Acute Tubular Necrosis 

Updated: Mar 15, 2021
Author: Sangeeta Mutnuri, MBBS; Chief Editor: Vecihi Batuman, MD, FASN 


Practice Essentials

Acute tubular necrosis (ATN) is the most common cause of acute kidney injury (AKI) in the renal category (that is, AKI in which the pathology lies within the kidney itself). The term ATN is actually a misnomer, as there is minimal cell necrosis and the damage is not limited to tubules.[1] See the ATN image below.

Acute tubular necrosis. Photomicrograph of a kidne Acute tubular necrosis. Photomicrograph of a kidney biopsy specimen shows renal medulla, which is composed mainly of renal tubules. Features suggesting acute tubular necrosis are the patchy or diffuse denudation of the renal tubular cells with loss of brush border (blue arrows); flattening of the renal tubular cells due to tubular dilation (orange arrows); intratubular cast formation (yellow arrows); and sloughing of cells, which is responsible for the formation of granular casts (red arrow). Finally, intratubular obstruction due to the denuded epithelium and cellular debris is evident (green arrow); note that the denuded tubular epithelial cells clump together because of rearrangement of intercellular adhesion molecules.

ATN follows a well-defined three-part sequence of initiation, maintenance, and recovery (see Pathophysiology). The initiation phase is characterized by an acute decrease in glomerular filtration rate (GFR) to very low levels, with a corresponding sudden increase in serum creatinine and blood urea nitrogen (BUN) concentrations.

The maintenance phase is characterized by a sustained severe reduction in GFR that persists 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 levels continue to rise.

The recovery phase, in which tubular function recovers, 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.

The tubule cell damage and cell death that characterize ATN usually result from an acute ischemic or toxic event. Nephrotoxic mechanisms of ATN include direct drug toxicity, intrarenal vasoconstriction, and intratubular obstruction (see Pathophysiology and Etiology). Most of the pathophysiologic features of ischemic ATN are shared by the nephrotoxic forms.[2]

The history, physical examination, and laboratory findings, especially the renal ultrasonogram and the urinalysis, are particularly helpful in identifying the cause of ATN (see Presentation and Workup).

Therapeutic mainstays are prevention, avoidance of further kidney damage, treatment of underlying conditions, and aggressive treatment of complications (see Treatment and Medication).

Go to Pediatric Acute Tubular Necrosis for complete information on this topic. For patient education information, see Acute Kidney Failure.


Acute tubular necrosis (ATN) follows a well-defined three-part sequence of initiation, maintenance, and recovery (see below). The tubule cell damage and cell death that characterize ATN usually result from an acute ischemic or toxic event. Most of the pathophysiologic features of ischemic ATN, as described below, are shared by the nephrotoxic forms.

Initiation phase

Ischemic ATN is often described as a continuum of prerenal azotemia. Indeed, the causes of the two conditions are the same. 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 the glomerular filtration rate (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).

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 (see the image below). Activation of the renal immune system—with damage to tubular cells stimulating local secretion of proinflammatory cytokines—in turn induces further necrosis.[3]

Acute tubular necrosis. Photomicrograph of a kidne Acute tubular necrosis. Photomicrograph of a kidney biopsy specimen shows renal medulla, which is composed mainly of renal tubules. Features suggesting acute tubular necrosis are the patchy or diffuse denudation of the renal tubular cells with loss of brush border (blue arrows); flattening of the renal tubular cells due to tubular dilation (orange arrows); intratubular cast formation (yellow arrows); and sloughing of cells, which is responsible for the formation of granular casts (red arrow). Finally, intratubular obstruction due to the denuded epithelium and cellular debris is evident (green arrow); note that the denuded tubular epithelial cells clump together because of rearrangement of intercellular adhesion molecules.

In addition, ischemia leads to decreased production of vasodilators (ie, nitric oxide, prostacyclin [prostaglandin I2, or 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.

Maintenance phase

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.

Recovery phase

The recovery phase of ATN is characterized by regeneration of tubular epithelial cells.[4] 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.

Normotensive ischemic acute tubular necrosis

This is a condition that develops in patients without an overt severe hypotensive episode. These patients have low-normal blood pressure but still have severe ATN. The most common reason for this condition is renal susceptibility to the lower blood pressure because of impairment of autoregulatory function of the kidney. Normally, the afferent arteriole dilates (via prostaglandins) and efferent arteriole constricts (via angiotensin-II)  to maintain the glomerular capillary pressure. Factors that impair this autoregulatory mechanisms include the following[5] :

  • Advanced age
  • Atherosclerosis, hypertension, and chronic kidney disease
  • Malignant hypertension
  • Medications impairing the autoregulatory mechanism (eg, nonsteroidal anti-inflammatory drugs [NSAIDs])
  • Afferent glomerular vasoconstriction  (eg, from sepsis, hypercalcemia, hepatorenal syndrome, cyclosporine/tacrolimus)
  • Drugs blocking efferent arteriolar vasoconstriction - Angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs)

