AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Background

The causes of acute renal failure (ARF) are conventionally and conveniently divided into 3 categories: prerenal, renal, and postrenal. Prerenal ARF involves an essentially normal kidney that is responding to hypoperfusion by decreasing the glomerular filtration rate (GFR). Renal or intrinsic ARF refers to a condition in which the pathology lies within the kidney itself. Postrenal failure is caused by an obstruction of the urinary tract. Acute tubular necrosis (ATN) is the most common cause of ARF in the renal category.

ATN is the second most common cause of all categories of ARF in hospitalized patients, with only prerenal azotemia occurring more frequently. The history, physical examination, and laboratory findings, especially the renal ultrasound and the urinalysis, are particularly helpful in identifying the cause of ARF. This article focuses on the pathophysiology, diagnosis, and management of ATN, the most common renal cause of ARF in hospitalized patients. Obstruction is the second most common cause of ARF (after prerenal azotemia) in outpatients. Glomerulonephritis and interstitial nephritis can also present as ARF.

Pathophysiology

Acute tubular necrosis

ATN usually occurs after an acute ischemic or toxic event, and it has a well-defined sequence of events. The initiation phase is characterized by an acute decrease in GFR to very low levels, with a sudden increase in serum creatinine and blood urea nitrogen (BUN) concentrations. The maintenance phase is characterized by a sustained severe reduction in GFR, and this phase continues for a variable length of time, most commonly 1-2 weeks. Because the filtration rate is so low during the maintenance phase, the creatinine and BUN continue to rise. The recovery phase, in which tubular function is restored, is characterized by an increase in urine volume (if oliguria was present during the maintenance phase) and by a gradual decrease in BUN and serum creatinine to their preinjury levels.

Ischemic acute tubular necrosis

Ischemic ATN is often described as a continuum of prerenal azotemia. Indeed, the causes of the 2 conditions are the same (see Causes). Ischemic ATN results when hypoperfusion overwhelms the kidney's autoregulatory defenses. Under these conditions, hypoperfusion initiates cell injury that often, but not always, leads to cell death. Injury of tubular cells is most prominent in the straight portion of the proximal tubules and in the thick ascending limb of the loop of Henle, especially as it dips into the relatively hypoxic medulla. The reduction in GFR that occurs from ischemic injury is a result not only of reduced filtration due to hypoperfusion but also of casts and debris obstructing the tubule lumen, causing back leak of filtrate through the damaged epithelium (ie, ineffective filtration).

In addition, ischemia leads to decreased production of vasodilators (ie, nitric oxide, prostacyclin [PGI2]) by the tubular epithelial cells, leading to further vasoconstriction and hypoperfusion.

On a cellular level, ischemia causes depletion of adenosine triphosphate (ATP), an increase in cytosolic calcium, free radical formation, metabolism of membrane phospholipids, and abnormalities in cell volume regulation. The decrease or depletion of ATP leads to many problems with cellular function, not the least of which is active membrane transport. With ineffective membrane transport, cell volume and electrolyte regulation are disrupted, leading to cell swelling and intracellular accumulation of sodium and calcium. Typically, phospholipid metabolism is altered, and membrane lipids undergo peroxidation. In addition, free radical formation is increased, producing toxic effects. Damage inflicted by free radicals apparently is most severe during reperfusion.

The earliest changes in the proximal tubular cells are apical blebs and loss of the brush border membrane followed by a loss of polarity and integrity of the tight junctions. This loss of epithelial cell barrier can result in the above-mentioned back leak of filtrate. Another change is relocation of Na⁺/K⁺-ATPase pumps and integrins to the apical membrane. Cell death occurs by both necrosis and apoptosis. Sloughing of live and dead cells occurs, leading to cast formation and obstruction of the tubular lumen.

The maintenance phase of ATN is characterized by a stabilization of GFR at a very low level, and it typically lasts 1-2 weeks. Complications (eg, uremic and others, see Complications) typically develop during this phase. The mechanisms of injury described above may contribute to continued nephron dysfunction, but tubuloglomerular feedback also plays a role. Tubuloglomerular feedback in this setting leads to constriction of afferent arterioles by the macula densa cells, which detect an increased salt load in the distal tubules.

The recovery phase of ATN is characterized by regeneration of tubular epithelial cells. During recovery, an abnormal diuresis sometimes occurs, causing salt and water loss and volume depletion. The mechanism of the diuresis is not completely understood, but it may in part be due to the delayed recovery of tubular cell function in the setting of increased glomerular filtration. In addition, continued use of diuretics (often administered during initiation and maintenance phases) may also add to the problem.

