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Acute Tubular Necrosis

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 NephrologyHypertension, 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

Acute Tubular Necrosis

Updated: Dec 21, 2015

Background
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). See the ATN images below.

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.

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 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 is restored, 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.[1]
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 the Diabetes Center, as well as Acute Kidney Failure.

Pathophysiology
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 kidneys
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 images below).

Acute tubular necrosis. Intratubular cast formation.

Sloughing of cells, which is responsible for the formation of granular casts, a feature of
acute tubular necrosis (ATN).

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. [2] 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.

Pathophysiologic mechanisms of selected types of nephrotoxicity

Nephrotoxicity can result from various drugs, such as aminoglycosides, amphotericin,

calcineurin inhibitors, foscarnet, ifosfamide, cisplatin, and crystal-forming drugs. Additionally,
conditions such as multiple myeloma and rhabdomyolysis can cause nephrotoxicity. Acute kidney
injury (AKI) can result, and the pathophysiologic mechanism for renal injury differs among the agents
and conditions.
AKI is observed in about 5% of all hospital admissions and in up to 30% of patients admitted
to the intensive care unit (ICU). ATN is the most common cause of AKI in the renal category, and the
second most common cause of all categories of AKI in hospitalized patients, with only prerenal
azotemia occurring more frequently.

Etiology
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

Disseminated intravascular coagulation

Renal

vasoconstriction:

cyclosporine,

amphotericin

B,

norepinephrine,

epinephrine,

hypercalcemia

Impaired renal autoregulatory responses: cyclooxygenase (COX) inhibitors, angiotensinconverting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs).

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 include the following:

Aminoglycoside-related toxicity occurs in 10-30% of patients receiving aminoglycosides, even

when blood levels are in apparently therapeutic ranges (risk factors for ATN include
preexisting liver disease, preexisting renal disease, concomitant use of other nephrotoxins [eg,
amphotericin B, radiocontrast media, cisplatin], advanced age, shock, female sex, and a 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 male sex, maximum daily dose
(nephrotoxicity is more likely to occur if >3 g is administered) and duration of therapy,
hospitalization in the critical care unit at the initiation of therapy, and concomitant use of
cyclosporine

Radiographic contrast media can cause contrast-induced nephropathy (CIN) or radiocontrast

nephropathy (RCN) (commonly occurs in patients with several risk factors, such as elevated
baseline serum creatinine, preexisting renal insufficiency, underlying diabetic nephropathy,
congestive 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. [3]

Cyclosporine and tacrolimus (calcineurin inhibitors)

Cisplatin

Ifosfamide

Foscarnet

Pentamidine, which is used to treat Pneumocystis jiroveci infection in individuals who are
immunocompromised (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

Mammalian target of rapamycin (mTOR) inhibitors (eg, everolimus, temsirolimus) [4]

Endogenous nephrotoxins that cause ATN include the following:

In, myoglobinuria, rhabdomyolysis is the most common cause of heme-pigment associated

AKI and can be caused by traumatic or nontraumatic injuries (most cases of rhabdomyolysis
are nontraumatic, such as related to alcohol abuse or drug-induced muscle toxicity [statins
alone or in combination with fibrates]).

In hemoglobinuria, AKI is a rare complication of hemolysis and hemoglobinuria, and most

often, it 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) [4]

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, but this condition is also associated with ingestion of certain
toxic substances (eg, ethylene glycol) or nontoxic substances (eg, vitamin C).

Multiple myeloma

Prognosis
For patients with ATN, the in-hospital survival rate is approximately 50%, with about 30% of
patients surviving for 1 year. Factors that are associated with an increased mortality rate include poor
nutritional status, male sex, the presence of oliguria, the need for mechanical ventilation, acute
myocardial infarction, stroke, or 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.[5]

History
The patients history is very important in the diagnosis of acute tubular necrosis (ATN). It
frequently reveals recent hypotension, sepsis, muscle necrosis, or volume depletion, as well as
exposure to nephrotoxic agents. Patients with rhabdomyolysis present with severe muscle pains and
generalized soreness.
ATN is more likely to occur in patients with a history of recent surgery, sepsis, or hypovolemia.
The history is also important in establishing risk factors for the development of ATN.