Endotoxemia (sepsis)-related ATN

Sepsis is a recognized cause of ATN. However, the hypothesis that ATN develops in these cases when sepsis-related hypotension leads to a reduction in renal blood flow has been challenged by several animal and human studies. Those studies have indicated that in fact, renal blood flow may increase in that setting, due to a mechanism leading to efferent arteriolar vasodilatation.[6]

Other suspected contributors to ATN in sepsis include the following:

  • Intra-renal vasoconstriction and redistribution of renal blood flow to the cortex
  • Activation of vasoactive intrarenal hormones (endothelin, renin-angiotensin- aldosterone)
  • Nitric oxide synthase induction and release of several cytokines



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

Causes of 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 gastrointestinal (GI) or renal losses, burns, fluid sequestration
  • Low cardiac output states: Heart failure and other diseases of myocardium, valvulopathy, arrhythmia, pericardial diseases, tamponade
  • Systemic vasodilation: Sepsis, anaphylaxis
  • Surgical procedures in which renal blood flow is compromised (eg, those that involve clamping of the renal artery, such as coronary artery bypass grafting [CABG], aortic dissection repair, renal cell carcinoma resection)

Causes of nephrotoxic acute tubular necrosis

The kidney is a particularly vulnerable target for toxins, both exogenous and endogenous. 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 that cause ATN

Aminoglycoside-related toxicity occurs in 10-30% of patients receiving aminoglycosides, even when blood levels are in apparently therapeutic ranges. Risk factors for ATN in these patients include the following:

  • Preexisting liver or kidney disease
  • Concomitant use of other nephrotoxins (eg, amphotericin B, radiocontrast media, cisplatin)
  • Shock
  • Advanced age
  • Female sex
  • Higher aminoglycoside level 1 hour after dose (a high trough level has not been shown to be an independent risk factor)

Amphotericin B nephrotoxicity risk factors include the following:

  • Male sex
  • High maximum daily dose (nephrotoxicity is more likely to occur if >3 g is administered)
  • Longer duration of therapy
  • Hospitalization in the critical care unit at the initiation of therapy
  • Concomitant use of cyclosporine

Radiographic contrast media can cause contrast-induced nephropathy (CIN) or radiocontrast nephropathy (RCN); this commonly occurs in patients with several risk factors, such as elevated baseline serum creatinine, preexisting renal insufficiency, underlying diabetic nephropathy, chronic heart failure [CHF], or high or repetitive doses of contrast media, as well as volume depletion and concomitant use of diuretics, ACE inhibitors, or ARBs. The 2011 UKRA guidelines recommend that patients at risk of CIN should have a careful evaluation of volume status and receive volume expansion with 0.9% sodium chloride or isotonic sodium bicarbonate before the procedure.[7]

Other exogenous nephrotoxins that can cause ATN include the following:

  • Cyclosporine and tacrolimus (calcineurin inhibitors)
  • Cisplatin
  • Ifosfamide
  • Foscarnet
  • Pentamidine, which is used to treat Pneumocystis jiroveci infection in immunocompromised individuals (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)
  • Sulfa drugs
  • Acyclovir and indinavir
  • Tenofovir
  • Mammalian target of rapamycin (mTOR) inhibitors (eg, everolimus, temsirolimus) [8]

Endogenous nephrotoxins that cause ATN

In myoglobinuria, rhabdomyolysis is the most common cause of heme pigment–associated acute kidney injury (AKI) and can result from traumatic or nontraumatic injuries. Most cases of rhabdomyolysis are nontraumatic, such as those related to alcohol abuse or drug-induced muscle toxicity (eg, statins alone or in combination with fibrates).

In hemoglobinuria, AKI is a rare complication of hemolysis and hemoglobinuria, and most often is associated with transfusion reactions (in contrast to myoglobin, hemoglobin has no apparent direct tubular toxicity, and AKI in this setting is probably related to hypotension and decreased renal perfusion).[8]

Acute crystal-induced nephropathy occurs when 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 (eg, ethylene glycol) or nontoxic substances (eg, vitamin C). Choudhry et al reported a case of AKI caused by ingestion of excessive quantities of calcium-containing antacids.[9]

In multiple myeloma, renal impairment results from the accumulation and precipitation of light chains, which form casts in the distal tubules that cause renal obstruction. In addition, myeloma light chains have a direct toxic effect on proximal renal tubules.[10]


For patients with ATN, the in-hospital survival rate is approximately 50%, with about 30% of patients surviving for 1 year. Factors associated with an increased mortality rate include the following:

  • Poor nutritional status
  • Male sex
  • Oliguria
  • Need for mechanical ventilation
  • Acute myocardial infarction
  • Stroke
  • Seizures

The mortality rate in patients with ATN 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%). 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 to 80%.

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. In addition, 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.