Nephrotoxic acute tubular necrosis

Most of the pathophysiologic features of ischemic ATN are shared by the nephrotoxic forms. Thus, the cellular events described above apply to nephrotoxic ATN as well. Nephrotoxic ATN has induction, maintenance, and recovery phases, and recovery can be associated with an abnormal diuresis as is described above in ischemic ATN.

Nephrotoxic injury to tubular cells occurs by multiple mechanisms. These include direct drug toxicity, intrarenal vasoconstriction, and intratubular obstruction.

Frequency

United States

The syndrome of ARF is observed in about 5% of all hospital admissions. In the ICU, it occurs in up to 30% of patients admitted. Prerenal causes are responsible for approximately half of all cases. The frequency of each type of intrinsic renal disease varies depending on the population studied, but ATN (other than prerenal azotemia) is the most common cause of ARF in hospitalized patients.

Mortality/Morbidity

As with other causes of ARF, complications associated with ATN are often life threatening. The in-hospital survival rate of patients with ATN is approximately 50%, with about 30% of patients surviving for 1 year. Factors that are associated with an increased mortality rate include poor nutritional status, male sex, the presence of oliguria, the need for mechanical ventilation, acute myocardial infarction, stroke, or seizures.

• Disturbances in fluid and electrolyte balance
  • Hyperkalemia can be associated with life-threatening cardiac arrhythmias (see Complications).
  • Salt and water retention often leads to hypertension, edema, and congestive heart failure (CHF).
  • Hyponatremia causes concern because of its effects on the central nervous system.
  • Other electrolyte disturbances include hyperphosphatemia, hypocalcemia, and hypermagnesemia.
  • Metabolic acidosis
• Uremia results from the accumulation of nitrogenous waste. It is a potentially life-threatening complication associated with ARF.
  • Neurologic impairment and pericarditis can occur.
  • Platelet dysfunction is common and can lead to life-threatening hemorrhage.
• Infections
  • For ARF, the mortality rate is 20-50% in patients with underlying medical illnesses, but the mortality rate is as high as 60-70% with patients in a surgical setting. If multiorgan failure is present, especially severe hypotension or acute respiratory distress syndrome, the mortality rate ranges from 50-80%.
  • With dialysis intervention, the frequency of uremia, hyperkalemia, and volume overload as causes of death have decreased. The most common causes of death now are sepsis, cardiovascular and pulmonary dysfunction, and withdrawal of life support.

CLINICAL

Section 3 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
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• References

History

The patient's history is very important in the diagnosis of ATN. It frequently reveals recent hypotension, sepsis, muscle necrosis, or volume depletion, as well as exposure to nephrotoxic agents. ATN is more likely to occur in patients with a history of recent surgery, sepsis, or hypovolemia. The history is also important in establishing risk factors for the development of ATN.

Physical

Physical examination findings may be unremarkable because ARF is often found incidentally during routine laboratory studies (ie, elevated BUN and creatinine levels). However, if symptoms are present, they may include a pericardial friction rub, asterixis, and/or excoriation marks related to uremic pruritus. Hypertension or edema may be noted. Otherwise, the physical examination findings are more likely to reflect the underlying disease process.

Causes

ATN is generally caused by an acute event, either ischemic or toxic.

Ischemic acute tubular necrosis

Ischemic ATN may be considered part of the spectrum of prerenal azotemia, and, indeed, ischemic ATN and prerenal azotemia have the same causes and risk factors. Specifically, these include the following:

• Hypovolemic states - Hemorrhage, volume depletion from GI or renal losses, burns, fluid sequestration
• Low cardiac output states - CHF and other diseases of myocardium, valvulopathy, arrhythmia, pericardial diseases, tamponade
• Systemic vasodilation - Sepsis, anaphylaxis
• Disseminated intravascular coagulation
• Renal vasoconstriction - Cyclosporine, amphotericin B, norepinephrine, epinephrine, hypercalcemia
• Impaired renal autoregulatory responses - Cyclooxygenase (COX) inhibitors, ACE inhibitors, angiotensin receptor blockers
  • Both angiotensin II and prostaglandins play central roles in the maintenance of GFR in the face of volume depletion. ACE inhibitors and angiotensin receptor blockers have gained popularity recently not only as antihypertensive agents but also as renoprotective agents that either slow or halt the progression of both diabetic kidney disease and nondiabetic kidney disease. They have also been shown in several studies to have a role in CHF as well as ventricular remodeling. The use of these agents is limited by the tendency to cause prerenal failure, especially in patients who are considered to be at high risk; risk factors include advanced age, underlying renovascular disease, concomitant use of diuretics or vasoconstrictors, such as nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, and calcineurin inhibitors, and elevated baseline serum creatinine.
  • Serum creatinine and electrolytes, especially potassium, should be measured before and at least 1 week after starting or changing the dose of the medication. An increase in serum creatinine of greater than 0.5 mg/dL if the initial serum creatinine is less than 2.0 mg/dL, or an increase in serum creatinine of greater than 1.0 mg/dL if the baseline serum creatinine is greater than 2.0 mg/dL, has been suggested as a threshold for discontinuation of therapy. An increase in serum creatinine of up to 30% is acceptable, but a continued rise of over 30% should prompt immediate discontinuation of the medication. Alternatively, discontinuation of ACE inhibitor or angiotensin receptor blocker therapy is not necessary if smaller increases in serum creatinine occur. If and when prerenal ARF does develop, one should commence looking for underlying heart disease, volume depletion, hypotension, concomitant use of vasoconstrictors, or renovascular disease.

