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Nephrology and Urology· Topic 9.1 Acute kidney injury and tubulointerstitial disease· 9.1.1
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Acute tubular necrosis

Acute tubular necrosis (ATN) is direct injury to the renal tubular epithelium from prolonged ischemia, sepsis, or nephrotoxins, and is the most common cause of intrinsic acute kidney injury in hospitalized patients. It is diagnosed from a compatible exposure history, muddy brown granular casts on urine microscopy, and a fractional excretion of sodium above 2%, and is managed with supportive care, since no pharmacologic therapy reverses established tubular injury.

13 min readReviewed 2026-07-19

Key facts

Most common cause of AKI in hospitalized patients
ATN from ischemia, sepsis, and/or nephrotoxins
Classic urine sediment
Coarse granular (muddy brown) casts and renal tubular epithelial cells
Key discriminator vs prerenal AKI
FENa >2% and FEurea >35% (vs <1% and <35% in prerenal); urine specific gravity ~1.010 (vs >1.020)
BUN:creatinine ratio
10-15:1 in ATN vs >20:1 in prerenal azotemia
Does not improve with volume
Unlike prerenal AKI, ATN does not rapidly reverse with restored perfusion
No specific pharmacotherapy
Treatment is supportive; no drug reverses established tubular injury
Prognosis marker
Nonoliguric ATN has a better renal prognosis than oliguric ATN
Recovery
Complete or partial renal recovery over days to weeks; some progress to dialysis-dependent ESKD

Overview

  • Direct structural injury to the renal tubular epithelium: acute tubular necrosis (ATN) is the most common cause of intrinsic acute kidney injury (AKI), produced by prolonged ischemia, sepsis, and/or nephrotoxin exposure.
  • Mechanistically distinct from prerenal azotemia: prerenal AKI is a functional, rapidly reversible response to hypoperfusion with intact tubular structure, whereas ATN reflects actual cellular injury and does not rapidly improve once intravascular volume and renal blood flow are restored.
  • A history-driven diagnosis: sepsis, documented protracted hypotension, or nephrotoxin exposure, together with hemodynamic and volume status assessment, are the key clues that point to ATN.
  • No specific pharmacologic therapy exists: management is supportive, and recovery, when it occurs, unfolds over days to weeks.

Epidemiology

  • The leading cause of AKI in hospitalized patients, most often from ischemia, sepsis, or nephrotoxin exposure, alone or in combination.
  • Common across critical illness and general wards alike, since sepsis, hypotension, and nephrotoxin exposure are frequent in both settings.

Risk factors

  • Sepsis and prolonged hypotension: the leading precipitants of ischemic ATN through sustained renal hypoperfusion.
  • Prolonged or unresolved prerenal state: any cause of persistent volume depletion or decreased effective arterial circulation that is not corrected can progress from reversible prerenal azotemia into ischemic ATN.
  • Nephrotoxin exposure: aminoglycosides, vancomycin (particularly combined with piperacillin-tazobactam), polymyxins, amphotericin B, cisplatin, foscarnet, tenofovir, cidofovir, carboplatin, ifosfamide, lithium, pentamidine, and iodinated contrast agents.
  • Older age, hypertension, atherosclerotic or renovascular disease, and CKD: impaired renal autoregulation allows normotensive ischemic ATN when blood pressure falls below a patient's accustomed baseline even within the normal range, and raises the risk of drug-induced ATN with concomitant nephrotoxin exposure.
  • Rhabdomyolysis and intravascular hemolysis: pigment nephropathy from myoglobin or hemoglobin release.
  • Osmotic/hyperosmolar exposures: sucrose-containing intravenous immunoglobulin, mannitol, hydroxyethyl starch, dextran, and contrast media can cause osmotic nephrosis.