A review of United States Renal Data System data (n = 1,070,490) for 2001 through 2010 found that although the incidence of end-stage renal disease (ESRD) attributed to ATN increased during that period, the prospects for renal recovery and survival also increased. Recovery of renal function was more likely in patients with ATN than in matched controls (cumulative incidence 23% vs. 2% at 12 weeks, 34% vs. 4% at 1 year), as was death (cumulative incidence 38% vs. 27% at 1 year). Hazards ratios for death declined in stepwise fashion to 0.83 in 2009-2010.[11]

For post AKI hospitalization outcomes and monitoring see Treatment/Long-Term Monitoring




The landmark PICARD (Program to Improve Care in Acute Renal Disease) study was an observational study of a cohort of 618 patients with acute kidney injury in the intensive care units of 5 academic centers in the United States. Ischemic ATN was the presumed etiology for 50% of all patients with renal failure, an additional ~12% due to unresolved pre-renal factors, and ~25% from nephrotoxic ATN.[12]  These data were similar to those from the Madrid Acute Renal Failure Study Group, which assessed 748 cases of acute injury from that region of Spain and estimated that the incidence of ATN was 88 cases per million population.[13]






The patient’s history is very important in the diagnosis of acute tubular necrosis (ATN), as it can establish the risk factors for the development of ATN. A careful historical timeline of events leading to acute kidney injury (AKI) can frequently identify the underlying cause. 

The history commonly reveals recent surgery, hypotension, sepsis, muscle necrosis, or volume depletion, as well as exposure to nephrotoxic agents. Several of those may be present simultaneously, which increases the risk and severity of ATN. 

In addition, pre-existing medical conditions or medication use (eg, diabetes mellitus, multiple myeloma, nonsteroidal anti-inflammatory drugs) may contribute to the worsening of renal function. Hence, a thorough medical and medication history can also be key to the diagnosis.



Physical Examination

Physical examination findings are often unremarkable and acute kidney injury (AKI) is incidentally detected on routine laboratory studies (ie, elevated blood urea nitrogen [BUN] and creatinine levels).

Findings may suggest hypovolemia (eg, low jugular venous pressure, loss of skin turgor, orthostatic hypotension, dry mucous membranes, tachycardia) as a cause. Abdominal distension may raise the concern of intra-abdominal hypertension and compartment syndrome as a potential cause of ATN. Muscle tenderness could potentially be due to rhabdomyolysis, which can lead to ATN. 







Approach Considerations

Blood studies and urinalysis, along with renal ultrasound findings, are particularly helpful in identifying the cause of acute tubular necrosis (ATN). Findings on some tests will vary depending on the cause of ATN. Careful monitoring of the fluid balance, ongoing medication details, and daily physical examinations should all be considered together with laboratory tests. 

Suggested testing includes the following:

  • Complete blood cell count (CBC)
  • Blood urea nitrogen (BUN) and serum creatinine
  • Serum electrolytes
  • Urinalysis
  • Urine electrolytes
  • Renal ultrasound, if indicated
  • Novel biomarkers, if available 

The CBC may reveal anemia. Erythropoietin production is decreased in acute kidney injury (AKI), and dysfunctional platelets (from uremia) also make bleeding more likely.

The BUN and serum creatinine concentrations are increased in AKI. This increase in creatinine can be monitored at regular intervals and used for staging AKI, as described below.

In addition, hyponatremia, hyperkalemia, hypermagnesemia, hypocalcemia, and hyperphosphatemia may be present. Metabolic acidosis is also found. There can be improvement or worsening of acid-base status and electrolytes on inititiation of dialysis, and further calculations and dose adjustments will be required.[14]

Findings in patients with nephrotoxicity from specific medications include the following:

  • Aminoglycoside nephrotoxicity – Patients usually present with nonoliguric renal failure, with onset of nephrotoxicity (manifested by an elevation in serum creatinine) occurring after 7-10 days of therapy. Characteristically, an elevated fractional excretion of sodium (FENa) is accompanied by wasting of potassium, calcium, and magnesium.
  • Nephrotoxicity from cyclosporine and tacrolimus – Patients may present with hypertension, and may also have hyperkalemia and tubular injury–induced urinary wasting of phosphate and magnesium.
  • Ifosfamide nephrotoxicity usually presents as a Fanconi syndrome (proximal tubule dysfunction), with significant hypokalemia.
  • Foscarnet nephrotoxicity is commonly associated with hypocalcemia
  • Pentamidine nephrotoxicity is frequently associated with hypomagnesemia and hyperkalemia
  • Acyclovir may lead to the formation of intratubular crystals, which appear as birefringent, needle-shaped crystals when viewed on microscopy.

Staging of AKI

The degree of acute kidney injury (AKI) is determined using the RIFLE (Risk of renal dysfunction, Injury to the kidney, Failure or Loss of kidney function, and End-stage renal disease) criteria.[15]

The primary goal of the Acute Dialysis Quality Initiative (ADQI), created in 2002, was to develop consensus- and evidence-based guidelines that could be used to treat and prevent AKI. A uniform, accepted definition of AKI was developed, and, as a result, the RIFLE criteria were proposed. The RIFLE criteria comprise a classification system for AKI.[15]

Since their creation in 2002, the RIFLE criteria have been validated by different groups around the world. The AKIN report proposed modifications to the RIFLE criteria to take into account evidence that smaller changes in serum creatinine than those first proposed in RIFLE are indicative of adverse outcomes. The AKIN staging system therefore requires only one measure (serum creatinine or urine output) to be satisfied to meet stage criteria.[16]

For more information on RIFLE and AKIN, see Classification Systems for Acute Kidney Injury.