Nephrotoxic acute tubular necrosis

The kidney is a particularly good target for toxins. Not only does it have a rich blood supply, receiving 25% of cardiac output, but it also helps in the excretion of these toxins by glomerular filtration and tubular secretion.

• Exogenous nephrotoxins
• • Aminoglycosides
    • ATN occurs in 10-30% of patients receiving aminoglycosides, even when blood levels are in apparently therapeutic ranges. Risk factors for the development of aminoglycoside-induced ATN include preexisting liver disease, preexisting renal disease, concomitant use of other nephrotoxins (eg, amphotericin B, radiocontrast media, cisplatin), advanced age, shock, female sex, and a higher aminoglycoside level 1 hour after dose. A high trough level has not been shown to be an independent risk factor. Patients usually present with nonoliguric renal failure, with onset of nephrotoxicity (manifested by an elevation in serum creatinine), that occurs after 7-10 days of therapy. Characteristically, an elevated fractional excretion of sodium (FENa) is usually accompanied by wasting of potassium, calcium, and magnesium.
    • Aminoglycosides preferentially affect the proximal tubular cells. These agents are freely filtered and quickly taken up by the proximal tubular epithelial cells, where they are incorporated into lysosomes after first interacting with phospholipids on the brush border membranes. They exert their main toxic effect within the tubular cell by altering phospholipid metabolism. In addition to their direct effect on cells, aminoglycosides cause renal vasoconstriction.
    • The 2 critical factors in the development of ARF secondary to aminoglycoside nephrotoxicity are namely dosing and duration of therapy.
    • Aminoglycoside uptake by the tubules is a saturable phenomenon, so uptake is limited after a single dose. Not surprisingly, a single daily large dose is preferable to 3 doses per day. One dose per day presumably causes less accumulation in the tubular cells once the saturation point is reached. In fact, clinical nephrotoxicity develops much more commonly with 3 doses per day than with 1 dose per day; in one study, 24% of patients receiving 3 daily doses developed clinical nephrotoxicity, compared to only 5% of patients receiving 1 daily dose. However, other studies comparing a single daily dose to multiple daily doses have failed to find a difference in the incidence of nephrotoxicity.
    • Therapeutic efficacy is not diminished by single daily dosing.
  • Amphotericin B
    • Amphotericin B tends to bind to sterols in cell membranes, thereby creating pores that compromise membrane integrity and increase membrane permeability. It binds not only to ergosterol in fungal cell walls but also to cholesterol in human cell membranes; this is what accounts for its nephrotoxicity. Multiple segments of the renal tubule are involved, namely, the proximal tubule, the medullary ascending limb of the loop of Henle, and the collecting duct. Characteristic electrolyte abnormalities include wasting of potassium and magnesium. The back-leak of hydrogen ions in the collecting duct leads to distal renal tubular acidosis (dRTA).
    • Several risk factors for the development of amphotericin B nephrotoxicity include male sex, maximum daily dose (nephrotoxicity is more likely to occur if > 3 g is administered) and duration of therapy, hospitalization in the critical care unit at the initiation of therapy, and concomitant use of cyclosporine.
    • Prevention is key in amphotericin B nephrotoxicity. By saline loading, maintenance of a high urine flow rate has been shown to be helpful. Likewise, various lipid formulations of amphotericin B have been developed, namely, amphotericin B colloid dispersion (ABCD), amphotericin B complex (ABLC), and liposomal amphotericin B; these lipid formulations are believed to be less nephrotoxic intrinsically. Whereas amphotericin B is suspended in bile salt deoxycholate, which has a detergent effect on cell membranes, such lipid formulations do not contain deoxycholate. The lipid formulations also bind more avidly to fungal cell wall ergosterol as opposed to the cholesterol in human cell membranes. Liposomal amphotericin B is preferred in patients with renal insufficiency or evidence of renal tubular dysfunction.
  • Radiographic contrast media
    • ARF occurring secondary to exposure to contrast media used in radiologic or angiographic procedures is referred to as contrast-induced nephropathy (CIN) or radiocontrast nephropathy (RCN). This type of nephropathy commonly occurs in patients with several risk factors, such as elevated baseline serum creatinine, preexisting renal insufficiency, underlying diabetic nephropathy, CHF, or high or repetitive doses of contrast media. Other risk factors include volume depletion and concomitant use of diuretics, ACE inhibitors, or angiotensin receptor blockers.
    • Although the pathogenesis of CIN remains incompletely understood, it is most likely the result of both renal vasoconstriction and direct renal tubular epithelial cell toxicity.
