Acute Kidney Injury (AKI)

Updated: Dec 10, 2022
Author: Biruh T Workeneh, MD, FASN; Chief Editor: Vecihi Batuman, MD, FASN 


Practice Essentials

Acute kidney injury (AKI) is a clinical syndrome manifested by a rapid or abrupt decline in kidney function and subsequent dysregulation of the body electrolytes and volume, and abnormal retention of nitrogenous waste. The widely accepted Kidney Disease: Improving Global Outcome (KDIGO) definition of AKI is based on the change of serum creatinine and urine output, as follows[1] : 

  • Rise in serum creatinine ≥0.3 mg/dL within 48 hours
  • Rise in serum creatinine  ≥1.5 times baseline, which is known or presumed to have occurred within the prior seven days
  • Urine output < 0.5 mL/kg/hour for six hours

Symptoms and signs

Most patients with AKI have no clinical symptoms related to AKI and are diagnosed on the basis of a routine laboratory blood test. Depending on the degree of kidney function impairment and the duration, however, they might have hypertension, edema, decreased urine output, shortness of breath, anorexia, nausea, sleep disturbances and altered mental status.  When evaluating a patient with AKI, the signs listed below may help in identifying the etiology associated with AKI. 


  • Livedo reticularis, digital ischemia, butterfly rash, and palpable purpura: Autoimmune disease and systemic vasculitis
  • Maculopapular rash: Allergic interstitial nephritis
  • Track marks (ie, intravenous drug abuse): Endocarditis


  • Keratitis, iritis, uveitis, dry conjunctivae: Autoimmune vasculitis
  • Jaundice: Liver disease
  • Band keratopathy (ie, hypercalcemia): Multiple myeloma
  • Signs of diabetes mellitus
  • Signs of hypertension
  • Atheroemboli: Retinopathy (ie, Hollenhorst plaque in cholesterol microembolism)


  • Hearing loss: Alport disease, aminoglycoside toxicity
  • Mucosal or cartilaginous ulcerations: granulomatosis with polyangiitis (previously Wegener granulomatosis)

Cardiovascular system:

  • Irregular rhythms (eg, atrial fibrillation): Thromboemboli, hypotension
  • Murmurs: Endocarditis, valvular heart disease
  • Pericardial friction rub: Uremic pericarditis
  • Increased jugular venous distention, rales, S 3: Cardiomyopathy


  • Pulsatile mass or bruit: Renal artery stenosis, atheroemboli
  • Abdominal or costovertebral angle tenderness: Pyelonephritis, nephrolithiasis, papillary necrosis, renal artery thrombosis, renal vein thrombosis
  • Pelvic, rectal masses; prostatic hyperplasia; distended bladder: Urinary obstruction

Pulmonary system:

  • Rales: Pulmonary edema, pulmonary infection
  • Hemoptysis: ANCA vasculitis, anti-glomerular basement membrane (Goodpasture syndrome or anti-GBM disease)

See Presentation for more detail.


The following tests can aid in the diagnosis and assessment of AKI:

  • Kidney function studies: Increased levels of blood urea nitrogen (BUN) and serum creatinine are the hallmarks of AKI; the ratio of BUN to creatinine can exceed 20:1 in conditions that favor the enhanced reabsorption of urea, such as volume contraction (this suggests prerenal AKI)

  • Complete blood count: Elevated WBC can indicate infection; risk-stratify for tumor lysis syndrome in an oncologic patient; low hemoglobin can suggest acute blood loss or chronic anemia; thrombocytopenia might indicate thrombotic microangiopathy or portal hypertension

  • Peripheral smear: Schistocytes may indicate hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura)

  • Serologic tests: May show evidence of systemic diseases associated with AKI, such as lupus nephritis, ANCA vasculitis, anti-GBM disease or Goodpasture syndrome

  • Complement testing: Pattern may indicate AKI related to endocarditis or various glomerulonephritidites

  • Fractional excretion of sodium and urea in the setting of oliguria

  • Bladder pressure: Patients with a bladder pressure above 25 mm Hg should be suspected of having AKI caused by abdominal compartment syndrome

  • Ultrasonography: Renal ultrasonography is helpful in evaluating existing renal disease (kidney length, presence of cortical echogenicity or cortical thinning) and urinary obstruction

  • Aortorenal angiography: Can help establish the diagnosis of renal vascular diseases, such as renal artery stenosis, renal atheroembolic disease, atherosclerosis with aortorenal occlusion, and instances of necrotizing vasculitis (eg, polyarteritis nodosa)

  • Kidney biopsy: Can be useful in identifying intrarenal causes of AKI and directing targeted therapy

See Workup for more detail.


In addition to treating the underlying etiology, maintenance of volume homeostasis and correction of biochemical abnormalities remain the primary goals of AKI treatment (supportive care) and may include the following measures:

  • Correction of fluid overload with loop diuretics and fluid restriction
  • Correction of severe acidosis with alkali administration

  • Correction of life-threatening hyperkalemia

  • Correction of hematologic abnormalities (eg, blood loss anemia, uremic platelet dysfunction) with measures such as RBC or platelet transfusions and administration of desmopressin or estrogens

  • Hemodialysis in patients with refractory acidosis, hypervolemia with pulmonary edema, life-threatening hyperkalemia, and uremic signs or symptoms

Dietary changes are an important facet of AKI treatment. Restriction of sodium, potassium, and fluids becomes crucial in the management of oliguric AKI with hyperkalemia, in which the kidneys do not adequately excrete either toxins or fluids.  

Non-targeted pharmacologic interventions for AKI have been attempted, but no large randomized controlled study has demonstrated significant benefit.  

See Treatment and Medication for more details.

For patient education information, see Acute Kidney Failure.


Acute kidney injury (AKI) is defined as an abrupt or rapid decline in renal filtration function. This condition is usually marked by a rise in serum creatinine concentration or azotemia (a rise in blood urea nitrogen [BUN] concentration).[2]  However, immediately after a kidney insult, BUN or serum creatinine levels may be normal. In the early phase, the only sign of a kidney injury may be decreased urine production. (See History.)

Furthermore, a rise in serum creatinine might not always be related to a decrease in kidney function; certain medications (eg, cimetidine, trimethoprim, Poly ADP-ribose polymerase [PARP] inhibitors, and cyclin-dependent kinase 4 and 6 [CDK4/6] inhibitors) can inhibit the kidney’s tubular secretion of creatinine independent of glomerular filtration rate (GFR). A rise in the BUN level can also occur without renal injury, as a result of gastrointestinal (GI) or mucosal bleeding, steroid use, or protein loading. Therefore, a careful inventory must be taken before concluding that a kidney injury is present. (See Etiology and History.)

See Chronic Kidney Disease and Acute Tubular Necrosis for complete information on these topics. For information on pediatric cases, see Chronic Kidney Disease in Children.

Categories of AKI

Traditionally, AKI may be classified into 3 general categories as follows:

  • Prerenal - As an adaptive response to severe volume depletion and hypotension, with structurally intact nephrons
  • Intrinsic - In response to cytotoxic, ischemic, or inflammatory insults to the kidney, with structural and functional damage
  • Postrenal - From obstruction to the passage of urine

While this classification helps guide the development of a differential diagnosis, many pathophysiologic features are shared among the different categories. (See Etiology.)

Oliguric and nonoliguric patients with AKI

Patients who develop AKI can be oliguric or nonoliguric, have a rapid or slow rise in creatinine levels and may have qualitative differences in urine solute concentrations and cellular content. (Approximately 50-60% of all causes of AKI are nonoliguric.) This lack of a uniform clinical presentation reflects the variable nature of the injury.

Classifying AKI as oliguric or nonoliguric on the basis of daily urine excretion has prognostic value. Oliguria is defined as a daily urine volume of less than 400-500 mL, which is the minimum amount of urine required to eliminate the average daily solute load and has a worse prognosis.

Anuria is defined as a urine output of less than 50-100 mL/day and, if abrupt in onset, suggests bilateral obstruction or catastrophic injury to both kidneys.

Stratification of kidney injury along these lines helps in diagnosis and decision-making (eg, timing of dialysis) and can be an important criterion for patient response to therapy.

RIFLE classification system

In 2004, the Acute Dialysis Quality Initiative workgroup set forth a definition and classification system for acute renal failure, described by the acronym RIFLE (Risk of renal dysfunction, Injury to the kidney, Failure or Loss of kidney function, and End-stage kidney disease).[3]  Investigators have since applied the RIFLE system to the clinical evaluation of AKI, although it was not originally intended for that purpose. AKI research increasingly uses RIFLE. See Table 1 below.

Table 1. RIFLE Classification System for Acute Kidney Injury (Open Table in a new window)


GFR Criteria

Urine Output Criteria



SCreat increased × 1.5


GFR decreased >25%

UO < 0.5 mL/kg/h × 6 h

High sensitivity (Risk >Injury >Failure)


SCreat increased × 2


GFR decreased >50%

UO < 0.5 mL/kg/h × 12 h


SCreat increased × 3


GFR decreased 75%


SCreat ≥4 mg/dL; acute rise ≥0.5 mg/dL

UO < 0.3 mL/kg/h × 24 h



anuria × 12 h


Persistent acute renal failure: complete loss of kidney function >4 wk

High specificity


Complete loss of kidney function >3 mo

ESKD—end-stage kidney disease; GFR—glomerular filtration rate; SCreat—serum creatinine; UO—urine output

Note: Patients can be classified by GFR criteria and/or UO criteria. The criteria that support the most severe classification should be used. The superimposition of acute on chronic failure is indicated with the designation RIFLE-FC; failure is present in such cases even if the increase in SCreat is less than 3-fold, provided that the new SCreat is greater than 4.0 mg/dL (350 µmol/L) and results from an acute increase of at least 0.5 mg/dL (44 µmol/L).

When the failure classification is achieved by UO criteria, the designation of RIFLE-FO is used to denote oliguria.

The initial stage, risk, has high sensitivity; more patients will be classified in this mild category, including some who do not actually have kidney failure. Progression through the increasingly severe stages of RIFLE is marked by decreasing sensitivity and increasing specificity.

Acute Kidney Injury Network classification system

The Acute Kidney Injury Network (AKIN) has developed specific criteria for the diagnosis of AKI. The AKIN defines AKI as abrupt (within 48 hours) reduction of kidney function, after excluding urinary obstruction and achieving adequate hydration, manifested by any 1 of the following [4]

  • An absolute increase in serum creatinine of 0.3 mg/dL or greater (≥26.4 µmol/L)
  • A percentage increase in serum creatinine of 50% or greater (1.5-fold from baseline)
  • A reduction in urine output, defined as less than 0.5 mL/kg/h for more than 6 hours

AKIN has proposed a staging system for AKI that is modified from RIFLE. In this system, either serum creatinine or urine output criteria can be used to determine the stage. See Table 2 below.

Table 2. Acute Kidney Injury Network Classification/Staging System for AKI  (Open Table in a new window)


Serum Creatinine Criteria

Urine Output Criteria


Increase of ≥0.3 mg/dL (≥26.4 µmol/L) or 1.5- to 2-fold increase from baseline

< 0.5 mL/kg/h for >6 h


> 2-fold to 3-fold increase from baseline

< 0.5 mL/kg/h for >12 h


> 3-fold increase from baseline, or increase of ≥ 4.0 mg/dL (≥35.4 µmol/L) with an acute increase of at least 0.5 mg/dL (44 µmol/L)

< 0.3 mL/kg/h for 24 h or anuria for 12 h

*Patients who receive renal replacement therapy (RRT) are considered to have met the criteria for stage 3 irrespective of the stage they are in at the time of RRT.