Examination of the centrifuged sediment of urine is particularly helpful because it may reveal pigmented, muddy brown, granular casts, suggesting that established ATN is present (see the image below). However, remember that these casts may be absent in 20-30% of patients with ATN.

Acute tubular necrosis. Pigmented, muddy brown, gr Acute tubular necrosis. Pigmented, muddy brown, granular casts are visible in the urine sediment of a patient with acute tubular necrosis (400x magnification).

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 listed in the following table.

Table. Laboratory Findings Used to Differentiate Prerenal Azotemia From ATN (Open Table in a new window)


Prerenal Azotemia

ATN and/or Intrinsic Renal Disease

Urine osmolarity



< 350

Urine sodium


< 20


Fractional excretion of sodium (FENa)


< 1


Fractional excretion of urea


< 35


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 × 100, where z is the substance, U and P represent urine and plasma concentrations, and Cr stands for creatinine.

In patients with contrast-induced nephropathy (CIN), FENa tends to be less than 1%. This is an exception to the rule that FENa below 1% usually indicates prerenal failure.

Although rhabdomyolysis is a common cause of endogenous nephrotoxic ATN, FENa tends to be less than 1%, characteristically. This is another exception to the rule, along with CIN. An important finding on urinalysis is that of a positive dipstick test for blood, with typical absence of red blood cells (RBCs) on microscopy. Furthermore, hyperkalemia, hyperphosphatemia, and hyperuricemia are characteristic.

In some patients with drug-induced nephrotoxic ATN, crystals (eg, calcium oxalate crystals in cases of ethylene glycol toxicity) will be visible in a centrifuged urine sediment.


Renal ultrasonography, preferably with Doppler methods, is a simple procedure that should be undertaken in all patients who present with AKI.[17] It is extremely useful to exclude obstructive uropathy and to measure kidney size and cortical thickness. According to The Renal Association (United Kingdom) 2019 guideline, all patients presenting with AKI should have baseline investigations performed, including a urinalysis and a renal tract ultrasound, within 24 hours (unless a clear cause of AKI is apparent or AKI is improving), and within 6 hours if pyonephrosis is suspected or there is a high index of suspicion for urinary tract obstruction.[7]


Abdominal Radiography

An abdominal radiograph is of limited benefit in AKI. The exception is in patients with suspected nephrolithiasis. However, up to 30% of renal calculi may not be visible on plain films.[17]

Computed Tomography

Noncontrast helical computed tomography (CT) is more sensitive than plain radiography for detection of renal calculi. CT scans can also be used to evaluate for ureteral obstruction, when ultrasonography shows hydronephrosis but a cause is not detectable.[17]

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) of the abdomen has a potential role for determining the cause of ureteral obstruction when ultrasonographic results are unclear. MRI with contrast is preferred, if not contraindicated.[17]

Histologic Findings

Kidney biopsy is rarely necessary in patients with suspected ATN. An urgent indication for kidney biopsy is in the setting of clinical and urinary findings that suggest renal vasculitis rather than ATN, in which case the diagnosis needs to be established quickly so that appropriate immunomodulatory therapy can be initiated. A biopsy may also be critically important in renal transplant recipients, to rule out rejection.[18, 19]  Otherwise, biopsy should be performed only when the exact renal cause of AKI is unclear and the course is protracted.

Kidney biopsy is performed under ultrasound or CT scan guidance after ascertaining the safety of the procedure. In most circumstances, the histology demonstrates the loss of tubular cells or the denuded tubules. As illustrated in the image below, 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.

Acute tubular necrosis. Photomicrograph of a kidne Acute tubular necrosis. Photomicrograph of a kidney biopsy specimen shows renal medulla, which is composed mainly of renal tubules. Features suggesting acute tubular necrosis are the patchy or diffuse denudation of the renal tubular cells with loss of brush border (blue arrows); flattening of the renal tubular cells due to tubular dilation (orange arrows); intratubular cast formation (yellow arrows); and sloughing of cells, which is responsible for the formation of granular casts (red arrow). Finally, intratubular obstruction due to the denuded epithelium and cellular debris is evident (green arrow); note that the denuded tubular epithelial cells clump together because of rearrangement of intercellular adhesion molecules.

