Acute Tubular Necrosis (ATN)

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Practice Essentials

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



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Acute tubular necrosis. Photomicrograph of a kidney biopsy specimen shows renal medulla, which is composed mainly of renal tubules. Features suggestin....

ATN follows a well-defined four-part sequence of initiation, extension, maintenance, and recovery, as follows:

See Pathophysiology for more detail.

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). Whether the cause is ischemia or nephrotoxicity, most of the pathophysiologic features of ATN are the same.[2]

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

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

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

Pathophysiology

ATN follows a well-defined four-part sequence of initiation, extension, maintenance, and recovery (see below).[3, 4] The tubule cell damage and cell death that characterize ATN usually result from an acute ischemic or toxic event.[5] The ischemic and the nephrotoxic forms of ATN share most of the same pathophysiologic features.

Initiation

Ischemic ATN is often described as a continuum of prerenal azotemia. Indeed, the causes of the two conditions are the same. Ischemic ATN results when hypoperfusion overwhelms the kidney’s autoregulatory defenses. Under these conditions, hypoperfusion initiates cell injury that often, but not always, leads to cell death.

Extension

Persistent hypoperfusion injures tubular cells in the straight portion of the proximal tubules and the thick ascending limb of the loop of Henle, especially as it dips into the relatively hypoxic medulla. The tubular epithelial cells of the S3 segment of the proximal tubule in the outer stripe of the medulla, at the corticomedullary junction, are most susceptible to ischemic injury as these cells live in a relatively hypoxic environment.

Continued hypoperfusion can also cause vascular endothelial injury and prolong the extension phase with compromised blood flow to injured tissues and inability to regulate the local vascular tone. As cells in segments S1 and S2 possess high rates of endocytosis, the injury from exogenous toxins is more commonly seen in S1 and S2 segments. The reduction in 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. The infiltrate thus leaks back through the damaged epithelium, resulting in 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 back-leak of filtrate mentioned above.

Another change is the relocation of Na+/K+-ATPase pumps and integrins to the apical membrane. Cell death occurs by both necrosis and apoptosis. Sloughing of live and dead cells occurs, leading to cast formation and obstruction of the tubular lumen (see the image below). Activation of the renal immune system—with damage to tubular cells stimulating local secretion of proinflammatory cytokines—in turn induces further necrosis.[6]



View Image

Acute tubular necrosis. Photomicrograph of a kidney biopsy specimen shows renal medulla, which is composed mainly of renal tubules. Features suggestin....

In addition, ischemia leads to decreased production of vasodilators (ie, nitric oxide, prostacyclin [prostaglandin I2, or PGI2]) by the tubular epithelial cells, worsening vasoconstriction and hypoperfusion. On a cellular level, ischemia causes depletion of adenosine triphosphate (ATP), an increase in cytosolic calcium, formation of free radicals, 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. Ineffective active membrane transport disrupts cell volume and electrolyte regulation, causing 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 is most severe during reperfusion.

Maintenance

The maintenance phase of ATN is characterized by a stabilization of GFR, typically lasting 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. The resulting decreased perfusion of the nephrons can perpetuate the kidney injury.

Recovery

The recovery phase of ATN is characterized by regeneration of tubular epithelial cells.[7]  During recovery, abnormal diuresis sometimes occurs, causing salt and water loss and volume depletion. The mechanism of the diuresis is not entirely understood. Still, 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.

ATN is reversible in some patients but not in all patients. The underlying mechanism is not very clear, especially the molecular switch. Upon severe or persistent kidney injury, the repair is incomplete or maladaptive. Maladaptive repair could result in permanent injury or kidney fibrosis. Various cell types and multiple injury pathways are involved in maladaptive repair, but the critical component is inflammation. Renal tubular cells could release cellular contents and cytokines to surrounding tissue and trigger an inflammatory response. Thus, the sustained necroinflammatory process could cause severe organ dysfunction and tissue injury in the kidney [8] .

Further, at molecular levels, regulated cell death through tubular cell apoptosis, necrosis, and cell loss drive AKI development upon a renal insult. Apoptosis, necroptosis, ferroptosis, MPT-RN (mitochondrial permeability transition regulated necrosis), and possible pyroptosis are potential molecular mechanisms of AKI induced by ischemic-reperfusion injury, toxin, cytokine storm, and crystals [9] .

The driving force of ATN is primarily tubular injury and hypoperfusion in peritubular capillaries. The combination of tubular injury and hypoperfusion could cause permanent nephron loss in those patients who cannot recover from ATN, eventually tissue fibrosis and CKD after acute injury.

 

Normotensive ischemic acute tubular necrosis

This condition develops in patients without an overt severe hypotensive episode. These patients have low to normal blood pressure but still have severe ATN. The most common reason for this condition is renal susceptibility to lower blood pressure because of impairment of autoregulatory function of the kidney. Normally, the afferent arteriole dilates (via prostaglandins) and efferent arteriole constricts (via angiotensin-II) to maintain the glomerular capillary pressure. Factors that impair this autoregulatory mechanism include the following[10] :

Endotoxemia (sepsis)-related ATN

Sepsis is a recognized cause of ATN. Development of AKI in the setting of sepsis will increase in-hospital mortality by five to six-fold[11, 12]  and increase the risk of progression to CKD in survivors [13] . Sepsis-induced ATN is hypothesized from a reduction in renal blood flow caused by sepsis-related hypotension. However, this has been challenged by several animal and human studies. These studies have indicated that, in fact, renal blood flow may increase in that setting due to a mechanism that leads to afferent arteriolar vasodilatation. [14]

Other suspected contributors to ATN in sepsis include the following:[15, 16, 17, 18]

 

Etiology

ATN is generally caused by an acute event, either ischemic or toxic. ATN is caused by sepsis in approximately 20% of intensive care unit (ICU) patients. Prerenal azotemia, obstruction, glomerulonephritis, vasculitis, acute interstitial nephritis, acute on chronic injury (in patients with chronic kidney disease [CKD]), and atheroembolic injury account for most of the remainder.[19, 20]

Causes of ischemic acute tubular necrosis

Ischemic ATN may be considered part of the spectrum of prerenal azotemia; indeed, ischemic ATN and prerenal azotemia have the same causes and risk factors. Specifically, these include the following:

Causes of ischemic ATN vary depending on the studied population. In developed countries, comorbidities, older age, and severity of illness during  ICU admission are more likely to result in AKI, as reported in the Acute Kidney Injury–Epidemiologic Prospective Investigation (AKI-EPI)[21] and Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) trials.[22, 23] These comorbidities include cancer, hypertension, chronic heart failure, cirrhosis, AIDS, chronic obstructive pulmonary disease, and diabetes mellitus. In low-income countries or rural areas, AKI occurs more commonly in younger patients and in association with conditions related to volume depletion and complications of pregnancy.[24] However, there is no detailed information on ATN in those settings.

Causes of nephrotoxic acute tubular necrosis

The kidney is a particularly vulnerable target for toxins, both exogenous and endogenous. Not only does it have a rich blood supply, receiving 25% of cardiac output, but it also helps in the excretion of these toxins by glomerular filtration and tubular secretion.

