AN EVALUATION OF ANTIOXIDANT EFFECTS ON RECOVERY FROM POSTISCHEMIC ACUTE-RENAL-FAILURE

Xanthine oxidase (XO) activity and hydroxyl radical (.OH) formation ar e widely proposed mediators of renal reperfusion injury, potentially a ltering the severity of, and recovery from, postischemic acute renal f ailure. The goal of this study was to ascertain whether combination XO inhibitor (oxypurinol) and .OH scavenger (No benzoate) therapy, given at the time of renal ischemia, alters the extent of: (1) tubular necr osis and filtration failure; (2) DNA fragmentation/apoptosis (assessed in situ by terminal deoxynucleotidyl transferase reactivity); (3) ear ly tubular regenerative responses (proliferating cell nuclear antigen expression; (H-3)thymidine incorporation); and (4) the rate and/or deg ree of functional and morphologic repair. The effects of XO inhibition , OH scavengers, and ''catalytic'' iron (FeSO4) on human proximal tubu lar cell proliferation in vitro were also assessed with a newly establ ished cell line (HK-2). Male Sprague-Daawley rats were subjected to 35 min of bilateral renal arterial occlusion with or without oxypurinol/ benzoate therapy. These agents did not alter the extent of tubular nec rosis or filtration failure, proliferating cell nuclear antigen expres sion or thymidine incorporation, or the rate/extent of renal functiona l/morphologic repair. DNA fragmentation did not precede tubular necros is, and it was unaffected by antioxidant therapy. By 5 days postischem ia, both treatment groups demonstrated regenerating epithelial fronds that protruded into the lumina. These structures contained terminal de oxynucleotidyl transferase-reactive, but morphologically intact, cells , suggesting the presence of apoptosis. Oxypurinol and OH scavengers ( benzoate; dimethylthiourea) suppressed in vitro tubular cell prolifera tion; conversely, catalytic Fe had a growth-stimulatory effect. These results suggest that: (1) XO inhibition/OH scavenger therapy has no di scernible net effect on postischemic acute renal failure; (2) DNA frag mentation does not precede tubular necrosis, suggesting that it is not a primary mediator of ischemic cell death; and (3) antioxidants can b e antiproliferative for human tubular cells, possibly mitigating their potential beneficial effects.