    • Patients usually present with nonoliguric renal failure, with an acute elevation in serum creatinine that is noted 24-48 hours after the contrast-requiring procedure; it may peak 3-5 days after the onset of renal failure and then may return to baseline within 7-10 days. More importantly, the temporal relationship between the time of administration of contrast media and the onset of elevation in serum creatinine is particularly suggestive of the diagnosis. One must differentiate CIN from atheroembolic renal disease, which occurs in the same scenario, but atheroembolic renal disease is characterized by embolic lesions (mottling of the skin over the lower extremities), peripheral eosinophilia, and serum hypocomplementemia, all of which are notably absent in CIN.
    • Most patients with CIN will have subsequent renal recovery; however, those patients with preexisting renal insufficiency may show a further decline in renal function.
    • Prevention is important in the management of CIN. Some investigators recommend the avoidance of contrast-requiring procedures, if at all possible. Magnetic resonance imaging (MRI) studies usually necessitate the use of gadolinium as a contrast agent, which, in several studies, has been shown to be less nephrotoxic than conventional contrast media.
    • Other risk factors should be corrected, including saline infusion to correct volume depletion and discontinuation of potential nephrotoxic agents, such as NSAIDs and COX-2 inhibitors. In those patients with underlying volume depletion, withholding ACE inhibitors and/or angiotensin receptor blockers may even be necessary. Using the lowest possible amount of contrast media in the procedure is also recommended.
    • To date, several interventions have been suggested to decrease the risk of CIN, such as furosemide, mannitol, dopamine, and fenoldopam, but none of these agents have been shown to be significantly effective. Recently, the use of N-acetylcysteine (NAC) as a prophylactic agent has gained popularity. Based on the theory that contrast media cause direct renal tubular epithelial cell toxicity as a result of exposure to reactive oxygen species (ROS), NAC is believed to have antioxidant properties that potentially counteract the effects of ROS.
    • Based on what is known now, making a strong, evidence-based recommendation for the use of NAC in the prevention of CIN is not possible. Recognizing that NAC is inexpensive and is not associated with significant complications, in the absence of other effective pharmacologic therapy, its use in clinical practice is not entirely inappropriate. Additional large randomized controlled trials of NAC are needed to better define its proper role inpreventing CIN.
    • Recently, several studies looked at the possibility of using theophylline as a prophylactic agent. Based on the idea that contrast media causes local release of adenosine, a known vasoconstrictor, and considered by some to have a potential role in the pathogenesis of CIN, theophylline is a known adenosine antagonist. Although theophylline appears to be promising, just as with NAC, further randomized trials are required to show any proven benefit of theophylline in the prevention of CIN.
    • The prevention of contrast nephrotoxicity has received attention. In susceptible patients, the use of nonionic, low-osmolar contrast media reduces the likelihood of clinical nephrotoxicity. Isotonic saline, given at 1 mL/kg of body weight/h for 24 hours, starting on the morning of the contrast-requiring procedure, has been shown to be superior to half normal saline infusions. A recent single center, randomized controlled trial has shown that isotonic sodium bicarbonate (3 mL/kg of body weight/h given 1 h prior to the contrast-requiring procedure and then continued at 1 mL/kg of body weight/h for 6 h postprocedure) may offer even greater protection than isotonic sodium chloride. The postulated mechanism is being attributed to the inhibition of oxidant injury by the administered alkali.
    • Studies have also suggested that pretreatment with oral NAC (600 mg or 1200 mg bid on the day prior and on the day of the contrast-requiring procedure) acts as an antioxidant, scavenging ROS, thereby reducing the nephrotoxicity of contrast media.
    • Similarly, theophylline, an adenosine antagonist, with a similar mechanism of action as NAC, is viewed as another potential agent to prevent CIN; the main difference being the lower risk profile associated with the latter.
    • Aside from the recommended prophylactic medications discussed above, other guidelines recommend withholding NSAIDs, COX inhibitors, diuretics, ACE inhibitors, and angiotensin receptor antagonists at least 24 hours before and after the procedure. Metformin should be withheld at least 48 hours before the procedure and until CIN has been ruled out.
  • Cyclosporine and tacrolimus (calcineurin inhibitors): These drugs cause ARF by inducing afferent arteriolar vasoconstriction. Usually, renal insufficiency is easily reversed by a reduction of the dosage. On the other hand, persistent injury can lead to interstitial fibrosis.
    • Clinically, patients may present with hypertension. They may also be hyperkalemic and have tubular injury induced urinary wasting of phosphate and magnesium.
    • Recently, tacrolimus has been shown to cause thrombotic microangiopathy as a result of endothelial injury.
  • Others: Cisplatin, ifosfamide, foscarnet, and pentamidine are other causes of drug-induced tubular toxicity.