Exogenous nephrotoxins that cause ATN

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

Amphotericin B nephrotoxicity risk factors include the following:

Radiographic contrast media can cause contrast-induced nephropathy (CIN). This commonly occurs in patients with several risk factors, including preexisting CKD, underlying diabetic nephropathy, chronic heart failure (CHF), or high or repetitive doses of contrast media, as well as volume depletion and concomitant use of diuretics, angiotensin-converting enzyme inhibitors (ACEi), or angiotensin II receptor blockers (ARBs). Prevention is paramount, so patients at risk of CIN should have a careful evaluation of volume status and receive volume expansion with 0.9% sodium chloride or crystalloids with less chloride content before the procedure.[25]

Other exogenous nephrotoxins that can cause ATN include the following:

Endogenous nephrotoxins that cause ATN

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

In hemoglobinuria, AKI is a rare complication of hemolysis and hemoglobinuria. It is often 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).[26]  A few  reports suggest intratubular casts as a culprit of ATN in patients with significant hemolysis.[27]  

Acute crystal-induced nephropathy occurs when crystals are generated endogenously due to high cellular turnover (ie, uric acid), as observed in certain malignancies or the treatment of malignancies. However, this condition is also associated with ingestion of certain toxic substances (eg, ethylene glycol) or nontoxic substances (eg, vitamin C). Choudhry et al reported an AKI case caused by ingesting excessive amounts of calcium-containing antacids.[28]

In multiple myeloma, renal impairment results from the accumulation and precipitation of light chains, which form casts in the distal tubules that cause renal obstruction. In addition, myeloma light chains have a direct toxic effect on proximal renal tubules.[29]

COVID-19

AKI is one of the most common complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) in hospitalized patients, occurring in about 25% to 50% of cases.[30, 31, 32, 33] In one study, only a third of all patients with AKI were discharged with recovery of kidney function.{ref64 Among all patients with AKI, 19-33.8% required renal replacement therapy.[34, 35] Preexisting medical conditions are associated with higher AKI incidence in COVID patients. Among patients with CKD, the incidence of AKI was close to 80%. Similar to the causes of AKI in other patient populations, the common risk factors for COVID-related AKI are old age, diabetes mellitus, hypertension, CKD, chronic heart failure, liver disease, male gender, obesity, and severe hypoxia on presentation.[36, 37, 38, 39, 40]

COVID-19 infection can cause proteinuria in 39-81% of AKI patients. Hematuria and leukocyturia are seen in 26-84% and 60% of COVID-AKI patients, respectively. Some patients develop nephrotic range proteinuria. The causes of AKI are commonly pre-renal, ischemic, and toxic ATN from hemodynamic instability, rhabdomyolysis, contrast exposure, or drugs.[41, 42] The major cause of AKI in COVID-19 is ATN. The pathological changes in COVID-AKI are mainly acute tubular injury (ATI); pigmented casts from rhabdomyolysis; different types of vascular injury, including frequent red blood cell aggregation occluding renal capillaries, endothelial swelling and foaming degeneration; and segmental fibrin thrombi from the hypercoagulable state. Hypercoagulation is frequently seen in COVID-19 infection.[43, 44]

AKI in patients with COVID-19 is also associated with significantly higher mortality.

Epidemiology

The landmark PICARD (Program to Improve Care in Acute Renal Disease) study was an observational study of a cohort of 618 patients with AKI in the intensive care units of 5 academic centers in the United States. Ischemic ATN was the presumed etiology for 50% of all patients with renal failure, an additional ~12% due to unresolved pre-renal factors, and ~25% from nephrotoxic ATN.[45]  These data were similar to those from the Madrid Acute Renal Failure Study Group, which assessed 748 cases of acute injury from that region of Spain and estimated that the incidence of ATN was 88 cases per million population.[46]

 

 

Prognosis

For patients with ATN, the in-hospital survival rate is approximately 50%, with about 30% surviving for one year. Critically ill patients with severe AKI have higher mortality in the first two months and less during long-term follow-up.[47]

Factors associated with an increased mortality rate in patients with ATN include the following:

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 in patients with nephrotoxin-related ATN (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 non-oliguric ATN. This probably is related to more severe necrosis and more significant disturbances in electrolyte balance. In addition, a rapid increase in serum Cr to a high level (ie, > 3 mg/dL) indicates a poorer prognosis. Again, this probably reflects more serious underlying injury.

Of the survivors of ATN, approximately 50% have some impairment of kidney function. About 5% continue to undergo a decline in kidney function. About 5% never recover kidney function and require dialysis.

A review of United States Renal Data System (USRDS) 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 kidney function was more likely in patients with ATN than in matched controls (patients with ESRD but not ATN; 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). Hazard ratios for death declined in stepwise fashion to 0.83 in 2009-2010.[48]

AKI in hospital inpatients has long-term implications after discharge. A meta-analysis of 13 cohort studies showed that patients with AKI had a higher risk for developing CKD (hazard ratio [HR] 8.8, 95% confidence index [CI] 3.1-25.5), ESRD (HR 3.1, 95%CI 1.9-5.0) and mortality (HR 2.0, 95% CI 1.3 - 3.1).[49] AKI was also independently associated with cardiovascular disease and CHF risk. Patients with AKI whose kidney function does not return to 25% of baseline have a higher risk of mortality and adverse renal outcomes.[50]

The United States Renal Data System (USRDS) annual report demonstrated that AKI-related hospital admission rates in Medicare recipients decreased for the first time in 2020, except in Blacks.[51] However, the percentage of hospitalized patients requiring dialysis for AKI increased, to 4.1% overall (ranging from 6.2% in those aged 66-69 years to1.8% in those aged ≥85 years). 

Rates of death or entrance into hospice care in patients with AKI ranged from about 17.5% for those not requiring dialysis to 41.8% for those requiring dialysis and 74.1% for those with COVID-19. After hospital discharge, an additional 13.8% died and 10.7% required re-admission. Of beneficiaries with pre-existing CKD, 17.5% progressed to advanced CKD, and 42.9% died two years after index hospitalization for AKI. Among patients with AKI requiring hemodialysis, only 29.7% recovered kidney function, 18.8% remained on dialysis, 35.7% progressed to ESRD, and 15.8% died by three months. Only 32.2% recovered kidney function by six months; 2.1% remained on hemodialysis, 48.8% progressed to ESRD, and 16.9% died.[51]

A retrospective study by Wald et al found that up to 25% of critically ill adult patients with AKI required dialysis.[52] Pre-existing CKD was associated with a higher rate of dialysis requirement. Worsening kidney function developed in the first months of follow-up and increased substantially three years after a severe AKI episode. The RENAL trial reported a similar long-term survival rate of 38%; most deaths occurred in the first three months.

Co-morbidities are the main factors affecting life expectancy after severe AKI attacks.[53, 54] In the ASSESS-AKI trial and other studies, about 5.7% to 9% of patients had kidney disease progression. Higher post-AKI urine albumin Cr ratio (ACR) was associated with the progression of kidney disease at median follow-up of 4.7 years (hazard ratio 1.53, 95% CI 1.45-1.62).[22, 55]

History

The history can establish the patient’s risk factors for developing acute tubular necrosis (ATN). Careful explication of the timeline of events leading to acute kidney injury (AKI) can frequently identify the underlying cause of ATN. 

The history commonly reveals risk factors such as recent surgery, hypotension, sepsis, muscle necrosis, volume depletion, or exposure to nephrotoxic agents. More than one of those may be present simultaneously, and as the number of risk factors increases, so too does the the risk of ATN occurrence and severity. 

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

 

 

Physical Examination

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

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

 

 

Approach Considerations

Blood studies, urinalysis, and 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. Suggested testing includes the following:

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

The BUN and serum Cr concentrations are increased in AKI. This increased Cr can be monitored regularly 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 initiation of dialysis, and further calculations and dose adjustments will be required.[56]

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

Staging of Acute Kidney Injury

The degree of AKI is determined using Kidney Disease Improving Global Outcomes (KDIGO). In 2012,  KDIGO published a practice guideline for AKI. AKI is classified into stages 1 to 3[57]  as below table. Acute kidney disease and disorders (AKD) is recently introduced, a classification for those who meet the criteria of AKI, but kidney damage persists for more than 7 days but less than 3 months.[58]  Subclinical AKI is defined for patients who have kidney damage with a positive biomarker for AKI, without clinical manifestations and kidney dysfunction.[59]

For more information on KDIGO, see Classification Systems for Acute Kidney Injury.

Table.



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See Table

 

Urinalysis

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.



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

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



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See Table

Fractional excretion of a substance (s) is calculated by the formula (U/P)s/(U/P)Cr × 100, where s is the substance, U and P represent urine and plasma concentrations, and Cr stands for Cr.

In patients with 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 a positive dipstick test for blood, with a typical absence of RBCs on microscopy. Furthermore, hyperkalemia, hyperphosphatemia, and hyperuricemia are characteristic.

In one center study, urine sodium, urine osmolality, urine specific gravity, and renal failure index have high specificity > 85% for prerenal AKI.  Similarly, urine sodium, urine specific gravity, and renal failure index have high sensitivity for ATN. Loop diuretics, ACEi/ARB, or pre-existing CKD have no impact in that study; further study or confirmatory study is needed [60] .