Although ATN was long considered to be synonymous with acute tubular injury (ATI), frank tubular epithelial necrosis is only 1 histologic pattern observed in clinical ATI. A systematic review of 292 studies comprising a total of 1987 patients identified 16 histologic descriptions of tubular injury, including the following[20] :

  • Tubular cell necrosis: 31.8%
  • Tubular cell sloughing: 39.4%
  • Tubular epithelial flattening/simplification: 37.7%
  • Tubular dilatation: 37.3%

The review found no difference in tubular injury histology between among kidney biopsy, transplant kidney biopsy, and autopsy, among different etiologies, or between biopsy samples taken before or after creatinine peaks in native kidneys.[20]

Novel Biomarkers

The most commonly used markers of kidney function—serum creatinine level, glomerular filtration rate (GFR), and urinary output—are limited in their ability to determine the magnitude of renal injury. This has led to research to find more accurate kidney function biomarkers (serum and/or urine),[21] in the hope that such biomarkers, once identified, will permit early diagnoses and will aid in rendering appropriate treatment strategies before permanent damage has occurred. Research has focused on the following potential biomarkers:

  • Neutrophil gelatinase-associated lipocalin (NGAL)
  • Interleukin-18 (IL-18)
  • Kidney injury molecule 1 (KIM-1)
  • Cystatin C
  • Sodium/hydrogen exchanger isoform 3 (NHE3)

In a multicenter, prospective cohort study of 102 patients with cirrhosis and acute kidney injury (AKI), Belcher and colleagues assessed multiple urinary biomarkers used to determine the three most common etiologies of AKI: ATN, prerenal azotemia, and hepatorenal syndrome (HRS). Median values of the following biomarkers were significantly higher in patient with ATN[22] :

  • NGAL
  • IL-18
  • KIM-1
  • Liver-type fatty acid binding protein (L-FABP)
  • Albumin

Further research is needed before novel renal biomarkers are incorporated into clinical practice.

Furosemide Stress Testing

In early acute kidney injury (AKI), urine output after a furosemide stress test (FST) can predict the development of stage 3 AKI. Response to the FST may be used to help the clinician determine when or whether to start renal replacement therapy.[23, 24]

Candidates for FST should be euvolemic and stable. For the test, furosemide is infused intravenously, in a dose of 1.0 or 1.5 mg/kg, and urine output is measured for 2 hours afterward. A 2-hour urinary output of 200 ml or less has been shown to have the best sensitivity and specificity to predict development of stage 3 AKI. To minimize the risk of hypovolemia, urine output may be replaced ml for ml each hour with Ringer lactate or normal saline for 6 hours after the FST, unless volume reduction is considered clinically desirable.[24]

In a study by Koyner et al, FST was significantly better than any urinary biomarker tested in predicting progression to stage 3 AKI (P< 0.05), and was the only test that significantly predicted receipt of renal replacement therapy. However, these authors found that a higher area under the curve (AUC) for prediction of adverse patient outcomes was achieved when FST was combined with biomarkers using specified cutoffs: urinary neutrophil gelatinase-associated lipocalin (NGAL) >150 ng/mL or urinary tissue inhibitor of metalloproteinases (TIMP-2) × insulinlike growth factor–binding protein-7 (IGFBP-7) >0.3.[23]



Approach Considerations

The first step in the management of acute tubular necrosis (ATN) is identification of patients at risk for it. Patients undergoing major surgery or presenting with shock or other conditions associated with development of ATN should be proactively followed and monitored. Measurement of fluid balances and urine output and daily measurement of creatinine and electrolytes will permit rapid diagnosis of acute kidney injury (AKI).

Another vulnerable group of patients are those with significant co-morbidities, who are likely to develop ATN with relatively minor injury and thus need more frequent and close follow up. This group includes patients with diabetes mellitus, significant coronary or peripheral vascular disease, multiple myeloma, or dehydration, as well as those receiving nephrotoxic medications or undergoing contrast-enhanced imaging studies. Prevention of ATN in these patients is group includes maintaining euvolemia, avoiding nephrotoxic medications, and supporting blood pressure with vasopressors if necessary. 

Kidney Disease: Improving Global Outcomes (KDIGO) guidelines suggest using a stage-based approach to management of AKI/ATN.[25]  The guidelines suggest that the following measures have no role in the prevention of AKI[25] :

  • Diuretics to prevent AKI
  • Diuretics to treat AKI, except in the management of volume overload
  • Low-dose dopamine to prevent or treat AKI
  • Fenoldopam to prevent or treat AKI
  • Atrial natriuretic peptide (ANP) to prevent or treat AKI

Correction of Oliguria

In the past, the use of diuretics to convert an oliguric AKI to non-oliguric AKI was sometimes recommended, to help with fluid management. However, several meta-analyses have shown no reduction in mortality or the need for renal replacement therapy with the use of diuretics.[26]  

The only indication of diuretics would be fluid overload after appropriate management of sepsis and cardiac dysfunction. 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 infused slowly because high doses can lead to hearing loss. If no response occurs, the treatment should be discontinued.