    • Cisplatin usually affects the proximal and distal tubules. Characteristically, it is associated with urinary wasting of magnesium. Cisplatin causes the release of toxic hydroxyl radicals when chloride ions in the cis position are replaced by water. The key is prevention by volume loading with saline. Some investigators advocate the use of amifostine, a thiol donor that serves as an antioxidant. Others prefer using carboplatin, a less nephrotoxic alternative.
    • Ifosfamide usually causes a Fanconi syndrome (proximal tubule dysfunction) presentation with significant hypokalemia. It is a known analog of cyclophosphamide. While the latter is not nephrotoxic, ifosfamide, by virtue of its metabolite chloroacetaldehyde, is, with preferential involvement of the proximal tubule.
    • Foscarnet is used to treat resistant cytomegalovirus (CMV) infections. It causes acute interstitial nephritis and intratubular crystal obstruction. It is notable for inhibiting proximal tubular reabsorption of phosphate (leading to hypophosphatemia) by virtue of it being a phosphate analog. Hypocalcemia is also noted, secondary to chelation of calcium.
    • Pentamidine is used to treat Pneumocystis carinii infection in individuals who are immunocompromised. Risk factors for nephrotoxicity include volume depletion and concomitant use of other nephrotoxic antibiotic agents, such as aminoglycosides, which is common practice in the immunosuppressed. It is noted for hypomagnesemia and hyperkalemia.
  • Sulfa drugs, acyclovir, and indinavir cause ARF by tubular obstruction due to crystal formation in the tubular urine. Acyclovir may lead to the formation of intratubular crystals, which appear as birefringent needle shaped crystals when viewed on microscopy. Occasionally, such crystals can also elicit an acute interstitial nephritis.
• Endogenous nephrotoxins
• • Myoglobinuria
    • Rhabdomyolysis refers to the breakdown of skeletal muscle fibers, which leads to the release of potentially nephrotoxic intracellular contents into the circulation. Rhabdomyolysis is the most common cause of heme-pigment associated ARF. Three mechanisms cause the development of ARF in this setting, as follows: renal vasoconstriction, heme-mediated proximal tubular epithelial cell toxicity, and intratubular cast formation. Heme-proteins are believed to be involved in the generation of ROS, which are known to cause tubular injury through peroxidation of membrane lipids and intracellular enzymes.
    • Rhabdomyolysis can be caused by traumatic or nontraumatic injuries. Most cases of rhabdomyolysis are nontraumatic (eg, alcohol abuse, drug-induced muscle toxicity [statins alone or in combination with fibrates]).
    • Clinically, patients present with severe muscle pains and generalized soreness. Physical examination may disclose tender "dough" muscles, with significant edema of the involved extremities. In severe cases, compartmental compression syndromes, particularly characterized by neurovascular compromise, may occur.
    • An important finding on urinalysis is that of a positive dipstick test for blood, with typical absence of RBCs on microscopy. Furthermore, hyperkalemia, hyperphosphatemia, and hyperuricemia are characteristic. Calcium tends to deposit in the injured muscle, thereby leading to hypocalcemia. Such deposited calcium is eventually released back into the circulation during the recovery phase, thereby accounting for transient hypercalcemia. For this reason, calcium administration is generally not recommended during the acute phase of rhabdomyolysis, unless the patient is symptomatic.
    • Preventive strategies include aggressive volume resuscitation with normal saline at 1000-1500 mL/h with a goal urine output of 300 mL/h. Caution should be exercised to avoid producing a compartment syndrome, especially in those patients who remain oligoanuric despite infusions of large volumes of fluid. In the presence of sufficient urine output, urine alkalinization to achieve a urine pH of greater than 6.5 is recommended to increase the solubility of the heme-proteins within the tubules. This has also been shown to reduce the generation of ROS. Mannitol has not been shown to be more efficacious as compared to volume expansion with normal saline alone.
  • Hemoglobinuria: ARF is a rare complication of hemolysis and hemoglobinuria. Most often, it is associated with transfusion reactions. In contrast to myoglobin, hemoglobin has no apparent direct tubular toxicity, and the ARF in this setting is probably related to hypotension and decreased renal perfusion.
  • Crystals: Acute crystal-induced nephropathy is encountered in conditions where the crystals are generated endogenously due to high cellular turnover (ie, uric acid, calcium phosphate), as observed in certain malignancies or the treatment of malignancies. However, this condition is also associated with ingestion of certain toxic substances, such as ethylene glycol, or nontoxic substances, such as vitamin C.
  • Multiple myeloma: Multiple myeloma causes renal failure by several mechanisms, such as prerenal azotemia due to volume contraction, cast nephropathy due to increased light chain proteins precipitated into the tubular lumen, hypercalcemia, uric acid nephropathy, and drug-induced interstitial nephritis.