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

Ultrasonography

Renal ultrasonography, preferably with Doppler methods, is a simple procedure that should be undertaken in all patients who present with AKI.[61] 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.[25]

 

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.[61]

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.[61]

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) of the abdomen can potentially determine the cause of ureteral obstruction when ultrasonographic results are unclear. MRI with contrast is preferred, whereby new-generation (Group II Gadolinium) contrast has minimal risk of systemic complication [62, 63]  [61]

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.[64, 65]  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; exfoliation of the tubular cells into the lumina; interstitial edema; white blood cells (WBC) in dilated vasa recta; dilated proximal tubules with thinning or loss of brush borders; and granular, hyaline or pigmented casts in the distal and collecting ducts. The earliest finding could be loss of the cellular brush border.



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Acute tubular necrosis. Photomicrograph of a kidney biopsy specimen shows renal medulla, which is composed mainly of renal tubules. Features suggestin....

Although ATN was long considered to be synonymous with acute tubular injury (ATI), frank tubular epithelial necrosis is only one 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 [66] :

The review found no difference in tubular injury histology among kidney biopsy, transplant kidney biopsy, and autopsy, among different etiologies, or between biopsy samples taken before or after Cr peaks in native kidneys. [66]

Novel Biomarkers

The most commonly used markers of kidney function—serum Cr level, GFR, and urinary output—are limited in determining the magnitude of renal injury. These markers are unable to identify underlying etiology. Furthermore, serum Cr only increases after GFR drops significantly. The rise in serum Cr commences on average two days post a renal insult. This creates a significant delay for preventive or corrective measures. AKI induces specific cellular and molecular changes involving the kidney nephron.[67] . Recent intense research to find more accurate kidney function biomarkers (serum and/or urine), [68] uncovered new biomarkers that permit early diagnoses and aid in rendering appropriate treatment strategies before permanent damage has occurred [69] . 

Research has focused on the following potential biomarkers:

In a multicenter, prospective cohort study of 102 patients with cirrhosis and 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 patients with ATN [70] :

Most recent studies revealed that the combination use of urinary tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFB-7) could identify early AKI or high-risk AKI patients to allow more targeted intervention of AKI. The pooled sensitivity and specificity in one meta-analysis were 0.77 and 0.76 [71, 72, 73] . FDA has approved a point-of-care test kit that could detect both proteins[74] . However, the above data are obtained in surgical patients; more research needs to be done in medical patients on the utilization of TIMP-2 and IGFB-7 [75] . KDIGO controversies conference suggested insufficient evidence to warrant incorporating biomarkers into the current definition of AKI, but biomarkers might be helpful in the stratification of AKI severity. Our group showed that a urine sample of NGAL upon admission to the ICU predicts AKI early and the need for renal replacement therapy. Additionally, urine NGAL can distinguish cardiogenic shock from other critical illnesses in the ICU [76] .  Further research is needed before novel renal biomarkers are incorporated into clinical practice.

Furosemide Stress Testing

In early AKI, urine output after a furosemide stress test (FST) can predict the development of stage 3 AKI. Response to the FST may help the clinician determine when or whether to start renal replacement therapy.[77, 78]

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 the 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. [78]

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 NGAL >150 ng/mL or urinary TIMP-2 ×IGFBP-7 >0.3.[77]

Approach Considerations

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

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

Kidney Disease: Improving Global Outcomes (KDIGO) guidelines suggest using a stage-based approach to the management of AKI/ATN.[79] However, the guidelines suggest that the following measures have no role in the prevention of AKI[79] :

Correction of Oliguria

In the past, the use of diuretics to convert an oliguric AKI to non-oliguric AKI was sometimes recommended, to help with fluid management. However, several meta-analyses have shown no reduction in mortality or the need for renal replacement therapy with the use of diuretics.[80]

The only indication for diuretics would be fluid overload after appropriate management of sepsis and cardiac dysfunction. Intravenous furosemide or bumetanide in a single high dose (ie, 100-200 mg of furosemide) is commonly used, although little evidence indicates that it changes the course of ATN. The drug should be infused slowly because high doses can lead to hearing loss. If no response occurs, the treatment should be discontinued.

There is no role for so-called renal-dose dopamine in the management of ATN.[81]

Dialysis

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

In patients without an indication for dialysis, initiating renal replacement therapy (RRT) prophylactically offers no benefit over performing RRT as and when required. Several trials and a meta-analysis have shown no improvement in outcome with early versus late RRT for patients with AKI.[82]

Dialysis modality 

Continuous renal replacement therapy (CRRT), sustained low-efficiency dialysis (SLED), and intermittent hemodialysis can all be used for renal replacement in ATN. None of those therapies offers significant benefit over the others, and KDIGO suggests using these modalities as complementary approaches, especially in hemodynamically unstable patients. The choice of therapy should be driven by local expertise. CRRT may be the preferred option for hemodynamically unstable patients.[79]

Elimination of Nephrotoxins

Generally, the treatment of choice for nephrotoxic ATN is to stop all nephrotoxic agents to prevent further damage to the kidney. Of note, calcium channel blockers may have some use in cyclosporine toxicity, as they may reduce the vasoconstrictive action of cyclosporine. However, their use is typically avoided because of possible hypotension.

Complications

Traditional complications of ATN include the following[83] :

Non-traditional complications of ATN include the following[83] :

Altered fluid and electrolyte balance

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

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

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

Hyponatremia is cause for concern because of its effects on the central nervous system. In general, correction of hyponatremia should be of sufficient rapidity and magnitude to reverse the manifestations of hypotonicity but not be so rapid or significant as to potentiate the risk of osmotic demyelination. The most recently published guidelines on treatment of hyponatremia recommend rates of correction of serum sodium ranging from 6-8 mmol/L per 24 h.[84] 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 calcium deposition in the injured muscle. The deposited calcium is eventually released back into the circulation during the recovery phase, thereby accounting for transient hypercalcemia. For this reason, calcium administration is generally not recommended for hypocalcemia during the acute phase of rhabdomyolysis unless the patient is symptomatic.

The goal of rhabdomyolysis treatment is to improve renal blood flow to minimize ischemia, increase urine flow rate to wash out obstructing casts, minimize the cytotoxic effects of myoglobin on tubular cells, and relieve any ongoing muscle compression. The American Association for the Surgery of Trauma Critical Care Committee recommends infusing normal saline or lactated Ringer solution to ensure urine output reaches 1-2 mL/kg/hr and stays at that level until myoglobin disappears from the urine or the creatine kinase level is lower than 10,000 units/L.[85] The previously suggested use of bicarbonate infusion to maintain urine pH above 6.5 is no longer recommended as it did not show any benefit on the incidence of AKI.

Go to Rhabdomyolysis for complete information on this topic.

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. Fortunately, uremia is becoming rarer with the earlier start of renal replacement therapy and better availability of resources, at least in the developed world. 

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 impairment of the immune system (eg, from uremia, inappropriate use of antibiotics) and increased use of indwelling urinary catheters and intravenous catheterization.

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 if necessary.

Diet

KDIGO guidelines for AKI/ATN suggests the following dietary measures, although most are supported with limited evidence[79] :

 ​

Prevention

Prevention of AKI

The KDIGO guideline proposes supportive care for patients at high risk for AKI. The KDIGO recommendations include the following[86] :

The PrevAKI trial documented that biomarker-guided implementation of the KDIGO recommendations decreased the incidence of AKI in high-risk patients.[87] However, subsequent research found that each intervention in the bundle does not share the same importance; avoidance of hyperglycemia and contrast exposure had no significant effect.[88]

Prevention of nephrotoxic acute tubular necrosis

Strategies for prevention of nephrotoxic ATN vary with different nephrotoxins.

With aminoglycosides, studies have demonstrated that once-daily dosing decreases the incidence of nephrotoxicity. In one study, 24% of patients receiving 3 daily doses of gentamicin developed clinical nephrotoxicity, compared with only 5% of patients receiving 1 daily dose.[89]  Therapeutic efficacy is not diminished by use of a single daily dose.

With amphotericin B, efforts should be made to minimize the use of the drug and ensure that extracellular fluid volume is adequate. Maintenance of a high urine flow rate with crystalloids is helpful. Likewise, various lipid formulations of amphotericin B have been developed: amphotericin B colloid dispersion (ABCD), amphotericin B complex (ABLC), and liposomal amphotericin B. These lipid formulations are believed to be intrinsically less nephrotoxic.

