Acute Tubular Necrosis Workup

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