Physical Examination
Physical examination findings may be unremarkable because acute kidney injury (AKI) is
often found incidentally on routine laboratory studies (ie, elevated blood urea nitrogen [BUN] and
creatinine levels). However, if symptoms are present, they may include a pericardial friction rub,
asterixis, and/or excoriation marks related to uremic pruritus. Hypertension or edema may be noted.
Otherwise, the physical examination findings are more likely to reflect the underlying disease
process. For example, in a patient with rhabdomyolysis, physical examination may disclose tender
doughy muscles, with significant edema of the involved extremities. In severe cases, compartmental
compression syndromes, particularly characterized by neurovascular compromise, may occur.
The 2011 UKRA AKI guidelines state that physiological observation should be performed for
all patients with AKI to find early signs of physiological deterioration that may require a rise in the
level of care.[3]

Complications of Acute Tubular Necrosis

Complications of ATN include fluid and electrolyte imbalances, uremia, infections, and
anemia. Specific 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.

Altered fluid and electrolyte balance

Clearly, the maintenance of fluid and electrolyte balance is critical. 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 causes concern because of its effects on the central nervous system. In general,
correction of hyponatremia should be of sufficient rapidity and magnitude as 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. [6] 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.
Such 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 UKRA guidelines recommend administering 0.9% sodium chloride and sodium
bicarbonate for intravenous volume expansion in patients at risk of developing AKI secondary to
rhabdomyolysis.[3] Metabolic acidosis may occur. It may be treated with bicarbonate or dialysis as well.

Uremia

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.
Infections

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 an impaired immune system (eg, uremia, inappropriate use of antibiotics) and
because of increased use of indwelling catheters and intravenous needles.
Anemia

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.

Diagnostic Considerations
The diagnosis of acute tubular necrosis (ATN) is made on a clinical basis, that is, with the help
of a detailed and accurate history, a thorough physical examination, and pertinent laboratory
examinations and imaging studies.
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 (see Etiology). Urinalysis
and urine electrolytes can be used to differentiate the 2 disorders (see Workup).
Renal vasculitis must be quickly differentiated from ATN. In patients with clinical and urinary
findings suggesting renal vasculitis (eg, acute onset of rash, arthralgias, hypertension, proteinuria,

microscopic hematuria), the diagnosis needs to be established quickly, with renal biopsy, so that
appropriate immunomodulatory therapy can be initiated.
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[7] :

Neutrophil gelatinase-associated lipocalin (NGAL)

Interleukin-18 (IL-18)

Kidney injury molecule-1 (KIM-1)

Liver-type fatty acid binding protein (L-FABP)

Albumin
The likelihood of being diagnosed with ATN increased stepwise with the number of biomarkers

above optimal diagnostic cutoffs.

Also see Nephritis, Interstitial and Acute Obstructive Uropathy Imaging.

Differential Diagnoses

Acute Glomerulonephritis

Acute Kidney Injury

Azotemia

Chronic Kidney Disease

Tubulointerstitial Nephritis

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 injuryinduced 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.

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.

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.

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 26mol/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.

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)

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.

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]

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]

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]

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]

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 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)

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 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).

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).

Treatment
Approach Considerations
The main goal of treatment of acute tubular necrosis (ATN) is to prevent further injury to the
kidney. Extracellular fluid (ECF) volume should be assessed promptly, either on clinical grounds or by
invasive means (Swan-Ganz catheter), and repletion of any deficit should be initiated promptly. The
2011 UKRA guidelines recommend optimizing hemodynamic status by appropriate fluid therapy,
giving vasopressors and/or inotropes and treating any underlying sepsis.[3]
All possible nephrotoxic drugs should be stopped. In addition, doses of all medications that are
eliminated by the kidney should be adjusted.
Any complications that develop must be aggressively treated.
Visit the Pediatric Acute Tubular Necrosis article for additional information.

