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Acute Tubular Necrosis Workup

  • Author: Edgar V Lerma, MD, FACP, FASN, FAHA, FASH, FNLA, FNKF; Chief Editor: Vecihi Batuman, MD, FACP, FASN  more...
 
Updated: Dec 21, 2015
 

Approach Considerations

Laboratory findings, especially those by urinalysis, along with renal ultrasound findings, are particularly helpful in identifying the cause of acute tubular necrosis (ATN).

Patients with aminoglycoside nephrotoxicity 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.

Patients with nephrotoxicity from cyclosporine and tacrolimus may present with hypertension and may also be hyperkalemic and have tubular injury–induced urinary wasting of phosphate and magnesium.

Ifosfamide usually causes a Fanconi syndrome (proximal tubule dysfunction) presentation with significant hypokalemia; foscarnet is commonly associated with hypocalcemia; pentamidine is frequently associated with hypomagnesemia and hyperkalemia; and acyclovir may lead to the formation of intratubular crystals, which appear as birefringent, needle-shaped crystals when viewed on microscopy.

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Assessment of Renal Injury

The degree of acute kidney injury (AKI) is determined using the RIFLE (R isk of renal dysfunction, I njury to the kidney, F ailure or L oss of kidney function, and E nd-stage renal disease) criteria.[8]

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.[8]

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.[9]

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

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Complete Blood Cell Count

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

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Serum Chemistries

By definition, blood urea nitrogen (BUN) and serum creatinine concentrations are increased in AKI. In addition, hyponatremia, hyperkalemia, hypermagnesemia, hypocalcemia, and hyperphosphatemia may be present. A metabolic acidosis is also found. Remember that hypercalcemia and hyperuricemia may suggest a malignant condition as a cause.

The 2011 UKRA guidelines recommend adopting the Kidney Disease: Improving Global Outcomes (KDIGO) definition of AKI, defined as presence of one of the following criteria:[3]

  • Serum creatinine rises by ≥ 26µmol/L within 48 hours or
  • Serum creatinine rises ≥ 1.5 fold from the reference value, which is known to or presumed to have been reached within 1 week or
  • Urine output is < 0.5 mL/kg/h for >6 hours in a row.
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Urinalysis

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

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 illustrated in the following table.

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

Finding Prerenal Azotemia ATN and/or Intrinsic Renal Disease
Urine osmolarity



(mOsm/kg)



>500 < 350
Urine sodium



(mmol/d)



< 20 >40
Fractional excretion of sodium (FENa)



(%)



< 1 >2
Fractional excretion of urea



(%)



< 35 >50
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.

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Ultrasonography

Renal ultrasonography, preferably with Doppler methods, is a simple procedure that should be undertaken in all patients who present with AKI.[10] It is extremely useful to exclude obstructive uropathy and to measure renal size and cortical thickness. According to the 2011 UKRA guidelines, all patients presenting with AKI should have baseline investigations performed, including a urinalysis and renal ultrasonography within 24 hours (on suspicion of renal tract obstruction).[3]

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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.[10]

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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 ureteral obstruction, when ultrasonography shows hydronephrosis but a cause is not detectable.[10]

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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.[10]

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Renal Biopsy

Renal biopsy is rarely necessary in patients with suspected ATN. An urgent indication for renal biopsy is in the setting of clinical and urinary findings that suggest renal vasculitis rather than ATN; the diagnosis needs to be established quickly so that appropriate immunomodulatory therapy can be initiated. A biopsy may also be critically important in the setting of a renal transplant patient to rule out rejection.[11, 12] Otherwise, biopsy should be performed only when the exact renal cause of AKI is unclear and the course is protracted.

Renal biopsy is performed under ultrasound or CT scan guidance after ascertaining the safety of the procedure. Renal biopsy findings are shown below.

A photomicrograph of renal biopsy shows renal medu A photomicrograph of renal biopsy shows renal medulla, which is composed mainly of renal tubules. Patchy or diffuse denudation of the renal tubular cells is observed, suggesting acute tubular necrosis (ATN) as the cause of acute kidney injury (AKI).
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Histologic Findings

In most circumstances, the histology demonstrates the loss of tubular cells or the denuded tubules. As illustrated in the top image of the images 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 (ATN). Flattening of the re Acute tubular necrosis (ATN). Flattening of the renal tubule cells due to tubular dilation.
Acute tubular necrosis. Intratubular cast formatio Acute tubular necrosis. Intratubular cast formation.
Acute tubular necrosis. Intratubular obstruction d Acute tubular necrosis. Intratubular obstruction due to the denuded epithelium and cellular debris. Note that the denuded tubular epithelial cells clump together due to rearrangement of intercellular adhesion molecules (ICAM).
Sloughing of cells, which is responsible for the f Sloughing of cells, which is responsible for the formation of granular casts, a feature of acute tubular necrosis (ATN).
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Novel Biomarkers

Researchers have identified several markers for kidney injury that have the potential to enhance early diagnosis and management. Further research is needed before these are incorporated into clinical practice.