KDIGO classification system

The KDIGO system, which is the most recent and widely accepted classification, was developed by merging the RIFLE and AKIN classifications into a single simplified one. It offers equivalent or superior sensitivity for AKI detection and prognostic performance compared with RIFLE and AKIN.[1]  

AKI is defined by any of the following:  

  • Rise in serum creatinine ≥0.3 mg/dL within 48 hours
  • Rise in serum creatinine ≥1.5 times baseline, which is known or presumed to have occurred within the prior seven days
  • Urine output < 0.5 ml/kg/hour for six hours

The criteria for AKI stages are similar to AKIN, except for stage 3 AKI, which comprises an increase in serum creatinine of ≥0.3 mg/dL (rather than ≥ 0.5 mg/dL) to ≥4 mg/dL. 

Cardiovascular complications

Cardiovascular complications (eg, heart failure, myocardial infarction, arrhythmias, cardiac arrest) have been observed in as many as 35% of patients with AKI. Fluid overload secondary to oliguric AKI is a particular risk for elderly patients with limited cardiac reserve. Additionally, AKI is associated with electrolyte and acid-base imbalance that can increase the risk of developing arrhythmia and decrease myocardial contractility. In cardiac patients who experience AKI either in the setting of acute decompensated heart failure or cardiac surgery, AKI is associated with worse morbidity and mortality.[5]

Pericarditis is a relatively rare complication of AKI. When pericarditis complicates AKI, consider additional diagnoses, such as systemic lupus erythematosus (SLE) and hepatorenal syndrome.

AKI also can be a complication of cardiac diseases, such as endocarditis, decompensated heart failure, or atrial fibrillation with emboli. Cardiac arrest in a patient with AKI should always arouse suspicion of hyperkalemia. Many authors recommend that in addition to ACLS measures in patients with PEA arrest, a trial of intravenous calcium chloride (or gluconate) should be considered in patients with AKI with known or suspected hyperkalemia.

Pulmonary complications

Pulmonary complications have been reported in approximately 54% of patients with AKI and are the single most significant risk factor for death in patients with AKI. Proposed mechanisms for acute lung injury during AKI include hypervolemia, increased proinflammatory cytokine levels, leukocyte infiltration, and increased pulmonary vascular permeability. In addition, diseases exist that commonly present with simultaneous pulmonary and renal involvement, including the following:

  • Goodpasture syndrome
  • Granulomatosis with polyangiitis (Wegener granulomatosis)
  • Polyarteritis nodosa
  • Cryoglobulinemia
  • Sarcoidosis

Hypoxia commonly occurs during hemodialysis and can be particularly significant in patients with pulmonary disease. This dialysis-related hypoxia is thought to occur secondary to white blood cell (WBC) lung sequestration and alveolar hypoventilation.

Gastrointestinal complications

Nausea, vomiting, and anorexia are frequent complications of AKI and represent one of the cardinal signs of uremia. GI bleeding occurs in approximately one-third of patients with AKI. Most episodes are mild, but GI bleeding accounts for 3-8% of deaths in patients with AKI.


Mild hyperamylasemia is commonly seen in AKI. Elevation of baseline amylase concentrations can complicate the diagnosis of pancreatitis in patients with AKI. Lipase measurement, frequently suppressed in AKI, should be considered in this light when there is suspicion of pancreatitis. Pancreatitis has been reported as a concurrent illness with AKI in patients with atheroemboli, vasculitis, and sepsis from ascending cholangitis.


Jaundice frequently complicates AKI. Etiologies of jaundice with AKI include hepatic congestion, blood transfusions, and sepsis.


Hepatitis occurring concurrently with AKI should prompt consideration of the following disorders in the differential diagnosis:

  • Common bile duct obstruction
  • Fulminant hepatitis 
  • HBV- and HCV-associated glomerulonephritis
  • Leptospirosis
  • Medication toxicity (eg, acetaminophen toxicity)
  • Amanita phalloides poisoning

Infectious complications

Infections commonly complicate the course of AKI and have been reported to occur in as many as 33% of patients with AKI. It is attributed to possible altered cytokine homeostasis and immune cell dysfunction associated with AKI. The most common sites of infection are the pulmonary and urinary tracts. Infections are the leading cause of morbidity and death in patients with AKI. Various studies have reported mortality rates of 11-72% in infections complicating AKI.

Neurologic complications

Neurologic symptoms of uremia have been reported in approximately 38% of patients with AKI. Neurologic sequelae include lethargy, somnolence, reversal of the sleep-wake cycle, and cognitive or memory deficits. Focal neurologic deficits are rarely caused solely by uremia.

The pathophysiology of neurologic symptoms is still unknown but is partially attributed to the possible accumulation of neurotoxic metabolites in patients with severe AKI that can lead to an imbalance in cellular water transportation and disturbance of the blood-brain barrier. However, these symptoms do not correlate well with levels of BUN or creatinine.

A number of diseases can present with concurrent neurologic and renal manifestations, including the following:

  • SLE
  • Thrombotic thrombocytopenic purpura (TTP)
  • Hemolytic uremic syndrome (HUS)
  • Endocarditis
  • Malignant hypertension

Also see Acute Kidney Injury (Renal Failure) in Emergency Medicine.


The driving force for glomerular filtration is the pressure gradient from the glomerulus to the Bowman space. Glomerular pressure depends primarily on renal blood flow (RBF) and is controlled by the combined resistances of renal afferent and efferent arterioles. Regardless of the cause of AKI, reductions in RBF represent a common pathologic pathway for a decrease in the glomerular filtration rate (GFR). The etiology of AKI consists of 3 main mechanisms: prerenal, intrinsic, and obstructive (postrenal).

In prerenal failure, GFR is depressed by compromised renal perfusion. Tubular and glomerular functions remain normal.

Intrinsic failure includes diseases of the kidney itself, predominantly affecting the glomerulus, interstitium, or tubule, which are associated with the release of renal afferent vasoconstrictors. Ischemia is the most common cause of intrinsic kidney failure. Patients with chronic kidney disease (CKD) may also present with superimposed AKI from prerenal failure and obstruction, as well as intrinsic kidney disease.

Obstruction of the urinary tract initially causes an increase in tubular pressure, which decreases the filtration driving force. This pressure gradient soon equalizes, and maintenance of a depressed GFR then depends on renal efferent vasoconstriction.

Depressed renal blood flow

Depressed RBF eventually leads to ischemia and cell death. This may happen without systemic hypotension is present and is referred to as normotensive ischemic AKI. The initial ischemic insult triggers a cascade of events, including production of oxygen free radicals, cytokines, and enzymes; endothelial activation and leukocyte adhesion; activation of coagulation; and initiation of apoptosis. These events continue to cause cell injury even after restoration of RBF.

Tubular cellular damage results in the disruption of tight junctions between cells, allowing back leak of glomerular filtrate and further depressing effective GFR. In addition, dying cells slough off into the tubules, forming obstructing casts, further decreasing GFR and leading to oliguria.

During this period of depressed RBF, the kidneys are particularly vulnerable to additional insults; this is when iatrogenic kidney injury is most common. The following are frequent combinations:

  • Radiocontrast agents, aminoglycosides, or cardiovascular surgery with preexisting kidney disease (eg, elderly, diabetic, jaundiced patients)
  • Angiotensin-converting enzyme (ACE) inhibitors with diuretics, small- or large-vessel renal arterial disease
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) with chronic heart failure, hypertension, or renal artery stenosis

Acute tubular necrosis

Frank necrosis is not prominent in most cases of acute tubular necrosis (ATN) and tends to be patchy. The following pathologic changes can be seen following ATN injury (see the image below):

  • Loss of brush border
  • Flattening of the epithelium
  • Detachment of cells
  • Presence of intratubular casts
  • Dilatation of the lumen
Photomicrograph of a kidney biopsy specimen shows Photomicrograph of a kidney biopsy specimen shows renal medulla, which is composed mainly of renal tubules. Features suggesting acute tubular necrosis are the patchy or diffuse denudation of the renal tubular cells with loss of brush border (blue arrows); flattening of the renal tubular cells due to tubular dilation (orange arrows); intratubular cast formation (yellow arrows); and sloughing of cells, which is responsible for the formation of granular casts (red arrow). Finally, intratubular obstruction due to the denuded epithelium and cellular debris is evident (green arrow); note that the denuded tubular epithelial cells clump together because of rearrangement of intercellular adhesion molecules.

Although these changes are observed predominantly in proximal tubules, injury to the distal nephron can also be demonstrated. In addition, the distal nephron may become obstructed by desquamated cells and cellular debris. See the image above.


In contrast to necrosis, the distal nephron is the principal site of apoptotic cell death. During the initial phase of ischemic injury, loss of integrity of the actin cytoskeleton leads to flattening of the epithelium, with loss of the brush border, loss of focal cell contacts, and subsequent disengagement of the cell from the underlying substratum.

Inflammatory response

Many endogenous growth factors that participate in the regeneration process following ischemic renal injury have not been identified. However, the administration of growth factors exogenously has been shown to ameliorate and hasten recovery from AKI.

Depletion of neutrophils and blockage of neutrophil adhesion reduces renal injury following ischemia, indicating that the inflammatory response is responsible, in part, for some features of ATN, especially in postischemic injury after transplant.


Intrarenal vasoconstriction is the dominant mechanism for reduced GFR in patients with ATN. The mediators of this vasoconstriction are unknown, but tubular injury seems to be an important concomitant finding. Urine backflow and intratubular obstruction (from sloughed cells and debris) are causes of reduced net ultrafiltration. The importance of this mechanism is highlighted by the improvement in renal function that follows the relief of such intratubular obstruction.

In addition, when obstruction is prolonged, intrarenal vasoconstriction is prominent in part due to the tubuloglomerular feedback mechanism, which is thought to be mediated by adenosine and activated when there is proximal tubular damage. The macula densa senses the increased chloride load and feeds back to cause arteriolar vasoconstriction.

Apart from the increased basal renal vascular tone, the stressed renal microvasculature is more sensitive to potentially vasoconstrictive drugs and otherwise-tolerated changes in systemic blood pressure. The vasculature of the injured kidney has an impaired vasodilatory response and loses its autoregulatory behavior.

This latter phenomenon has important clinical relevance because the frequent reduction in systemic pressure during intermittent hemodialysis may provoke additional damage that can delay recovery from ATN. Often, injury results in atubular glomeruli, where the glomerular function is preserved, but the lack of tubular outflow precludes its function.


A physiologic hallmark of ATN is a failure to dilute or concentrate urine (isosthenuria) maximally. This defect is not responsive to pharmacologic doses of vasopressin. The injured kidney fails to generate and maintain a high medullary solute gradient because solute accumulation in the medulla depends on normal distal nephron function.

Failure to excrete concentrated urine, even in the presence of oliguria, is a helpful diagnostic clue in distinguishing prerenal from intrinsic AKI. In prerenal azotemia, urine osmolality is typically more than 500 mOsm/kg, whereas, in intrinsic kidney disease, urine osmolality is less than 300 mOsm/kg.

Restoration of renal blood flow and associated complications

Recovery from AKI is first dependent upon the restoration of RBF. Early RBF normalization predicts a better prognosis for recovery of renal function. In prerenal failure, restoration of circulating blood volume is usually sufficient. Rapid relief of urinary obstruction in postrenal failure results in a prompt decrease of vasoconstriction. With intrinsic renal failure, removing tubular toxins and initiating therapy for glomerular diseases decreases renal afferent vasoconstriction.

Once RBF is restored, the remaining functional nephrons increase their filtration and eventually undergo hypertrophy. GFR recovery depends on the size of this remnant nephron pool. If the number of remaining nephrons is below a critical threshold, continued hyperfiltration results in progressive glomerular sclerosis, eventually leading to increased nephron loss.

A vicious cycle ensues: continued nephron loss causes more hyperfiltration until complete kidney failure results. This has been termed the hyperfiltration theory of kidney failure and explains the scenario in which progressive failure is frequently observed after apparent recovery from AKI.