DIFFERENTIALS

Section 4 of 10  

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Other Problems to be Considered

Prerenal azotemia
Acute interstitial nephritis
Renal vasculitis
Obstructive uropathy

WORKUP

Section 5 of 10  

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Lab Studies

• Serum chemistries: By definition, BUN and serum creatinine concentrations are increased in ARF. In addition, hyponatremia, hyperkalemia, hypermagnesemia, hypocalcemia, and hyperphosphatemia may be present. A metabolic acidosis is also found. Remember that hypercalcemia and hyperuricemia may suggest a malignant condition as a cause.
• CBC count: CBC count may reveal anemia. Erythropoietin production is decreased in ARF, and dysfunctional platelets (from uremia) also make bleeding more likely.
• Urinalysis: The centrifuged sediment of urine is particularly helpful because it may reveal pigmented, muddy brown, granular casts, suggesting that established ATN is present. However, remember that these casts may be absent in 20-30% of patients with ATN. In addition to the routine urinalysis, urine electrolytes may also help differentiate ATN from prerenal azotemia. The urinary sediment, electrolyte, and osmolality findings that can help to separate ATN from prerenal azotemia are illustrated in the following Table.

  Laboratory Findings Used to Differentiate Prerenal Azotemia From ATN

  Finding	Prerenal Azotemia	ATN and/or Intrinsic Renal Disease
  Urine osmolarity (mOsm/kg)	>500	<350
  Urine sodium (mmol/d)	<20	>40
  Fractional excretion of sodium (%)	<1	> 2
  Fractional excretion of urea (%)	<35	>50
  Urine sediment	Bland and/or nonspecific	May show muddy brown granular casts

• Fractional excretion of a substance is calculated by the formula (U/P)z/(U/P)Cr X 100, where z is the substance, U and P represent urine and plasma concentrations, and Cr stands for creatinine.

Imaging Studies

• An abdominal radiograph is of limited benefit in ARF, with the exception of diagnosing (or helping to exclude) nephrolithiasis.
• Ultrasound, CT scan, or MRI are extremely useful, both to exclude obstructive uropathy and to measure renal size and cortical thickness. Renal ultrasound is a simple procedure that should be undertaken in all patients who present with ARF.

Procedures

• Biopsy is rarely necessary. It should be performed only when the exact renal cause of ARF is unclear and the course is protracted. Prerenal and postrenal causes must be ruled out first. The diagnosis of ATN is made on a clinical basis, that is, with the help of a detailed and accurate history, a thorough physical examination, and pertinent laboratory examinations and imaging studies. A more urgent indication for renal biopsy is in the setting of clinical and urinary findings that suggest renal vasculitis rather than ATN; the diagnosis needs to be established quickly so that appropriate immunomodulatory therapy can be initiated. The biopsy is performed under ultrasound or CT scan guidance after ascertaining the safety of the procedure. A biopsy may also be more critically important in the setting of a renal transplant patient to rule out rejection.

Histologic Findings

In most circumstances, the histology demonstrates the loss of tubular cells or the denuded tubules. As illustrated in Image 1, the tubular cells reveal swelling, formation of blebs over the cellular surface, and exfoliation of the tubular cells into the lumina. The earliest finding could be loss of the cellular brush border.

