ACUTE TUBULAR NECROSIS

Essentials of Diagnosis

Acute kidney injury.

Clinical scenario consistent with diagnosis (ischemic or toxic insult).

Urine sediment with pigmented granular casts and renal tubular epithelial cells is pathognomonic but not essential.
General Considerations
Acute renal failure due to tubular damage is termed acute tubular necrosis and accounts for 85% of intrinsic acute renal failure. The two major causes of acute tubular necrosis are ischemia and toxin exposure. Ischemia causes tubular damage from states of low perfusion and is often preceded by a state of prerenal azotemia. Ischemic acute renal failure is characterized not only by inadequate GFR but also by renal blood flow inadequate to maintain parenchymal cellular formation. This occurs in the setting of prolonged hypotension or hypoxemia, such as dehydration, shock, and sepsis. Major surgical procedures can involve prolonged periods of hypoperfusion, which are exacerbated by vasodilating anesthetic agents.
The other major cause of acute tubular necrosis is nephrotoxin exposure. Exogenous nephrotoxins more commonly cause damage than endogenous nephrotoxins.
EXOGENOUS NEPHROTOXINS
Up to 25% of hospitalized patients receiving therapeutic levels of aminoglycosides sustain some degree of acute tubular necrosis. Nonoliguric renal failure typically occurs after 5–10 days of exposure. Predisposing factors include underlying renal damage, dehydration, and advanced age. Aminoglycosides can remain in renal tissues for up to a month, so renal function may not recover for some time after stopping the medication. Monitoring of peak and trough levels is important, but trough levels are more helpful in predicting renal toxicity. Gentamicin is as nephrotoxic as tobramycin; streptomycin is the least nephrotoxic of the aminoglycosides, likely due to the number of cationic amino side chains present on each molecule. Amphotericin B is typically nephrotoxic after a dose of 2–3 g. This causes severe vasoconstriction with distal tubular damage and can lead to distal renal tubular acidosis with hypokalemia and nephrogenic diabetes insipidus. Vancomycin, intravenous acyclovir, and several cephalosporins have been known to cause acute tubular necrosis.
Radiographic contrast media can be directly nephrotoxic. Contrast nephropathy is the third leading cause of new acute renal failure in hospitalized patients. It probably results from the synergistic combination of direct renal tubular epithelial cell toxicity and renal medullary ischemia. Predisposing factors include advanced age, preexisting renal disease (serum creatinine > 2 mg/dL), volume depletion, diabetic nephropathy, congestive heart failure, multiple myeloma, repeated doses of contrast, and recent exposure to other nephrotoxic agents, including NSAIDs and ACE inhibitors. The combination of diabetes mellitus and renal dysfunction poses the greatest risk (15–50%) for contrast nephropathy. Lower volumes of contrast with lower osmolality are recommended in high-risk patients. Toxicity usually occurs 24–48 hours after the radiocontrast study. Nonionic contrast media may be less toxic, but this has never been proved. Prevention should be the goal when using these agents. The mainstay of therapy is a liter of 0.9% saline over 12 hours both before and after the contrast administration—cautiously in patients with preexisting cardiac dysfunction. Neither mannitol nor furosemide offers benefit over saline hydration. In fact, furosemide may lead to increased rates of renal dysfunction in this setting. In some but not all studies, N-acetylcysteine given before and after contrast decreased the incidence of dye-induced nephrotoxicity. Its benefit seems more pronounced in subjects with a lower GFR. Acetylcysteine is a thiol-containing antioxidant with little toxicity whose mechanism of action is unclear. With little harm and possible benefit, administering acetylcysteine 600 mg orally every 12 hours twice, before and after a dye load, for patients at risk for acute renal failure, is a reasonable strategy. Intravenous N-acetylcysteine has shown benefit compared with placebo, and may be a good option if a patient acutely needs contrast dye. Investigators have shown a benefit using sodium bicarbonate rather than normal saline as the isotonic volume expander. Other nephrotoxic agents should be avoided during the day before and after dye administration.