Prerenal AKI

Prerenal AKI represents the most common form of kidney injury and often leads to intrinsic AKI if it is not promptly corrected. Volume loss can provoke this syndrome; the source of the loss may be GI, renal, or cutaneous (eg, burns) or from internal or external hemorrhage. Prerenal AKI can also result from decreased renal perfusion in patients with heart failure or shock (eg, sepsis, anaphylaxis). In patients taking calcium channel blockers, use of the antibiotic clarithromycin can result in AKI, due to a drug-drug interaction that markedly raises plasma calcium channel blocker concentrations and causes hypotension, with subsequent ischemic damage to the kidney.[6]

Several classes of medications can induce prerenal AKI in volume-depleted states, including ACE inhibitors and angiotensin receptor blockers (ARBs), which are otherwise safely tolerated and beneficial in most patients with chronic kidney disease (CKD). Aminoglycosides, amphotericin B, and radiologic contrast agents may also do so.

Arteriolar vasoconstriction leading to prerenal AKI can occur in hypercalcemic states, as well as with the use of radiocontrast agents, NSAIDs, amphotericin, calcineurin inhibitors, norepinephrine, and other pressor agents. The hepatorenal syndrome can also be considered a form of prerenal AKI, because functional kidney failure develops from diffuse vasoconstriction in vessels supplying the kidney.[7]

To summarize, volume depletion can be caused by the following:

  • Renal losses - Diuretics, polyuria
  • GI losses - Vomiting, diarrhea
  • Cutaneous losses - Burns, Stevens-Johnson syndrome
  • Hemorrhage
  • Pancreatitis

Decreased cardiac output can be caused by the following:

  • Heart failure
  • Pericardial effusion/tamponade
  • Pulmonary embolus
  • Acute myocardial infarction
  • Severe valvular disease
  • Abdominal compartment syndrome - Tense ascites

Systemic vasodilation can be caused by the following:

  • Sepsis
  • Anaphylaxis
  • Anesthetics
  • Drug overdose
  • Cancer-specific etiologies: Capillary leak syndrome, engraftment syndrome, chimeric antigen receptor (CAR) T-cell therapy, all-trans retinoic acid (ATRA), gemcitabine, interleukin-2 (IL-2), granulocyte-macrophage colony-stimulating factor  (GM-CSF) 

Afferent arteriolar vasoconstriction can be caused by the following:

  • Hypercalcemia
  • Drugs - NSAIDs, amphotericin B, calcineurin inhibitors, norepinephrine, radiocontrast agents
  • Hepatorenal syndrome and and sinusoidal obstruction syndrome (post hematopoietic stem cell transplantation [HSCT])

Diseases that decrease effective arterial blood volume include the following:

  • Hypovolemia
  • Heart failure
  • Liver failure
  • Sepsis

Renal arterial diseases that can result in AKI include renal arterial stenosis, especially in the setting of hypotension or initiation of ACE inhibitors or ARBs. Renal artery stenosis typically results from atherosclerosis or fibromuscular dysplasia, but is also a feature of the genetic syndromes type 1 neurofibromatosis, Williams syndrome, and Alagille syndrome.

Patients can also develop septic embolic disease (eg, from endocarditis) or cholesterol emboli, often as a result of instrumentation or cardiovascular surgery.

Intrinsic AKI

Structural injury in the kidney is the hallmark of intrinsic AKI; the most common form is ATN, either ischemic or cytotoxic. Glomerulonephritis can be a cause of AKI and usually falls into a class referred to as rapidly progressive glomerulonephritis (RPGN). Glomerular crescents (glomerular injury) are found in RPGN on biopsy; presence of crescents in more than 50% of glomeruli usually corresponds to a significant decline in renal function. Although comparatively rare, acute glomerulonephritides should be part of the diagnostic consideration in cases of AKI.

To summarize, vascular (large- and small-vessel) causes of intrinsic AKI include the following:

  • Renal artery obstruction - Thrombosis, emboli, dissection, vasculitis
  • Renal vein obstruction - Thrombosis
  • Microangiopathy - TTP, HUS, disseminated intravascular coagulation (DIC), preeclampsia
  • Malignant hypertension
  • Scleroderma renal crisis
  • Transplant rejection
  • Atheroembolic disease

Glomerular causes include the following:

  • Anti–glomerular basement membrane (GBM) disease - As part of Goodpasture syndrome or renal limited disease

  • Pauci-immune glomerulonephritis - Antineutrophil cytoplasmic antibody (ANCA)–associated glomerulonephritis such granulomatosis with polyangiitis (Wegener granulomatosis), eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), microscopic polyangiitis

  • Immune complex glomerulonephritis - Lupus nephritis, postinfectious glomerulonephritis, IgA nephropathy, cryoglobulinemia, primary membranoproliferative glomerulonephritis

Tubular etiologies may include ischemia or cytotoxicity. Cytotoxic etiologies include the following:

  • Heme pigment - Rhabdomyolysis, intravascular hemolysis
  • Crystals - Tumor lysis syndrome, dysproteinemia, seizures, ethylene glycol poisoning, megadose vitamin C, acyclovir, indinavir, methotrexate
  • Drugs - Aminoglycosides, lithium, amphotericin B, pentamidine, cisplatin, pemetrexed, zoledronic acid, ifosfamide, radiocontrast agents
  • Lysozyme-induced nephropathy

Interstitial causes include the following:

  • Drugs - Penicillins, cephalosporins, NSAIDs, proton pump inhibitors, allopurinol, rifampin, indinavir, mesalamine, sulfonamides [8]
  • Infection - Pyelonephritis, viral nephritides (eg, BK virus nephropathy in HSCT recipients)
  • Immunotherapy and targeted therapy - Immune checkpoint inhibitors (ICIs), lenalidomide, certain tyrosine kinase inhibitors (TKIs), BRAF inhibitors
  • Systemic disease - Sjögren syndrome, sarcoid, lupus, lymphoma, leukemia, tubulonephritis, uveitis

Anticoagulant-related nephropathy is a form of AKI in which over-anticoagulation causes profuse glomerular hemorrhage. Kidney biopsies in these patients show red blood cells and red cell casts filling numerous renal tubules.[9]  Studies of anticoagulation for atrial fibrillation have shown that in elderly and Asian patients, the risk of anticoagulant-related nephropathy is greater with warfarin than with direct oral anticoagulants (eg, apixaban, rivaroxaban, dabigatran).[10, 11]

Postrenal AKI

Mechanical obstruction of the urinary collecting system, including the renal pelvis, ureters, bladder, or urethra, results in obstructive uropathy or postrenal AKI. Causes of obstruction include the following:

  • Stone disease
  • Stricture
  • Intraluminal, extraluminal, or intramural tumors
  • Thrombosis or compressive hematoma
  • Fibrosis

If the site of obstruction is unilateral, then a rise in the serum creatinine level may not be apparent because of the preserved function of the contralateral kidney. Nevertheless, even with unilateral obstruction, a significant loss of GFR occurs, and patients with partial obstruction may develop progressive loss of GFR if the obstruction is not relieved.

Bilateral obstruction is usually a result of prostate enlargement or tumors in men and urologic or gynecologic tumors in women. Patients who develop anuria typically have an obstruction at the level of the bladder or downstream to it.

To summarize, causes of postrenal AKI include the following:

  • Ureteric obstruction - Stone disease, tumor, fibrosis, ligation during pelvic surgery
  • Bladder neck obstruction - Benign prostatic hyperplasia (BPH), prostate cancer, neurogenic bladder, tricyclic antidepressants, ganglion blockers, bladder tumor, stone disease, hemorrhage/clot
  • Urethral obstruction - Strictures, tumor, phimosis
  • Intra-abdominal hypertension - Tense ascites
  • Renal vein thrombosis

Diseases causing urinary obstruction from the level of the renal tubules to the urethra include the following:

  • Tubular obstruction from crystals - Eg, uric acid, calcium oxalate, acyclovir, sulfonamide, methotrexate, myeloma light chains

  • Ureteral obstruction - Retroperitoneal tumor, retroperitoneal fibrosis (methysergide, propranolol, hydralazine), urolithiasis, papillary necrosis, BK virus infection

  • Urethral obstruction - BPH; prostate, cervical, bladder, or colorectal carcinoma; bladder hematoma; bladder stone; obstructed Foley catheter; neurogenic bladder; stricture

Etiology in newborns and infants

Prerenal AKI

The patient's age has significant implications for the differential diagnosis of AKI. In newborns and infants, causes of prerenal AKI include the following:

  • Perinatal hemorrhage - Twin-twin transfusion, complications of amniocentesis, abruptio placenta, birth trauma
  • Neonatal hemorrhage - Severe intraventricular hemorrhage, adrenal hemorrhage
  • Perinatal asphyxia and hyaline membrane disease (newborn respiratory distress syndrome) - Both may result in preferential blood shunting away from the kidneys to the central circulation

Intrinsic AKI

Causes of intrinsic AKI include the following:

  • ATN - Can occur in the setting of perinatal asphyxia; ATN also has been observed secondary to medications (eg, aminoglycosides, NSAIDs) given to the mother perinatally

  • ACE inhibitors - Can traverse the placenta, resulting in a hemodynamically mediated form of AKI

  • Acute glomerulonephritis – Rare; most commonly the result of maternal-fetal transfer of antibodies against the neonate's glomeruli or transmission of chronic infections (syphilis, cytomegalovirus) associated with acute glomerulonephritis

Postrenal AKI

Congenital malformations of the urinary collecting systems should be suspected in cases of postrenal AKI.

Etiology in children

Prerenal AKI

In children, gastroenteritis is the most common cause of hypovolemia and can result in prerenal AKI. Congenital and acquired heart diseases are also important causes of decreased renal perfusion in this age group.

Intrinsic AKI

Intrinsic AKI may result from any of the following:

  • Acute poststreptococcal glomerulonephritis - Should be considered in any child who presents with hypertension, edema, hematuria, and kidney failure

  • HUS - Often cited as the most common cause of AKI in children

The most common form of HUS is associated with a diarrheal prodrome caused by Escherichia coli O157:H7. These children usually present with microangiopathic anemia, thrombocytopenia, colitis, mental status changes, and kidney failure. TTP is not as strongly associated with AKI. 