Whereas amphotericin B is suspended in bile salt deoxycholate, which has a detergent effect on cell membranes, the lipid formulations do not contain deoxycholate. The lipid formulations also bind more avidly to fungal cell wall ergosterol as opposed to the cholesterol in human cell membranes. Liposomal amphotericin B is preferred in patients with kidney 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, kidney 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 kidney injury is volume loading with crystalloid  Some investigators advocate the adjunctive use of amifostine, a thiol donor that serves as an antioxidant. Others prefer using carboplatin, a less nephrotoxic alternative to cisplatin.

Prevention of contrast-induced nephropathy

Intravenous contrast use should not be withheld when there is a life-threatening indication. Recent literature demonstrated that the risk of severe AKI related to IV contrast exposure seems to be less than previously reported [90, 91, 92] . The reduction in the risks of CIN is ascribed to use of newer agents, prevention strategies, and hypervigilance for AKI. Healthcare providers should discuss with patients and weigh the benefits and risks prior to IV contrast administration. Isotonic sodium chloride solution infusion has proven beneficial as a preventive measure. 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 kidney insufficiency and DM. This has been shown to be superior to half-normal saline infusions.​[93]

A single-center, randomized, controlled trial demonstrated that isotonic sodium bicarbonate (3 mL/kg/h given 1 h prior to the contrast-requiring procedure and then continued at 1 mL/kg/h for 6 h post procedure) may offer even greater protection than isotonic sodium chloride.[94]  The postulated mechanism is the inhibition of oxidant injury by the administered alkali.

The use of N-acetylcysteine (NAC) as a prophylactic agent had gained popularity 2 decades ago upon the work of Tepel et al.[95] , where NAC was used with IV hydration. Several subsequent metanalysis studies and systematic reviews did not support the prophylactic use of NAC to prevent CIN [96, 97, 98, 99] .

The Prevention of Serious Adverse Events Following Angiography (PRESERVE) trial in 2018 demonstrated no benefit of either sodium bicarbonate or NAC over saline hydration for prevention of CIN, prevention of death, the need for renal replacement therapy (RRT) or a persistent Cr increase of at least 50% from baseline at 90 days[100] . So, the NAC and IV bicarbonate infusion have lost their popularity[101] .

The volume and composition of fluid administration have been studied in detail. Intravenous volume expansion reduces the risks of CIN as compared to no volume expansion. Intensive fluid hydration offers more benefits than standard fluid hydration to prevent CIN [102, 103] . However, it is very difficult to give IV fluid for such a long time in an outpatient setting. American College of Radiology recommends normal saline at 100 ml/hr beginning 6 -12 hours before and 4-12 hours after the IV contrast exposure. Of note, IV fluid might be less helpful in hemodynamically unstable patients, especially those with decreased cardiac function or shock patients.

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

Some investigators recommend the avoidance of contrast-requiring procedures, if at all possible. MRI usually necessitates using gadolinium as a contrast agent, which, in several studies, is less nephrotoxic than conventional contrast media. Using the lowest possible amount of contrast media in the procedure is also recommended.

Aside from the recommended prophylactic medications discussed above, other guidelines recommend withholding potential nephrotoxic agents, such as NSAIDs.

In patients with underlying volume depletion, withholding ACEi and/or ARBs may be necessary. The use of ACEi and ARBs is limited by the tendency to cause prerenal failure, especially in patients at high risk. Risk factors include advanced age, underlying renovascular disease, concomitant use of diuretics or vasoconstrictors (e.g., NSAIDs, COX-2 inhibitors, and calcineurin inhibitors), and elevated baseline serum Cr.

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

Prevention of rhabdomyolysis

Preventive strategies for rhabdomyolysis include aggressive volume resuscitation with normal saline at 1000-1500 mL/h with a goal urine output of 300 mL/h. Caution should be exercised to avoid producing a compartment syndrome, especially in those patients who remain oliguric or anuric 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 could be beneficial to increase the solubility of the heme proteins within the tubules, but it increases the risk of calcium-phosphorus precipitation.  Urine alkalinization has also been shown to reduce the generation of ROS. However, subsequent studies failed to show any benefit on the incidence of AKI by alkalizing urine. 

Long-Term Monitoring

Patients hospitalized with AKI are an elevated risk for adverse outcomes (see Overview/Prognosis), so they require follow-up after discharge. KDIGO guidelines recommend a 3-month follow-up after an episode of AKI to determine whether the patient has experienced renal recovery or new-onset or progressive CKD.[79] Longer follow-up may benefit all patients but may be especially valuable in patients with a higher risk of poor outcomes. Higher-risk features are as follows[104] :

After an AKI episode, recovery of the glomerular filtration rate (GFR) can take up to one year.[105] AKI is now recognized as a risk factor for CKD; the risk persists even after normalization of serum creatinine levels.[106, 107, 108, 109] In the Severe Acute kidney injury Long-Term Outcomes (SALTO) study, the cumulative incidence of worsening kidney function was about 8.5% at 3 years and 20.6% at 4 years after severe AKI episodes.[110]

In large multi-center studies, different initiation strategies for renal replacement therapy have not shown any difference in short-term outcomes. The exception is the Early Versus Delayed Initiation of RRT in Critically Ill Patients with AKI (ELAIN) trial, which showed a lower mortality rate after 90 days in the early initiation group.[111, 112]

Investigational Treatments

Targeted treatment based on molecular pathways involved in the pathogenesis of ATN is promising and hopefully will become an approach to prevention and treatment of ATN in the future. Preclinical research findings have included the following:

Medication Summary

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

What is acute tubular necrosis (ATN)?What are the sequences of disease progression in acute tubular necrosis (ATN)?What causes tubule cell damage and cell death in acute tubular necrosis (ATN)?How is the cause of acute tubular necrosis (ATN) identified?How is acute tubular necrosis (ATN) managed?What is the pathophysiology of acute tubular necrosis (ATN)?What is the pathophysiology of the initiation phase of acute tubular necrosis (ATN)?What is the pathophysiology of the maintenance phase of acute tubular necrosis (ATN)?What is the pathophysiology of the recovery phase of acute tubular necrosis (ATN)?What is the pathophysiology of normotensive ischemic acute tubular necrosis (ATN)?What is the pathophysiology of endotoxemia (sepsis)-related acute tubular necrosis (ATN)?What causes ischemic acute tubular necrosis (ATN)?What causes nephrotoxic acute tubular necrosis (ATN)?What are the risk factors for aminoglycoside caused acute tubular necrosis (ATN)?What are the risk factors for amphotericin B nephrotoxicity caused acute tubular necrosis (ATN)?Which exogenous nephrotoxins can cause acute tubular necrosis (ATN)?Which endogenous nephrotoxins cause acute tubular necrosis (ATN)?What is the prevalence of acute tubular necrosis (ATN)?What is the in-hospital survival rate among patients with acute tubular necrosis (ATN)?What is the mortality rate of acute tubular necrosis (ATN)?What is the prognosis of oliguric acute tubular necrosis (ATN)?What is the prevalence of end-stage renal disease (ESRD) in acute tubular necrosis (ATN)?Which clinical history is characteristic of acute tubular necrosis (ATN)?What are the physical findings characteristic of acute tubular necrosis (ATN)?What are the differential diagnoses for Acute Tubular Necrosis (ATN)?Which tests should be performed in the workup of acute tubular necrosis (ATN)?What is the role of lab testing in the workup of acute tubular necrosis (ATN)?Which nephrotoxicity findings suggest a specific medication causing acute tubular necrosis (ATN)?What is the role of urinalysis in the workup of acute tubular necrosis (ATN)?What is the role of ultrasonography in the workup of acute tubular necrosis (ATN)?What is the role of abdominal radiography in the workup of acute tubular necrosis (ATN)?What is the role of CT scanning in the workup of acute tubular necrosis (ATN)?What is the role of MRI in the workup of acute tubular necrosis (ATN)?What is the role of renal biopsy in the workup of acute tubular necrosis (ATN)?What is the role of biomarkers in the workup of acute tubular necrosis (ATN)?What is the role of furosemide stress testing in the workup of acute tubular necrosis (ATN)?How is the degree of acute kidney injury (AKI) determined in acute tubular necrosis (ATN)?How are patients at risk for acute tubular necrosis (ATN) proactively managed?Which group of patients are likely to develop acute tubular necrosis (ATN)?What are the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for managing acute tubular necrosis (ATN)?What is the role of diuretics in the treatment of acute tubular necrosis (ATN)?When is dialysis indicated in the treatment of acute tubular necrosis (ATN)?What can the options for renal replacement therapy in acute tubular necrosis (ATN)?What is the treatment of choice for nephrotoxic acute tubular necrosis (ATN)?What are possible complications of acute tubular necrosis (ATN)?What are complications of altered fluid and electrolyte balance in acute tubular necrosis (ATN)?What are the signs and symptoms of uremia in acute tubular necrosis (ATN)?What is the prevalence of infections in acute tubular necrosis (ATN)?What are the causes of anemia in acute tubular necrosis (ATN)?What are KDIGO dietary guidelines for acute tubular necrosis (ATN)?What is the role of N-acetylcysteine (NAC) in the prevention of acute tubular necrosis (ATN)?How is nephrotoxic acute tubular necrosis (ATN) prevented?How is contrast-induced nephropathy (CIN) in acute tubular necrosis (ATN) prevented?What is the efficacy of isotonic sodium bicarbonate for the prevention of contrast-induced nephropathy (CIN) in acute tubular necrosis (ATN)?What is the role of nonionic contrast media in the prevention of acute tubular necrosis (ATN)?What should be avoided to prevent contrast-induced nephropathy (CIN) in acute tubular necrosis (ATN)?Which interventions to decrease the risk of contrast-induced nephropathy (CIN) in acute tubular necrosis (ATN) lack evidence of efficacy?How is rhabdomyolysis prevented in acute tubular necrosis (ATN)?What is included in long-term monitoring of acute tubular necrosis (ATN)?What is the role of medications in the management of acute tubular necrosis (ATN)?