There is no role for so-called renal dose dopamine in the management of ATN.[27]



Indications for urgent dialysis in patients with ATN include the following:

  • Refractory fluid overload
  • Severe hyperkalemia
  • Signs of uremia (eg, pericarditis, encephalopathy, altered mental status)
  • Severe metabolic acidosis (pH < 7.1)

In patients without one of those indications for dialysis, initiating renal replacement therapy (RRT) prophylactically offers no benefit over performing RRT as and when required. Several trials and a recent meta-analysis have shown no improvement in outcome with early versus late RRT for patients with AKI.[28]

Dialysis modality 

Continuous renal replacement therapy (CRRT), sustained low-efficiency dialysis (SLED), and intermittent hemodialysis can all be used for renal replacement in ATN. None of those therapies offers significant benefit over the others, and KDIGO suggests using these modalities as complementary approaches, especially in hemodynamically unstable patients. The choice of therapy should be driven by local expertise. CRRT may be the preferred option for hemodynamically unstable patients.[25]

Elimination of Nephrotoxins

Generally, the treatment of choice for nephrotoxic ATN 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, as they may reduce the vasoconstrictive action of cyclosporine. However, their use is typically avoided because of possible hypotension.


Traditional complications of ATN include the following[29] :

  • Volume overload
  • Acid-base and electrolyte imbalances, especially hyperkalemia, acidosis, hyperphosphatemia, and hypocalcemia
  • Uremia, leading to problems such as prolonged bleeding, altered mental status, and pericardial disease

Non-traditional complications of ATN include the following[29] :

  • Infections
  • Respiratory disorders
  • Cardiac disorders
  • Chronic kidney disease

Altered fluid and electrolyte balance

Specific fluid imbalances vary with the phase of illness. During oliguria, salt and water retention often leads to hypertension, edema, and heart failure. The polyuric phase of ATN may lead to hypovolemia and create a setting for prerenal azotemia and perpetuation of ATN.

Clearly, the maintenance of fluid and electrolyte balance is critical. ATN may lead to dangerous electrolyte imbalances, especially hyperkalemia and hyponatremia. 

Hyperkalemia can be associated with life-threatening cardiac arrhythmias (eg, ventricular tachycardia or fibrillation, complete heart block, bradycardia, asystole). Arrhythmias have been reported in up to 30% of patients. On electrocardiography (ECG), hyperkalemia manifests as peaked T waves, prolonged PR interval, P wave flattening, and a widened QRS complex. In addition to these worrisome cardiac effects, hyperkalemia can also lead to neuromuscular dysfunction and, potentially, respiratory failure. Hyperkalemia can be treated with glucose and insulin, binding resins, or, if necessary, dialysis.

Hyponatremia is cause for concern because of its effects on the central nervous system. In general, correction of hyponatremia should be of sufficient rapidity and magnitude to reverse the manifestations of hypotonicity, but not be so rapid or large as to potentiate the risk of osmotic demyelination. The most recent published guidelines on treatment of hyponatremia recommend rates of correction of serum sodium ranging from 8 to 12 mmol/L per 24 h.[30]  Go to Hyponatremia for complete information on this topic.

Other electrolyte disturbances include hyperphosphatemia, hypocalcemia, and hypermagnesemia. 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.

In rhabdomyolysis, hypocalcemia results from deposition of calcium in the injured muscle. The 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 for hypocalcemia during the acute phase of rhabdomyolysis, unless the patient is symptomatic.

The 2011 UK Renal Association guidelines recommend administering 0.9% sodium chloride and sodium bicarbonate for intravenous volume expansion in patients at risk of developing AKI secondary to rhabdomyolysis.[7]  Metabolic acidosis may occur. It may be treated with bicarbonate or dialysis as well.


Uremia results from the accumulation of nitrogenous waste. It is a potentially life-threatening complication associated with AKI. This may manifest as pericardial disease, gastrointestinal symptoms (ie, nausea, vomiting, cramping), and/or neurologic symptoms (ie, lethargy, confusion, asterixis, seizures). Platelet dysfunction is common and can lead to life-threatening hemorrhage. Fortunately, uremia is becoming rarer with the earlier start of renal replacement therapy and better availability of resources, at least in the developed world. 


Aggressive treatment of infections is prudent. Infections remain the leading cause of morbidity and mortality and can occur in 30-70% of patients with AKI. Infections are more likely in these patients because of impairment of the immune system (eg, from uremia, inappropriate use of antibiotics) and because of increased use of indwelling catheters and intravenous needles.


Anemia may develop from many possible causes. Erythropoiesis is reduced in AKI. Patients with ATN-related uremia may have platelet dysfunction and subsequent hemorrhage leading to anemia. In addition, volume overload may lead to hemodilution, and red cell survival time may be decreased. Anemia can be corrected with blood transfusions.


KDIGO guidelines for AKI/ATN suggests the following dietary measures, although most are supported with limited evidence[25] :

  • Total energy intake of 20–30 kcal/kg/d
  • Avoid restriction of protein intake
  • Administer 0.8–1.0 g/kg/d of protein in noncatabolic AKI patients without need for dialysis and 1.0–1.5 g/kg/d in patients with AKI on renal replacement and up to a maximum of 1.7 g/kg/d in patients on continuous renal replacement therapy (CRRT) and in hypercatabolic patients.
  • Entreral nutrition is preferential than parenteral



Prevention of nephrotoxic acute tubular necrosis

Strategies for prevention of nephrotoxic ATN vary with different nephrotoxins.