In a study of 521 pediatric trauma patients with posttraumatic rhabdomyolysis, AKI occurred in 70 (13.4%) patients. Independent risk factors for AKI were a creatine kinase level of ≥3,000, an Injury Severity Score of ≤15, a Glasgow Coma Scale score of ≤8, an abdominal Abbreviated Injury Scale (AIS) score of ≤3, imaging studies with contrast, blunt mechanism of injury, administration of nephrotoxic agents, and requirement for the administration of fluids in the emergency department.[12]

Cardiopulmonary bypass and AKI

Longer time on extracorporeal cardiopulmonary bypass is commonly accepted as a risk factor for AKI. However, a study by Mancini et al. found that extracorporeal cardiopulmonary bypass time did not predict AKI requiring dialysis, suggesting that a risk assessment may be a more reliable marker.[13]  Achieving moderate glucose control and using balanced crystalloid solutions perioperatively have been associated with decreased risk of AKI.[14, 15]  Similarly, implementing the KDIGO “bundle of care” in high-risk patients has been associated with decreased risk of AKI postoperatively.[16] This bundle consists of the following:

  • Discontinuation of nephrotoxic agents for 48 hours postoperatively
  • Avoidance of hyperglycemia for 72 hours postoperatively
  • Close monitoring of UOP and serum creatinine
  • Consideration of alternatives to radiocontrast agent
  • Optimization of volume status and perfusion pressure using a prespecified algorithm
  • Functional hemodynamic monitoring

COVID-19 and AKI

Kidney involvement is frequent in patients with severe COVID-19. More than 40% of patients have proteinuria on hospital admission, and approximately 20–40% of patients admitted to intensive care units in Europe and the United States have AKI.[17]  In patients with COVID-19, severe AKI is an ominous development associated with high mortality. In a study of over 89,000 US veterans who were 30-day survivors of COVID-19, the risk of AKI, estimated GFR decline, and ESKD were significantly greater than non-infected controls, and those who were hospitalized and admitted to the intensive care unit had the highest risk for adverse renal outcomes.[18, 19]  

AKI in COVID-19 is multifactorial and may have a distinct pathophysiology that includes the following[20, 21] :

  • Hypotension and decreased kidney perfusion secondary to hemodynamic or hemostatic factors or associated sepsis
  • Endothelial dysfunction, with hypercoagulability and complement activation
  • Nephrotoxins (medications, contrast agents)
  • Organ crosstalk among the injured lungs, heart, and kidney
  • Direct infection of kidney tubules with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that induces cytoplasmic renal tubular inclusions; this can explain both AKI in acute COVID-19 and the development of CKD in individuals with long COVID. [22]

Cancer and AKI 

Cancer patients have an increased risk of developing AKI due to multiple risk factors, including old age, chemotherapy/immunotherapy-associated nephrotoxicity, increased prevalence of CKD, and factors associated with cancer itself.[23]  The reported overall risk of developing AKI during hospitalization for cancer has ranged from 12 to 21%, with the majority of cases, 50-75%, being mild (stage 1) and with less than 5% of the patients requiring renal replacement therapy (RRT).[23, 24, 25] However, the incidence of AKI can increase up to 68% in patients with hematologic malignancy and in a critical care setting.  Patients with hematologic, renal, hepatic, and gastrointestinal malignancy have the highest rate of AKI.[24, 25]  Hypovolemia and ATN are the most common etiologies, as they are in non-cancer patients, with sepsis and nephrotoxins being the leading causes of ATN.[26, 27]  Other cancer-specific etiologoies are listed below.[28, 29, 30, 31]

Prerenal AKI related to cancer may have the following causes:

  • Cardio-renal: Malignant pericardial effusion, cardiotoxic chemotherapy (eg, trastuzumab, anthracyclines such as doxorubicin) 
  • Hepato-renal: Budd Chiari syndrome, extensive metastatic liver disease, hepatic veno-occlusive disease in HSCT recipients
  • Systemic: Cytokine release syndrome/capillary leak syndrome (engraftment syndrome post HSCT), certain cancer therapies (eg, CAR T-cell, ATRA, gemcitabine, IL-2)  

Intrinsic AKI related to cancer may have the following causes:

  • Glomerular pathology: Paraneoplastic glomerulonephritis or medication-associated glomerulonephritis (eg, from anthracyclines, pamidronate, interferon, mechanistic target of rapamycin [mTOR] inhibitors, TKIs, ICIs)
  • Thrombotic microangiopathy (TMA): Paraneoplastic TMA, medication-associated TMA (eg, from carfilzomib, bortezomib, cisplatin, gemcitabine, anthracycline, VGEF-targeting agents, TKIs, mTOR inhibitors) 
  • Tubulointerstitial injury: Tumor infiltration or metastasis, lenalidomide, BRAF inhibitors, BK virus nephropathy in HSCT recipients, TKIs, ICIs
  • Acute tubular injury: Lysozyme-induced nephropathy, cytokine release syndrome/capillary leak syndrome, tumor lysis syndrome, medications (eg, cisplatin, pemetrexed, ifosfamide, CAR T-cell therapy)
  • Crystal nephropathy: Tumor lysis syndrome, multiple myeloma, methotrexate 

Postrenal AKI related to cancer may have the following causes:

  • Ureteral compression (by obstructing tumor, lymphadenopathy, retroperitoneal fibrosis, or BK virus infection), blood clots
  • Urinary bladder obstruction

Recovery from AKI is variable and depends on the underlying etiology. In the majority of patients, AKI resolves after hospital discharge. Up to 23% of the patients with severe AKI requiring RRT who survive critical illness are expected to require long-term hemodialysis.[25, 32, 33]

In addition, AKI is associated with increased mortality (up to 6-fold), increased hospital length of stay, cost of treatment, hematologic malignancy relapse, and higher mortality rates than in cancer patients with no AKI.[23, 26, 32, 34, 35]  


In the United States, approximately 1% of patients admitted to hospitals have AKI at the time of admission. The estimated incidence rate of AKI during hospitalization is 2-5%. AKI develops within 30 days postoperatively in approximately 1% of general surgery cases and arises in more than 50% of intensive care unit (ICU) patients.[36, 37] In recipients of solitary kidney transplants, 21% developed AKI within the first 6 months after transplantation.[38]

Harding et al calculated that in the United States from 2000 to 2015, hospitalization rates for dialysis-requiring AKI in adults increased considerably while mortality decreased. In adults with diabetes, rates increased from 26.4 to 41.1 per 100,000 population, with relative increases greater in younger versus older adults. In adults without diabetes, rates increased from 4.8 to 8.7 per 100,000 population between 2000 and 2009, and then plateaued. Mortality declined significantly in patients both with and without diabetes.[39]

In a prospective national cohort study in Wales that used an electronic AKI alert (a centralized laboratory system that automatically compares measured creatinine values in an individual patient with previous results to generate alerts), the incidence of AKI was 577 per 100,000 population. Community-acquired AKI accounted for 49.3% of all incident episodes, and 42% occurred in the context of preexisting chronic kidney disease. The 90-day mortality rate was 25.6%, and 23.7% of episodes progressed to a higher AKI stage.[40]

In a Canadian study of severely ill children admitted to pediatric intensive care units, 30.3% developed AKI and 12.2% developed severe AKI. The incidence rate for critical illness–associated AKI was 34 per 100,000 children-year, and the rate of severe AKI was 14 per 100,000 children-year. Severe AKI was more common in boys (incidence rate ratio, 1.55) and in infants younger than 1 year old (incidence rate ratio, 14.77). The AKI-associated mortality rate was 2.3 per 100,000 children-year.[41]

Approximately 95% of consultations with nephrologists are related to AKI. Feest and colleagues calculated that the appropriate nephrologist referral rate is approximately 70 cases per million population.[42]


The prognosis for patients with AKI is directly related to the cause of the injury and, to a great extent, to the presence or absence of preexisting kidney disease (estimated GFR [eGFR] < 60 mL/min), as well as to the duration of kidney dysfunction prior to therapeutic intervention. In the past, AKI was thought to be completely reversible, but long-term follow-up of patients with this condition has shown otherwise.

A study from Canada showed a much higher incidence of AKI than did previous reports, with a rate of 18.3% (7856 of 43,008) in hospitalized patients.[43]  The incidence of AKI correlated inversely with eGFR and was associated with a higher mortality rate and a higher incidence of subsequent end-stage kidney disease (ESKD) at each level of baseline eGFR.

However, the greatest impact on mortality was seen in individuals with an eGFR of greater than 60 mL/min who developed AKI. Those with stage 3 AKI (AKIN criteria; see Background) had a mortality rate of 50%, while mortality in individuals with an eGFR of greater than 60 mL/min but who did not develop AKI was only 3%. Among individuals with an eGFR of less than 30, the mortality rate was 12.1% in those who did not develop AKI, versus 40.7% among patients with stage 3 AKI.[43]

In one study, survivors of severe AKI had worse health-related quality of life (QOL) than the general population, even after adjusting for their reduced kidney function. Both physical and mental components were affected. Increasing age and reduced kidney function were associated with poorer physical QOL.[44]

Mortality rates and associated factors

If AKI is defined by a sudden increment of serum creatinine of 0.5-1 mg/dL and is associated with a mild to moderate rise in creatinine, the prognosis tends to be worse. (Increments of 0.3 mg/dL in serum creatinine, especially at lower ranges of serum creatinine, have important prognostic significance).

The mortality rate for ICU patients with AKI is higher (> 50% in most studies), particularly when AKI is severe enough to require dialysis treatment.[45]  ICU patients with sepsis-associated AKI have significantly higher mortality rates than do nonseptic AKI patients.[46]

In addition, the pooled estimate for general ICU patients with AKI shows a stepwise increase in relative risk for death through the risk, injury, and failure classifications of the RIFLE criteria in AKI patients versus non-AKI patients.[47]  This reflects the fact that the high mortality rate in patients with AKI who require dialysis may not be related to the dialysis procedure or accompanying comorbidities and that AKI is an independent indicator of mortality. The survival rate is nearly 0% among patients with AKI who have an Acute Physiology and Chronic Health Evaluation II (APACHE II) score higher than 40. In patients with APACHE II scores of 10-19, the survival rate is 40%.

Fluid balance and mortality

In a post hoc analysis of the Fluid and Catheter Treatment Trial (FACTT), which examined liberal versus conservative fluid management in intubated ICU patients, fluid balance and diuretic use were identified as prognostic factors for mortality in individuals with AKI. Specifically, greater cumulative fluid accumulation over an average of 6 days (10.2 L vs 3.7 L in the liberal vs conservative group, respectively) was associated with a higher mortality rate, and higher furosemide use (cumulatively, 562 mg vs 159 mg, respectively) was associated with a lower mortality rate.[48]

Of note, more than half of the individuals in FACTT had stage 1 AKI (AKIN criteria), so whether these results apply to more severe AKI stages is unclear. One interpretation of this study is that patients who can be stabilized with less volume resuscitation fare better. From a practical standpoint, one conclusion is that aggressive, prolonged volume resuscitation does not improve prognosis in AKI in the ICU setting. [48]

Additional prognostic factors

Other prognostic factors include the following:

  • Older age
  • Multiorgan failure - Ie, the more organs that fail, the worse the prognosis
  • Oliguria
  • Hypotension
  • Vasopressor support
  • Number of transfusions
  • Noncavitary surgery
  • Occurrence of AKI by itself  [49] - Has significant negative prognostic implications

Prerenal azotemia from volume contraction is treated with volume expansion; if left untreated for a prolonged period, tubular necrosis may result and may not be reversible. If left untreated for a long time, postrenal AKI may result in irreversible kidney damage. Procedures such as catheter placement, lithotripsy, prostatectomy, stent placement, and percutaneous nephrostomy can help to prevent permanent kidney damage.


Timely identification of pyelonephritis, proper treatment, and further prevention using prophylactic antibiotics may improve the prognosis, especially in females. Early diagnosis of acute interstitial nephritis and crescentic glomerulonephritis via kidney biopsy and other appropriate tests may enhance early renal recovery because appropriate therapy can be initiated promptly and aggressively. For example, the number of crescents, the type of crescents (ie, cellular vs fibrous), and the serum creatinine level at the time of presentation may dictate the prognosis for renal recovery in these patients.


