DESCRIPTION

• Acute renal failure (ARF) or insufficiency is an abrupt decline in renal function.
• Azotemia is an elevation of BUN and/or creatinine levels.
• Acute tubular necrosis (ATN) is renal tubule dysfunction and patchy tubular necrosis.
• Acute interstitial nephritis (AIN) is clinically similar to ATN.
• Nephrotic syndrome is proteinuria above 3.5 g/day associated with albumin less than 2.5 g/dl, hyperlipidemia, and edema

PATHOPHYSIOLOGY

Prerenal factors account for 40% to 80% of all cases of ARF.

EPIDEMIOLOGY

• Most common nephrotoxic lesions are intrinsic renal injuries (i.e., acute tubular necrosis and acute interstitial nephritis).
• Nephrotoxic effects are usually mild to moderate, but irreversible renal failure may occur.

RISK FACTORS

• Pre-existing renal disease
• Simultaneous exposure to multiple nephrotoxic agents

Section Outline:

• DESCRIPTION
• PATHOPHYSIOLOGY
• EPIDEMIOLOGY
• RISK FACTORS

DIFFERENTIAL DIAGNOSIS

Prerenal

• Volume depletion
  • Dehydration is caused by many drugs.
  • Caustic gastrointestinal injury.
  • Hemorrhage.
• Cardiac dysfunction can be caused by doxorubicin, beta-blockers, calcium channel blockers, and cardiac glycosides.
• Decreased renal artery perfusion can be caused by nonsteroidal antiinflammatory drugs (NSAIDs), cyclosporine, angiotensin-converting enzyme (ACE) inhibitors, ergot alkaloids, clonidine, beta-blockers, and antihypertensive medications, as well as hepatorenal syndrome.
• Other drugs, such as amphotericin and methotrexate, can cause renal dysfunction.

Renal Parenchymal Disorders

• ATN can be caused by: acyclovir, allopurinol, aminoglycosides, amphotericin, amyl nitrite, aniline, arsenic, arsine, barium, bismuth, borates, bromides, captopril, carbamazepine, cephaloridine, cephalothin, chlorates, chromium, cisplatin, cortinarius mushrooms, cyclosporine, dapsone, diquat, elemental mercury, fluorinated anesthetics, glycols, halogenated hydrocarbons, insect venoms, methylbromide, methotrexate, mithramycin, naphthalene, neuroleptics, paraquat, phenazopyridine, radiocontrast media, snake venom, sulfonamides, rifampin, trichloroethylene, tetrachloroethylene, yellow phosphorus, and heme pigments.
• AIN has been associated with allopurinol, NSAIDs, cephalosporins, penicillins (especially methicillin, penicillin, and ampicillin), rifampin, sulfonamides, and vancomycin.
• Acute glomerular nephritis has been caused by captopril, heavy metals, heroin, amphetamines, hydralazine, NSAIDs, yellow phosphorous, penicillamine, rifampin, and sulfonamides.
• Nephrotic syndrome suggests use of an ACE inhibitor, dapsone, heroin, gold, mercury, NSAIDs, penicillamine, phenolphthalein, probenecid, trimethadione, or paramethadione.
• An unknown mechanism of a renal parenchymal disorder is associated with fluoride.

Acute Urinary Tract Obstruction

• Tubular. Obstruction can be caused by ethylene glycol, diethylene glycol, fluorinated anesthetics, myoglobin, and phenylbutazone.
• Ureteral. Obstruction can be caused by bromocriptine, methylsergide, LSD, milk alkali syndrome from milk or calcium-containing antacids, sulfonamides, vitamin C (chronic ingestion), vitamin D (chronic ingestion), and uric acid deposition.
• Bladder. Obstruction can be caused by anticholinergics and tricyclic antidepressants.

SIGNS AND SYMPTOMS

Vital Signs

Fever suggests a hypersensitivity reaction, metal fume fever, or cadmium fume pneumonitis.

Dermatologic

• Dermatitis, stomatitis, alopecia, and hypersensitivity pneumonitis suggest exposure to gold salts or gold-containing drugs.
• A "boiled lobster" appearance and desquamation associated with nausea and vomiting suggests exposure to borates.
• Burns suggest exposure to yellow phosphorus.
• Poor peripheral perfusion may indicate volume depletion or ingestion of clonidine, beta-blockers, or antihypertensive medications or ergot alkaloids.

