Role of Hypoxia in Renal Failure Caused by Nephrotoxins and Hypertonic Solutions

Hypoxia plays a role in the pathogenesis of acute kidney injury under diverse clinical settings, including nephrotoxicity. Although some nephrotoxins exert direct renal parenchymal injury, likely with consequent altered oxygenation, others primarily reduce renal parenchymal oxygenation, leading to hypoxic tubular damage. As outlined in this review, nephrotoxin-related renal hypoxia may result from an altered renal oxygen supply (cyclosporine), enhanced oxygen consumption for tubular transport (agents inducing osmotic diuresis), or their combination (nonsteroidal anti-inflammatory drugs, radiocontrast agents, and others). Most agents causing hypoxic renal injury further supress physiologic low medullary Po₂, in which a limited regional blood supply barely matches the intense regional tubular transport and oxygen consumption. The medullary tubular transport and blood supply are finely matched, securing oxygen sufficiency. Predisposition to hypoxia-mediated nephrotoxicity by medical conditions, such as chronic kidney disease or diabetes, may be explained by malfunctioning of control systems that normally maintain medullary oxygenation. However, this propensity may be diminished by hypoxia-mediated adaptive responses governed by hypoxia-inducible factors. Recent reports have suggested that inhibitors of sodium-glucose cotransporters and the administration of hypertonic saline may be added to the growing list of common therapeutic interventions that intensify medullary hypoxia, and potentially could lead to hypoxic acute kidney injury.