Acute Kidney Injury (AKI)

Updated: Jun 10, 2022
  • Author: Biruh T Workeneh, MD, PhD, FASN; Chief Editor: Vecihi Batuman, MD, FASN  more...
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Practice Essentials

Acute kidney injury (AKI) is defined as an abrupt or rapid decline in renal filtration function. See the image below.

Photomicrograph of a renal biopsy specimen shows r Photomicrograph of a renal 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.

Signs and symptoms


Skin examination may reveal the following in patients with AKI:

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


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 (ie, Hollenhorst plaque in cholesterol microembolism)


Examination of the patient’s ears may reveal the following signs:

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

Cardiovascular system

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


The following signs of AKI may be discovered during an abdominal examination:

  • 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

Pulmonary system

Pulmonary examination may reveal the following:

  • Rales: pulmonary edema, infectious pulmonary process
  • Hemoptysis: ANCA vasculitis, anti–glomerular basement membrane (anti-GBM, Goodpasture) syndrome

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 creatinine are the hallmarks of renal failure; 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 (can indicate infection; acute blood loss or chronic anemia; thrombotic microangiopathy)

  • Peripheral smear (eg, schistocytes such as hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura)

  • Serologic tests: These may show evidence of conditions associated with AKI, such as in lupus nephritis, ANCA vasculitis or anti-GBM disease or syndrome

  • Complement testing: Pattern may indicate AKI related to endocartis 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 useful for evaluating existing renal disease and obstruction of the urinary collecting system

  • Aortorenal angiography : Can be helpful in establishing the diagnosis of renal vascular diseases, such as renal artery stenosis, renal atheroembolic disease, atherosclerosis with aortorenal occlusion, and certain cases of necrotizing vasculitis (eg, polyarteritis nodosa)

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

See Workup for more detail.


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

  • Correction of fluid overload with furosemide
  • Correction of severe acidosis with alkali administration, which can be important as a bridge to dialysis

  • Correction of life-threatening hyperkalemia

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

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

Pharmacologic treatment of AKI has been attempted on an empiric basis, with varying success rates.

See Treatment and Medication for more detail.

For patient education information, see Acute Kidney Failure.



Acute kidney injury (AKI)—or acute renal failure (ARF), as it was previously termed—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 by azotemia (a rise in blood urea nitrogen [BUN] concentration). [1] However, immediately after a kidney injury, BUN or creatinine levels may be normal, and the only sign of a kidney injury may be decreased urine production. (See History.)

A rise in the creatinine level can result from medications (eg, cimetidine, trimethoprim) that inhibit the kidney’s tubular secretion, while a rise in the BUN level can also occur without renal injury, resulting instead from such sources as 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

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 is useful in establishing 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, can 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 mL and has a worse prognosis.

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

Stratification of renal 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 work group 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). [2] 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 renal 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, manifested by any 1 of the following [3] :

  • 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 stage. See Table 2, below.

Table 2. Acute Kidney Injury Network Classification/Staging System for AKI [3] (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.

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. 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. [4]

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 always should arouse suspicion of hyperkalemia. Many authors recommend a trial of intravenous calcium chloride (or gluconate) in all patients with AKI who experience cardiac arrest.

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. 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 the patient with pulmonary disease. This dialysis-related hypoxia is thought to occur secondary to white blood cell (WBC) lung sequestration and alveolar hypoventilation.

GI 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 commonly is seen in AKI (2-3 times controls). Elevation of baseline amylase concentrations can complicate diagnosis of pancreatitis in patients with AKI. Measurement of lipase, which commonly is not elevated in AKI, often is necessary to make the diagnosis of pancreatitis. Pancreatitis has been reported as a concurrent illness with AKI in patients with atheroemboli, vasculitis, and sepsis from ascending cholangitis.


Jaundice has been reported to complicate AKI in approximately 43% of cases. 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 B
  • Leptospirosis
  • 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. 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 signs of uremia are a common complication of AKI and 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 these symptoms do not correlate well to levels of BUN or creatinine.

