Etiology of AKI may be multifactorial, generally classified into prerenal, intrinsic, and postrenal causes.[17]

  • Prerenal azotemia can be due to various causes of reduced renal perfusion, such as hypovolemia, hemorrhage, sepsis, third spacing of fluid (such as in severe pancreatitis), overdiuresis, or other causes of reduced renal perfusion such as heart failure. Hepatorenal syndrome, a form of prerenal azotemia not responsive to fluid administration, is seen in cases of severe liver disease. Renovascular disease, especially with the recent addition of an ACE inhibitor to a patient with bilateral renal artery stenosis, is also a consideration, as this sometimes leads to acute tubular necrosis (ATN).

  • Intrinsic renal failure may be multifactorial. ATN, rapidly progressive glomerulonephritis, and interstitial nephritis are the most common etiologies. Vascular diseases, including hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, scleroderma renal crisis, atheromatous embolization, and thrombosis, are also potential causes. Severe ischemic injury may result in cortical necrosis.

  • Postrenal injury results from mechanical obstruction of the urinary outflow tract. Retroperitoneal fibrosis, lymphoma, tumor, prostate hyperplasia, strictures, renal calculi, ascending urinary infection (including pyelonephritis), and urinary retention are common causes.


Prerenal azotemia results from impaired renal perfusion and the changes seen are appropriate physiologic responses. The renal response to a lower perfusion pressure is to enhance sodium and water reabsorption. Baroreceptors in the carotid artery and aortic arch respond to lower blood pressure with sympathetic stimulation. This, along with vasoconstriction of the glomerular efferent arteriole and dilation of the afferent arteriole, is intended to maintain glomerular filtration within a relatively narrow range. Decreasing perfusion promotes activation of the renin/angiotensin/aldosterone system. Angiotensin II, a potent vasoconstrictor, stimulates aldosterone release, promoting sodium and water resorption at the collecting duct. Low blood volume is also a stimulus to the hypothalamus promoting antidiuretic hormone release and increased tubular water reabsorption, concentrating the urine.

Acute tubular necrosis (ATN) due to prolonged or severe ischemia, the most common form of AKI, is preceded by impaired renal perfusion and tissue hypoxemia, yielding direct microvascular endothelial injury and tubular ischemia typically most severe in the early proximal tubule and the outer medullary segments.[18][19] Hypoxemia results in increased reactive oxygen species, reduction in available adenosine triphosphate, and cellular dysfunction and death.[20] Additionally, complement system activation, direct neutrophil activation, membrane attack complex activation, cytokines, chemokines, and vasoactive hormones have been studied and may be contributory.[21][22][23][24][25][26][27][28][29] ATN may also result from exposure to drugs, endotoxins, or radiocontrast media. Animal models suggest direct cytotoxic effects of the contrast as well as renal vasoconstriction resulting in impaired medullary blood flow, increased viscosity, and hypoxemia.[30][31][32][33][34][35] However, the association with radiocontrast exposure is controversial, as population studies do not replicate risk.[36][37][38]

Renal injury associated with obstruction results from increased intratubular pressure yielding tubular ischemia and atrophy. Evidence also suggests injury results from an influx of monocytes and macrophages. Cytokines, free radicals, proteases, and tumor necrosis factor-beta are released, causing irreversible tubular injury and fibrosis when obstruction becomes chronic.[39][40][41][42]

There is preliminary evidence that a genetic predisposition for AKI may exist, especially with apolipoprotein E (APO-E) genes.[43] Genome-wide searches have found other protective candidates, but much more work is needed to validate these findings.[44]


Kidney Disease: Improving Global Outcomes (KDIGO) definition of AKI[1]

Any of the following:

  • Increase in serum creatinine by ≥0.3 mg/dL within 48 hours; or

  • Increase in serum creatinine to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or

  • Urine volume <0.5 mL/kg/hour for 6 hours.

Classification based on pathophysiology[5]

  • Prerenal: failure due to impaired renal perfusion, with an appropriate renal response.

  • Intrinsic: failure due to direct injury to renal parenchyma.

  • Postrenal: failure due to obstruction of urinary outflow.

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