Pathophysiology

  • Ischemic ATN follows sustained hypoperfusion: severe or prolonged ischemia from hypotension, a protracted prerenal state, or sepsis triggers cytokine release, oxygen free-radical and enzyme production, endothelial activation, leukocyte adhesion, and coagulation activation, culminating in tubular cell apoptosis.
  • Three converging mechanisms drop the glomerular filtration rate: renal vasoconstriction, tubular back-leak of filtrate into the bloodstream, and intratubular obstruction from sloughed cellular debris.
  • Direct tubular toxicity underlies drug-induced ATN: aminoglycosides cause nonoliguric ATN via direct toxicity (creatinine rise 5-7 days after starting therapy); cisplatin injures via direct toxicity, vasoconstriction, and inflammation; amphotericin B causes dose-related injury via vasoconstriction and direct toxicity (lipid-based preparations reduce this risk); contrast agents cause nonoliguric ATN via vasoconstriction and oxygen free-radical injury (creatinine rise within 24-48 hours). Vancomycin nephrotoxicity tracks with trough >15 mg/L, dose ≥4 g/day, prolonged therapy, or a concomitant nephrotoxin (aminoglycoside, piperacillin-tazobactam).
  • Osmotic nephrosis produces vacuolization and swelling of proximal tubular cells from hyperosmolar substances (sucrose-containing immunoglobulin, mannitol, hydroxyethyl starch, dextran, contrast), causing tubular obstruction and damage.
  • Pigment nephropathy from myoglobin (rhabdomyolysis) or hemoglobin (intravascular hemolysis) causes injury through volume depletion, renal vasoconstriction, direct proximal tubular toxicity, and tubular obstruction; hypomagnesemia, hypokalemia, hypophosphatemia, hypocalcemia, and metabolic acidosis can reflect underlying tubular injury from any cause.

Clinical features

  • A rise in serum creatinine in the setting of a clear precipitant: sepsis, documented hypotension, or a nephrotoxin exposure, often identified through the medication and exposure history.
  • Urine output pattern varies and does not reliably distinguish ATN from prerenal AKI: ATN can be oliguric or nonoliguric; nonoliguric ATN, more typical of aminoglycoside or contrast-induced injury, carries a better prognosis than oliguric ATN.
  • No rapid response to volume repletion: unlike prerenal AKI, ATN does not improve quickly with restoration of intravascular volume and renal blood flow, a key bedside discriminator.
  • Signs of the underlying precipitant dominate the presentation: fever and hypotension in sepsis, evidence of hemorrhage or gastrointestinal losses in ischemic ATN, or a temporal link to a recently started nephrotoxic drug or contrast administration.
  • Symptoms of uremia, volume overload, or hyperkalemia develop with more severe or prolonged ATN: nausea, dyspnea, edema, and, in severe cases, arrhythmia or encephalopathy.

Differential diagnosis

  • Prerenal azotemia: BUN:creatinine ratio >20:1, urine osmolality >500 mOsm/kg, urine sodium <20 mEq/L, FENa <1%, FEurea <35%, and specific gravity >1.020 with a bland or hyaline-cast sediment, versus ATN's ratio of 10-15:1, FENa >2%, FEurea >35%, and muddy brown casts; response to a volume challenge (improved urine output and creatinine) supports prerenal disease over ATN.
  • Acute interstitial nephritis: leukocytes, erythrocytes, and leukocyte casts on urinalysis, with a temporal link to a culprit drug rather than ischemia or a direct nephrotoxin, distinguish it from ATN's granular casts and tubular epithelial cells.
  • Acute glomerulonephritis: proteinuria with dysmorphic erythrocytes and erythrocyte casts, often with hypertension, edema, and a positive serologic workup, differentiate it from ATN.
  • Postrenal (obstructive) AKI: hydronephrosis on renal ultrasound identifies obstruction; urinalysis is variable but typically bland, unlike the muddy brown casts of ATN.
  • Contrast-associated nephropathy: a specific ATN subtype identified by a creatinine rise beginning 24-48 hours after contrast exposure with a nonoliguric course, which the temporal link to contrast (rather than an unclear ischemic or toxic trigger) confirms.
  • Atheroembolic disease: a slow, stuttering creatinine rise days to weeks after a vascular procedure, often with livedo reticularis and digital ischemia, distinguishes it from the more abrupt course of ischemic or toxic ATN.
  • Thrombotic microangiopathy (TTP/HUS): concurrent microangiopathic hemolytic anemia and thrombocytopenia distinguish it from isolated ATN.
  • Multiple myeloma cast nephropathy: other myeloma features (anemia, hypercalcemia, bone lesions) plus a monoclonal protein on serum/urine immunofixation with Bence-Jones proteinuria, absent in typical ATN, confirms this cause instead.
  • Rhabdomyolysis/pigment nephropathy: creatine kinase typically >5000 U/L (rhabdomyolysis) or hemolysis markers (elevated LDH, decreased haptoglobin) plus a urine dipstick positive for blood without erythrocytes on microscopy identify a pigment-mediated cause of ATN rather than an unclear ischemic or toxic trigger.