Cyclosporine toxicity is usually dose dependent. It causes distal tubular dysfunction from severe vasoconstriction. Regular blood level monitoring is important to prevent nephrotoxicity. With patients who are taking cyclosporine for renal transplant rejection, kidney biopsy is often necessary to distinguish transplant rejection from cyclosporine toxicity. Renal function usually improves after reducing the dose or stopping the drug.
Other exogenous nephrotoxins include antineoplastics, such as cisplatin and organic solvents, and heavy metals such as mercury, cadmium, and arsenic.
ENDOGENOUS NEPHROTOXINS
Endogenous nephrotoxins include heme-containing products, uric acid, and paraproteins. Myoglobinuria as a consequence of rhabdomyolysis leads to acute tubular necrosis. Necrotic muscle releases large amounts of myoglobin, which is freely filtered across the glomerulus. The myoglobin is reabsorbed by the renal tubules, and direct damage can occur. Distal tubular obstruction from pigmented casts and intrarenal vasoconstriction can also cause damage. This type of renal failure occurs in the setting of crush injury, or muscle necrosis from prolonged unconsciousness, seizures, cocaine, and alcohol abuse. Dehydration and acidosis predispose to the development of myoglobinuric acute renal failure. Patients may complain of muscular pain and often have signs of muscle injury. Rhabdomyolysis of clinical importance commonly occurs with a serum creatine kinase (CK) greater than 20,000–50,000 IU/L. One study showed that 58% of patients with acute renal failure from rhabdomyolysis had CK levels greater than 16,000 IU/L. Only 11% of patients without renal failure had CK values greater than 16,000 IU/L. The globin moiety of myoglobin will cause the urine dipstick to read falsely positive for hemoglobin: the urine appears dark brown, but no red cells are present. With lysis of muscle cells, patients also become hyperkalemic, hyperphosphatemic, and hyperuricemic. The mainstay of treatment is hydration. Other adjunctive treatments include mannitol for free radical clearance and diuresis as well as alkalinization of the urine. These modalities have not been proved to change outcomes in human trials.
Hemoglobin can cause a similar form of acute renal tubular necrosis. Massive intravascular hemolysis is seen in transfusion reactions and in certain hemolytic anemias. Reversal of the underlying disorder and hydration are the mainstays of treatment.
Hyperuricemia can occur in the setting of rapid cell turnover and lysis. Chemotherapy for germ cell neoplasms and leukemia and lymphoma are the primary causes. Acute renal failure occurs with intratubular deposition of uric acid crystals; serum uric acid levels are often greater than 20 mg/dL and urine uric acid levels greater than 600 mg/24 h. A urine uric acid to urine creatinine ratio greater than 1.0 indicates risk of acute renal failure.
Bence Jones protein seen in conjunction with multiple myeloma can cause direct tubular toxicity and tubular obstruction. Other renal complications from multiple myeloma include hypercalcemia and proximal renal tubular acidosis (see Multiple Myeloma, below).
Clinical Findings
SYMPTOMS AND SIGNS
See Acute Renal Failure.
LABORATORY FINDINGS
Urinalysis may show evidence of acute tubular damage. The urine may be brown. On microscopic examination, an active sediment may show pigmented granular casts or "muddy brown" casts. Renal tubular epithelial cells and epithelial cell casts can be present (see Table 22–1). Hyperkalemia and hyperphosphatemia are commonly encountered.
Treatment
Treatment is aimed at hastening recovery and avoiding complications. Preventive measures should be taken to avoid volume overload and hyperkalemia. Loop diuretics have been used in large doses (eg, furosemide in doses ranging from 20 mg to 160 mg orally or intravenously twice daily, or as a continuous infusion) to effect adequate diuresis, and may help convert oliguric to nonoliguric renal failure. Such a conversion has never been shown to affect outcomes such as mortality, though. One recent retrospective study has shown potentially worse outcomes in patients who receive doses of furosemide, including nonrecovery of renal function and an increased risk of death. A more recent prospective randomized controlled trial has shown no