A large cohort study demonstrated that proteinuria coupled with low baseline GFR is associated with a higher incidence of AKI and should be considered as an identifying factor for individuals at risk. [49]  A retrospective, population-based study in a cohort of patients with and without known preoperative kidney dysfunction undergoing elective inpatient surgery found that proteinuria was associated with postoperative AKI and 30-day unplanned readmission independent of preoperative eGFR.[50]


The relationship between statins and AKI is complex.[51]  In addition to rare cases of statins causing rhabdomyolysis, the use of high-potency statins has been associated with an increased rate of diagnosis for AKI in hospital admissions, compared with the use of low-potency statins, particularly in the first 120 days after initiation of statin treatment.[52] On the other hand, preprocedural statin therapy has been shown to reduce contrast-induced AKI in patients undergoing coronary angiography.[53, 54]

Research on perioperative statins has yielded mixed results. A retrospective study in more than 200,000 patients older than 66 years who underwent elective surgery suggested that patients taking statins had a lesser incidence and lower severity of AKI, as well as lower mortality, than did individuals not on statins.[55]  In a meta-analysis of patients undergoing major surgery, preoperative statin therapy was associated with a significant risk reduction for cumulative postoperative AKI and postoperative AKI requiring renal replacement therapy. Still, when the analysis was restricted to randomized controlled trials, the protective effect was not significant.[56]

A meta-analysis in adult patients who required surgery with cardiac bypass found no association between preoperative statin use and a decrease in the incidence of AKI.[57]  Similarly, a meta-analysis in patients undergoing cardiac surgery (mainly myocardial revascularization) found that preoperative statin treatment did not influence perioperative kidney failure.[58]  In contrast, in another meta-analysis of patients undergoing cardiac surgery, preoperative statin therapy significantly reduced the incidence of postoperative kidney dysfunction and the need for postoperative renal replacement therapy.[59]

Long-term prognosis

In contrast to previous beliefs, it is now known that survivors of AKI do not universally have a benign course. On long-term follow-up (1-10 years), approximately 12.5% of survivors of AKI are dialysis dependent; rates range widely, from 1-64%, depending on the patient population. From 19-31% of survivors experience partial recovery of kidney function and have chronic kidney disease.[37]

In a long-term follow-up study of 350 patients from the randomized RENAL trial who survived AKI in the ICU, researchers found that the overall mortality rate was 62% at a median of 42.4 months after randomization. Median survival did not significantly differ between patients who received high- or low-intensity renal replacement therapy. At follow-up, 42.1% of the surviving patients had microalbuminuria or macroalbuminuria. Only 5.4% of the patients surviving at day 90 required maintenance dialysis. Predictors of long-term mortality included age, APACHE III score, and serum creatinine levels at baseline.[60]  In patients who survived AKI, cancer and cardiovascular disease is the most common etiology for death after hospitalization. [61]

Patient Education

Educating patients about the nephrotoxic potential of common therapeutic agents is always helpful. Nonsteroidal anti-inflammatory drugs (NSAIDs) provide a good example; most patients are unaware of their nephrotoxicity, and their universal availability makes them a constant concern.

For patient education information, see Acute Kidney Failure.




A detailed and accurate history is crucial for diagnosing acute kidney injury (AKI) and determining treatment. Distinguishing AKI from chronic kidney disease is important, yet making the distinction can be difficult; chronic kidney disease is itself an important risk factor for AKI.[62]  A history of chronic symptoms—months of fatigue, weight loss, anorexia, nocturia, sleep disturbance, and pruritus—suggests chronic kidney disease. AKI can cause identical symptoms, but over a shorter course.

It is important to elicit a history of any of the following etiologic factors:

  • Volume restriction (eg, low fluid intake, gastroenteritis)
  • Nephrotoxic drug ingestion (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], aminoglycosides) [62] Ref 60
  • Exposure to iodinated contrast agents within the past week  [62]
  • Trauma or unaccustomed exertion
  • Blood loss or transfusions
  • Exposure to toxic substances, such as ethyl alcohol or ethylene glycol
  • Exposure to mercury vapors, lead, cadmium, or other heavy metals, which can be encountered in welders and miners

People with the following comorbid conditions are at a higher risk for developing AKI:

  • Hypertension
  • Chronic heart failure
  • Diabetes
  • Liver disease
  • Obesity [63, 64, 65, 66]
  • Multiple myeloma
  • Chronic infection
  • Myeloproliferative disorder
  • Connective tissue disorders
  • Autoimmune diseases

Urine output history can be useful. Oliguria generally favors AKI. Abrupt anuria suggests acute urinary obstruction, acute severe glomerulonephritis, or embolic renal artery occlusion. A gradually diminishing urine output may indicate a urethral stricture or bladder outlet obstruction due to prostate enlargement.

Because of a decrease in functioning nephrons, even a trivial nephrotoxic insult may cause AKI to be superimposed on chronic kidney insufficiency.

AKI has a long differential diagnosis. The history can help to classify the pathophysiology of AKI as prerenal, intrinsic, or postrenal failure, and it may suggest some specific etiologies. (See Overview/Etiology.)

Prerenal failure

Patients commonly present with symptoms related to hypovolemia, including thirst, decreased urine output, dizziness, and orthostatic hypotension. Ask about volume loss from vomiting, diarrhea, sweating, polyuria, or hemorrhage. Patients with advanced heart failure leading to depressed renal perfusion may present with orthopnea and paroxysmal nocturnal dyspnea.

Elders with vague mental status change are commonly found to have prerenal or normotensive ischemic AKI. Insensible fluid losses can result in severe hypovolemia in patients with restricted fluid access and should be suspected in elderly patients and in comatose or sedated patients.

Intrinsic kidney failure

Patients can be divided into those with glomerular etiologies and those with tubular etiologies of AKI. Nephritic syndrome of hematuria, edema, and hypertension indicates a glomerular etiology for AKI. Query about prior throat or skin infections. Acute tubular necrosis (ATN) should be suspected in any patient presenting after a period of hypotension secondary to cardiac arrest, hemorrhage, sepsis, drug overdose, or surgery.

A careful search for exposure to nephrotoxins should include a detailed list of all current medications and any recent radiologic examinations (ie, exposure to radiologic contrast agents). Pigment-induced AKI should be suspected in patients with possible rhabdomyolysis (muscular pain, recent coma, seizure, intoxication, excessive exercise, limb ischemia) or hemolysis (recent blood transfusion). Allergic interstitial nephritis should be suspected with fevers, rash, arthralgias, and exposure to certain medications, including NSAIDs and antibiotics.

Postrenal failure

Postrenal failure usually occurs in older men with prostatic obstruction and symptoms of urgency, frequency, and hesitancy. Patients may present with asymptomatic, high-grade urinary obstruction because of the chronicity of their symptoms. A history of prior gynecologic surgery or abdominopelvic malignancy often can be helpful in providing clues to the level of obstruction.

Flank pain and hematuria should raise concern about renal calculi or papillary necrosis as the source of urinary obstruction. Use of acyclovir, methotrexate, triamterene, indinavir, or sulfonamides implies the possibility that crystals of these medications have caused tubular obstruction.

Physical Examination

Obtaining a thorough physical examination is extremely important when collecting evidence about the etiology of AKI. Clues may be found in any of the following:

  • Skin
  • Eyes
  • Ears
  • Cardiovascular system
  • Abdomen
  • Pulmonary system


Skin examination may reveal the following:

  • Livido reticularis, digital ischemia, butterfly rash, palpable purpura - Systemic vasculitis
  • Maculopapular rash - Allergic interstitial nephritis
  • Track marks (ie, intravenous drug abuse) - Endocarditis

Petechiae, purpura, ecchymosis, and livedo reticularis provide clues to inflammatory and vascular causes of AK. Infectious diseases, thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation (DIC), and embolic phenomena can produce typical cutaneous changes.

Eyes and ears

Eye examination may reveal the following:

  • Keratitis, iritis, uveitis, dry conjunctivae - Autoimmune vasculitis
  • Jaundice - Liver diseases
  • Band keratopathy (ie, hypercalcemia) - Multiple myeloma
  • Signs of diabetes mellitus
  • Signs of hypertension
  • Atheroemboli - Retinopathy

Evidence of uveitis may indicate interstitial nephritis and necrotizing vasculitis. Ocular palsy may indicate ethylene glycol poisoning or necrotizing vasculitis. Findings suggestive of severe hypertension, atheroembolic disease, and endocarditis may be observed on careful examination of the eyes.

Ear examination may reveal the following:

  • Hearing loss - Alport disease, aminoglycoside toxicity, and platinum compound toxicity
  • Mucosal or cartilaginous ulcerations - granulomatosis with polyangiitis (Wegener granulomatosis)

Cardiovascular system

The most important part of the physical examination is the assessment of cardiovascular and volume status. The physical examination must include the following:

  • Pulse rate and blood pressure measured in the supine and the standing position
  • Close inspection of the jugulovenous pulse
  • Careful examination of the heart and lungs, skin turgor, and mucous membranes
  • Assessment for peripheral edema

Cardiovascular examination may reveal the following:

  • Irregular rhythms (ie, atrial fibrillation) - Thromboemboli
  • Murmurs - Endocarditis
  • Pericardial friction rub - Uremic pericarditis
  • Increased jugulovenous distention, rales, S 3 - Heart failure

In hospitalized patients, accurate daily records of fluid intake and urine output, as well as daily measurements of patient weight, are important. Hypovolemia leads to hypotension; however, hypotension may not necessarily indicate hypovolemia.

Severe heart failure may also cause hypotension. Although patients with heart failure may have low blood pressure, volume expansion is present and effective renal perfusion is poor, which can result in AKI.

Severe hypertension with kidney failure suggests one of the following disorders:

  • Renovascular disease
  • Glomerulonephritis
  • Vasculitis
  • Atheroembolic disease
  • Subcapsular hematoma


Abdominal examination may reveal the following:

  • Pulsatile mass or bruit - Atheroemboli
  • Abdominal or costovertebral angle tenderness - Nephrolithiasis, papillary necrosis, renal artery thrombosis, renal vein thrombosis
  • Pelvic, rectal masses; prostatic hypertrophy; distended bladder – Urinary obstruction
  • Limb ischemia, edema - Rhabdomyolysis

Abdominal examination findings can be useful in helping to detect obstruction at the bladder outlet as the cause of renal failure; such obstruction may be due to cancer or to an enlarged prostate.

The presence of tense ascites can indicate elevated intra-abdominal pressure that can retard renal venous return and result in AKI. The presence of an epigastric bruit suggests renal vascular hypertension, which may predispose to AKI.

Pulmonary system

Pulmonary examination may reveal the following:

  • Rales - Goodpasture syndrome, granulomatosis with polyangiitis (Wegener granulomatosis)
  • Hemoptysis - Wegener granulomatosis


Diagnostic Considerations

Although acute kidney injury (AKI) is a potentially reversible condition, it can occur in patients with chronic kidney diseae. Every effort should be made to identify reversibility, even if improvement in kidney function is marginal. The best way to identify reversibility is by tracking the rate of deterioration of kidney function. If the rate fo deterioration accelerates, the cause should be sought and treated.

Differentials to consider in AKI include the following:

  • Abdominal aneurysm
  • Alcohol toxicity
  • Alcoholic ketoacidosis
  • Chronic kidney disease
  • Dehydration
  • Diabetic ketoacidosis
  • Gastrointestinal (GI) bleeding
  • Heart failure
  • Metabolic acidosis
  • Obstructive uropathy
  • Protein overloading
  • Renal calculi
  • Sickle cell anemia
  • Steroid use
  • Urinary obstruction
  • Urinary tract infection

Urine output in differential diagnosis

Changes in urine output generally correlate poorly with changes in the glomerular filtration rate (GFR). Approximately 50-60% of all causes of AKI do not produce oliguria. However, the identification of anuria, oliguria, and nonoliguria may be useful in the differential diagnosis of AKI, as follows:

  • Anuria (< 100 mL/day) - Urinary tract obstruction, renal artery obstruction, rapidly progressive glomerulonephritis, bilateral diffuse renal cortical necrosis

  • Oliguria (100-400 mL/day) - Prerenal failure, hepatorenal syndrome, and severe AKI

  • Nonoliguria (> 400 mL/day) - Acute interstitial nephritis, acute glomerulonephritis, partial obstructive nephropathy, nephrotoxic and ischemic acute tubular necrosis, radiocontrast-induced AKI, and rhabdomyolysis

Differential Diagnoses



Approach Considerations

Several laboratory tests, including the following, are useful for assessing the etiology of acute kidney injury (AKI) and can aid in proper management of the disease:

  • Complete blood count (CBC)
  • Serum biochemistries
  • Urine analysis with microscopy
  • Urine electrolytes

In some cases, renal imaging is useful, especially if kidney failure is secondary to obstruction. The American College of Radiology recommends ultrasonography, preferably with Doppler methods, as the most appropriate imaging method in AKI.[67]

In early AKI, a furosemide stress test can be performed to help determine the patient's prognosis. Low urinary output after the infusion of furosemide predicts the development of stage 3 AKI (see Furosemide Stress Testing, below).[68, 69]

Kidney Function Studies

Although increased levels of blood urea nitrogen (BUN) and creatinine are the hallmarks of renal failure, the rate of rise depends on the degree of renal insult and, with respect to BUN, on protein intake. BUN may be elevated in patients with gastrointestinal (GI) or mucosal bleeding, steroid treatment, or protein loading.