Correction of Oliguria
Despite some controversy in the literature, in general, if oliguria is present, make an attempt to
increase urine output using intravenous loop diuretics. Use diuretics only if ECF volume and cardiac
function are first carefully assessed and found adequate.
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 administered slowly because high doses can lead to hearing loss. If no response occurs, the
treatment should be discontinued.
Dopamine, a selective renal vasodilator, has also been used to increase urine output, but this
treatment has little benefit and is no longer recommended.

Dialysis
In general, there is no clear consensus on when or how often to perform hemodialysis in the
setting of acute kidney injury (AKI). Some studies have suggested that early initiation may be
beneficial, but in one prospective trial, aggressive dialysis did not improve recovery or survival rates.
However, hemodialysis is still considered standard therapy in severe AKI. In addition, continuous
hemodialysis (continuous venovenous hemodiafiltration [CVVHD] and continuous arteriovenous
hemofiltration with dialysis [CAVHD]) and peritoneal dialysis are also available.
The 2011 UKRA AKI guidelines recommend starting renal replacement therapy (hemodialysis,
CVVHD, CAVHD, or peritoneal dialysis) once AKI is firmly established but before overt
complications arise.[3] .
No compelling studies suggest that one mode of dialysis is better than another. In general,
patients with multiorgan failure and hemodynamic instability may benefit from a continuous mode
because it is typically less hemodynamically taxing. The 2011 UKRA AKI guidelines recommend
lowering the threshold for starting dialysis in the case of multiorgan failure.[3]

Some studies suggest that the use of biocompatible membranes instead of cuprophane
membranes may improve the recovery rate and decrease the mortality rate in AKI. The 2011 UKRA
AKI guidelines recommend using synthetic or modified cellulosic membranes rather than unmodified
celluloid membranes if a choice is available. In addition, UKRA guidelines recommend bicarbonate as
the preferred buffer for dialysate and replacement fluid in continuous dialysis.[3]
According to the 2011 UKRA guidelines, regardless of whether dialysis is performed
intermittently or continuously, the prescribed dose should be assessed at each hemodialysis session.[3]
The 2011 UKRA guidelines recommend venovenous access rather than arteriovenous access for
dialysis. Access should be placed by an experienced or supervised staff member, using real-time
ultrasound as a guide to placement.[3]

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, where they may reduce the vasoconstrictive action of the drug. However, their
use is typically avoided because of possible hypotension.

Dietary Measures
Aggressive and early nutritional support improves survival rates. Adequate protein and caloric
intake is essential because marked increase in protein catabolism is often observed, especially in
patients with shock, sepsis, or rhabdomyolysis. The risks of this catabolism include malnutrition and
an impaired immune system. According to the 2011 UKRA AKI guidelines, patients with AKI who are
receiving dialysis should be referred to a dietician for individual evaluation. The UKRA also
recommends nutritional support with 25-35 kcal/kg/day, and up to1.7 g amino acids/kg/day, for
patients receiving dialysis who are hypercatabolic.[3]

Prevention of Acute Tubular Necrosis

The approach to prevention differs with ischemic ATN and nephrotoxic ATN.

Prevention of ischemic acute tubular necrosis

Be attentive to optimizing cardiovascular function as well as to maintaining intravascular

volume, especially in patients with preexisting risk factors or those taking nephrotoxic medications.
Medicines that reduce systemic resistance (eg, afterload reducers) may cause renal vasoconstriction or
affect the kidneys autoregulatory response (eg, angiotensin-converting enzyme [ACE] inhibitors,
cyclooxygenase [COX] inhibitors) and also should be used with caution.

Prevention of nephrotoxic acute tubular necrosis

Prevention of nephrotoxic ATN depends on the possible nephrotoxin under consideration.

With aminoglycosides, studies have demonstrated that once-daily dosing decreases the incidence of
nephrotoxicity. In one study, 24% of patients receiving 3 daily doses developed clinical nephrotoxicity,
compared to only 5% of patients receiving 1 daily dose. However, other studies comparing a single
daily dose to 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
ECF 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 less nephrotoxic intrinsically.

