenal ARF, ie, urinary obstruction related renal failure, causes renal damage due to increased pressure proximal to the obstruction, which results in a thinning of the renal cortex. If left untreated for a long time, it may result in irreversible renal damage. Simple procedures such as catheter placement, lithotripsy, prostatectomy, stent placement, or percutaneous nephrostomy can help prevent permanent renal damage.

• Timely identification of pyelonephritis, proper treatment, and further prevention using prophylactic antibiotics may improve the prognosis, especially in females.

• Early diagnosis of crescentic glomerulonephritis via renal biopsy and other appropriate tests may enhance early renal recovery because appropriate therapy can be initiated promptly and aggressively.

• The number of crescents, the type of crescents (ie, cellular vs fibrous), and the serum creatinine level at the time of presentation may dictate prognosis for renal recovery in this subgroup of patients.

Patient Education:
 

• Educating patients about the nephrotoxic potential of common therapeutic agents is always helpful. A good example is NSAIDs; most patients are unaware of their nephrotoxicity, and their universal availability makes them a constant concern.

Medical/Legal Pitfalls:
 

• Although ARF potentially is a reversible condition, it can occur in patients with chronic renal failure. Every effort should be made to identify reversibility, even if improvement in renal function is marginal. The best way to identify reversibility is by tracking the rate of deterioration of renal function. If the rate of worsening renal function accelerates, the cause should be sought and treated.

• Renal recovery is usually observed within the first 2 weeks, and many nephrologists tend to diagnose patients with end-stage (ie, irreversible) renal failure 6-8 weeks after onset of ARF. It is always better to check these patients periodically because some patients may regain renal function much later.

Special Concerns:
 

• Great controversy exists regarding the timing of dialysis. Dialysis, especially hemodialysis, may delay the recovery of patients with ARF. Most authorities prefer using biocompatible membrane dialyzers for hemodialysis. Continuous renal replacement therapy is indicated in patients who are critically ill, hypercatabolic, and hemodynamically unstable. Such patients may not tolerate the rapid shift of fluid and electrolytes caused during conventional hemodialysis. Peritoneal dialysis can also be used in acute cases and probably is tolerated better hemodynamically than conventional hemodialysis.

• Indications for dialysis in patients with ARF are as follows:

• Volume expansion that cannot be managed with diuretics

• Hyperkalemia

• Correction of severe acid-base disturbances

• Severe azotemia (BUN >100)

• Symptoms of uremic pericarditis, gastritis, seizures, or encephalopathy