The ratio of BUN to creatinine is an important finding. The ratio can exceed 20:1 in conditions in which enhanced reabsorption of urea is favored (eg, in volume contraction); this suggests prerenal AKI.

Assuming that the patient has no renal function, the rise in BUN over 24 hours can be roughly predicted using the following formula:

(24-hour protein intake in milligrams × 0.16) ÷ total body water

The result is expressed in mg/dL and added to the baseline BUN value to yield the predicted BUN.

Assuming no kidney function, the rise in creatinine can be predicted using the following formulas:

  • For males: Weight in kilograms × [28 - 0.2(age)] ÷ total body water, with the result in mg/dL added to the creatinine value
  • For females: Weight in kilograms × [23.8 - 0.17(age)] ÷ total body water, with the result in mg/dL added to the creatinine value

As a general rule, if serum creatinine increases to more than 1.5 mg/dL/day, rhabdomyolysis must be ruled out.

In 2014 the US Food and Drug Administration (FDA) approved NephroCheck, the first laboratory test to evaluate the risk of developing moderate to severe AKI in hospitalized, critically ill patients. The test identifies the presence of two AKI-associated proteins (insulinlike growth factor–binding protein 7, tissue inhibitor of metalloproteinases) in urine. Based on the level of these proteins, a score is derived that indicates the likelihood that a patient will develop AKI within the next 12 hours.[70]

Approval for NephroCheck was based on two studies, which compared results from the test with the clinical diagnosis of over 500 critically ill patients. In patients with AKI, NephroCheck was 92% accurate in detecting the condition in one study and 76% accurate in the other. In both studies, however, the test reported false-positives in about 50% of patients without AKI.

CBC, Peripheral Smear, and Serology

The peripheral smear may show schistocytes in conditions such as hemolytic uremic syndrome (HUS) or thrombotic thrombocytopenic purpura (TTP). A finding of increased rouleaux formation suggests multiple myeloma, and the workup should be directed toward immunoelectrophoresis of serum and urine.

The presence of the following, along with related findings, may help to further define the etiology of AKI:

  • Myoglobin or free hemoglobin - Eg, pigment nephropathy
  • Increased serum uric acid level - Eg, tumor lysis syndrome
  • Elevated serum lactate dehydrogenase (LDH) - Eg, renal infarction

Although serologic tests can be informative, the costs can be prohibitive if these tests are not ordered judiciously. Possible tests include the following:

  • Complement levels
  • Antinuclear antibody (ANA)
  • Antineutrophil cytoplasmic antibody (ANCA)
  • Anti–glomerular basement membrane (anti-GBM) antibody
  • Hepatitis B and C virus studies
  • Antistreptolysin (ASO)


Findings of granular, muddy brown casts in urine sediment are highly suggestive of acute tubular necrosis (ATN) (see the image below). The presence of tubular cells or tubular cell casts also supports the diagnosis of ATN. Often, oxalate crystals are observed in cases of ATN.

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

Reddish brown or cola-colored urine suggests the presence of myoglobin or hemoglobin, especially in the setting of a positive dipstick for heme and no red blood cells (RBCs) on the microscopic examination. The dipstick assay may reveal significant proteinuria as a result of tubular injury.

The presence of RBCs in the urine is always pathologic. Eumorphic RBCs suggest bleeding along the collecting system. Dysmorphic RBCs or RBC casts indicate glomerular inflammation, suggesting glomerulonephritis is present.

The presence of white blood cells (WBCs) or WBC casts suggests pyelonephritis or acute interstitial nephritis. 

The presence of eosinophils, as visualized with Wright stain or Hansel stain, might suggest interstitial nephritis. However, it has poor sensitivity in AIN diagnosis and can be also seen in urinary tract infections, glomerulonephritis, and atheroembolic disease.

The presence of uric acid crystals may represent ATN associated with uric acid nephropathy. Calcium oxalate crystals are usually present in cases of ethylene glycol poisoning.

Fractional Excretion of Sodium and Urea


Urine electrolyte findings also can serve as valuable indicators of functioning renal tubules. The fractional excretion of sodium (FENa) is the commonly used indicator. However, the interpretation of results from patients in nonoliguric states, those with glomerulonephritis, and those receiving or ingesting diuretics can lead to an erroneous diagnosis.

FENa can be a valuable test for helping to detect extreme renal avidity for sodium in conditions such as hepatorenal syndrome. The formula for calculating the FENa is as follows:

FENa = (UNa/PNa) / (UCr/PCr) × 100

Calculating the FENa is useful in AKI only in the presence of oliguria. In patients with prerenal azotemia, the FENa is usually less than 1%. In ATN, the FENa is greater than 1%. Exceptions to this rule are ATN caused by any of the following:

  • Radiocontrast nephropathy
  • Severe burns
  • Acute glomerulonephritis
  • Rhabdomyolysis

In patients with liver disease and heart failure, FENa can be less than 1% in the presence of ATN. On the other hand, because administration of diuretics may cause the FENa to be greater than 1%, these findings cannot be used as the sole indicators in AKI.


In patients who are receiving diuretics, a fractional excretion of urea (FEUrea) can be obtained, since urea transport is not affected by diuretics. (FEUrea of less than 35% is suggestive of a prerenal state.) The formula for calculating the FEUrea is as follows:

FEUrea = (Uurea/Purea) / (UCr/PCr) × 100

Bladder Pressure

An intra-abdominal pressure of less than 10 mm Hg is considered normal and suggests that abdominal compartment syndrome is not the cause of AKI. An intra-abdominal pressure above 10 mm Hg is abnormal, but patients who have pressures of 15-25 mm Hg are at particular risk for abdominal compartment syndrome, and those with bladder pressures above 25 mm Hg should be suspected of having AKI as a result of abdominal compartment syndrome.

Emerging Biomarkers

Creatinine elevation is a late marker for kidney dysfunction and reflects a severe reduction in glomerular filtration rate (GFR). Consequently, a number of biomarkers are being investigated to risk stratify and predict AKI in patients at risk for the disease.

One of the most promising biomarker to date is urinary neutrophil gelatinase-associated lipocalin (NGAL), which has been shown to detect AKI in patients undergoing cardiopulmonary bypass surgery.[71]

Breidthardt et al studied a model that combined the markers plasma B-type natriuretic peptide (BNP) and NGAL and found it to be a strong predictor of early AKI in patients with lower respiratory tract infection. The presence of a BNP level of over 267 pg/mL or an NGAL level of greater than 231 ng/mL correctly identified 15 of 16 early AKI patients, with a sensitivity of 94% and a specificity of 61%.[72]

A study of adults on the first day of meeting AKI criteria found that urine protein biomarkers and microscopy findings offer a significant improvement over clinical determination of prognosis. In this study, the risk for worsened AKI stage or inhospital death was approximately 3-fold higher for upper values than it was for lower ones for NGAL, kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), and microscopy score for casts and tubular cells.[73]

In addition, multiple studies have suggested that when stress biomarkers such as insulinlike growth factor–binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases 2 (TIMP-2) are positive after a kidney insult, timely initiation of preventive strategies is effective at preventing AKI and decreasing the need for renal replacement therapy (RRT).[74, 75, 76]  Supported by this data, the current recommendation by the Acute Disease Quality Initiative (ADQI) encourages the use of validated biomarkers to identify patient populations for whom preventive interventions have been shown to improve outcomes (grade A recommendation).[77]  However, there are still multiple limitations for their routine use in clinical practice, including the variable cutoff values in published articles and lack of standardization, risk of confounding by comorbidities, and high expenses.[78]

Cystatin C is another biomarker that has been studied for potential early detection of AKI and prediction of disease outcomes.[79] In multiple studies of patients undergoing cardiac surgery, cystatin C was found to have modest to moderately good discrimination ability for development of AKI, with the area under the receiver operating characteristic curve ranging from 0.63 to 0.77.[80, 81, 82]

In addition, several studies reported similar performance of cystatin C compared with serum creatinine for AKI detection postoperatively.[81, 83, 84] Similarly, cystatin C level performed comparably to serum creatinine level in predicting dialysis requirement and in-hospital death in hospitalized patients. In a heterogeneous emergency department population, a single-center prospective cohort study that included 616 patients found that cystatin C outperformed serum creatinine in early detection of AKI and and differentiated between prerenal azotemia and AKI.[85]

For more information, see Novel Biomarkers of Renal Function.

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 be used to help the clinician determine when or whether to start renal replacement therapy.[68, 69]

Candidates for FST should be euvolemic and stable. For the test, furosemide is infused intravenously, in a dose of 1.0 or 1.5 mg/kg, and urine output is measured for 2 hours afterward. A 2-hour urinary output of 200 ml or less has been shown to have the best sensitivity and specificity to predict development of stage 3 AKI. To minimize the risk of hypovolemia, urine output may be replaced mL for mL each hour with Ringers lactate or normal saline for 6 hours after the FST, unless volume reduction is considered clinically desirable.[69]

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 for prediction of adverse patient outcomes was achieved when FST was combined with biomarkers using specified cutoffs: urinary neutrophil gelatinase-associated lipocalin (NGAL) > 150 ng/mL or urinary tissue inhibitor of metalloproteinases (TIMP-2) × insulinlike growth factor–binding protein-7 (IGFBP-7) > 0.3.[68]


Renal ultrasonography is useful for evaluating existing renal disease and obstruction of the urinary collecting system. Obtaining images of the kidneys can be technically difficult in patients who are obese, however, as well as in those with abdominal distention from ascites, gas, or retroperitoneal fluid collection.

The degree of hydronephrosis found on an ultrasonogram does not necessarily correlate with the degree of obstruction. Mild hydronephrosis may be observed with complete obstruction if found early. Small kidneys suggest chronic kidney disease.

Doppler ultrasonography

Doppler scans are useful for detecting the presence and nature of renal blood flow. Because renal blood flow is reduced in prerenal and intrarenal AKI, findings are of little use in the diagnosis of AKI. However, Doppler scans can be quite useful in the diagnosis of thromboembolic or renovascular disease. Increased resistive indices can be observed in patients with hepatorenal syndrome.

Nuclear Scanning

Radionuclide imaging with technetium-99m-mercaptoacetyltriglycine (99m Tc-MAG3),99m Tc-diethylenetriamine penta-acetic acid (99m Tc-DTPA), or iodine-131 (131 I)-hippurate can be used to assess renal blood flow, as well as tubular function. There is, however, a marked delay in the tubular excretion of radionuclide in prerenal and intrarenal AKI, limiting the value of nuclear scans.

Aortorenal Angiography

Aortorenal angiography can be helpful in establishing the diagnosis of renal vascular diseases, including the following:

  • Renal artery stenosis
  • Renal atheroembolic disease
  • Atherosclerosis with aortorenal occlusion
  • Certain cases of necrotizing vasculitis (eg, polyarteritis nodosa)

Kidney Biopsy

A kidney biopsy can be useful in identifying intrarenal causes of AKI and can be justified if the results may change management (eg, initiation of immunosuppressive medications). See the image below.  A kidney biopsy may also be indicated when kidney function does not return for a prolonged period and a prognosis is required to develop long-term management. In as many as 40% of cases, kidney biopsy results reveal an unexpected diagnosis.

Acute cellular or humoral rejection in a transplanted kidney can be definitively diagnosed only by performing a biopsy.

Photomicrograph of a kidney biopsy specimen shows 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.


Approach Considerations

Measures to correct underlying causes of acute kidney injury (AKI) should begin at the earliest indication of kidney dysfunction. Serum creatinine does not rise to abnormal levels until a large proportion of the renal mass is damaged, because the relationship between the glomerular filtration rate (GFR) and the serum creatinine level is not linear, especially early in disease. Indeed, the rise of serum creatinine may not be evident before 50% of the GFR is lost.