TREATMENT

Section 6 of 10  

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• Follow-up
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• References

Medical Care

• Prevention
• • Ischemic ATN: Be attentive to optimizing cardiovascular function as well as maintaining intravascular volume, especially in patients with preexisting risk factors or those taking nephrotoxic medications. Medicines that reduce systemic resistance (eg, afterload reducers) may cause renal vasoconstriction or affect the kidney's autoregulatory response (eg, ACE inhibitors, COX inhibitors) and also should be used with caution.
  • Nephrotoxic ATN
    • Aminoglycosides: Studies have demonstrated that once daily dosing of aminoglycosides decreases the incidence of nephrotoxicity.
    • Amphotericin B: Minimize the use of this drug and ensure that extracellular fluid (ECF) volume is adequate.
    • Cyclosporin and tacrolimus: Regular monitoring of blood levels can help maintain therapeutic levels and prevent nephrotoxicity.
    • Radiocontrast dye: Isotonic sodium chloride solution infusion has proven benefits in the prevention of CIN. Typically, isotonic sodium chloride solution (0.9%) administered at a rate of 1 mL/kg/h 12 hours before and 12 hours after the administration of the dye load is most effective, especially in the setting of prior renal insufficiency and diabetes mellitus. Nonionic contrast media is also protective in patients with both diabetic nephropathy and renal insufficiency. Recently, NAC has been tried with success in high-risk patients to prevent contrast-induced nephrotoxicity.
• Treatment
• • General treatment
    • The main goal of treatment is to prevent further injury to the kidney. ECF volume should be assessed promptly, either on clinical grounds or by invasive means (Swan-Ganz catheter), and repletion of any deficit should be initiated promptly. A renal ultrasound should be performed to exclude obstruction. All possible nephrotoxic drugs should be stopped. Despite some controversy in the literature, in general, if oliguria is present, make an attempt to increase urine output using intravenous loop diuretics. Only use diuretics if ECF volume and cardiac function are first carefully assessed and found adequate.
    • Intravenous furosemide or bumetanide in a single high dose (ie, 100-200 mg of furosemide) is commonly used, although little evidence indicates that it changes the course of ATN. The drug should be administered slowly because high doses can lead to hearing loss. If no response occurs, the treatment should be discontinued. Dopamine, a selective renal vasodilator, has also been used to increase urine output, but this treatment has little benefit and is no longer recommended.
    • Aggressively treat any complications that develop. For example, hyperkalemia can be treated with glucose and insulin, binding resins, or, if necessary, dialysis. Metabolic acidosis may be treated with bicarbonate or dialysis as well. Anemia can be corrected with blood transfusions.
    • Recall that sepsis is a common cause of death with severe ARF, so aggressive treatment of infections is prudent.
    • Also, adjust doses of all medications if the kidney eliminates them.
  • Dialysis treatment
    • In general, no clear consensus is established on when or how often to perform hemodialysis in the setting of ARF. Some studies have suggested that early initiation may be beneficial, but, in one prospective trial, aggressive dialysis did not improve recovery or survival rates. However, hemodialysis is still considered standard therapy in severe ARF. In addition, continuous hemodialysis (continuous venovenous hemodiafiltration [CVVHD] and continuous arteriovenous hemofiltration with dialysis [CAVHD]) and peritoneal dialysis are also available. No compelling studies suggest that one mode is better than another. In general, patients with multiorgan failure and hemodynamic instability may benefit from a continuous mode because it is typically less taxing on the hemodynamics.
    • Some studies suggest that the use of biocompatible membranes instead of cuprophane membranes may improve the recovery rate and decrease the mortality rate in ARF.
  • Treatment of nephrotoxic ATN: Generally, the treatment of choice is to stop all nephrotoxic agents to prevent further damage to the kidney. Of note, calcium channel blockers may have some use in cyclosporine toxicity, where they may reduce the vasoconstrictive action of the drug. However, their use is typically avoided because of possible hypotension.

Diet

Clearly, the maintenance of fluid and electrolyte balance is critical. Aggressive and early nutritional support also improves survival rates. Adequate protein and caloric intake is essential because marked increase in protein catabolism is often observed, especially in patients with shock, sepsis, or rhabdomyolysis. The risks of this catabolism include malnutrition and an impaired immune system.

MEDICATION

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Medications have not been effective in treating ATN. Therapeutic mainstays are prevention, avoidance of further kidney damage, treatment of underlying conditions, and aggressive treatment of complications.

Drug Category: Antioxidants

May prevent reperfusion damage as well as improve renal hemodynamics.

Drug Category: Diuretics

Help maintain a nonoliguric state, which has a better overall survival rate.

