Cold ischemia in the absence of alloreactivity induces chronic transplant nephropathy through a process mediated by the platelet-activating factor

Background. Ischemia-reperfusion injury is considered a risk factor for the development of chronic transplant nephropathy (CTN) although the mechanism s that mediate its effects have not been completely established. We have pr eviously shown that treatment with a platelet-activating factor (PAF) recep tor antagonist (UR12670) protected kidneys from the progression to chronic nephropathy induced by warm ischemia. Here we examine the contribution of c old ischemia to the development of late functional and structural kidney ch anges in rats subjected to syngeneic renal transplantation and the role of PAF in this chronic nephropathy. Subjects and Methods. Lewis rats were used as kidney donors and recipients, which were transplanted either immediately or after a cold ischemia period of 5 hr. Contralateral nephrectomy was performed on the seventh day after transplantation, Cyclosporine was administered for 15 days after transplant ation. Groups were as follows: Sy, immediate transplantation; SyI, transpla ntation after 5 hr of cold ischemia; SyIUr, transplantation after 5 hr of c old ischemia plus UR12670 from the transplantation day to the end of the st udy, at 24 weeks. Serum creatinine, creatinine clearance, and proteinuria w ere determined every 4 weeks. Urinary PAF excretion was determined in the 2 4th week. At the end of the study, kidney tissue was processed for histolog ical study (number of infiltrating macrophages, tubulointerstitial damage, and percentage of interstitial area). Results. Rats grafted with ischemic kidneys (SyI) developed renal insuffici ency and proteinuria, increased their urinary PAF excretion, and had histol ogical lesions that resemble CTN, In contrast, rats grafted with nonischemi c kidneys (Sy) maintained a stable renal function, without proteinuria, and showed no histological abnormalities in the kidney. Long-term treatment wi th UR12670 (SyIUr) ameliorated renal function, lowered urinary PAF excretio n, and reduced the number of infiltrating macrophages, tubulointerstitial d amage, and the percentage of interstitial area. Conclusions. In the absence of alloreactivity, cold ischemia induces CTN, w hich is associated with enhanced urinary PAF excretion, The protecting effe ct of UR12670 confirms that PAF is involved in the progression to CTN.