It cannot be overstated that the current treatment for AKI is mainly supportive in nature; no therapeutic modalities to date have shown efficacy in treating the condition. Therapeutic agents (eg, dopamine, nesiritide, fenoldopam, mannitol) are not indicated in the management of AKI and may be harmful for the patient.

Maintenance of volume homeostasis and correction of biochemical abnormalities remain the primary goals of treatment and may include the following measures:

  • Correction of fluid overload with furosemide
  • Correction of severe acidosis with bicarbonate administration, which can be important as a bridge to dialysis
  • Correction of hyperkalemia
  • Correction of hematologic abnormalities (eg, anemia, uremic platelet dysfunction) with measures such as transfusions and administration of desmopressin or estrogens

Volume overload

Furosemide can be used to correct volume overload when the kidneys are still responsive; this often requires high intravenous (IV) doses. Furosemide plays no role in converting an oliguric AKI to a nonoliguric AKI or in increasing urine output when a patient is not hypervolemic. However, response to furosemide can be taken as a good prognostic sign.


Hyperkalemia in patients with AKI can be life-threatening. Approaches to lowering serum potassium include the following:

  • Decreasing the intake of potassium in diet or tube feeds
  • Exchanging potassium across the gut lumen using potassium-binding resins
  • Promoting intracellular shifts in potassium with insulin, dextrose solutions, and beta agonists
  • Instituting dialysis

Nephrotoxic agents

In AKI, the kidneys are especially vulnerable to the toxic effects of various chemicals. All nephrotoxic agents (eg, radiocontrast agents, antibiotics with nephrotoxic potential, heavy metal preparations, cancer chemotherapeutic agents, nonsteroidal anti-inflammatory drugs [NSAIDs]) should be avoided or used with extreme caution. Similarly, all medications cleared by renal excretion should be avoided, or their doses should be adjusted appropriately.

A 2013 study indicated that triple therapy using NSAIDs with 2 antihypertensive medications—a diuretic along with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB)—significantly increases the risk of hospitalization for AKI, particularly in the first 30 days of treatment with these drugs. The retrospective, case-controlled study involved a cohort of 487,372 users of antihypertensive drugs between 1997 and 2008. During a mean follow-up of almost 6 years, 2215 cases of AKI were identified (incidence rate of 7 per 10 000 person-years), and each was compared with up to 10 matched controls.[86, 87]

A retrospective, observational cohort study of 500 adult patients who received vancomycin for ≥72 h found that the incidence of AKI correlated with vancomycin trough levels, ranging from 8.02% with first trough levels below 10 µg/mL to 31.82% with first trough levels of 20 µg/mL or higher On multivariate logistic regression, factors significantly associated with increased incidence of AKI included first or average trough levels above 15 µg/mL as well as methicillin-resistant Staphylococcus aureus infection and morbid obesity.[88]


Nephrology consultation should be sought early in the course of AKI. A nephrologist can help to optimize management and avoid the preventable complications of AKI.[89]


The rationale for vasodilator therapy in AKI is that improved renal perfusion may reduce kidney damage. Strong evidence in support of this approach is lacking, however.

A meta-analysis of 16 randomized studies concluded that the vasodilator fenoldopam reduces the need for renal replacement therapy and lowers the mortality rate in patients with AKI.[90]  However, larger trials need to be conducted before the use of fenoldopam can be recommended.

Dopamine in small doses (eg, 1-5 mcg/kg/min) causes selective dilatation of the renal vasculature, enhancing renal perfusion. Dopamine also reduces sodium absorption; this enhances urine flow, which helps to prekvent tubular cast obstruction. However, most clinical studies have failed to establish this beneficial role of low-dose dopamine infusion, and one study demonstrated that low-dose dopamine may worsen renal perfusion in patients with AKI.[90]

Dietary Modification

Dietary changes are an important facet of AKI treatment. Restriction of salt and fluid becomes crucial in the management of oliguric kidney failure, wherein the kidneys do not adequately excrete either toxins or fluids.

Because potassium and phosphorus are not excreted optimally in patients with AKI, blood levels of these electrolytes tend to be high. Restriction of these elements in the diet may be necessary, with guidance from frequent measurements. In the polyuric phase of AKI, potassium and phosphorus may be depleted, so that patients may require dietary supplementation and IV replacement.

Calculation of the nitrogen balance can be challenging, especially in the presence of volume contraction, hypercatabolic states, GI bleeding, and diarrheal disease. Critically ill patients should receive at least 1 g/kg/day protein but should avoid hyperalimentation, which can lead to an elevated blood urea nitrogen (BUN) level and water loss resulting in hypernatremia.


Dialysis, especially hemodialysis, may delay the recovery of patients with AKI. Most authorities prefer using biocompatible membrane dialyzers for hemodialysis. Indications for dialysis (ie, renal replacement therapy [RRT]) in patients with AKI are as follows:

  • Volume expansion that cannot be managed with diuretics
  • Hyperkalemia refractory to medical therapy
  • Correction of severe acid-base disturbances that are refractory to medical therapy
  • Severe azotemia (BUN > 80-100)
  • Uremia

Timing and intensity

Great controversy exists regarding the timing of dialysis. Older studies suggested decreased mortality with early, versus late, initiation of dialysis, but timing of dialysis initiation has not been assessed in large, randomized, controlled trials.[91] Approaches vary widely at present.

The Acute Renal Failure Trial Network (ATN) Study found that increasing the intensity of dialysis (either intermittent or continuous) did not improve clinical outcomes (morbidity/mortality).[92]  The current recommendation by Kidney Disease: Improving Global Outcomes (KDIGO) in dialysis-dependent AKI patients is to deliver a kt/v of 3.9 per week when using intermittent or extended RRT and an effluent volume of 20-25 mg/kg/hr when using continuous renal replacement therapy (CRRT).[1]

Continuous renal replacement therapy

There seems to be no difference in outcome between the use of intermittent hemodialysis and CRRT, but this question is currently under investigation. CRRT may have a role in patients who are hemodynamically unstable and who have had prolonged renal failure after a stroke or liver failure. Such patients may not tolerate the rapid shift of fluid and electrolytes caused during conventional hemodialysis.

Peritoneal dialysis

Peritoneal dialysis is not frequently used in patients with AKI. Nevertheless, it can technically be used in acute cases and probably is tolerated better hemodynamically than is conventional hemodialysis.

Prevention of Contrast-Induced Nephropathy


In patients undergoing imaging studies with contrast, prophylactic administration of IV fluid has been shown to decrease the incidence of contrast nephropathy. Although controversy exists regarding the ideal fluid, normal saline and isotonic sodium bicarbonate have proved to be effective. A normal saline solution of 1 mL/kg/h administered 6-12 hours before the procedure and then 6-12 hours after the procedure is recommended for most  hospitalized patients. A recent large, randomized clinical trial did not find an additional benefit when using sodium bicarbonate over normal saline in decreasing contrast nephropathy.[93]


Another prophylactic agent, used with varying success, is oral N-acetylcysteine at a dosage of 1200 mg every 12 hours. This used to be administered to high-risk patients the day before performing a contrast study, but it provided borderline benefit.[94]  More recent data from a large randomized trial did not demonstrate a reduction in AKI incidence using N-acetylcysteine.[93]


A meta-analysis found that statin treatment before coronary angiography can reduce contrast-induced AKI. Risk was 3.91% in the statin group versus 6.98% in the control group. On subanalysis, benefit was highly significant benefit in patients whose GFR was ≥60 mL/min (relative risk [RR] 0.40, P < 0.0001).[53]

A meta-analysis of intensive statin therapy before coronary angiography and percutaneous coronary intervention reported that in patients with acute coronary syndrome (ACS), statin treatment significantly reduced the incidence of contrast-induced AKI (RR 0.37, P < 0.0001). In patients without ACS, however, only a nonsignificant positive trend was seen (RR 0.65, P=0.07), so there is no recommendation in these patients to initiate a statin prior to receiving contrast for solely preventing contrast-related AK.[54]

Forced diuresis

A study in 92 patients undergoing coronary angiography documented a significantly increased risk of contrast-induced nephropathy in patients who received forced euvolemic diuresis with saline, mannitol, and furosemide, compared with those who received saline hydration.[95]  A systematic review and meta-analysis of mannitol administration for AKI prevention concluded that mannitol is in fact detrimental for contrast-induced nephropathy.[96]

However, studies of forced diuresis with matched controlled hydration have reported a decrease in the incidence of AKI.[97, 98, 99] These studies have used a device, the RenalGuard System (RenalGuard Solutions, Inc; Milford, MA), that matches saline infusion rates to the patient’s urine output by volume and time. The device is commercially available in Europe but is still under study in the United States.[100]

ACE Inhibitors and ARBs

There are conflicting results based on randomized and non-randomized studies about the association of ACE inhibitors and ARBs with the risk for contrast-induced nephropathy (CIN); some of these studies suggested possible increased risk while others showed either no difference or even decreased risk of AKI when comparing patients who were on an ACE inhibitor or an ARB versus controls prior to angiography.[101, 102, 103, 104]  Similar findings were reported in the subgroup of patients with chronic kidney disease (eGFR < 60 mL/min).[105, 106]

Long-Term Monitoring

Renal recovery in most cases is not complete, with the kidneys remaining vulnerable to the nephrotoxic effects of all therapeutic agents. Therefore, agents with nephrotoxic potential are best avoided.

Renal recovery is usually observed within the first 2 weeks, and many nephrologists tend to diagnose patients with end-stage (ie, irreversible) kidney failure 6-8 weeks after the onset of AKI. It is always better to check these patients periodically, because some patients may regain kidney function much later.

Prevention of Perioperative Nephropathy

Remote ischemic preconditioning (RIPC) is a novel investigative method for preventing perioperative AKI. The rationale is that producing ischemia in a patient’s extremity immediately before surgery will stimulate the release of endogenous protective molecules, thereby reducing the likelihood that the surgery will precipitate AKI.[107]

In a randomized trial in 240 patients who were undergoing on-pump coronary bypass grafting and were at moderate to high risk for perioperative AKI, 37.5% of patients who received RIPC developed AKI within 72 hours after surgery, compared with 52.5% of controls (P = 0.02). In patients who developed AKI, 5.8% who had received RIPC required renal replacement therapy versus 15.8% of those in the control arm (10% absolute risk reduction). [107]

In this study, remote ischemia was induced by inflating a blood pressure cuff to 200 mm Hg on one upper extremity for 5 minutes; this was repeated twice, for a total of three cycles. Control patients received three cycles of blood pressure cuff inflation to 20 mm Hg for 5 minutes.[107]  However, two multicenter randomized clinical trials reported no reduction of postoperative AKI among other outcomes using RIPC.[108, 109]

Pharmacologic agents

A review of randomized, controlled trials of pharmacologic measures used to protect kidney function perioperatively found no reliable evidence that any of the following interventions are effective[110] :

  • Dopamine and its analogues
  • Diuretics
  • Calcium channel blockers
  • Angiotensin-converting enzyme (ACE) inhibitors
  • N-acetylcysteine [111]
  • Atrial natriuretic peptide (ANP)
  • Sodium bicarbonate
  • Antioxidants
  • Erythropoietin (EPO)
  • Specific hydration fluids


Medication Summary

Pharmacologic treatment of acute kidney injury (AKI) has been attempted on an empiric basis with varying success rates. Several promising experimental therapies in animal models are awaiting human trials. Experimental therapies include growth factors, vasoactive peptides, adhesion molecules, endothelin inhibitors, and bioartificial kidneys. Aminophylline has also been used experimentally for prophylaxis against kidney failure.

