CELLULAR AND MOLECULAR PREDICTORS OF CHRONIC RENAL DYSFUNCTION AFTER INITIAL ISCHEMIA REPERFUSION INJURY OF A SINGLE KIDNEY/

Background. Initial ischemia/reperfusion injury occurring secondary to organ retrieval, storage, and transplantation has been associated wit h late renal allograft deterioration and failure. In addition, there i s an apparent synergy, reported in several clinical series, between th e initial injuries of ischemia/reperfusion and acute rejection; the lo ng-term results of graft survival are significantly deceased after bot h events in combination as compared with either alone or if no such ep isodes occur. Methods. In the present study, we examined patterns of p roteinuria, cellular infiltration, cytokine expression, and glomerulos clerosis over time in Lewis and Fischer 344 rats after 45 min of warm ischemia of a single kidney and with or without contralateral nephrect omy. Both early (4 hr to 7 days) and late (2-52 weeks) events were stu died serially in the affected kidneys morphologically, by immunohistol ogy and by reverse transcriptase polymerase chain reaction. Results. I ntercellular adhesion molecule 1, endothelin, and major histocompatibi lity complex class II expression were up-regulated within 2 to 5 days after injury; T cells and macrophages increased transiently. Proteinur ia developed after approximately 8 weeks only in animals bearing a sin gle injured kidney, and not in those with a retained native organ. Pro gressive morphological changes occurred after 16 weeks, including glom erulosclerosis, arterial obliteration, and interstitial fibrosis. Afte r a period of relative quiescence, expression of intercellular adhesio n molecule 1 again increased in relation to progressive macrophage inf iltration and their associated products, particularly, interleukin 1, tumor necrosis factor-cc, transforming growth factor-beta, and inducib le nitric oxide synthase. Monocyte chemotactic protein 1 was intensely up-regulated by 24 weeks, coincident with a dramatic rise in this inf iltrating population. These changes remained virtually at baseline in animals with a retained native kidney. Conclusions. These data imply t hat chronic injury after significant initial ischemia and reperfusion occurs when there is already a 50% renal mass reduction, but not when two kidneys remain in place. Permanent nephron loss resulting from suc h an insult could account for this phenomenon. Early ischemia and repe rfusion, if severe enough in a single kidney, may be an important anti gen-independent risk factor for later renal deterioration and failure. In the context of a renal allograft, it may contribute to chronic rej ection.