I. What every physician needs to know.

Acute kidney injury (AKI) is defined as an abrupt decline in kidney function. The traditional paradigm classifies AKI into prerenal, intrinsic renal, and postrenal etiologies based on the portion of renal anatomy most affected. Acute tubular necrosis (ATN), an intrinsic renal etiology of AKI, occurs with prolonged ischemic or toxic injury to the kidney resulting in tubular cell injury. Although “acute renal failure”, AKI, and ATN are frequently used interchangeably, it should be recognized that there are many different causes of AKI other than ATN. Three major causes of ATN include renal ischemia, sepsis and nephrotoxins.

Post-ischemic ATN occurs in the setting of severe renal ischemia from any cause (severe prerenal disease, prolonged hypotension, surgery, or sepsis). It typically progresses through four phases:

  • Initiation: This phase usually last hours to days. During this time, glomerular filtration rate (GFR) will decrease caused by a decrease in renal blood flow. Casts within the tubules obstruct the flow of filtrate, and there is backflow of filtrate through injured tubular epithelium.

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  • Extension: The GFR continues to decrease or remains low. There is continued ischemic injury to tubule cells and significant inflammation.

  • Maintenance: Typically lasts 1-2 weeks. Urine output is at its lowest and uremic symptoms may arise. During this phase, there is proliferation of cells and reestablishment of the tubule epithelium.

  • Recovery: Marked by tubular cell repair and regeneration. GFR will slowly improve to premorbid conditions. The recovery phase can be complicated by a brisk diuresis caused by the delayed recovery of epithelial call function.

Nephrotoxic medications that can induce ATN include: aminoglycosides, amphotericin, cyclosporin and tacrolimus, sulfa drugs, cisplatin, acyclovir, contrast media, and pentamidine although there are others.

Endogenous toxins that can cause ATN include: myoglobinuria, hemaglobinuria, crystalline induced nephropathy (as is seen with tumor lysis syndrome), and multiple myeloma.

ATN should not be viewed as a benign condition. It is well recognized that ATN and other causes of AKI are associated with undesirable short term outcomes including prolonged hospitalization, increased costs, and mortality. ATN has also been associated with negative long term outcomes including progression to chronic kidney disease, end-stage renal disease, and long term mortality. Mortality associated with ATN is 37% in hospitalized patients and 78% in intensive care unit (ICU) patients. While most patients recover from an acute episode of ATN, the percentage of patients with end-stage renal disease due to ATN is rising and most recently found to be 3.5% based on national data.

II. Diagnostic Confirmation: Are you sure your patient has acute tubular necrosis?

The diagnosis of AKI was defined by The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines as one or more of three criteria: rise in serum creatinine of 0.3 mg/dL over a 48-hour period, increase in serum creatinine by 1.5 times baseline within the prior 7 days, or urine volume <0.5 mg/kg/hr for 6 hours. Once the diagnosis of AKI is established, the etiology must be determined. ATN most frequently needs to be distinguished from another common cause of AKI in hospitalized patients: prerenal disease.

Prerenal disease is characterized by a low perfusion state of the kidneys without evidence of tubular damage. Laboratory evaluations that may point toward a low perfusion state of the kidneys and prerenal disease include low urine sodium, decreased fractional excretion of sodium (FENa) (less than 1.0%), elevated urine osmolality, and elevated blood urea nitrogen/creatinine ratio. All these findings indicate preserved tubular function and appropriate response to hypoperfused state.

With prolonged hypoperfusion and subsequent injury of the tubular cells, ATN develops. Urine sodium and FENa will increase along with a decrease in urine osmolality. However, in advanced chronic renal failure, diuretic therapy, myoglobinuria, sepsis, cirrhosis, and contrast-induced nephropathy, these indices may be unreliable. The presence of renal tubular epithelial cells, epithelial cell casts, and muddy brown granular casts on microscopic analysis of centrifuged urine will help to make the diagnosis.

The gold standard for distinguishing between prerenal disease and ATN is response to fluid repletion. If sufficient fluid repletion is given to correct volume depletion, and serum creatinine does not return to normal within 24-72 hours, this is considered to represent ATN.