Cardiovascular

Cardiac dysfunction suggests ingestion of doxorubicin, a beta-blocker, a calcium channel blocker, or a cardiac glycoside.

Pulmonary

• Pneumonitis associated with stomatitis and gingivitis suggests exposure to elemental mercury vapor.
• Pneumonitis involving a progressive fibronodular interstitial process suggests exposure to beryllium.
• Pulmonary fibrosis following episodes of bloody vomiting and diarrhea suggests paraquat.

Gastrointestinal

Nausea, mucosal burns, hematemesis, diarrhea, and abdominal pain suggest exposure to iron, arsenic, inorganic mercury, or other caustics.

Hepatic

Jaundice, hepatitis, and hepatic failure suggest exposure to acetaminophen, carbon tetrachloride, tetrachloroethylene, isoniazid, yellow phosphorus, or a cyclopeptide-containing mushroom.

Renal

• Diabetes insipidus suggests lithium, furosemide, ethacrynic acid, propoxyphene.
• Hemoglobinuria suggests a venom, phenol, aniline, arsine, or methylchloride exposure.

Hematologic

• Coagulopathy suggests exposure to anticoagulants or crotalid snake venom.
• Hypochromic, microcytic anemia and basophilic stippling suggests chronic lead toxicity.
• Hemolysis associated with generalized weakness, headache, "bronze" skin, and abdominal pain suggests exposure to arsine or stibine gas.
• Hemolysis suggests any cause of methemoglobinemia, as well as exposure to naphthalene, phenazopyridine, copper sulfate, or brown recluse spider bite in a child.

Fluids and Electrolytes

• Electrolyte abnormality suggest diuretic abuse; hyperkalemia suggests potassium-sparing diuretic.
• Anion gap metabolic acidosis with or without crystalluria suggests exposure to ethylene glycol or diethylene glycol.
• Severe hypokalemia suggests diuretics or barium.
• Hypercalcemia suggests vitamin D.
• Hypokalemia and hyperchloremia, with normal or increased anion gap metabolic acidosis, suggests toluene exposure.

Musculoskeletal

• Rhabdomyolysis suggests exposure to sympathomimetic agents, barbiturates, PCP, sedative-hypnotics (with coma), cyanide, carbon monoxide, zinc phosphate, copper sulfate, CNS stimulants, or snake and insect venoms.
• Teeth discoloration, painful microfractures due to osteomalacia, anemia, and generalized pain suggest cadmium exposure.
• Gout suggests chronic lead toxicity.

Neurologic

• Tremor, hyperreflexia, clonus, and altered mental status suggest lithium ingestion.
• CNS depression is associated with trichloroethylene.
• Altered mental status and ataxia suggest lead exposure.

Genitourinary

Retroperitoneal fibrosis suggests exposure to methysergide, LSD, or bromocriptine.

PROCEDURES AND LABORATORY TESTS

Renal dysfunction can be diagnosed by means of laboratory findings:

• ATN. Muddy-brown pigmented cellular casts or renal tubular cells are found on urine analysis.
• AIN. Eosinophiluria, hematuria, leukocyturia, a mononuclear cell infiltrate separating tubular structures on renal biopsy, and eosinophilia are diagnostic.
• Acute Glomerular Nephritis. Findings include hematuria, red blood cell casts, and proteinuria.

Microscopic Analysis of Urinary Sediment

Casts

• Hyaline casts suggest prerenal azotemia or obstructive nephropathy.
• Red blood cell casts suggest glomerulonephritis.
• Broad casts (diameter greater than 2 to 3 white cells) suggest chronic renal failure.
• Brown pigmented granular casts and positive dipstick for blood, but without red cells suggests hemoglobinuria or myoglobinuria.

Cells

• Red cells without casts suggest calculi
• Predominantly polymorphonuclear leukocytes suggest diffuse interstitial nephritis or papillary necrosis.

Crystals

• Urate crystals suggest uric acid nephropathy.
• Oxalate and hippurate crystals suggest ethylene glycol exposure.

Chemical Analysis of Urine (Prior to Intravenous Fluid or Diuretics)

Prerenal Azotemia

• Urine sodium is less than 20 mmol/L.
• Urine osmolality is greater than 500 mOsm/kg.
• Urine analysis is normal.
• Urine to plasma creatinine ratio is greater than 40.
• BUN is elevated out of proportion to the plasma creatinine concentration.
• The fractional excretion of sodium (FENa) is less than 1.

