Acute renal failure pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Serge Korjian; Yazan Daaboul; Rim Halaby

Pathophysiology

Pre-renal Azotemia

Prerenal AKI, known as prerenal azotemia, is by far the most common cause of AKI representing 30-50% of all cases. It is provoked by inadequate renal blood flow commonly due to decreased effective circulating blood flow. This causes a decrease in the intraglomerular hydrostatic pressure required to achieve proper glomerular filtration.[1]

The pathophysiology of prerenal azotemia is often a combination of 2 factors, the first being a drop in renal plasma flow and the second being a blunted or inadequate renal compensation leading to further drop in the glomerular filtration rate. Under physiologic conditions, minor drops in blood flow to the renal circulation are counteracted by changes in the resistances across the afferent and efferent arterioles of individual glomerular capillary beds.[2]

In order to increase blood flow to the glomerulus, the afferent arteriole vasodilates via 2 mechanisms. The myogenic reflex, leading to medial smooth muscle relaxation in states of decrease perfusion pressure, vasodilates the afferent arteriole leading to increased blood flow. Additionally, intrarenal synthesis of vasodilatory prostaglandins such as prostacyclin and prostaglandin E2 causes further dilation of the afferent arteriole[1]. Hence, the intake of NSAIDs in this context inhibits this autoregulatory mechanism possibly leading to acute kidney injury.[3]

At the level of the efferent arteriole, an increase in resistance is crucial for appropriate maintenance of glomerular hydrostatic pressure. This is achieved by an increase in the production of angiotensin II (via the Renin-Angiotensin System) which acts preferentially on the efferent arteriole leading to vasoconstriction. Important medications that target angiotensin II production and action are ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) which may be responsible for renal decompensation in patients dependent on the action of angiotensin II to maintain glomerular perfusion pressure. Such is the case in chronic kidney disease patients, whose autoregulatory mechanisms are typically operating at maximum capacity[4].

Both afferent and efferent arteriolar autoregulatory mechanisms work in conjunction to maintain proper renal plasma flow and avoid a major decrease in GFR. However, these mechanisms are at times unable to overcome a significant decrease in perfusion pressure. Even in healthy adults, these autoregulatory mechanisms seldom compensate a failing GFR if systolic blood pressure falls below 80 mmHg [5].

Physiology of renal adaptation mechanisms to decrease in renal plasma flow and pathophysiology of prerenal azotemia.

Prerenal AKI may also be present with forms of intrinsic renal AKI. A sustained period of prerenal azotemia may result in acute tubular necrosis (ATN) secondary to ischemic injury to the renal parenchyma. However, by definition, if prerenal azotemia exits on its own, there should not be any renal parenchymal damage. Hence prerenal azotemia should be readily reversible once renal hemodynamics are reestablished[6].

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.

Recovery Phase

  • This stage essentially involves regeneration of renal tubular epithelial cells and restoration of urine output.
  • This phase may be sometimes complicated by a diuretic phase. This diuretic phase occurs to wash out the retained salt and water from the body.

Post-renal Acute Renal Failure

  • Urinary tract obstruction is responsible for less than 5% of cases of acute renal failure.
  • As one kidney can compensate for the other poorly functioning kidney, a bilateral urinary tract obstruction is required for it to cause the kidney's to fail. Hence, conditions like bladder neck obstruction, bilateral ureteric obstruction or unilateral ureteric obstruction with other diseased kidney can cause renal failure.
  • Initial stages may involve a modest increase in renal blood flow, however vasoconstriction superimposes and eventually causes decrease in glomerular filtration rate.

References

  1. 1.0 1.1 Badr KF, Ichikawa I (1988). "Prerenal failure: a deleterious shift from renal compensation to decompensation". N Engl J Med. 319 (10): 623–9. doi:10.1056/NEJM198809083191007. PMID 3045546.
  2. Blantz RC (1998). "Pathophysiology of pre-renal azotemia". Kidney Int. 53 (2): 512–23. doi:10.1046/j.1523-1755.2003_t01-1-00784.x. PMID 9461116.
  3. Brater DC (2002). "Anti-inflammatory agents and renal function". Semin Arthritis Rheum. 32 (3 Suppl 1): 33–42. doi:10.1053/sarh.2002.37216. PMID 12528072.
  4. Pannu N, Nadim MK (2008). "An overview of drug-induced acute kidney injury". Crit Care Med. 36 (4 Suppl): S216–23. doi:10.1097/CCM.0b013e318168e375. PMID 18382197.
  5. Sharfuddin AA, Molitoris BA (2011). "Pathophysiology of ischemic acute kidney injury". Nat Rev Nephrol. 7 (4): 189–200. doi:10.1038/nrneph.2011.16. PMID 21364518.
  6. Lameire NH, Vanholder R (2004). "Pathophysiology of ischaemic acute renal failure". Best Pract Res Clin Anaesthesiol. 18 (1): 21–36. PMID 14760872.

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