A renal biopsy is usually not necessary to make the diagnosis of ATN. However, when the history, clinical features and laboratory findings are confusing, a kidney biopsy may establish the diagnosis.

A. History Part I: Pattern Recognition:

The history is extremely important to determining the cause of ATN. Patients diagnosed with ATN are frequently asymptomatic from the kidney injury itself, and the presenting symptoms are usually due to the underlying cause of the renal dysfunction.

For example, a patient who is found to have ATN from prolonged renal hypoperfusion may present with symptoms associated with volume depletion (orthostasis, history of vomiting or diarrhea, etc.). Likewise, ATN caused by rhabdomyolysis may present with diffuse muscle pains.

Medication reconciliation must be done while noting medications associated with AKI including non-steroidal anti-inflammatory drugs, aminoglycosides, chemotherapy and recent radiocontrast administration. Any symptoms of infection, with or without signs of sepsis should be elicited.

B. History Part 2: Prevalence:

The incidence and prevalence of ATN are not well known due to varying definitions used to determine AKI. This is further compounded by the fact that many epidemiologic studies of AKI do not determine an etiology. A 2012 meta-analysis using the KDIGO criteria estimated the incidence of hospital acquired AKI at 21%. Previous studies have shown that ATN is the most common etiology of AKI and accounts for approximately 45% of cases.

C. History Part 3: Competing diagnoses that can mimic acute tubular necrosis


D. Physical Examination Findings.

ATN usually presents without significant physical exam findings. When changes to the physical exam occur, they are usually due to either uremia or to the underlying cause of ATN. Attention must be paid to volume status as hypovolemia may indicate the underlying cause of ATN and severe volume overload may indicate a need for emergent dialysis.

Examples of uremic findings include pericardial friction rub, asterixis and excoriations of the skin. Evaluation of the patient may reveal diffuse muscle tenderness associated with rhabdomyolysis or orthostatic hypotension due to volume depletion. As part of the physical exam, urine output should be measured to determine if the patient is oliguric or anuric.

E. What diagnostic tests should be performed?

The diagnostic evaluation for AKI generally involves identifying if the disorder is prerenal, intrinsic renal, or postrenal. Likewise, in trying to determine if a patient has ATN, prerenal and postrenal causes should be ruled out. Once the disorder is determined to be a “renal” cause, the diagnostic work-up switches to determining which “renal” pathology has occurred.

Therefore, the initial evaluation should include:

  • Urine analysis – both microscopic and chemical will be useful. The presence of coarsely granular, muddy brown casts, or renal tubular epithelial cells on urine microscopy indicate that there is tubular injury. The urine analysis will also alert one to the possibility of glomerulonephritis (red blood cell casts, dysmorphic red blood cells), myoglobinuria (positive chemical evaluation for blood, but absence of red blood cells on microscopy).

  • Urine electrolytes – Both urine sodium and FENa have been used to distinguish prerenal disease from ATN, however FENa is the preferred test. A FENa which is calculated (plasma creatinine [PCr] x urine sodium [Una]) / (plasma sodium [PNa] x urine creatinine [UCr]) x 100; less than 1%, indicates that the kidney is being underperfused, but that the concentrating ability for the kidney is intact. As hypoperfusion or toxic drug effects cause tubular cell injury, the tubules are no longer able to retain sodium and concentrate the urine, leading to an increase in the FENa. A FENa of greater than 2% is usually used at the cut-off for ATN.

    Chronic kidney disease or diuretic use may alter the accuracy or completely invalidate the FENa. Additionally, ATN in the setting of myoglobinuria, sepsis, contrast-induced nephropathy, and other disease processes may cause a low urine sodium and a FENa less than 1%. Therefore, the FENa can be useful in helping with the diagnosis, but the entire clinical scenario must be taken into account.

    The fractional excretion of urea is thought to be unaffected by diuretics and therefore able to provide more accuracy in low perfusion states in which the urine sodium is elevated. Fractional excretion of urea (FEUrea) less than 35% leans toward renal hypoperfusion and greater than 50% points to renal tubular pathology.