Diagnosis

  • ATN is a clinical diagnosis established by a compatible exposure history (sepsis, protracted hypotension, or nephrotoxin exposure) together with urine studies showing FENa >2% (or FEurea >35% if the patient is on diuretics) and muddy brown granular casts with tubular epithelial cells on microscopy; kidney biopsy is not routinely needed and is reserved for AKI with no apparent cause.
  • First, review prior creatinine values and take a targeted history: vasoactive and nephrotoxic medications (including over-the-counter drugs, herbal products, and recreational drugs), recent iodinated contrast exposure, and predisposing conditions for hypoperfusion or sepsis; note that the rise in serum creatinine is delayed 24-36 hours after the actual onset of tubular injury.
  • Next, assess hemodynamics and volume status on exam: blood pressure, heart rate, jugular venous pressure, skin turgor, and bladder percussion/palpation to exclude an obstructive component.
  • Then, send urine studies: urinalysis with microscopy (muddy brown casts and tubular epithelial cells support ATN; specific gravity around 1.010) and, in oliguric patients, FENa (>2% supports ATN, <1% supports prerenal disease) or FEurea (>35% supports ATN, <35% supports prerenal disease) if the patient has received diuretics; note FENa can be falsely low in ATN from contrast nephropathy, pigment nephropathy, glomerulonephritis, or early obstruction.
  • Obtain renal ultrasonography to exclude urinary tract obstruction and when the underlying cause of AKI is unclear; a normal or near-normal kidney size supports an acute rather than chronic process.
  • Send supporting labs: complete blood count, electrolytes (including magnesium, phosphate, calcium), and creatine kinase or hemolysis markers (LDH, haptoglobin) when pigment nephropathy is suspected.
  • Reserve kidney biopsy for AKI of no apparent cause, suspected glomerulonephritis, or unexplained systemic disease, since typical ATN does not require histologic confirmation.

Clinical pearl. ATN does not rapidly improve after a volume challenge the way prerenal azotemia does; if urine output and creatinine fail to improve within hours of adequate volume repletion, stop chasing prerenal etiology and work up ATN and its precipitants (sepsis source, nephrotoxin list, contrast timeline).

Management

  • First, identify and treat the underlying precipitant, since no drug reverses established tubular injury and treatment is otherwise supportive: source-control sepsis, restore perfusion in hypotension or hypovolemia, and stop any implicated nephrotoxic drug (aminoglycoside, vancomycin, amphotericin B, cisplatin, NSAID) immediately.
  • Then, optimize volume status: give isotonic IV fluids to correct hypovolemia and maintain perfusion, avoiding overload once euvolemic; for normotensive ischemic ATN from over-treated hypertension, reduce antihypertensive medications to let blood pressure return toward the patient's accustomed baseline.
  • If hyperkalemia develops with ECG changes (peaked T waves, QRS widening), give calcium gluconate 1 g IV for membrane stabilization, then insulin 10 units IV with dextrose to shift potassium intracellularly, and monitor magnesium, phosphate, and calcium.
  • If volume overload develops and the patient still makes urine, give furosemide 40 mg IV (or the equivalent of the total daily oral dose given intravenously), titrated to decongestion; diuretics manage volume only and do not shorten the course of ATN.
  • If AEIOU criteria are refractory to medical management, start renal replacement therapy: refractory Acidosis, Electrolyte imbalance (especially hyperkalemia), Intoxication with a dialyzable toxin, volume Overload unresponsive to diuretics, or Uremia (pericarditis, encephalopathy); also consider it with GFR typically <10 mL/min/1.73 m2 and declining urine output.
  • For patients at risk of contrast-associated ATN (eGFR <30 mL/min/1.73 m2 or existing AKI), give prophylactic isotonic 0.9% saline IV, 6-12 hours before contrast exposure and continued 6-12 hours after:
    • 1 mL/kg/hr standard rate
    • 0.5 mL/kg/hr if left ventricular ejection fraction is reduced or there is clinical evidence of volume overload
  • Do not use sodium bicarbonate infusion or oral N-acetylcysteine for contrast prophylaxis, as neither has shown consistent efficacy; avoid nephrotoxic drugs and repeat contrast exposure during recovery, and adjust renally cleared medication doses to current kidney function.

