Several drugs (non-steroidal anti-inflammatory drugs, mannitol, amphotericin, polyene antibiotics), radiocontrast agents, and endogenous toxins (myoglobin) can precipitate medullary hypoxia in rat kidney. Synergism among simultaneous insults, mediated by distinct mechanisms, is often observed in the pathogenesis of ARF. Renal hypoperfusion combined with administration of nephrotoxic agents (gentamicin, radiocontrast, indomethacin) induces intrarenal injury, possibly in part by disrupting the balance between medullary oxygen demand and supply. The kidney is subjected to both dimished oxygen supply and increased oxygen demand due to reduced perfusion and enhanced sodium reabsorption respectively. As nephrotoxins accumulate in zones prone to hypoxia (medulla), oxygen demand may be further increased by toxin-induced mitochondrial and cellular membrane injury. Additional processes observed in combined hypoxic and toxic insults include disruption of renal defensive mechanisms (non-steroidal anti-inflammatory drugs), enhanced tubuloglomerular feedback, and precipitation of crystals. Synergism between renal hypoperfusion and toxic insults in regions of poor oxygenation may constitute a major mechanism of ARF. Sufficient volume repletion and judicious use of nephrotoxic agents defends against combined renal insults and curbs the incidence of ARF ( Brez.is,jnd...Rosen 1995).
Aminoglycoside nephrotoxicity complicates between 0.5 and 30 per cent of patients treated. Suggested modes of toxicity include mitochondrial disruption, cell membrane damage, and immune mechanisms. Renal failure typically occurs roughly a week after treatment onset, with recovery occurring about a week after cessation of the drug. Important risk factors include age, prior renal or hepatic dysfunction, peak and/or trough levels, and duration of therapy ( Linton 1990).
Amphotericin causes dose-related ARF via direct tubular epithelial cell membrane toxicity. Volume depletion predisposes patients to gentamicin, cisplatin, and amphotericin nephrotoxicity, and aggressive volume repletion clearly obviates drug-induced ARF. In the setting of cardiac failure, nitroprusside reduces systemic vascular resistance more than renal vascular resistance. This may generate a steal phenomenon, diverting blood flow from the kidney and precipitating ARF ( Linton 1990).
Contrast nephropathy more often afflicts those patients with combined risk factors, particularly prior renal dysfunction, diabetes mellitus, and volume depletion. Suggested pathogenetic mechanisms of contrast-induced ARF include direct tubular cell toxicity, intraluminal precipitation of proteinaceous casts or uric acid crystals, intrarenal vasoconstriction, alterations in red cell morphology, and immune complex injury (iHeyman.eta/ 1994). Endothelial-derived vasorelaxors (nitric oxide and prostaglandins) are impaired in patients with diseases frequently associated with contrast nephropathy, namely diabetes mellitus, hypertension, and atherosclerosis.
Hence impaired endothelial-derived vasorelaxation may play an important role in contrast nephropathy, inducing severe vasoconstriction and medullary hypoxia
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