The most commonly used markers of renal function are serum creatinine levels, the glomerular filtration rate (GFR), and urinary output. Although imperfect, these measures are used to determine the magnitude of renal injury. This has led to research to find more accurate kidney function biomarkers (serum and/or urine),[13] with 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, interleukin-18, kidney injury molecule 1, cystatin C, sodium/hydrogen exchanger isoform 3 (NHE3).

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Contributor Information and Disclosures
Author

Edgar V Lerma, MD, FACP, FASN, FAHA, FASH, FNLA, FNKF Clinical Professor of Medicine, Section of Nephrology, Department of Medicine, University of Illinois at Chicago College of Medicine; Research Director, Internal Medicine Training Program, Advocate Christ Medical Center; Consulting Staff, Associates in Nephrology, SC

Edgar V Lerma, MD, FACP, FASN, FAHA, FASH, FNLA, FNKF is a member of the following medical societies: American Heart Association, American Medical Association, American Society of Hypertension, American Society of Nephrology, Chicago Medical Society, Illinois State Medical Society, National Kidney Foundation, Society of General Internal Medicine

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Otsuka, Mallinckrodt, ZS Pharma<br/>Author for: UpToDate, ACP Smart Medicine.

Coauthor(s)

Mahendra Agraharkar, MD, MBBS, FACP FASN, Clinical Associate Professor of Medicine, Baylor College of Medicine; President and CEO, Space City Associates of Nephrology

Mahendra Agraharkar, MD, MBBS, FACP is a member of the following medical societies: American College of Physicians, American Society of Nephrology, National Kidney Foundation

Disclosure: Received ownership interest/medical directorship from South Shore DaVita Dialysis Center for other; Received ownership/medical directorship from Space City Dialysis /American Renal Associates for same; Received ownership interest from US Renal Care for other.

Brent Kelly, MD Assistant Professor, Department of Dermatology, University of Texas Medical Branch, Galveston, Texas

Brent Kelly, MD is a member of the following medical societies: Alpha Omega Alpha, American Medical Association

Disclosure: Nothing to disclose.

Chief Editor

Vecihi Batuman, MD, FACP, FASN Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Renal Section, Southeast Louisiana Veterans Health Care System

Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, International Society of Nephrology

Disclosure: Nothing to disclose.

Acknowledgements

George R Aronoff, MD Director, Professor, Departments of Internal Medicine and Pharmacology, Section of Nephrology, Kidney Disease Program, University of Louisville School of Medicine

George R Aronoff, MD is a member of the following medical societies: American Federation for Medical Research, American Society of Nephrology, Kentucky Medical Association, and National Kidney Foundation

Disclosure: Nothing to disclose.

F John Gennari, MD Associate Chair for Academic Affairs, Robert F and Genevieve B Patrick Professor, Department of Medicine, University of Vermont College of Medicine

F John Gennari, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Federation for Medical Research, American Heart Association, American Physiological Society, American Society for Clinical Investigation, American Society of Nephrology, and International Society of Nephrology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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A photomicrograph of renal biopsy shows renal medulla, which is composed mainly of renal tubules. Patchy or diffuse denudation of the renal tubular cells is observed, suggesting acute tubular necrosis (ATN) as the cause of acute kidney injury (AKI).
Acute tubular necrosis (ATN). Flattening of the renal tubule cells due to tubular dilation.
Acute tubular necrosis. Intratubular cast formation.
Acute tubular necrosis. Intratubular obstruction due to the denuded epithelium and cellular debris. Note that the denuded tubular epithelial cells clump together due to rearrangement of intercellular adhesion molecules (ICAM).
Sloughing of cells, which is responsible for the formation of granular casts, a feature of acute tubular necrosis (ATN).
Table. Laboratory Findings Used to Differentiate Prerenal Azotemia From ATN
Finding Prerenal Azotemia ATN and/or Intrinsic Renal Disease
Urine osmolarity



(mOsm/kg)



>500 < 350
Urine sodium



(mmol/d)



< 20 >40
Fractional excretion of sodium (FENa)



(%)



< 1 >2
Fractional excretion of urea



(%)



< 35 >50
Urine sediment Bland and/or nonspecific May show muddy brown granular casts
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