Author

Charlene (Xiaoying) Deng, MD, PhD, MBA, FACP, FASN, Assistant Professor of Medicine, Division of Nephrology, Hypertension and Transplantation, Thomas Jefferson University Hospital, Sidney Kimmel Medical College of Thomas Jefferson University

Disclosure: Nothing to disclose.

Coauthor(s)

Omar H Maarouf, MD, Associate Professor of Medicine, Director of Renal Course, Division of Nephrology, Sidney Kimmel Medical College of Thomas Jefferson University; Director of Acute Dialysis Unit, Associate Program Director of Renal Fellowship, Jefferson Renal Associates, Thomas Jefferson University Hospital

Disclosure: Nothing to disclose.

Seyed Mehrdad Hamrahian, MD, Associate Professor of Medicine (Nephrology), Sidney Kimmel Medical College of Thomas Jefferson University; Director of American Society of Hypertension-Designated Jefferson Hypertension Center; Medical Director, Jefferson Nephrology Outpatient Clinic; Medical Director, Jefferson Home Hemodialysis Program; Medical Director of Chronic Dialysis Unit, DaVita City Line Dialysis

Disclosure: Nothing to disclose.

Chief Editor

Vecihi Batuman, MD, FASN, Professor of Medicine, Section of Nephrology-Hypertension, Deming Department of Medicine, Tulane University School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

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

Disclosure: Nothing to disclose.

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

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Astra Zeneca<br/>Author for: UpToDate, ACP Smart Medicine, Elsevier, McGraw-Hill, Wolters Kluwer.

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

Disclosure: Nothing to disclose.

Nikhil A Shah, MBBS, DNB(Neph), Clinical Research Fellow in Home Dialysis, Nephrologist, University of Alberta Faculty of Medicine and Dentistry, Canada

Disclosure: Nothing to disclose.

Sangeeta Mutnuri, MBBS, Nephrologist, Space City Associates 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