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.[14] 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 of body weight/h given 1 h prior to the contrast-requiring procedure and then continued at 1
mL/kg of body weight/h for 6 h post procedure) may offer even greater protection than isotonic
sodium chloride.[15] 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.[16] Studies have also suggested that pretreatment with oral NAC (600 mg
or 1200 mg bid on the day prior to and on the day of the contrast-requiring procedure) acts as an
antioxidant, scavenging ROS, thereby reducing the nephrotoxicity of contrast media.
Based on what is known now, 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.
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. 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, theophylline is
a known adenosine antagonist. Although theophylline appears to be promising, further randomized
trials are required to show any proven 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) and COX-2 inhibitors. In those patients with underlying volume depletion, withholding
ACE inhibitors and/or angiotensin receptor blockers (ARBs) may even be necessary. Metformin
should be withheld at least 48 hours before the procedure and until CIN has been ruled out.
Angiotensin II and prostaglandins play central roles in the maintenance of the glomerular
filtration rate (GFR) in the face of volume depletion. ACE inhibitors and ARBs have gained popularity
not only as antihypertensive agents but also as renoprotective agents that either slow or halt the
progression of diabetic and nondiabetic kidney disease. They have also been shown in several studies
to have a role in chronic heart failure as well as ventricular remodeling.
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, COX2 inhibitors, and calcineurin inhibitors), and elevated baseline serum creatinine.
Serum creatinine and electrolytes, especially potassium, should be measured before and at least
1 week after starting or changing the dose of the medication. A threshold for discontinuation of therapy
has been suggested to be (1) an increase in serum creatinine of more than 0.5 mg/dL if the initial
serum creatinine is less than 2.0 mg/dL or (2) an increase in serum creatinine of more than 1.0 mg/dL
if the baseline serum creatinine is greater than 2.0 mg/dL.
An increase in serum creatinine of up to 30% is acceptable, but a continued rise of over 30%
should prompt immediate discontinuation of the medication. Alternatively, discontinuation of ACE
inhibitor or angiotensin receptor blocker therapy is not necessary if smaller increases in serum
creatinine occur.
If and when prerenal AKI does develop, one should commence looking for underlying heart
disease, volume depletion, hypotension, concomitant use of vasoconstrictors, or renovascular disease.

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.

Medication Summary
Medications have only an ancillary role in the treatment of acute tubular necrosis (ATN).
Antioxidants and diuretics may be helpful in specific circumstances. Therapeutic mainstays are
prevention, avoidance of further kidney damage, treatment of underlying conditions, and aggressive
treatment of complications.

Antioxidants
Class Summary

Antioxidants may prevent reperfusion damage as well as improve renal hemodynamics.

View full drug information
N-acetylcysteine (Mucomyst, Mucosil)

N-acetylcysteine is used for acetaminophen toxicity. It has been shown to prevent renal
deterioration in patients with acetaminophen toxicity and hepatorenal syndrome. This finding led to its
study in the prevention of contrast-induced nephropathy (CIN). It may work by improving renal

hemodynamics and by preventing direct oxidative tissue damage. The use of N-acetylcysteine (NAC)
is believed to have antioxidant properties that potentially counteract the effects of ROS.

Diuretics
Class Summary

Diuretics help maintain a nonoliguric state, which has a better overall survival rate. Loop
diuretics work to increase urine output. Diuretics should only be used if ECF volume and cardiac
function are first carefully assessed and found to be adequate.
View full drug information
Furosemide (Lasix)

Furosemide increases excretion of water by interfering with the chloride-binding cotransport

system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and
the distal renal tubule. Individualize the dose to the patient. Depending on the response, administer
furosemide at increments of 20-40 mg, no sooner than 6-8 hours after the previous dose, until the
desired diuresis occurs. When treating infants, titrate with 1 mg/kg per dose increments until a
satisfactory effect is achieved.
View full drug information
Bumetanide

Bumetanide is a loop diuretic that increases the excretion of water by interfering with the
chloride-binding co-transport system, which, in turn, inhibits sodium, potassium, and chloride
reabsorption in the ascending loop of Henle. These effects increase urinary excretion of sodium,
chloride, and water, resulting in profound diuresis. Renal vasodilation occurs following administration,
renal vascular resistance decreases, and renal blood flow is enhanced.
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