With aminoglycosides, studies have demonstrated that once-daily dosing decreases the incidence of nephrotoxicity. In one study, 24% of patients receiving 3 daily doses of gentamicin developed clinical nephrotoxicity, compared with only 5% of patients receiving 1 daily dose.[31] However, other studies comparing a single daily dose with multiple daily doses have failed to find a difference in the incidence of nephrotoxicity. Therapeutic efficacy is not diminished by single daily dosing.

With amphotericin B, efforts should be made to minimize the use of the drug and ensure that extracellular fluid volume is adequate. 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 intrinsically less nephrotoxic.

Whereas amphotericin B is suspended in bile salt deoxycholate, which has a detergent effect on cell membranes, the 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.

With cyclosporine and tacrolimus (calcineurin inhibitors), regular monitoring of blood levels can help maintain therapeutic levels and prevent nephrotoxicity. Usually, renal insufficiency is easily reversed by a reduction of the dosage. On the other hand, persistent injury can lead to interstitial fibrosis.

With cisplatin, the key to preventing renal injury is 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.

Prevention of contrast-induced nephropathy

For contrast-induced nephropathy (CIN) from the use of radiocontrast dye, isotonic sodium chloride solution infusion has proven benefits as a preventive measure.[32]  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. This has been shown to be superior to half normal saline infusions.

A single-center, randomized, controlled trial demonstrated that isotonic sodium bicarbonate (3 mL/kg/h given 1 h prior to the contrast-requiring procedure and then continued at 1 mL/kg/h for 6 h post procedure) may offer even greater protection than isotonic sodium chloride.[33]  The postulated mechanism is being attributed to the inhibition of oxidant injury by the administered alkali.

Nonionic contrast media are also protective in patients with diabetic nephropathy and renal insufficiency. In susceptible patients, the use of nonionic, low-osmolar contrast media reduces the likelihood of clinical nephrotoxicity.

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. 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.

The use of N-acetylcysteine (NAC) as a prophylactic agent has gained popularity, on the basis of the theory that contrast media cause direct renal tubular epithelial cell toxicity via exposure to reactive oxygen species (ROS), and NAC is believed to have antioxidant properties that potentially counteract the effects of ROS.[34]  Studies have also suggested that pretreatment with oral NAC (600 mg or 1200 mg bid on the day before and the day of the contrast-requiring procedure) acts as an antioxidant, scavenging ROS and thereby reducing the nephrotoxicity of contrast media.

Based on what is currently known, 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 in preventing CIN. The recently published PRESERVE trial demonstrated no benefit of either sodium bicarbonate or NAC for prevention of CIN, compared to saline hydration.[35]

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. Its use is based on the idea that contrast media cause local release of adenosine, a known vasoconstrictor considered by some to have a potential role in the pathogenesis of CIN, and theophylline is a known adenosine antagonist. Although theophylline appears to be promising, further randomized trials are required to confirm its benefit in the prevention of CIN.

Aside from the recommended prophylactic medications discussed above, other guidelines recommend withholding potential nephrotoxic agents, such as nonsteroidal anti-inflammatory drugs (NSAIDs).

In patients with underlying volume depletion, withholding ACE inhibitors and/or angiotensin receptor blockers (ARBs) may even be necessary. The use of ACE inhibitors and ARBs 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 (eg, NSAIDs, COX-2 inhibitors, and calcineurin inhibitors), and elevated baseline serum creatinine.

Metformin should be withheld at least 48 hours before a contrast imaging procedure and if AKI develops.

Prevention of rhabdomyolysis

Preventive strategies for rhabdomyolysis 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 than volume expansion with normal saline alone.

Long-Term Monitoring

AKI in hospital inpatients has long-term implications after discharge. A meta-analysis of 13 cohort studies showed that patients with AKI had higher risk for developing chronic kidney disease (CKD) (hazard ratio [HR] 8.8, 95% confidence index [CI] 3.1-25.5), end-stage renal disease (HR 3.1, 95%CI 1.9-5.0) and mortality (HR 2.0, 95% CI 1.3 - 3.1).[36] AKI was also independently associated with risk of cardiovascular disease and congestive heart failure. Patients with AKI whose kidney function does not return to 25% of baseline have higher risk of mortality and renal outcomes.[37]

KDIGO guidelines recommend a 3-month follow-up after an AKI to determine whether the patient has experienced renal recovery or new-onset or progressive CKD.[25] Longer followup may benefit all patients, but may be especially valuable in patients with higher risk of poor outcomes. Higher-risk features are as follows[38] :

  • AKI requiring dialysis
  • Pre-existing CKD
  • Failure of kidney function to return to baseline
  • History of diabetes, heart failure, or cancer




Medication Summary

Medications have only an ancillary role in the treatment of acute tubular necrosis (ATN).  Therapeutic mainstays are prevention, avoidance of further kidney damage, treatment of underlying conditions, and aggressive treatment of complications.