References

  1. Hanif MO, Bali A, Ramphul K. Acute Renal Tubular Necrosis. 2023 Jan. [View Abstract]
  2. Lee HT, Kim JY, Kim M, Wang P, Tang L, Baroni S, et al. Renalase protects against ischemic AKI. J Am Soc Nephrol. 2013 Feb. 24(3):445-55. [View Abstract]
  3. Ronco C, Bellomo R, Kellum JA. Acute kidney injury. Lancet. 2019 Nov 23. 394 (10212):1949-1964. [View Abstract]
  4. Molitoris BA, Sutton TA. Endothelial injury and dysfunction: role in the extension phase of acute renal failure. Kidney Int. 2004 Aug. 66 (2):496-9. [View Abstract]
  5. Ricci Z, Cruz DN, Ronco C. Classification and staging of acute kidney injury: beyond the RIFLE and AKIN criteria. Nat Rev Nephrol. 2011 Apr. 7 (4):201-8. [View Abstract]
  6. Kundert F, Platen L, Iwakura T, Zhao Z, Marschner JA, Anders HJ. Immune mechanisms in the different phases of acute tubular necrosis. Kidney Res Clin Pract. 2018 Sep. 37 (3):185-196. [View Abstract]
  7. Verghese E, Ricardo SD, Weidenfeld R, et al. Renal primary cilia lengthen after acute tubular necrosis. J Am Soc Nephrol. 2009 Jul 16. [View Abstract]
  8. Kolbrink B, von Samson-Himmelstjerna FA, Murphy JM, Krautwald S. Role of necroptosis in kidney health and disease. Nat Rev Nephrol. 2023 May. 19 (5):300-314. [View Abstract]
  9. Sanz AB, Sanchez-Niño MD, Ramos AM, Ortiz A. Regulated cell death pathways in kidney disease. Nat Rev Nephrol. 2023 May. 19 (5):281-299. [View Abstract]
  10. Abuelo JG. Normotensive ischemic acute renal failure. N Engl J Med. 2007 Aug 23. 357 (8):797-805. [View Abstract]
  11. Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005 Aug 17. 294 (7):813-8. [View Abstract]
  12. Thakar CV, Christianson A, Himmelfarb J, Leonard AC. Acute kidney injury episodes and chronic kidney disease risk in diabetes mellitus. Clin J Am Soc Nephrol. 2011 Nov. 6 (11):2567-72. [View Abstract]
  13. Murugan R, Kellum JA. Acute kidney injury: what's the prognosis?. Nat Rev Nephrol. 2011 Apr. 7 (4):209-17. [View Abstract]
  14. Wan L, Langenberg C, Bellomo R, May CN. Angiotensin II in experimental hyperdynamic sepsis. Crit Care. 2009. 13 (6):R190. [View Abstract]
  15. Gómez H, Kellum JA, Ronco C. Metabolic reprogramming and tolerance during sepsis-induced AKI. Nat Rev Nephrol. 2017 Mar. 13 (3):143-151. [View Abstract]
  16. Gomez H, Ince C, De Backer D, Pickkers P, Payen D, Hotchkiss J, et al. A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury. Shock. 2014 Jan. 41 (1):3-11. [View Abstract]
  17. Howell GM, Gomez H, Collage RD, Loughran P, Zhang X, Escobar DA, et al. Augmenting autophagy to treat acute kidney injury during endotoxemia in mice. PLoS One. 2013. 8 (7):e69520. [View Abstract]
  18. Bihorac A, Chawla LS, Shaw AD, Al-Khafaji A, Davison DL, Demuth GE, et al. Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication. Am J Respir Crit Care Med. 2014 Apr 15. 189 (8):932-9. [View Abstract]
  19. Mehta RL, Pascual MT, Soroko S, Savage BR, Himmelfarb J, Ikizler TA, et al. Spectrum of acute renal failure in the intensive care unit: the PICARD experience. Kidney Int. 2004 Oct. 66 (4):1613-21. [View Abstract]
  20. Liaño F, Pascual J. Epidemiology of acute renal failure: a prospective, multicenter, community-based study. Madrid Acute Renal Failure Study Group. Kidney Int. 1996 Sep. 50 (3):811-8. [View Abstract]
  21. Hoste EA, Bagshaw SM, Bellomo R, Cely CM, Colman R, Cruz DN, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015 Aug. 41 (8):1411-23. [View Abstract]
  22. Hsu CY, Chinchilli VM, Coca S, Devarajan P, Ghahramani N, Go AS, et al. Post-Acute Kidney Injury Proteinuria and Subsequent Kidney Disease Progression: The Assessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury (ASSESS-AKI) Study. JAMA Intern Med. 2020 Mar 1. 180 (3):402-410. [View Abstract]
  23. Ikizler TA, Parikh CR, Himmelfarb J, Chinchilli VM, Liu KD, Coca SG, et al. A prospective cohort study of acute kidney injury and kidney outcomes, cardiovascular events, and death. Kidney Int. 2021 Feb. 99 (2):456-465. [View Abstract]
  24. Hoste EA, Bagshaw SM, Bellomo R, Cely CM, Colman R, Cruz DN, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015 Aug. 41 (8):1411-23. [View Abstract]
  25. [Guideline] Kanagasundaram S, Ashley C, Bhojani S, Caldwell A, Ellam T, Kaur A, et al. Clinical Practice Guideline: Acute Kidney Injury (AKI). The Renal Association. Available at https://www.karger.com/Article/Pdf/328075. August 2019; Accessed: December 8, 2020.
  26. Izzedine H, Escudier B, Rouvier P, Gueutin V, Varga A, Bahleda R, et al. Acute tubular necrosis associated with mTOR inhibitor therapy: a real entity biopsy-proven. Ann Oncol. 2013 Sep. 24(9):2421-5. [View Abstract]
  27. Dvanajscak Z, Walker PD, Cossey LN, Messias NC, Boils CL, Kuperman MB, et al. Hemolysis-associated hemoglobin cast nephropathy results from a range of clinicopathologic disorders. Kidney Int. 2019 Dec. 96 (6):1400-1407. [View Abstract]
  28. Choudhry WM, Nori US, Nadasdy T, Satoskar AA. An unexpected cause of acute kidney injury in a patient with ANCA associated vasculitis. Clin Nephrol. 2016 May. 85 (5):289-95. [View Abstract]
  29. Dimopoulos MA, Kastritis E, Rosinol L, Bladé J, Ludwig H. Pathogenesis and treatment of renal failure in multiple myeloma. Leukemia. 2008 Aug. 22 (8):1485-93. [View Abstract]
  30. Volbeda M, Jou-Valencia D, van den Heuvel MC, Zijlstra JG, Franssen CFM, van der Voort PHJ, et al. Acute and chronic histopathological findings in renal biopsies in COVID-19. Clin Exp Med. 2023 Aug. 23 (4):1003-1014. [View Abstract]
  31. Kolhe NV, Fluck RJ, Selby NM, Taal MW. Acute kidney injury associated with COVID-19: A retrospective cohort study. PLoS Med. 2020 Oct. 17 (10):e1003406. [View Abstract]
  32. Hirsch JS, Ng JH, Ross DW, Sharma P, Shah HH, Barnett RL, et al. Acute kidney injury in patients hospitalized with COVID-19. Kidney Int. 2020 Jul. 98 (1):209-218. [View Abstract]
  33. Adamczak M, Surma S, Więcek A. Acute kidney injury in patients with COVID-19: Epidemiology, pathogenesis and treatment. Adv Clin Exp Med. 2022 Mar. 31 (3):317-326. [View Abstract]
  34. Chan L, Chaudhary K, Saha A, et al. AKI in Hospitalized Patients with COVID-19. J Am Soc Nephrol. 2021 Jan. 32 (1):151-160. [View Abstract]
  35. Gupta A, Thorson P, Penmatsa KR, Gupta P. Rhabdomyolysis: Revisited. Ulster Med J. 2021 May. 90 (2):61-69. [View Abstract]
  36. Tan BWL, Tan BWQ, Tan ALM, Schriver ER, Gutiérrez-Sacristán A, Das P, et al. Long-term kidney function recovery and mortality after COVID-19-associated acute kidney injury: An international multi-centre observational cohort study. EClinicalMedicine. 2023 Jan. 55:101724. [View Abstract]
  37. Kolhe NV, Fluck RJ, Selby NM, Taal MW. Acute kidney injury associated with COVID-19: A retrospective cohort study. PLoS Med. 2020 Oct. 17 (10):e1003406. [View Abstract]
  38. Chan L, Chaudhary K, Saha A, Chauhan K, Vaid A, Zhao S, et al. AKI in Hospitalized Patients with COVID-19. J Am Soc Nephrol. 2021 Jan. 32 (1):151-160. [View Abstract]
  39. Gupta A, Thorson P, Penmatsa KR, Gupta P. Rhabdomyolysis: Revisited. Ulster Med J. 2021 May. 90 (2):61-69. [View Abstract]
  40. Brogan M, Ross MJ. COVID-19 and Kidney Disease. Annu Rev Med. 2023 Jan 27. 74:1-13. [View Abstract]
  41. Hirsch JS, Ng JH, Ross DW, Sharma P, Shah HH, Barnett RL, et al. Acute kidney injury in patients hospitalized with COVID-19. Kidney Int. 2020 Jul. 98 (1):209-218. [View Abstract]
  42. Mohamed MMB, Lukitsch I, Torres-Ortiz AE, Walker JB, Varghese V, Hernandez-Arroyo CF, et al. Acute Kidney Injury Associated with Coronavirus Disease 2019 in Urban New Orleans. Kidney360. 2020 Jul 30. 1 (7):614-622. [View Abstract]
  43. Su H, Yang M, Wan C, Yi LX, Tang F, Zhu HY, et al. Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China. Kidney Int. 2020 Jul. 98 (1):219-227. [View Abstract]
  44. Santoriello D, Khairallah P, Bomback AS, Xu K, Kudose S, Batal I, et al. Postmortem Kidney Pathology Findings in Patients with COVID-19. J Am Soc Nephrol. 2020 Sep. 31 (9):2158-2167. [View Abstract]
