There is evidence to suggest that oxidant injury plays a part in the pathogenesis of renal impairment in a number of conditions. Rhabdomyolysis and liver disease were studied because oxidant stress has been previously implicated in the renal impairment of these conditions. In this thesis oxidative stress was assessed by quantification of the plasma, urine and tissue F2-isoprostanes, which are prostaglandin-like compounds formed by peroxidation of arachidonic acid and have been shown to be excellent markers of lipid peroxidation in vivo. These compounds also possess biological activity and can cause renal vasoconstriction, raising the possibility that they may themselves be modulators of renal dysfunction. Studies in the acute bile duct ligated animal, a model of renal dysfunction in liver disease, there was marked lipid peroxidation but treatment with effective anti-oxidants confers some, but incomplete protection against renal impairment. Moreover, N-acetylcysteine conferred good protection against development of renal failure, but was relatively ineffective at inhibiting lipid peroxidation, suggesting that a mechanism other than lipid peroxidation is involved. A pilot study demonstrated that N-acetylcysteine improved renal function in patients with the hepatorenal syndrome. By contrast the studies in patients with rhabdomyolysis as well as in an animal model of this syndrome demonstrate that oxidant injury and lipid peroxidation is important in the pathogenesis of this form of renal failure. However, in contrast to previous studies that implicate free iron as the initiator of oxidant injury, the work in this thesis implicates myoglobin itself, involving redox cycling of the haem iron, which remains co-ordinated within the protein. Alkalinization of the urine decreases oxidant injury to the kidney by stabilising one of the higher oxidation states of myoglobin. This has led to preliminary experimental work suggesting that antioxidants may be useful in preventing rhabdomyolysis-induced acute renal failure