  • Renal ultrasound – this test is useful for two reasons. First, it allows one to rule out hydronephrosis and therefore makes postrenal causes less likely. Secondly, it may provide evidence of chronic renal disease (small shrunken kidney, polycystic kidneys), which may be particularly helpful when considering ATN in the absence of a baseline creatinine.

  • Investigational biomarkers – there has been recent interest in using serum and/or urinary biomarkers for the early diagnosis of tubular injury and ATN, but currently none are approved for use in the United States.

As stated above a renal biopsy is usually not necessary in the evaluation of patients with ATN and is usually employed by nephrologists when the history and laboratory findings suggest some diagnosis other than ATN.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.


III. Default Management

Once the diagnosis of ATN is made, little has been shown to reliably change the course of renal recovery. Therefore, strategies to prevent development of ATN in hospitalized patients are paramount. Attention should be paid to patients at highest risk of developing ATN including those undergoing major surgery, sepsis, pancreatitis, or severe volume depletion. Patients with comorbid chronic kidney disease, diabetes, obesity, advanced malignancy, and poor nutrition are also at high risk of postischemic ATN.

In those at highest risk, close monitoring of volume status, management of antihypertensives to avoid large drops in blood pressure, and avoidance of nephrotoxins can be helpful. Measures to prevent contrast-induced nephropathy include utilizing low-volume contrast, intravenous hydration, and avoiding closely spaced contrasted studies.

Loop diuretics, dopamine, and a variety of other pharmacologic therapies have been investigated for treatment of ATN, but none have proven to improve outcomes. The KDIGO guidelines recommend against using loop diuretics for treatment of AKI except as needed for volume management. Continued attention should be paid toward avoiding any additional nephrotoxicity and managing complications of the AKI.

A. Immediate management

Cessation of nephrotoxic medications such as non-steroidal anti-inflammatory drugs (NSAIDs), aminoglycosides and contrast dye is necessary. Care should be taken not to inadvertently start additional medications that may either decrease renal perfusion or be directly nephrotoxic. Animal models have shown alterations in autoregulation and renal blood flow after ischemia ATN. Renal biopsies from patients with protracted ATN showed fresh necrotic tubular cells, indicating recurrent ischemic damage.

These studies should lead one to believe that once ATN has developed, the kidney is incredibly susceptible to even mild decreases in renal perfusion. These may come from fluctuations in blood pressure caused by volume depletion, dialysis, sepsis, and antihypertensive medications.

If necessary, vasopressors should be used to maintain mean arterial pressure. It is unknown what vasopressors are best to maintain renal perfusion. Using “low-dose” or “renal-dosed” dopamine has been proved ineffective in clinical trials. In order to prevent recurrent injury due to hemodynamic fluctuations, maintaining adequate volume status is paramount. Daily weights and strict monitoring of input and output is mandatory.

If ATN is suspected, a nephrologist should be consulted to assist with diagnostic evaluation and treatment. One study reveals that early consultation with a nephrologist in ICU patients with acute renal failure improves mortality and length of ICU stay. That being said, there is no consensus on when renal replacement therapy (RRT) should be initiated or what type of dialysis should be used.

The KDIGO guidelines recommend initiating RRT emergently when life threatening changes in fluid, electrolyte or acid-base status exist. If these indications do not exist, the broader clinical context as well as trends in laboratory values including blood urea nitrogen and creatinine should be used to determine when to start RRT. Whether early or prophylactic renal replacement therapy is of benefit is an ongoing area of investigation.

ATN induces protein catabolism, and the more severe the catabolic state, the higher the mortality. There is excessive release of amino acids from skeletal muscle with an accompanying increase in gluconeogenesis. This catabolic state can be enhanced by pre-existing malnutrition, sepsis and initiation of dialysis.

Consulting a dietician for individual evaluation in order to determine the optimal protein and caloric intake for patients may help in providing optimal nutritional support.

B. Physical Examination Tips to Guide Management.

See above.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

In general, daily monitoring of serum electrolytes should be monitored while the patient is developing AKI, during the maintenance phase and while the patient is recovering. Initially, labs will be used for monitoring for hyperkalemia and acidosis as well as monitoring for continued rise in serum creatinine.