FOLLOW-UP

Section 8 of 10  

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Complications

• ATN and ARF have several complications.
• Electrolyte abnormalities
• • Hyperkalemia: Higher levels are associated with ECG abnormalities (eg, peaked T waves, prolonged PR interval, P wave flattening, widened QRS) and risk of developing life-threatening arrhythmias (eg, ventricular tachycardia or fibrillation, complete heart block, bradycardia, asystole). Arrhythmias have been reported in up to 30% of patients. In addition to these worrisome cardiac effects, hyperkalemia can also lead to neuromuscular dysfunction and, potentially, respiratory failure.
  • Hyponatremia
  • Hyperphosphatemia
  • Hypermagnesemia
  • Hypocalcemia: Hypocalcemia may be secondary to both deposition of calcium phosphate and reduced levels of 1,25 dihydroxyvitamin D. It is usually asymptomatic, but hypocalcemia may result in nonspecific ECG changes, muscle cramps, or seizures.
  • Metabolic acidosis
• Intravascular volume overload: In its most severe manifestation, this may lead to respiratory failure from pulmonary edema.
• Hypertension: Hypertension is suspected to mainly be due to salt and water retention. About 25% of patients with ARF develop some hypertension.
• Uremic syndrome: This may manifest as pericardial disease, GI symptoms (ie, nausea, vomiting, cramping), and/or neurologic symptoms (ie, lethargy, confusion, asterixis, seizures).
• Anemia: Anemia may develop from many possible causes. Indeed, erythropoiesis is reduced in ARF, but platelet dysfunction is also observed in the setting of uremia, which may predispose to hemorrhage. In addition, volume overload may lead to hemodilution, and red cell survival time may be decreased.
• Polyuric phase of ATN: This complication can lead to hypovolemia and create a setting for prerenal azotemia and perpetuation of ATN. One must be wary of the potential for multiple electrolyte deficiencies (eg, hypokalemia, hypocalcemia) during this period as a result of increased urinary excretion.
• Infections: Infections remain the leading cause of morbidity and mortality and can occur in 30-70% of patients with ARF. Infections are more likely in these patients because of an impaired immune system (eg, uremia, inappropriate use of antibiotics) and because of increased use of indwelling catheters and intravenous needles.

Prognosis

• As mentioned earlier, the mortality rate of ATN is about 50%. However, this is probably related more to the severity of the underlying disease than to ATN itself. For example, the mortality rate in patients with ATN after sepsis or severe trauma is much higher (about 60%) than the mortality rate in patients with ATN that is nephrotoxin related (about 30%). However, remember the following points:
• • First, patients with oliguric ATN have a worse prognosis than patients with nonoliguric ATN. This probably is related to more severe necrosis and more significant disturbances in electrolyte balance.
  • Second, a rapid increase in serum creatinine (ie, > 3 mg/dL) probably also indicates a poorer prognosis. Again, this probably reflects a more serious underlying disease.
• Of the survivors of ATN, approximately 50% have some impairment of renal function. Some (about 5%) continue to undergo a decline in renal function. About 5% never recover kidney function and require dialysis.

Patient Education

• For excellent patient education resources, visit eMedicine's Diabetes Center. Also, see eMedicine's patient education article Acute Kidney Failure.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Media file 1:  A photomicrograph of renal biopsy shows renal medulla, which is composed mainly of renal tubules. Patchy or diffuse denudation of the renal tubular cells is observed, suggesting acute tubular necrosis (ATN) as the cause of acute renal failure (ARF).
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Media file 2:  Acute tubular necrosis (ATN). Flattening of the renal tubule cells due to tubular dilation.
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Media file 3:  Acute tubular necrosis. Intratubular cast formation.
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Media file 4:  Acute tubular necrosis. Intratubular obstruction due to the denuded epithelium and cellular debris. Note that the denuded tubular epithelial cells clump together due to rearrangement of intercellular adhesion molecules (ICAM).
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Media type:  Photo

Media file 5:  Sloughing of cells, which is responsible for the formation of granular casts, a feature of acute tubular necrosis (ATN).
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Media type:  Photo

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

• Fauci A, Hauser SL. Acute renal failure. In: Harrison's Principles of Internal Medicine. 14th ed. New York, NY:. McGraw-Hill;1998:1505-7.
• Klahr S, Miller SB. Acute oliguria. N Engl J Med. Mar 5 1998;338(10):671-5. [Medline].
• Merten GJ, Burgess WP, Gray LV, et al. Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA. May 19 2004;291(19):2328-34. [Medline].
• Mueller C, Buerkle G, Buettner HJ, et al. Prevention of contrast media-associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty. Arch Intern Med. Feb 11 2002;162(3):329-36. [Medline].
• Schrier R, Gottschalk C. Acute Renal Failure. In: Diseases of the Kidney. 6th ed. Philadelphia, Pa:. Lippincott, Williams and Wilkins;1997:1013-302.
• Tepel M, van der Giet M, Schwarzfeld C, et al. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med. Jul 20 2000;343(3):180-4. [Medline].
• Thadhani R, Pascual M, Bonventre JV. Acute Renal Failure. New Engl J Med. 1996;338 (10):1448-1457. [Medline].
• Tierney L, McPhee S, Papadakis M. Acute renal failure In: Current Medical Diagnosis & Treatment. New York, NY:. McGraw-Hill;1998:853-7.

Article Last Updated: Dec 5, 2006