OXIDANT MECHANISMS IN TOXIC ACUTE-RENAL-FAILURE

Over the last decade, there has been accumulating evidence for a role of reactive oxygen metabolites in the pathogenesis of a variety of ren al diseases, including gentamicin, glycerol, and cyclosporine A models of toxic acute renal failure, Gentamicin has been shown in both in vi tro and in vivo studies to enhance the generation of reactive oxygen m etabolites, Iron is important in models of tissue injury, presumably b ecause it is capable of catalyzing free radical formation, Gentamicin has been shown to cause release of iron from renal cortical mitochondr ia, Scavengers of reactive oxygen metabolites as well as iron chelator s provide protection in gentamicin-induced nephrotoxicity. In glycerol -induced acute renal failure, an animal model of rhabdomyolysis, there is enhanced generation of hydrogen peroxide, and scavengers of reacti ve oxygen metabolites and iron chelators provide protection, Although the dogma is that the myoglobin is the source of iron, the results of recent studies suggest that cytochrome P-450 may be an important sourc e of iron in this model, In addition, there are marked alterations in antioxidant defenses, such as glutathione, as well as changes in heme oxygenase, Cyclosporine A has been shown to enhance the generation of hydrogen peroxide in vitro and lipid peroxidation in vitro and in vivo , Antioxidants have been shown to be protective in cyclosporine A neph rotoxicity, This collective body of evidence suggests an important rol e for reactive oxygen metabolites in toxic acute renal failure and may provide therapeutic opportunities of preventing or treating acute ren al failure in humans. (C) 1997 by the National Kidney Foundation, Inc.