There is no specific pharmacologic therapy proven to treat AKI secondary to hypoperfusion and/or sepsis. The only therapeutic or preventive intervention that has an established beneficial effect in the management of AKI is the intravenous (IV) administration of crystalloid solution. It should be given in quantities sufficient to keep the patient euvolemic or even hypervolemic.

Diuretics, Loop

Class Summary

Although diuretics seem to have no effect on the outcome of established AKI, they appear to be useful in fluid homeostasis and are used extensively. They have also been used to reduce the requirement for renal replacement therapy. The use of isotonic sodium chloride solution in conjunction with diuretics is debatable.

Furosemide (Lasix)

Furosemide increases the excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the thick ascending loop of Henle and the distal renal tubule. It is a potent and rapid-acting agent with peak action at 60 minutes and a 6- to 8-hour duration of action.

In renal failure, higher doses must be used for greater diuretic effect. Doses as high as 600 mg/day may be needed under monitored conditions.

Frequently, IV doses are needed in AKI to maintain urine output. IV infusions are often helpful in intensive care settings, in which larger doses are necessary. This method promotes a sustained natriuresis with reduced ototoxicity compared with conventional intermittent bolus dosing.

Inotropic Agents

Dopamine (Intropin)

Dopamine stimulates adrenergic and dopaminergic receptors. Its hemodynamic effect is dose dependent. In small doses (eg, 0.5-3.0 mcg/kg/min), dopamine predominantly stimulates dopaminergic receoptors, which, in turn produce vasodilation of the renal vasculature, enhancing renal perfusion. Dopamine also reduces sodium absorption, thereby decreasing the energy requirement of the damaged tubules. This enhances urine flow, which, in turn, helps to prevent tubular cast obstruction. The clinical benefit of low-dose dopamine remains uncertain.  Higher doses produce cardiac stimulation and renal vasodilation. Potential complications of dopamine use include cardiac arrhythmias, myocardial ischemia, and intestinal ischemia. 


Fenoldopam (Corlopam)

Fenoldopam is a selective dopamine-receptor agonist that acts as a rapid-acting vasodilator. It is 6 times more potent than dopamine in producing renal vasodilation. It increases renal blood flow to the cortex and medullary regions in the kidney, increases diuresis , and has minimal adrenergic effects. Fenoldopam is indicated for the treatment of severe hypertension, including patients with renal compromise. 

Calcium Channel Blockers

Class Summary

These drugs are effective in animal models of AKI, but their efficacy has not been proven in humans. The effects of calcium channel blockers are believed to be mediated through vasodilation, and they are increasingly used to enhance the function of transplanted kidneys.

Nifedipine (Adalat, Procardia, Afeditab CR, Nifediac CC, Nifedical XL)

Nifedipine relaxes smooth muscle and produces vasodilation, which, in turn, improves blood flow and oxygen delivery.

Antidotes, Other

N-acetylcysteine (Acetadote)

N -acetylcysteine is used for the prevention of contrast toxicity in susceptible individuals, such as those with diabetes mellitus. The mechanism by which it prevents contrast-induced nephropathy is presumed to be its ability to scavenge free radicals and improve endothelium-dependent vasodilation.


Questions & Answers


How is acute kidney injury (AKI) defined?

What are the dermatologic signs and symptoms of acute kidney injury (AKI)?

What are the ocular signs and symptoms of acute kidney injury (AKI)?

What are the otolaryngologic signs and symptoms of acute kidney injury (AKI)?

What are the cardiovascular signs and symptoms of acute kidney injury (AKI)?

What are the abdominal signs and symptoms of acute kidney injury (AKI)?

What are the pulmonary signs and symptoms of acute kidney injury (AKI)?

Which tests are performed in the workup of acute kidney injury (AKI)?

How is acute kidney injury (AKI) treated?

What is acute kidney injury (AKI)?

How is acute kidney injury (AKI) classified?

What is oliguric and nonoliguric acute kidney injury (AKI)?

What is the RIFLE (Risk of renal dysfunction, Injury to the kidney, Failure or Loss of kidney function, and End-stage kidney disease) classification system for acute kidney injury (AKI)?

What is the acute kidney injury network (AKIN) classification system?

What are the cardiovascular complications of acute kidney injury (AKI)?

What are the pulmonary complications of acute kidney injury (AKI)?

What are the GI complications of acute kidney injury (AKI)?

How is pancreatitis diagnosed in acute kidney injury (AKI)?

What causes jaundice in acute kidney injury (AKI)?

Which conditions should be included in the differential diagnoses of acute kidney injury (AKI) with hepatitis?

What is the mortality and morbidity associated with infections in acute kidney injury (AKI)?

What are the signs and symptoms of neurologic complications in acute kidney injury (AKI)?

Which conditions should be included in the differential diagnosis of acute kidney injury (AKI) with neurologic manifestations?

What is the pathophysiology of acute kidney injury (AKI)?

What is the role of depressed renal blood flow in the pathophysiology of acute kidney injury (AKI)?

What is the role of acute tubular necrosis in the pathophysiology of acute kidney injury (AKI)?

What is the role of apoptosis in the pathophysiology of acute kidney injury (AKI)?

What is the role of inflammatory response in the pathophysiology of acute kidney injury (AKI)?

What is the role of vasoconstriction in the pathophysiology of acute kidney injury (AKI)?

What is the role of isosthenuria in the pathophysiology of acute kidney injury (AKI)?

What are the complications of restored renal blood flow in the pathophysiology of acute kidney injury (AKI)?

What causes prerenal acute kidney injury (AKI) in newborns and infants?

What causes prerenal acute kidney injury (AKI)?

What causes volume depletion in acute kidney injury (AKI)?

What causes decreased cardiac output in acute kidney injury (AKI)?

What causes systemic vasodilation in acute kidney injury (AKI)?

What causes afferent arteriolar vasoconstriction in acute kidney injury (AKI)?

What causes decreased effective arterial blood volume in acute kidney injury (AKI)?

Which renal arterial diseases cause acute kidney injury (AKI)?

What causes intrinsic acute kidney injury (AKI)?

What are the vascular causes of intrinsic acute kidney injury (AKI)?

What are the glomerular causes of intrinsic acute kidney injury (AKI)?

What are the tubular and cytotoxic causes of acute kidney injury (AKI)?

What are the interstitial causes of intrinsic acute kidney injury (AKI)?

What causes postrenal acute kidney injury (AKI)?

What causes intrinsic acute kidney injury (AKI) in newborns and infants?

What causes postrenal acute kidney injury (AKI) in newborns and infants?

What causes prerenal acute kidney injury (AKI) in children?

What causes intrinsic acute kidney injury (AKI) in children?

How does cardiopulmonary bypass affect the risk of acute kidney injury (AKI)?

What is the role of COVID-19 in the etiology of acute kidney injury (AKI)?

What is the prevalence of acute kidney injury (AKI)?

What is the prognosis of acute kidney injury (AKI)?

What are mortality rates of acute kidney injury (AKI)?

How does fluid balance affect the prognosis of acute kidney injury (AKI)?

What are prognostic factors of acute kidney injury (AKI)?

How does nephritis affect the prognosis of acute kidney injury (AKI)?

How does proteinuria affect the prognosis of acute kidney injury (AKI)?

How do statins affect the prognosis of acute kidney injury (AKI)?

What is the long-term prognosis of acute kidney injury (AKI)?

What is included in patient education about acute kidney injury (AKI)?


How is acute kidney injury (AKI) differentiated from chronic kidney disease?

What are the etiologic factors for acute kidney injury (AKI)?

Which comorbid conditions increase the risk of acute kidney injury (AKI)?

Which urine output findings are characteristic of acute kidney injury (AKI)?

Which clinical history findings are characteristic of prerenal acute kidney injury (AKI)?

Which clinical history findings are characteristic of intrinsic acute kidney injury (AKI)?

Which clinical history findings are characteristic of postrenal acute kidney injury (AKI)?

Which physical findings are characteristic of acute kidney injury (AKI)?

Which dermatologic findings are characteristic of acute kidney injury (AKI)?

Which findings on eye exam suggest acute kidney injury (AKI)?

Which ear exam findings suggest acute kidney injury (AKI)?

What is included in the physical exam to assess cardiovascular and volume status in suspected acute kidney injury (AKI)?

Which cardiovascular findings suggest acute kidney injury (AKI)?

What disorders are suggested by severe hypertension with renal failure during the evaluation of acute kidney injury (AKI)?

What are the abdominal findings characteristic of acute kidney injury (AKI)?

Which pulmonary findings suggest acute kidney injury (AKI)?


Which conditions are included in the differential diagnoses of acute kidney injury (AKI)?

What is the role of urine output in the differential workup of acute kidney injury (AKI)?

What are the differential diagnoses for Acute Kidney Injury (AKI)?


What is the role of lab tests in the workup of acute kidney injury (AKI)?

What is the role of renal imaging in the workup of acute kidney injury (AKI)?

What is the role of kidney function studies in the workup of acute kidney injury (AKI)?

How is the rise in creatinine predicted in the workup of acute kidney injury (AKI)?

What is the role of NephroCheck in the workup of acute kidney injury (AKI)?

What is the role of peripheral smear in the workup of acute kidney injury (AKI)?

What is the role of serologic testing in the workup of acute kidney injury (AKI)?

What is the role of urinalysis in the workup of acute kidney injury (AKI)?

What is the role of urine electrolyte testing in the workup of acute kidney injury (AKI)?

What is the role of bladder pressure testing in the workup of acute kidney injury (AKI)?

What is the role of biomarkers in the workup of acute kidney injury (AKI)?

What is the role of a furosemide stress test in the workup of acute kidney injury (AKI)?

What is the role of renal ultrasonography in the workup of acute kidney injury (AKI)?

What is the role of Doppler ultrasonography in the workup of acute kidney injury (AKI)?

What is the role of nuclear scanning in the workup of acute kidney injury (AKI)?

What is the role of aortorenal angiography in the workup of acute kidney injury (AKI)?

What is the role of renal biopsy in the workup of acute kidney injury (AKI)?


When should treatment of kidney injury (AKI) be initiated?

How is volume homeostasis maintained in the treatment of acute kidney injury (AKI)?

What is the role of furosemide in the treatment of acute kidney injury (AKI)?

How is hyperkalemia treated in acute kidney injury (AKI)?

What is the role of nephrotoxic agents in the treatment of acute kidney injury (AKI)?

Which specialist consultations are beneficial to patients with acute kidney injury (AKI)?

What is the role of vasodilators in the treatment of acute kidney injury (AKI)?

Which dietary modifications are used in the treatment of acute kidney injury (AKI)?

What is the role of dialysis in the treatment of acute kidney injury (AKI)?

What is the timing and intensity of dialysis in the treatment of acute kidney injury (AKI)?

What is the role of continuous renal replacement therapy (CRRT) in the treatment of acute kidney injury (AKI)?

What is the role of peritoneal dialysis in the treatment of acute kidney injury (AKI)?

What is the role of saline in the treatment of acute kidney injury (AKI)?

What is the role of sodium bicarbonate in the treatment of acute kidney injury (AKI)?

What is the role of N -acetylcysteine in the treatment of acute kidney injury (AKI)?

What is the role of statins in the treatment of acute kidney injury (AKI)?

What is the role of forced diuresis in the treatment of acute kidney injury (AKI)?

What is included in the long-term monitoring of acute kidney injury (AKI)?

How is acute kidney injury (AKI) prevented?


What is the role of medications in the treatment of acute kidney injury (AKI)?

Which medications in the drug class Antidotes, Other are used in the treatment of Acute Kidney Injury (AKI)?

Which medications in the drug class Calcium Channel Blockers are used in the treatment of Acute Kidney Injury (AKI)?

Which medications in the drug class Vasodilators are used in the treatment of Acute Kidney Injury (AKI)?

Which medications in the drug class Inotropic Agents are used in the treatment of Acute Kidney Injury (AKI)?

Which medications in the drug class Diuretics, Loop are used in the treatment of Acute Kidney Injury (AKI)?