  45. Mehta RL, Pascual MT, Soroko S, Savage BR, Himmelfarb J, Ikizler TA, et al. Spectrum of acute renal failure in the intensive care unit: the PICARD experience. Kidney Int. 2004 Oct. 66 (4):1613-21. [View Abstract]
  46. Liaño F, Pascual J. Epidemiology of acute renal failure: a prospective, multicenter, community-based study. Madrid Acute Renal Failure Study Group. Kidney Int. 1996 Sep. 50 (3):811-8. [View Abstract]
  47. Chaïbi K, Ehooman F, Pons B, Martin-Lefevre L, Boulet E, Boyer A, et al. Long-term outcomes after severe acute kidney injury in critically ill patients: the SALTO study. Ann Intensive Care. 2023 Mar 13. 13 (1):18. [View Abstract]
  48. Foley RN, Sexton DJ, Reule S, Solid C, Chen SC, Collins AJ. End-stage renal disease attributed to acute tubular necrosis in the United States, 2001-2010. Am J Nephrol. 2015. 41 (1):1-6. [View Abstract]
  49. Coca SG, Singanamala S, Parikh CR. Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis. Kidney Int. 2012 Mar. 81 (5):442-8. [View Abstract]
  50. Pannu N, James M, Hemmelgarn B, Klarenbach S, Alberta Kidney Disease Network. Association between AKI, recovery of renal function, and long-term outcomes after hospital discharge. Clin J Am Soc Nephrol. 2013 Feb. 8 (2):194-202. [View Abstract]
  51. United States Renal Data System. 2022 Annual Data Report. USRDS. Available at https://usrds-adr.niddk.nih.gov/2022. Accessed: October 3, 2023.
  52. Wald R, Shariff SZ, Adhikari NK, Bagshaw SM, Burns KE, Friedrich JO, et al. The association between renal replacement therapy modality and long-term outcomes among critically ill adults with acute kidney injury: a retrospective cohort study*. Crit Care Med. 2014 Apr. 42 (4):868-77. [View Abstract]
  53. Greenberg JH, Coca S, Parikh CR. Long-term risk of chronic kidney disease and mortality in children after acute kidney injury: a systematic review. BMC Nephrol. 2014 Nov 21. 15:184. [View Abstract]
  54. Kahan BD. Summary on therapeutic drug monitoring for renal transplantation. Transplant Proc. 1990 Jun. 22 (3):1348-51. [View Abstract]
  55. Legouis D, Galichon P, Bataille A, Chevret S, Provenchère S, Boutten A, et al. Rapid Occurrence of Chronic Kidney Disease in Patients Experiencing Reversible Acute Kidney Injury after Cardiac Surgery. Anesthesiology. 2017 Jan. 126 (1):39-46. [View Abstract]
  56. Al-Jaghbeer M, Kellum JA. Acid-base disturbances in intensive care patients: etiology, pathophysiology and treatment. Nephrol Dial Transplant. 2015 Jul. 30 (7):1104-11. [View Abstract]
  57. Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. 2012. 120 (4):c179-84. [View Abstract]
  58. Kellum JA, Romagnani P, Ashuntantang G, Ronco C, Zarbock A, Anders HJ. Acute kidney injury. Nat Rev Dis Primers. 2021 Jul 15. 7 (1):52. [View Abstract]
  59. Turgut F, Awad AS, Abdel-Rahman EM. Acute Kidney Injury: Medical Causes and Pathogenesis. J Clin Med. 2023 Jan 3. 12 (1):[View Abstract]
  60. Buckenmayer A, Siebler N, Haas CS. Evaluation of simple diagnostic parameters in acute kidney injury in hospitalized patients-diagnostic recommendations for non-nephrologists. Intern Emerg Med. 2023 Sep. 18 (6):1769-1776. [View Abstract]
  61. American College of Radiology. ACR Appropriateness Criteria: Renal Failure. Available at https://acsearch.acr.org/docs/69492/Narrative/. 2020; Accessed: December 8, 2020.
  62. Woolen SA, Shankar PR, Gagnier JJ, MacEachern MP, Singer L, Davenport MS. Risk of Nephrogenic Systemic Fibrosis in Patients With Stage 4 or 5 Chronic Kidney Disease Receiving a Group II Gadolinium-Based Contrast Agent: A Systematic Review and Meta-analysis. JAMA Intern Med. 2020 Feb 1. 180 (2):223-230. [View Abstract]
  63. Weinreb JC, Rodby RA, Yee J, Wang CL, Fine D, McDonald RJ, et al. Use of Intravenous Gadolinium-based Contrast Media in Patients with Kidney Disease: Consensus Statements from the American College of Radiology and the National Kidney Foundation. Radiology. 2021 Jan. 298 (1):28-35. [View Abstract]
  64. Perdiz LB, Furtado GH, Linhares MM, et al. Incidence and risk factors for surgical site infection after simultaneous pancreas-kidney transplantation. J Hosp Infect. 2009 Aug. 72(4):326-31. [View Abstract]
  65. Mattoso R, Khouri N, de Jesus L, et al. Risk factors for graft dysfunction in the late period of renal transplantation. Transplant Proc. 2009 Jun. 41(5):1594-8. [View Abstract]
  66. Wen Y, Yang C, Menez SP, Rosenberg AZ, Parikh CR. A Systematic Review of Clinical Characteristics and Histologic Descriptions of Acute Tubular Injury. Kidney Int Rep. 2020 Nov. 5 (11):1993-2001. [View Abstract]
  67. Barasch J, Zager R, Bonventre JV. Acute kidney injury: a problem of definition. Lancet. 2017 Feb 25. 389 (10071):779-781. [View Abstract]
  68. Devarajan P. Emerging biomarkers of acute kidney injury. Contrib Nephrol. 2007. 156:203-12. [View Abstract]
  69. Srisawat N, Kellum JA. The Role of Biomarkers in Acute Kidney Injury. Crit Care Clin. 2020 Jan. 36 (1):125-140. [View Abstract]
  70. Belcher JM, Sanyal AJ, Peixoto AJ, Perazella MA, Lim J, Thiessen-Philbrook H, et al. Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury. Hepatology. 2014 Aug. 60(2):622-32. [View Abstract]
  71. Su LJ, Li YM, Kellum JA, Peng ZY. Predictive value of cell cycle arrest biomarkers for cardiac surgery-associated acute kidney injury: a meta-analysis. Br J Anaesth. 2018 Aug. 121 (2):350-357. [View Abstract]
  72. Meersch M, Küllmar M, Schmidt C, Gerss J, Weinhage T, Margraf A, et al. Long-Term Clinical Outcomes after Early Initiation of RRT in Critically Ill Patients with AKI. J Am Soc Nephrol. 2018 Mar. 29 (3):1011-1019. [View Abstract]
  73. Göcze I, Jauch D, Götz M, Kennedy P, Jung B, Zeman F, et al. Biomarker-guided Intervention to Prevent Acute Kidney Injury After Major Surgery: The Prospective Randomized BigpAK Study. Ann Surg. 2018 Jun. 267 (6):1013-1020. [View Abstract]
  74. Kellum JA, Romagnani P, Ashuntantang G, Ronco C, Zarbock A, Anders HJ. Acute kidney injury. Nat Rev Dis Primers. 2021 Jul 15. 7 (1):52. [View Abstract]
  75. Ostermann M, Bellomo R, Burdmann EA, Doi K, Endre ZH, Goldstein SL, et al. Controversies in acute kidney injury: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference. Kidney Int. 2020 Aug. 98 (2):294-309. [View Abstract]
  76. Katz-Greenberg G, Malinchoc M, Broyles DL, Oxman D, Hamrahian SM, Maarouf OH. Urinary Neutrophil Gelatinase-Associated Lipocalin Predicts Intensive Care Unit Admission Diagnosis: A Prospective Cohort Study. Kidney360. 2022 Sep 29. 3 (9):1502-1510. [View Abstract]
  77. Koyner JL, Davison DL, Brasha-Mitchell E, Chalikonda DM, Arthur JM, Shaw AD, et al. Furosemide Stress Test and Biomarkers for the Prediction of AKI Severity. J Am Soc Nephrol. 2015 Aug. 26 (8):2023-31. [View Abstract]
  78. Chawla LS, Davison DL, Brasha-Mitchell E, Koyner JL, Arthur JM, Shaw AD, et al. Development and standardization of a furosemide stress test to predict the severity of acute kidney injury. Crit Care. 2013 Sep 20. 17 (5):R207. [View Abstract]
  79. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney inter., Suppl. 2:1-138.
  80. Maxwell RA, Bell CM. Acute Kidney Injury in the Critically Ill. Surg Clin North Am. 2017 Dec. 97 (6):1399-1418. [View Abstract]
  81. Jones D, Bellomo R. Renal-dose dopamine: from hypothesis to paradigm to dogma to myth and, finally, superstition?. J Intensive Care Med. 2005 Jul-Aug. 20 (4):199-211. [View Abstract]
  82. Bhatt GC, Das RR. Early versus late initiation of renal replacement therapy in patients with acute kidney injury-a systematic review & meta-analysis of randomized controlled trials. BMC Nephrol. 2017 Feb 28. 18 (1):78. [View Abstract]
  83. Faubel S, Shah PB. Immediate Consequences of Acute Kidney Injury: The Impact of Traditional and Nontraditional Complications on Mortality in Acute Kidney Injury. Adv Chronic Kidney Dis. 2016 May. 23 (3):179-85. [View Abstract]