During the recovery phase, a patient may develop significant post-ATN diuresis with resulting hypokalemia and hypovolemia, propagating additional renal failure. Once the AKI has stabilized, frequency of monitoring chemistries can be decreased.

D. Long-term management.


E. Common Pitfalls and Side-Effects of Management


IV. Management with Co-Morbidities


A. Renal Insufficiency.

No change in standard management.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure

Blood pressure medications, including angiotensin-converting enzyme inhibitors (ACE-Is) should be held in ATN for the reasons related to alterations in renal perfusion mentioned above. While loop diuretics do not change the course of ATN as mentioned above, they would still be indicated for volume overload in heart failure patients. One must realize that the patient may not respond to loop diuretics while there is tubular injury.

D. Coronary Artery Disease or Peripheral Vascular Disease

No change in standard management.

E. Diabetes or other Endocrine issues

Metformin should be avoided in renal failure patients due to risk of lactic acidosis. While ATN can produce a state of insulin resistance, the effects of exogenous insulin may also be prolonged due to decreased renal clearance. Therefore, modifications to standard sliding scales should be made if one chooses to order an insulin sliding scale.

F. Malignancy

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc.).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard management.

I. Gastrointestinal or Nutrition Issues

Nutrition issues as documented above. Otherwise, no change in standard management.

J. Hematologic or Coagulation Issues

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment

No change in standard management.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

As stated above, management of ATN largely involves monitoring for and treating complications of AKI. Check out may include checking chemistries, especially if the patient has had problems with hyperkalemia or acidosis. It may also be anticipated that monitoring of urine output would be necessary, especially in the early stages of ATN, when non-oliguric renal failure may progress to oliguric renal failure.

B. Anticipated Length of Stay.

The length of stay can vary greatly depending upon the complications that accompany the patient’s ATN and the etiology of renal injury. Duration of stay may range from 2-3 days for relatively mild ATN due to hypovolemic hypoperfusion of the kidney to weeks for very ill patients requiring renal replacement therapy.

C. When is the Patient Ready for Discharge.

Patients will need to have either stabilization of their serum creatinine and concurrent metabolic disorders, or determination that they will need long-term dialysis and arrangements for outpatient dialysis. As mentioned above, some patients may develop a quite significant post-ATN diuresis. Patients may need to stay hospitalized in severe cases of post-ATN diuresis. These patients are susceptible to volume depletion and hypokalemia.

D. Arranging for Clinic Follow-up


1. When should clinic follow up be arranged and with whom.

AKI has been found to be an independent risk factor for progression to chronic kidney disease or end-stage renal disease. Therefore, at a minimum, renal function should be evaluated 3 months after an episode of ATN to determine either resolution or progression to chronic kidney disease. Closer follow-up may be warranted if acute electrolyte or volume issues are not fully resolved at discharge.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

Serum chemistries documenting creatinine at discharge.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

Serum chemistries to documents creatinine and electrolytes at follow-up.

E. Placement Considerations.

In severe cases of ATN renal replacement therapy may be needed and recovery can be prolonged necessitating outpatient dialysis placement.

F. Prognosis and Patient Counseling.

The majority of patients recover from ATN with the renal failure phase typically lasting 7-21 days. However, depending on the severity of the initial insult, time to renal recovery can often be prolonged and patients may require dialysis for months.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.


B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.


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Coca, SG,, Singanamala, S,, Parikh, CR. “Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis.”. Kidney Int.. vol. 81. 2012. pp. 442-8.

McCullough, PA,, Shaw, AD,, Haase, M. “Diagnosis of acute kidney injury using functional and injury biomarkers: workgroup statements from the tenth Acute Dialysis Quality Initiative Consensus Conference.”. Contrib Nephrol. vol. 182. 2013. pp. 13-29.

Perazella, MA,, Coca, SG,, Kanbay, M,, Brewster, UC. “Diagnostic value of urine microscopy for differential diagnosis of acute kidney injury in hospitalized patients.”. Clin J Am Soc Nephrol. vol. 3. 2008. pp. 1615-9.

Gill, N,, Nally, JV,, Fatica, RA. “Renal failure secondary to acute tubular necrosis: epidemiology, diagnosis, and management.”. Chest.. vol. 128. 2005. pp. 2847-63.

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