Complications

  • Progression to dialysis-dependent end-stage kidney disease: patients with severe ATN requiring acute dialysis often recover function, but some do not and remain dialysis-dependent.
  • Uremic complications: pericarditis, encephalopathy, and bleeding diathesis with severe, prolonged AKI.
  • Volume overload and hyperkalemia, particularly in oliguric ATN, which carries a worse renal prognosis than nonoliguric ATN.
  • Metabolic acidosis from impaired renal acid excretion.
  • Increased long-term risk of CKD and cardiovascular events after an episode of AKI/ATN, independent of complete apparent recovery of serum creatinine.

Prognosis

  • Complete or partial renal recovery over days to weeks is typical, since ATN largely reflects reversible cellular injury with intact tubular basement membranes.
  • Nonoliguric ATN has a better renal prognosis than oliguric ATN.
  • Advanced pre-existing CKD lowers the likelihood of recovering kidney function compared with a normal baseline or early CKD.
  • Severe ATN requiring acute dialysis often recovers, but some patients progress to dialysis-dependent end-stage kidney disease.
  • An episode of AKI/ATN independently raises long-term risk of CKD and end-stage kidney disease, warranting follow-up even after apparent creatinine normalization.

Prevention

  • Give prophylactic isotonic 0.9% saline 1 mL/kg/hr IV, 6-12 hours before and after contrast, for eGFR <30 mL/min/1.73 m2 or existing AKI; consider it for eGFR 30-44 mL/min/1.73 m2 with added risk factors, and withhold it for stable eGFR ≥45 mL/min/1.73 m2.
  • Minimize contrast volume and avoid repeat contrast exposure within a short interval in patients with reduced eGFR.
  • Dose aminoglycosides and vancomycin by weight and renal function, keep vancomycin trough below 15 mg/L when feasible, and avoid combining vancomycin with piperacillin-tazobactam or an aminoglycoside when alternatives exist.
  • Use lipid-based amphotericin B instead of conventional amphotericin B for prolonged or high-dose therapy, to reduce nephrotoxicity.
  • Avoid NSAIDs and other nephrotoxins in sepsis, hypovolemia, or CKD, and correct hypovolemia promptly to prevent progression from a reversible prerenal state to established ATN.

Key points

  • ATN is direct tubular epithelial injury from ischemia, sepsis, and/or nephrotoxins, and is the most common cause of intrinsic AKI in hospitalized patients.
  • FENa >2% (or FEurea >35% on diuretics) and muddy brown granular casts with tubular epithelial cells distinguish ATN from prerenal azotemia (FENa <1%, FEurea <35%, bland or hyaline-cast sediment).
  • Unlike prerenal AKI, ATN does not rapidly improve with volume repletion, a key bedside clue.
  • There is no specific drug therapy; management is supportive (treat the precipitant, optimize volume, correct electrolytes, dialyze for refractory AEIOU criteria).
  • Nonoliguric ATN has a better prognosis than oliguric ATN, and recovery, when it occurs, unfolds over days to weeks.
  • Contrast-associated ATN is prevented with periprocedural isotonic saline (1 mL/kg/hr, 6-12 hours before and after) in patients with eGFR <30 mL/min/1.73 m2 or AKI; sodium bicarbonate and N-acetylcysteine are not recommended.

Practice questions

Board-style vignettes on this article, free with it. Pick an answer to see why each choice is right or wrong.