difference between the administration of large doses of diuretics versus placebo on either recovery from acute renal failure or death. Widespread use of diuretics in critically ill patients with acute renal failure should be discouraged. Side effects of supranormal dosing include deafness. This is mainly due to peak furosemide levels and can be avoided by the use of a furosemide drip. A starting dose of 0.2–0.6 mg/kg/h is appropriate, increasing to a maximum of 1 mg/kg/h. A bolus of the hourly dose should be administered at the beginning of treatment. Intravenous thiazide diuretics can be used to augment urinary output; chlorothiazide, 500 mg intravenously every 8–12 hours, is a reasonable choice. Short-term effects also include activation of the renin–angiotensin system. Nutritional support should maintain adequate intake while preventing excessive catabolism. Dietary protein restriction of 0.6 g/kg/d helps prevent metabolic acidosis. Hypocalcemia and hyperphosphatemia can be improved with diet and phosphate-binding agents such as aluminum hydroxide (500 mg orally with meals) over the short term, calcium carbonate (500–1500 mg orally three times daily), calcium acetate (667 mg, two or three tablets, orally before meals), or sevelamer (800–1600 mg orally three times daily). Lanthanum carbonate (1000 mg orally with meals) is a new but less well-studied option. Hypocalcemia should not be treated in patients with rhabdomyolysis unless they are symptomatic. Hypermagnesemia can occur because of reduced magnesium excretion by the renal tubules, so magnesium-containing antacids and laxatives should be avoided in these patients. Dosages must be adjusted according to the estimated degree of renal impairment for drugs eliminated by the kidney.
Indications for dialysis in acute renal failure from acute tubular necrosis or other intrinsic disorders are as follows: life-threatening electrolyte disturbances (such as hyperkalemia), volume overload unresponsive to diuresis, worsening acidosis, and uremic complications (eg, encephalopathy, pericarditis, and seizures). In gravely ill patients, less severe but worsening abnormalities may also be indications for dialytic support.
Course & Prognosis
The clinical course of acute tubular necrosis is often divided into three phases: initial injury, maintenance, and recovery. The maintenance phase is expressed as either oliguric (urinary output < 500 mL/d) or nonoliguric. Nonoliguric acute tubular necrosis has a better outcome. Conversion from oliguric to nonoliguric states may be attempted but has not been shown to change the prognosis. Drugs such as dopamine and diuretics are sometimes used for this purpose but have not been shown to improve outcomes. In numerous studies, dopamine use in this setting has been shown to have no benefit. Average duration of the maintenance phase is 1–3 weeks but may be several months. Cellular repair and removal of tubular debris occur during this period. The recovery phase is heralded by diuresis. GFR begins to rise; BUN and serum creatinine fall. Other treatments for acute tubular necrosis, such as atrial natriuretic peptide use, have not proven beneficial. Ongoing randomized controlled studies are looking at the usefulness of intensive versus conventional renal replacement therapy for a survival benefit.
The mortality rate from acute renal failure is 20–50% in medical illness and up to 70% in a surgical setting. Increased mortality is associated with advanced age, severe underlying disease, and multisystem organ failure. Leading causes of death are infections, fluid and electrolyte disturbances, and worsening of underlying disease. Mortality rates have not changed significantly over 20 years, making prevention of acute renal failure a high priority.
When to Refer

A patient with acute renal failure should be referred to a nephrologist when the etiology is unclear or renal function continues to worsen despite intervention.

Also, referral is appropriate if fluid, electrolyte, and acid-base abnormalities are recalcitrant.

Studies have shown that nephrology referral improves outcome in acute renal failure.
When to Admit
Admission is appropriate when a patient has signs or symptoms of acute renal failure that require immediate intervention, such as intravenous fluids, dialytic therapy, or a team approach that cannot be coordinated as an outpatient.