Aetiology

Aetiology of AKI may be multifactorial, generally classified into pre-kidney, intrinsic, and post-kidney causes.[22]

  • Pre-kidney AKI can be due to various causes of reduced kidney perfusion, such as hypovolaemia, haemorrhage, sepsis, third spacing of fluid (such as in severe pancreatitis), overdiuresis, or other causes of reduced kidney perfusion such as heart failure. Hepatorenal syndrome, a form of pre-kidney AKI not responsive to fluid administration, is seen in cases of severe liver disease. Renovascular disease usually presents as hypertension and chronic kidney disease but may result in acute tubular necrosis (ATN) and AKI, for example when ACE-inhibitors are prescribed to patients with severe bilateral renal artery stenosis or severe renal artery stenosis of a single functioning kidney.

  • Intrinsic kidney failure may be multifactorial. ATN, rapidly progressive glomerulonephritis, and interstitial nephritis are the most common aetiologies. Vascular diseases, including haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura, scleroderma renal crisis, atheromatous embolisation, and thrombosis, are also potential causes. Severe ischaemic injury may result in cortical necrosis.

  • Post-kidney AKI results from mechanical obstruction of the urinary outflow tract. Retroperitoneal fibrosis, lymphoma, tumour, prostate hyperplasia, strictures, renal calculi, ascending urinary infection (including pyelonephritis), and urinary retention are common causes.

Pathophysiology

Pre-kidney AKI results from impaired kidney perfusion and the changes seen are appropriate physiological responses. The kidney's response to a lower perfusion pressure is to enhance sodium and water re-absorption. 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 reabsorption at the collecting duct. Low blood volume is also a stimulus to the hypothalamus promoting antidiuretic hormone release and increased tubular water re-absorption, concentrating the urine.

Acute tubular necrosis (ATN) due to prolonged or severe ischaemia, the most common form of AKI, is preceded by impaired kidney perfusion and tissue hypoxaemia, yielding direct microvascular endothelial injury and tubular ischaemia typically most severe in the early proximal tubule and the outer medullary segments.[23][24]​ Hypoxaemia results in increased reactive oxygen species, reduction in available adenosine triphosphate, and cellular dysfunction and death.[25] Additionally, complement system activation, direct neutrophil activation, membrane attack complex activation, cytokines, chemokines, and vasoactive hormones have been studied and may be contributory.[26][27][28][29][30][31][32][33][34]​ ATN may also result from exposure to drugs, endotoxins, or radiocontrast media. Animal models suggest direct cytotoxic effects of the contrast as well as vasoconstriction in the kidney resulting in impaired medullary blood flow, increased viscosity, and hypoxaemia.​​[35]​​[36][37]​ However, the association with radiocontrast exposure is controversial, as these findings are not replicated in human population studies: use of contrast may be a marker rather than a mediator of risk.[38][39][40][41]​

Kidney injury associated with obstruction results from increased intratubular pressure yielding reductions in filtration pressure and potential tubular ischaemia and atrophy. Evidence also suggests injury results from an influx of monocytes and macrophages. Cytokines, free radicals, proteases, and tumour necrosis factor-beta are released, causing irreversible tubular injury and fibrosis when obstruction becomes chronic.[42][43][44][45]

There is preliminary evidence that a genetic predisposition for AKI may exist, especially with apolipoprotein E (APO-E) genes.[46] Genome-wide searches have found other protective candidates, but much more work is needed to validate these findings.[47]

Classification

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

Any of the following:

  • Increase in serum creatinine by ≥26 micromol/L (≥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]

  • Pre-kidney (pre-renal) AKI: injury due to impaired kidney perfusion.

  • Intrinsic AKI: direct injury to the kidney parenchyma.

  • Post-kidney (post-renal) AKI: injury due to urinary outflow obstruction.

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