Acute renal failure pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]

Pathophysiology

Pre-renal Failure

• Pre-renal and intrinsic renal failure fall on a spectrum of manifestations of renal hypoperfusion.
• Hypovolemia from any cause leads to a fall in systemic blood pressure. This causes several auto-regulatory mechanisms to come into play. Kidneys maintain their perfusion during low pressure states by increasing the inflow of blood into the glomerulus through the afferent renal arteriolar and selective constriction of the efferent renal arteriole.
• Reduced renal blood flow causes activation of stretch receptors in the wall of the afferent renal arteriole. This results in relaxation of smooth muscles of the vessel wall which in turn causes increased blood flow, consequently increasing the filtration pressure across glomeruli. Synthesis of prostaglandins (PGE2 and prostacyclin) is also enhanced, and these compounds preferentially dilate the afferent renal arteriole.
• Hormones like angiotensin II, aldosterone and vasopressin (ADP) cause constriction of efferent renal arteriole, resulting in decrease outflow causing increased filtration pressure in the glomeruli.
• Renal filtration function is preserved during low pressure/ low volume states. However, more severe decrease in renal perfusion results in decreased urine output, causing nitrogenous waste products to accumulate in the body (acute renal failure).
• The kidney maintain their structural integrity in prerenal failure. If the renal blood flow/ filtration pressure is restored before permanent damage occurs, the kidney function normally without any compromise in the its functions.
• However, if the decline in renal blood flow is severe, ischemia of tubular cells results in intrinsic renal failure.
• Lesser degrees of hypotension can cause prerenal failure in at risk population, for e.g, elderly, patients with diseases affecting the integrity of afferent arteriole like diabetic nephropathy and hypertensive nephrosclerosis.
• Drugs which interfere with the autoregulatory mechanisms of the afferent and efferent renal arterioles may precipitate acute renal failure, for e.g, NSAIDS, ACE inhibitors and angiotensin II blockers. Therefore, these drugs should be used carefully in high risk population.
• NSAIDS do not affect the caliber of afferent arteriole in healthy individuals, but may precipitate acute renal failure in patients with hypovolemia and chronic renal insufficiency, in which renal blood flow is maintained by the prostaglandins.
• ACE inhibitors should be used in caution in patients with bilateral or unilateral renal artery stenosis.

Intrinsic Renal Failure

• Severe forms of hypoperfusion cause ischemic injury to the renal parenchymal cells, especially the renal tubular epithelium. The damaged tubular epithelium get sloughed off and takes 1 to 2 weeks to regenerate.
• In extreme forms, it results in renal cortical necrosis and irreversible renal failure.
• Intrinsic renal failure most commonly occurs as a complication of cardiovascular surgery, hemorrhage, sepsis or severe trauma
• Other forms of insults that can cause intrinsic renal failure are nephrotoxic agents or a pre-existing renal disease.
• Three stages of intrinsic renal failure have been defined:
  • Initiation phase
  • Maintenance phase
  • Recovery phase

Initiation Phase

• This phase lasts for hours to days. It involves reduction in glomerular filtration rate from decreased renal blood flow. Ischemic injury to the tubular epithelial cells and renal parenchyma causes the tubular cells to slough off and form casts that block the flow of glomerular filtrate down the nephron.
• The casts in the renal tubule causes fluid to backleak through the tubular epithelium.
• Ischemic injury affects the medullary segment of the renal tubule and thick segment of loop of Henle as they as relatively ischemic even under normal basal conditions. These segments have the highest oxygen consumption because of higher ATP dependent solute transport.
• Depletion of ATP causes inhibition of sodium transport, impairment of water balance, calcium accumulation inside the cells, loss of cell to cell adhesion, injury from oxygen free radicals consequently causing cellular swelling and apoptosis.
• Restoring renal perfusion at this stage prevents further progression of renal injury.

Maintenance phase

• This stage is irreversible and the progression of renal injury cannot be stopped.
• Renal vasoconstriction is thought to contribute to further reduction in urine output secondary to decrease in glomerular filtration rate. Although vasoactive agents contribute to renal injury, the exact mechanisms leading to the vasoconstriction are still to be explored.