  84. Nagler EV, Vanmassenhove J, van der Veer SN, Nistor I, Van Biesen W, Webster AC, et al. Diagnosis and treatment of hyponatremia: a systematic review of clinical practice guidelines and consensus statements. BMC Med. 2014 Dec 11. 12:1. [View Abstract]
  85. Kodadek L, Carmichael Ii SP, Seshadri A, Pathak A, Hoth J, Appelbaum R, et al. Rhabdomyolysis: an American Association for the Surgery of Trauma Critical Care Committee Clinical Consensus Document. Trauma Surg Acute Care Open. 2022. 7 (1):e000836. [View Abstract]
  86. [Guideline] Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. 2012. 120 (4):c179-84. [View Abstract]
  87. Meersch M, Schmidt C, Hoffmeier A, Van Aken H, Wempe C, Gerss J, et al. Prevention of cardiac surgery-associated AKI by implementing the KDIGO guidelines in high risk patients identified by biomarkers: the PrevAKI randomized controlled trial. Intensive Care Med. 2017 Nov. 43 (11):1551-1561. [View Abstract]
  88. Zarbock A, Küllmar M, Ostermann M, Lucchese G, Baig K, Cennamo A, et al. Prevention of Cardiac Surgery-Associated Acute Kidney Injury by Implementing the KDIGO Guidelines in High-Risk Patients Identified by Biomarkers: The PrevAKI-Multicenter Randomized Controlled Trial. Anesth Analg. 2021 Aug 1. 133 (2):292-302. [View Abstract]
  89. Prins JM, Büller HR, Kuijper EJ, Tange RA, Speelman P. Once versus thrice daily gentamicin in patients with serious infections. Lancet. 1993 Feb 6. 341 (8841):335-9. [View Abstract]
  90. Ostermann M, Bellomo R, Burdmann EA, Doi K, Endre ZH, Goldstein SL, et al. Controversies in acute kidney injury: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference. Kidney Int. 2020 Aug. 98 (2):294-309. [View Abstract]
  91. McDonald JS, McDonald RJ, Williamson EE, Kallmes DF, Kashani K. Post-contrast acute kidney injury in intensive care unit patients: a propensity score-adjusted study. Intensive Care Med. 2017 Jun. 43 (6):774-784. [View Abstract]
  92. McDonald JS, McDonald RJ, Williamson EE, Kallmes DF, Kashani K. Erratum to: Post-contrast acute kidney injury in intensive care unit patients: a propensity score-adjusted study. Intensive Care Med. 2017 Jun. 43 (6):956. [View Abstract]
  93. Mueller C, Buerkle G, Buettner HJ, et al. Prevention of contrast media-associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty. Arch Intern Med. 2002 Feb 11. 162(3):329-36. [View Abstract]
  94. Merten GJ, Burgess WP, Gray LV, et al. Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA. 2004 May 19. 291(19):2328-34. [View Abstract]
  95. Tepel M, van der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med. 2000 Jul 20. 343 (3):180-4. [View Abstract]
  96. Kshirsagar AV, Poole C, Mottl A, Shoham D, Franceschini N, Tudor G, et al. N-acetylcysteine for the prevention of radiocontrast induced nephropathy: a meta-analysis of prospective controlled trials. J Am Soc Nephrol. 2004 Mar. 15 (3):761-9. [View Abstract]
  97. Pannu N, Manns B, Lee H, Tonelli M. Systematic review of the impact of N-acetylcysteine on contrast nephropathy. Kidney Int. 2004 Apr. 65 (4):1366-74. [View Abstract]
  98. Nallamothu BK, Shojania KG, Saint S, Hofer TP, Humes HD, Moscucci M, et al. Is acetylcysteine effective in preventing contrast-related nephropathy? A meta-analysis. Am J Med. 2004 Dec 15. 117 (12):938-47. [View Abstract]
  99. Gonzales DA, Norsworthy KJ, Kern SJ, Banks S, Sieving PC, Star RA, et al. A meta-analysis of N-acetylcysteine in contrast-induced nephrotoxicity: unsupervised clustering to resolve heterogeneity. BMC Med. 2007 Nov 14. 5:32. [View Abstract]
  100. Weisbord SD, Gallagher M, Jneid H, Garcia S, Cass A, Thwin SS, et al. Outcomes after Angiography with Sodium Bicarbonate and Acetylcysteine. N Engl J Med. 2017 Nov 12. [View Abstract]
  101. Rosner MH. Prevention of Contrast-Associated Acute Kidney Injury. N Engl J Med. 2018 Feb 15. 378 (7):671-672. [View Abstract]
  102. Saadat-Gilani K, Zarbock A, Meersch M. Perioperative Renoprotection: Clinical Implications. Anesth Analg. 2020 Dec. 131 (6):1667-1678. [View Abstract]
  103. Michel P, Amione-Guerra J, Sheikh O, Jameson LC, Bansal S, Prasad A. Meta-analysis of intravascular volume expansion strategies to prevent contrast-associated acute kidney injury following invasive angiography. Catheter Cardiovasc Interv. 2021 Nov 15. 98 (6):1120-1132. [View Abstract]
  104. Silver SA, Siew ED. Follow-up Care in Acute Kidney Injury: Lost in Transition. Adv Chronic Kidney Dis. 2017 Jul. 24 (4):246-252. [View Abstract]
  105. Brito GA, Balbi AL, Abrão JM, Ponce D. Long-term outcome of patients followed by nephrologists after an acute tubular necrosis episode. Int J Nephrol. 2012. 2012:361528. [View Abstract]
  106. Kellum JA, Levin N, Bouman C, Lameire N. Developing a consensus classification system for acute renal failure. Curr Opin Crit Care. 2002 Dec. 8 (6):509-14. [View Abstract]
  107. Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005 Aug 17. 294 (7):813-8. [View Abstract]
  108. de Mendonça A, Vincent JL, Suter PM, Moreno R, Dearden NM, Antonelli M, et al. Acute renal failure in the ICU: risk factors and outcome evaluated by the SOFA score. Intensive Care Med. 2000 Jul. 26 (7):915-21. [View Abstract]
  109. Dépret F, Hollinger A, Cariou A, Deye N, Vieillard-Baron A, Fournier MC, et al. Incidence and Outcome of Subclinical Acute Kidney Injury Using penKid in Critically Ill Patients. Am J Respir Crit Care Med. 2020 Sep 15. 202 (6):822-829. [View Abstract]
  110. Chaïbi K, Ehooman F, Pons B, Martin-Lefevre L, Boulet E, Boyer A, et al. Long-term outcomes after severe acute kidney injury in critically ill patients: the SALTO study. Ann Intensive Care. 2023 Mar 13. 13 (1):18. [View Abstract]
  111. Meersch M, Küllmar M, Schmidt C, Gerss J, Weinhage T, Margraf A, et al. Long-Term Clinical Outcomes after Early Initiation of RRT in Critically Ill Patients with AKI. J Am Soc Nephrol. 2018 Mar. 29 (3):1011-1019. [View Abstract]
  112. Gaudry S, Palevsky PM, Dreyfuss D. Extracorporeal Kidney-Replacement Therapy for Acute Kidney Injury. N Engl J Med. 2022 Mar 10. 386 (10):964-975. [View Abstract]
  113. Hernandez A, Patil NK, Brewer M, Delgado R, Himmel L, Lopez LN, et al. Pretreatment with a novel Toll-like receptor 4 agonist attenuates renal ischemia-reperfusion injury. Am J Physiol Renal Physiol. 2023 May 1. 324 (5):F472-F482. [View Abstract]
  114. Zhang T, Li Y, Wise AF, Kulkarni K, Aguilar MI, Samuel CS, et al. The protective effects of a novel AT(2) receptor agonist, β-Pro(7)Ang III in ischemia-reperfusion kidney injury. Biomed Pharmacother. 2023 May. 161:114556. [View Abstract]
  115. Yang Q, Hu J, Ning Y, Zhao S, Chen W, Ren T, et al. A NOVEL RAT MODEL OF CONTRAST-INDUCED ACUTE KIDNEY INJURY BASED ON RENAL CONGESTION AND THE RENO-PROTECTION OF MITOCHONDRIAL FISSION INHIBITION. Shock. 2023 Jun 1. 59 (6):930-940. [View Abstract]
  116. Tonnus W, Meyer C, Steinebach C, Belavgeni A, von Mässenhausen A, Gonzalez NZ, et al. Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury. Nat Commun. 2021 Jul 20. 12 (1):4402. [View Abstract]

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.

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.

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

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.

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

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.

StageSerum CreatinineUrine output
11.5-1.9 times baseline< 0.5 ml/kg/hr  for 6 - 12 hours
 OR 
 ≥ 0.3 mg/dl (≥ 25.5 μmol/l) increase 
22.0-2.9 times baseline< 0.5 ml/kg/hr for ≥ 12 hours
33.0 times baseline< 0.3 ml/kg/hr for ≥ 24 hours
 OROR 
 Increase in serum creatinine to ≥ 4 mg/dl (≥ 353.6 μmol/l)Anuria for ≥ 12 hours
 OR 
 Initiation of renal replacement therapy 
 OR, inpatients < 18 years, decrease in eGFR to < 35 ml/min per 1.73 m2 
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 sedimentBland and/or nonspecificMay show muddy brown granular casts