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 mechanisms that mediate its effects have not been completely established. We have previously shown that treatment with a platelet-activating factor (PAF) receptor antagonist (UR12670) protected kidneys from the progression to chronic nephropathy induced by warm ischemia. Here we examine the contribution of cold ischemia to the development of late functional and structural kidney changes 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 transplantation. Groups were as follows: Sy, immediate transplantation; SyI, transplantation after 5 hr of cold ischemia; SyIUr, transplantation after 5 hr of cold ischemia plus UR12670 from the transplantation day to the end of the study, at 24 weeks. Serum creatinine, creatinine clearance, and proteinuria were determined every 4 weeks. Urinary PAF excretion was determined in the 24th week. At the end of the study, kidney tissue was processed for histological study (number of infiltrating macrophages, tubulointerstitial damage, and percentage of interstitial area). Results. Rats grafted with ischemic kidneys (SyI) developed renal insufficiency and proteinuria, increased their urinary PAF excretion, and had histological lesions that resemble CTN, In contrast, rats grafted with nonischemic kidneys (Sy) maintained a stable renal function, without proteinuria, and showed no histological abnormalities in the kidney. Long-term treatment with UR12670 (SyIUr) ameliorated renal function, lowered urinary PAF excretion, and reduced the number of infiltrating macrophages, tubulointerstitial damage, and the percentage of interstitial area. Conclusions. In the absence of alloreactivity, cold ischemia induces CTN, which is associated with enhanced urinary PAF excretion, The protecting effect of UR12670 confirms that PAF is involved in the progression to CTN.