Vignette
A 64-year-old man is evaluated in the ICU on hospital day 3 for septic shock due to pneumonia. Urine output has been 10 mL/h for 24 hours despite escalating doses of intravenous furosemide. Baseline creatinine was 1.0 mg/dL. Temperature is 38.2 °C (100.8 °F), blood pressure is 86/50 mm Hg on norepinephrine and vasopressin, pulse rate is 116/min, respiration rate is 18/min, and oxygen saturation is 89% with an Fio2 of 0.6. Diffuse crackles are present. Laboratory studies: Blood urea nitrogen: 70 mg/dL Creatinine: 4.6 mg/dL Potassium: 6.0 mEq/L Bicarbonate: 12 mEq/L Arterial pH: 7.15 (normal, 7.38-7.44) Urinalysis: muddy brown granular casts Chest radiograph: bilateral infiltrates with vascular congestion Which of the following is the most appropriate next step in management?
Vignette
A 58-year-old woman is evaluated in the hospital for new rigors and lightheadedness. She was admitted 2 days ago for left leg cellulitis treated with intravenous cefazolin. She weighs 70 kg. Temperature is 39.2 °C, blood pressure 84/48 mm Hg, pulse rate 122/min, respiration rate 24/min and oxygen saturation 96% breathing ambient air. Mucous membranes are dry, jugular veins are flat, the lungs are clear, and there is no peripheral edema. Urine output has been 20 mL/h for 6 hours. Potassium is 4.3 mEq/L, bicarbonate 20 mEq/L, creatinine 1.3 mg/dL (0.9 mg/dL on admission) and lactate 3.8 mmol/L (normal, 0.7-2.1 mmol/L). Blood cultures are drawn and broad-spectrum antibiotics started. Which of the following is the most appropriate next step in management?
Vignette
high-yield
A 66-year-old woman is evaluated for new dyspnea on postoperative day 3 after emergency colectomy for perforated diverticulitis. She had 6 hours of preoperative septic shock; norepinephrine was stopped yesterday. She is 6 L net positive, and urine output was 320 mL over 24 hours. Temperature is 37.4 °C (99.3 °F), blood pressure is 142/84 mm Hg, pulse rate is 92/min, respiration rate is 24/min, and oxygen saturation is 91% on 4 L/min oxygen. Jugular venous pressure is 14 cm H2O, with bilateral crackles and 2+ leg edema. Creatinine: 3.2 mg/dL (0.8 mg/dL on admission) Potassium: 5.3 mEq/L Urinalysis: specific gravity 1.010; granular casts Which of the following is the most appropriate next step in management?
Vignette
high-yield
An 82-year-old woman is evaluated on hospital day 4 for rising creatinine after coronary angiography and stenting, during which blood pressure was 84/50 mm Hg for 40 minutes. She is drinking normally, with urine output of 1100 mL/day. She has hypertension and stage 3a chronic kidney disease. Temperature is 36.8 °C (98.2 °F), blood pressure is 124/72 mm Hg, pulse rate is 78/min, respiration rate is 16/min, and oxygen saturation is 96% on ambient air. Jugular venous pressure is 7 cm H2O, with clear lungs and no edema. Creatinine: 2.1 mg/dL (1.3 mg/dL on admission) Potassium: 5.2 mEq/L Urinalysis: specific gravity 1.010; granular casts; tubular epithelial cells Which of the following is the most appropriate next step in management?
Vignette
high-yield
A 59-year-old man is evaluated in the intensive care unit on hospital day 8 for 2 days of increasing confusion. He was admitted with septic shock and developed oliguric acute kidney injury, with urine output of 400 mL/24 h. Temperature is 37.1 °C (98.8 °F), blood pressure is 146/84 mm Hg, pulse rate is 98/min, respiration rate is 18/min, and oxygen saturation is 95% on ambient air. He is disoriented. A pericardial friction rub is heard, and the lungs are clear. Potassium is 5.4 mEq/L, bicarbonate is 17 mEq/L, BUN is 124 mg/dL, and creatinine is 7.1 mg/dL. Arterial pH is 7.31 (normal, 7.38-7.44). ECG shows no ST-segment changes. Which of the following is the most appropriate next step in management?
Vignette
high-yield
A 72-year-old man is evaluated on postoperative day 3 after open abdominal aortic aneurysm repair for urine output of 300 mL over 24 hours. Intraoperative systolic blood pressure was 75-85 mm Hg for 2 hours. He received perioperative cefazolin. Temperature is 37.3 °C (99.1 °F), blood pressure is 134/78 mm Hg, pulse rate is 88/min, respiration rate is 18/min, and oxygen saturation is 95% on ambient air. The feet are warm without skin discoloration. BUN: 42 mg/dL Creatinine: 3.0 mg/dL (1.1 mg/dL preoperatively) Sodium: 138 mEq/L Urine sodium: 68 mEq/L (normal, varies) Urine creatinine: 30 mg/dL (normal, varies) Urinalysis: specific gravity 1.010; 0-2 leukocytes/hpf; numerous pigmented granular casts Ultrasound shows no hydronephrosis. Which of the following is the most likely diagnosis?

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