Questions & Answers


What is acute tubular necrosis (ATN)?

What are the sequences of disease progression in acute tubular necrosis (ATN)?

What causes tubule cell damage and cell death in acute tubular necrosis (ATN)?

How is the cause of acute tubular necrosis (ATN) identified?

How is acute tubular necrosis (ATN) managed?

What is the pathophysiology of acute tubular necrosis (ATN)?

What is the pathophysiology of the initiation phase of acute tubular necrosis (ATN)?

What is the pathophysiology of the maintenance phase of acute tubular necrosis (ATN)?

What is the pathophysiology of the recovery phase of acute tubular necrosis (ATN)?

What is the pathophysiology of normotensive ischemic acute tubular necrosis (ATN)?

What is the pathophysiology of endotoxemia (sepsis)-related acute tubular necrosis (ATN)?

What causes ischemic acute tubular necrosis (ATN)?

What causes nephrotoxic acute tubular necrosis (ATN)?

What are the risk factors for aminoglycoside caused acute tubular necrosis (ATN)?

What are the risk factors for amphotericin B nephrotoxicity caused acute tubular necrosis (ATN)?

Which exogenous nephrotoxins can cause acute tubular necrosis (ATN)?

Which endogenous nephrotoxins cause acute tubular necrosis (ATN)?

What is the in-hospital survival rate among patients with acute tubular necrosis (ATN)?

What is the mortality rate of acute tubular necrosis (ATN)?

What is the prognosis of oliguric acute tubular necrosis (ATN)?

What is the prevalence of end-stage renal disease (ESRD) in acute tubular necrosis (ATN)?

What is the prevalence of acute tubular necrosis (ATN)?


Which clinical history is characteristic of acute tubular necrosis (ATN)?

What are the physical findings characteristic of acute tubular necrosis (ATN)?


What are the differential diagnoses for Acute Tubular Necrosis?


Which tests should be performed in the workup of acute tubular necrosis (ATN)?

What is the role of lab testing in the workup of acute tubular necrosis (ATN)?

Which nephrotoxicity findings suggest a specific medication causing acute tubular necrosis (ATN)?

How is the degree of acute kidney injury (AKI) determined in acute tubular necrosis (ATN)?

What is the role of urinalysis in the workup of acute tubular necrosis (ATN)?

What is the role of ultrasonography in the workup of acute tubular necrosis (ATN)?

What is the role of abdominal radiography in the workup of acute tubular necrosis (ATN)?

What is the role of CT scanning in the workup of acute tubular necrosis (ATN)?

What is the role of MRI in the workup of acute tubular necrosis (ATN)?

What is the role of renal biopsy in the workup of acute tubular necrosis (ATN)?

What is the role of biomarkers in the workup of acute tubular necrosis (ATN)?

What is the role of furosemide stress testing in the workup of acute tubular necrosis (ATN)?


How are patients at risk for acute tubular necrosis (ATN) proactively managed?

Which group of patients are likely to develop acute tubular necrosis (ATN)?

What are the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for managing acute tubular necrosis (ATN)?

What is the role of diuretics in the treatment of acute tubular necrosis (ATN)?

When is dialysis indicated in the treatment of acute tubular necrosis (ATN)?

What can the options for renal replacement therapy in acute tubular necrosis (ATN)?

What is the treatment of choice for nephrotoxic acute tubular necrosis (ATN)?

What are possible complications of acute tubular necrosis (ATN)?

What are complications of altered fluid and electrolyte balance in acute tubular necrosis (ATN)?

What are the signs and symptoms of uremia in acute tubular necrosis (ATN)?

What is the prevalence of infections in acute tubular necrosis (ATN)?

What are the causes of anemia in acute tubular necrosis (ATN)?

What are KDIGO dietary guidelines for acute tubular necrosis (ATN)?

What is the role of N-acetylcysteine (NAC) in the prevention of acute tubular necrosis (ATN)?

How is nephrotoxic acute tubular necrosis (ATN) prevented?

How is contrast-induced nephropathy (CIN) in acute tubular necrosis (ATN) prevented?

What is the efficacy of isotonic sodium bicarbonate for the prevention of contrast-induced nephropathy (CIN) in acute tubular necrosis (ATN)?

What is the role of nonionic contrast media in the prevention of acute tubular necrosis (ATN)?

What should be avoided to prevent contrast-induced nephropathy (CIN) in acute tubular necrosis (ATN)?

Which interventions to decrease the risk of contrast-induced nephropathy (CIN) in acute tubular necrosis (ATN) lack evidence of efficacy?

How is rhabdomyolysis prevented in acute tubular necrosis (ATN)?

What is included in long-term monitoring of acute tubular necrosis (ATN)?


What is the role of medications in the management of acute tubular necrosis (ATN)?