Acute Tubular Necrosis (ATN)

At a Glance

Acute tubular necrosis (ATN) refers to acute kidney injury as a result of severe tubular damage. Ischemia and exposure to nephrotoxins are the primary causes of ATN.

Ischemic damage is due to prolonged hypoperfusion characterized by inadequate glomerular filtration rate (GFR) and poor parenchymal cell function. Hypovolemia, septic shock, and major surgery are risk factors for ischemic ATN.

Nephrotic ATN may be precipitated by exogenous (more common) or endogenous agents. Exogenous nephrotoxins include aminoglycoside antibiotics (gentamicin, tobramycin), antifungal drugs (amphotericin B), chemotherapeutic agents (cisplatin), immunosuppressants (cyclosporine), radiocontrast media, organic solvents (ethylene glycol), and heavy metals (arsenic, cadmium, mercury). Both glycopeptide (vancomycin) and β-lactam (cephalosporins) antibiotics have been reported to induce ATN. Endogenous nephrotoxins include heme-containing compounds (myoglobin, hemoglobin), uric acid, and paraproteins (Bence Jones protein). Recent exposure to toxic medications, radiocontrast agents, or endogenous toxins increases the risk of nephrotoxic ATN.

Individuals of advanced age, with pre-existing kidney disease, diabetic nephropathy, coronary heart failure, multiple myeloma, or volume depletion or who have been subjected to repeat doses of contrast media, are at higher risk for developing ATN.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Laboratory testing should be performed to evaluate general renal function and tubular function.(Table 1)

Table 1.
Urea Nitrogen (Serum or plasma) Creatinine (Serum or plasma) Urea/creatinine ratio Fractional excretion of sodium
Increased Increased <20:1 FENa > 1%

Measure urea and creatinine in serum or plasma to assess overall renal function. In ATN, urea nitrogen (8-22 mg/dL) and creatinine (0.7-1.5 mg/dL) are increased, although the urea/creatinine ratio (10-20:1) remains normal. GFR can be estimated from serum creatinine concentration or measured.

Tubular function is assessed by determining proximal tubular reabsorptive capability and concentrating ability of the loop of Henle. For substances filtered and reabsorbed, clearance relative to GFR provides a measure of tubular function. Potassium, magnesium, bicarbonate, phosphate, uric acid, and glucose are filtered by the glomerulus and reabsorbed in the proximal tubule. Low plasma concentrations of these analytes (except glucose) and high urine glucose, with normal plasma glucose concentration, indicate tubular damage.

Urine output is often normal (nonoliguric) in cases of drug-induced ATN; shock-induced ATN usually shows decreased urine output (oliguria). In oliguria (urine output <400 mL/d), urine osmolality and electrolyte concentrations can establish renal tubular dysfunction as the cause. Osmolality is the best test of kidney concentrating ability. In ATN, urine osmolality approximates plasma osmolality (275-295 mOsm/kg) and free water clearance. The difference between urine volume (total water clearance) and required water clearance (osmolar clearance) is negligible.

Excretion tests monitor concentrating sufficiency of the loop of Henle and distal nephron as fractional excretion. Fractional excretion of sodium (FENa) relates sodium clearance to creatinine clearance and measures the ability of tubules to conserve sodium. In ATN, inability to reabsorb sodium produces a high fractional excretion (FENa >1%).

Routine urinalysis, including microscopic examination of urine sediment, should be performed. Urine may be brown in color. Tubular injury allows loss of small compounds, such as glucose, bicarbonate, and potassium, as well as some proteins. Glucose and protein may be positive by dipstick. Microscopic examination may reveal increased numbers of renal tubular epithelial cells. Hyaline casts or granular casts composed of intact or degenerating epithelial cells, Tamm-Horsfall protein, and pigments may be present.

Measurement of small molecular weight proteins in urine and detection of the enzyme N-acetylglucosaminidase, which is present in significant concentration in renal tubular epithelial cells, are sensitive tests of proximal tubular damage. Small proteins lost to the urine because of tubular compromise can be visualized by urine protein electrophoresis. In addition to albumin, found in specimens from intact kidneys, additional bands in the pre-alpha1 and alpha2 regions appear with tubular damage. Proteins, such as retinol binding protein, β2-microglobulin, and lysozyme, can be measured quantitatively.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Urine electrolytes should not be used to test for tubular damage in nonoliguric patients or patients taking diuretics.

What Lab Results Are Absolutely Confirmatory?

Observation of pigmented granular casts and increased numbers of renal tubular epithelial cells in urine sediment is pathognomonic.

Additional Issues of Clinical Importance

Large amounts of water and electrolytes can be lost in urine. In severe cases, urine solute concentration resembles plasma composition. Sodium may be greater than 100 mmol/L (43-260 mmol/d), potassium less than 10 mmol/L (25-125 mmol/d), and creatinine below 20 mg/dL (1-2 g/d). Measurement of urine electrolytes is useful to fit replacement to losses.

Renal tubular epithelial (RTE) cells can be difficult to distinguish from transitional epithelial cells. RTE cells can be identified by staining with labeled antibodies to Tamm-Horsfall protein.

Errors in Test Selection

Although specific gravity and osmolality are both measures of total solute concentration, urine specific gravity depends on solute weight and will be higher when high molecular weight substances (glucose, proteins, radiocontrast agents) are present. Urine osmolality is a measure of molar solute concentration and provides a more accurate indication of tubular function.

Notes on Interpretation of Test Results

FENa is high in most cases of ischemic ATN, but is often low in patients with ATN due to sepsis or nephrotoxic ATN resulting from heme or radiocontrast agents.

Detection of oxalate crystals in urine sediment should prompt consideration of ethylene glycol poisoning as the precipitating cause of ATN and initiate performance of appropriate toxicological studies.

Hyperuricemia and urate crystals in urine sediment support ATN because of tumor lysis in the context of recent chemotherapy.

Positive dipstick heme, without hematuria, indicates rhabdomyolysis or hemolysis (transfusion reaction).

Dipstick negative proteinuria in ATN due to multiple myeloma can be evaluated by urine protein electrophoresis.