We evaluated the hypothesis that postischemic renal failure is caused primarily at reperfusion by oxygen-derived free radicals in a swine model designed to realistically mimick human cadaveric renal transplantation. Both kidneys were removed, flushed with Euro-Collins solution, stored 24 hr at 4 degrees C, and then transplanted to a second pig. Experiments were paired, each pig receiving one treated and one control kidney. All pigs received the optimal conventional regimen of hydration, phenoxybenzamine, furosemide, and mannitol to allow assessment of free radical treatment superimposed thereupon. Two days later creatinine clearance (CCR) was measured from each kidney via separate ureterostomies. Untreated kidneys developed severe functional impairment, CCR falling from a normal level of 25.5 +/- 6.3 ml/min (n = 8) to 7.7 +/- 0.9 ml/min (n = 14, P less than .05 vs. control). The infusion of 20 mg of the free radical scavenger superoxide dismutase (SOD) into the renal artery at reperfusion substantially ameliorated this injury (CCR = 15.9 +/- 1.7 ml/min, n = 18, P less than 0.05 vs. control). A dose-response curve to SOD showed no effect of doses of 0.2 mg (CCR = 8.0 +/- 1.1 ml/min, n = 4) or 2 mg (CCR = 7.7 +/- 0.9, n = 5), and no greater benefit from 100 mg (CCR = 16.1 +/- 2.1 ml/min, n = 3, P less than 0.05 vs. control). Blocking the generation of superoxide radicals from xanthine oxidase with allopurinol (50 mg/kg) afforded similar protection (CCR = 18.2 +/- 1.8; n = 11, P less than 0.01 vs. control). On the other hand, following an 18-hr period of cold ischemia, little damage was sustained by the untreated (control) kidneys (CCR = 22.1 +/- 0.6 ml/min). Consequently, under these conditions the ablation of free radical generation with allopurinol provided no significant benefit. These findings suggest that after a critical period of cold ischemic preservation, metabolic changes take place within the kidney that lead to free radical generation and consequent tissue injury upon reperfusion, despite optimal preservation by conventional methods. This damage can be prevented by simple nontoxic measures--which, therefore, show great promise for use in the prevention of early renal failure following cadaveric renal transplantation.