ATN or AIN

• Urine sodium is greater than 40 mmol/L.
• Urine osmolality is less than 400 mOsm/kg.
• The urine to plasma creatinine ratio is less than 20.
• FENa is greater than 1.
• Uric acid nephropathy. Urinary uric acid to urinary creatinine ratio is greater than 1, and serum uric acid is in excess of 20 mg/dl.

Serum Electrolytes, BUN, Creatinine, Calcium, Phosphate, and Magnesium

• Elevations in both the BUN and creatinine concentrations are common in all forms of renal failure. A disproportionately high creatinine may suggest rhabdomyolysis, due to the conversion of muscle creatine to creatinine.
• Hyperkalemia due to decreased elimination is common. A high potassium level suggests hemolysis or rhabdomyolysis.
• Serum uric acid level is usually higher than 20 mg/dl in acute uric acid nephropathy.
• Complete blood count. Anemia may indicate chronic renal failure. Leukocytosis is consistent with infection.
• Serum ethylene glycol level should be determined if metabolic acidosis is present.
• Quantitation of the appropriate toxin (aminoglycoside, heavy metal) should be determined as appropriate.
• Postvoid residual catheter volume greater than 100 cc suggests postrenal obstruction.

Imaging

• Intravenous pyelography (IVP) should be performed with caution in patients with evidence of renal insufficiency.
• CT scan should be considered in situations where IVP is contraindicated.

Section Outline:

• DIFFERENTIAL DIAGNOSIS
  • Prerenal
  • Renal Parenchymal Disorders
  • Acute Urinary Tract Obstruction
• SIGNS AND SYMPTOMS
  • Vital Signs
  • Dermatologic
  • Cardiovascular
  • Pulmonary
  • Gastrointestinal
  • Hepatic
  • Renal
  • Hematologic
  • Fluids and Electrolytes
  • Musculoskeletal
  • Neurologic
  • Genitourinary
• PROCEDURES AND LABORATORY TESTS
  • Microscopic Analysis of Urinary Sediment
  • Chemical Analysis of Urine (Prior to Intravenous Fluid or Diuretics)
  • Serum Electrolytes, BUN, Creatinine, Calcium, Phosphate, and Magnesium

DIRECTING PATIENT COURSE

Monitor fluid intake and output. Correct electrolyte abnormalities as needed.

DECONTAMINATION

If acute renal failure is present, decontamination would not be expected to be effective.

ANTIDOTES

There is no specific antidote for most causes.

ADJUNCTIVE TREATMENT

• Hypocalcemia and metabolic acidosis associated with ATN rarely require treatment.
• Allopurinol can be used to treat gouty nephropathy. Allopurinol prior to administration of cytotoxic drugs may prevent acute uric acid nephropathy.
• Aluminum hydroxide can be used to treat hyperphosphatemia.
• Calcium chloride, sodium bicarbonate, insulin and glucose, and sodium polystyrene sulfonate can be used to treat hyperkalemia.
• Life-threatening hyperkalemia and hyperphosphatemia should be corrected with dialysis.
• Urine alkalinization may limit methotrexate nephrotoxicity.

Oliguria

• In the oliguric patient in whom prerenal causes have been excluded, the administration of a loop diuretic or mannitol may be useful.
• Administration of renal doses of dopamine (1 to 3 µg/kg/min) may increase renal blood flow and allow a diuretic response.

Section Outline:

• DIRECTING PATIENT COURSE
• DECONTAMINATION
• ANTIDOTES
• ADJUNCTIVE TREATMENT
  • Oliguria

• BUN or serum creatinine concentration at the upper end of the laboratory normal range may represent significant renal impairment.
• Trimethoprim and cimetidine block renal creatinine secretion, resulting in a reversible increase in serum creatinine.
• Elevated levels of serum acetone may artifactually increase the serum creatinine.
• Administration of diuretics or crystalloid fluid may interfere with urine analysis.

RECOMMENDED READING

Feinfeld DA. Principles of nephrotoxicity. In: Goldfrank LR, et al., eds. Goldfrank's toxicologic emergencies, 6th ed. Norwalk, CT: Appleton & Lange, 1998.

Author: Edwin K. Kuffner

Reviewer: Richard C. Dart