A number of diseases express themselves 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 decreasing glomerular filtration rate (GFR). The etiology of AKI consists of 3 main mechanisms: prerenal, intrinsic, and obstructive.

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

Intrinsic renal failure includes diseases of the kidney itself, predominantly affecting the glomerulus or tubule, which are associated with the release of renal afferent vasoconstrictors. Ischemic renal injury is the most common cause of intrinsic renal failure. Patients with chronic kidney disease may also present with superimposed AKI from prerenal failure and obstruction, as well as intrinsic renal 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 before frank 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 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, which further decrease GFR and lead to oliguria.

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

  • Radiocontrast agents, aminoglycosides, or cardiovascular surgery with preexisting renal disease (eg, elderly, diabetic, jaundiced patients)

  • Angiotensin-converting enzyme (ACE) inhibitors with diuretics, small- or large-vessel renal arterial disease

  • NSAIDs with chronic heart failure, hypertension, or renal artery stenosis

Acute tubular necrosis

Frank necrosis is not prominent in most human cases of ATN and tends to be patchy. Less obvious injuries include the following (see the image below):

  • Loss of brush borders
  • Flattening of the epithelium
  • Detachment of cells
  • Formation of intratubular casts
  • Dilatation of the lumen
Photomicrograph of a renal biopsy specimen shows r Photomicrograph of a renal 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 principal site of apoptotic cell death is the distal nephron. 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 process of regeneration following ischemic renal injury have not been identified. However, administration of growth factors exogenously has been shown to ameliorate and hasten recovery from AKI.

Depletion of neutrophils and blockage of neutrophil adhesion reduce 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 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 and the macula densa is presented with increased chloride load.

Apart from the increase in 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 maximally dilute or concentrate urine (isosthenuria). This defect is not responsive to pharmacologic doses of vasopressin. The injured kidney fails to generate and maintain a high medullary solute gradient, because the accumulation of solute 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 renal disease. In prerenal azotemia, urine osmolality is typically more than 500 mOsm/kg, whereas in intrinsic renal disease, urine osmolality is less than 300 mOsm/kg.

Restoration of renal blood flow and associated complications

Recovery from AKI is first dependent upon restoration of RBF. Early RBF normalization predicts 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, removal of tubular toxins and initiation of 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 renal failure results. This has been termed the hyperfiltration theory of renal failure and explains the scenario in which progressive renal 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. [5]

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. 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 renal failure develops from diffuse vasoconstriction in vessels supplying the kidney. [6]

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
  • 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

Afferent arteriolar vasoconstriction can be caused by the following:

  • Hypercalcemia
  • Drugs - NSAIDs, amphotericin B, calcineurin inhibitors, norepinephrine, radiocontrast agents
  • Hepatorenal syndrome

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 (RP) glomerulonephritis. Glomerular crescents (glomerular injury) are found in RP glomerulonephritis on biopsy; if more than 50% of glomeruli contain crescents, this usually results in 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:

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

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

Interstitial causes include the following:

  • Drugs - Penicillins, cephalosporins, NSAIDs, proton-pump inhibitors, allopurinol, rifampin, indinavir, mesalamine, sulfonamides [7]
  • Infection - Pyelonephritis, viral nephritides
  • Systemic disease - Sjögren syndrome, sarcoid, lupus, lymphoma, leukemia, tubulonephritis, uveitis

Anticoagulant-related nephropathy is a form of AKI in which overanticoagulation causes profuse glomerular hemorrhage. Kidney biopsies in these patients show red blood cells and red cell casts filling numerous renal tubules. [8] Studies in patients receiving anticoagulation for atrial fibrillation have shown that in elderly patients as well as Asian patients, the risk of anticoagulant-related nephropathy is greater with warfarin than with direct oral anticoagulants (eg, apixaban, rivaroxaban, dabigatran). [9, 10]

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 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 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 hypertrophy (BPH), cancer of the prostate (CA prostate or prostatic CA), 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, or papillary necrosis

  • Urethral obstruction - Benign prostatic hypertrophy; 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 (ie, prerenal) to 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 transfer 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 renal failure

  • HUS - Often is 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 renal failure.

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 administration of fluids in the emergency department. [11]

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. [12]

COVID-19 and AKI

Kidney involvement is frequent in patients with severe COVID-19. More than 40% of patients have abnormal proteinuria on hospital admission, and  approximately 20–40% of patients admitted to intensive care units in Europe and the USA have AKI. [13] In patients with COVID-19, severe AKI is an ominous development that is associated with high mortality. [14]

AKI in COVID-19 is probably multifactorial, and may have a distinct pathophysiology that includes the following [15, 16] :

  • 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


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 [17] and arises in more than 50% of intensive care unit (ICU) patients. [18] In recipients of solitary kidney transplants, 21% developed AKI within the first 6 months after transplantation. [19]

Harding et al calculated that in the US 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 between 2000 and 2009, from 4.8 to 8.7 per 100,000 population, and then plateaued. Mortality declined significantly in patients both with and without diabetes. [20]

In a prospective national cohort study in Wales that used an electronic AKI alert (a centralized laboratory system that automatically compares measured creatinine values on 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. [21]

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. [22]

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. [23]



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 renal 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. [24] The incidence of AKI correlated inversely with eGFR and was associated with a higher mortality rate and a higher incidence of subsequent end-stage renal disease (ESRD) 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 Overview) 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. [24]

In one study, survivors of severe AK had worse health-related quality of life (HRQOL) compared with general population, even after adjustment for their reduced renal function. Both physical and mental components were affected. Increasing age and reduced renal function were associated with poorer physical QOL. [25]

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 inhospital mortality rate for AKI is 40-50%. The mortality rate for ICU patients with AKI is higher (>50% in most studies), particularly when AKI is severe enough to require dialysis treatment. [26] ICU patients with sepsis-associated AKI have significantly higher mortality rates than do nonseptic AKI patients. [27]

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. [28] 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. [29]

Of note, more than half of the individuals in FACTT had stage 1 AKI (AKIN criteria), so whether these results apply to more severe stages of AKI is not clear. 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. [29]

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 [30] - 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. Postrenal AKI, if left untreated for a long time, also may result in irreversible renal damage. Procedures such as catheter placement, lithotripsy, prostatectomy, stent placement, and percutaneous nephrostomy can help to prevent permanent renal damage.


Timely identification of pyelonephritis, proper treatment, and further prevention using prophylactic antibiotics may improve the prognosis, especially in females. Early diagnosis of crescentic glomerulonephritis via renal biopsy and other appropriate tests may enhance early renal recovery, because appropriate therapy can be initiated promptly and aggressively. The number of crescents, the type of crescents (ie, cellular vs fibrous), and the serum creatinine level at the time of presentation may dictate 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. [30]  A retrospective, population-based study in a cohort of patients with and without known preoperative renal dysfunction undergoing elective inpatient surgery found that proteinuria was associated with postoperative AKI and 30-day unplanned readmission independent of preoperative estimated GFR. [31]


The relationship between statins and AKI is complex. [32] In addition to rare cases of statins causing rhabdomyolysis, use of high-potency statins has been associated with an increased rate of diagnosis for AKI in hospital admissions, compared with use of low-potency statins, particularly in the first 120 days after initiation of statin treatment. [33]

On the other hand, preprocedural statin therapy has been shown to reduce contrast-induced AKI in patients undergoing coronary angiography. [34, 35]

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. [36] 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 preplacement therapy, but when the analysis was restricted to randomized controlled trials, the protective effect was not significant. [37]

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. [38] Similarly, a meta-analysis in patients undergoing cardiac surgery (mainly, myocardial revascularization), found that preoperative statin treatment had no influence on perioperative renal failure. [39] In contrast, in another meta-analysis of patients undergoing cardiac surgery, preoperative statin therapy significantly reduced the incidence of postoperative renal dysfunction and the need for postoperative renal replacement therapy. [40]

Long-term prognosis

In contrast to previous belief, 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. [18]

In a long-term follow-up study of 350 patients from the randomized RENAL trial who survived AKI in the intensive care unit, 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. [41]


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.