Prevention of cold ischaemia-reperfusion injury by an endothelin receptor antagonist in experimental renal transplantation

Background. Endothelin (ET) is known to play a role in the pathogenesis of warm ischaemic renal damage, however, little is known about its involvement in renal cold ischaemia. This study was designed to investigate the respon se of ET after kidney cold ischaemia, and to assess the potential protectiv e effect of bosentan, a dual, non-selective ETA/ETB receptor antagonist, ag ainst cold ischaemia-reperfusion injury in a rat model of syngeneic renal t ransplantation. Methods. Kidneys from Lewis rats were transplanted, either immediately or a fter 5h of cold preservation. After 48h, contralateral nephrectomy was perf ormed. Rats were organized into three groups: Tr-NoISC, no cold ischaemia; Tr-ISC, 5h cold ischaemia; and Tr-BOS, 5h cold ischaemia plus bosentan (100 mg/kg/day, from the day before transplantation until the seventh day post- transplantation). On day 7, plasma and tissue immunoreactive ET (irET), as well as ET mRNA tissue expression, were evaluated. Renal function was measu red by means of serum creatinine on days 3, 4, 5 and 7, and by creatinine c learance on day 7. Conventional histology was performed. Results, The ischaemic group had significantly higher plasma irET levels th an the non-ischaemic group and significantly lower levels than the bosentan group. Tissue irET levels and ET mRNA expression were similar in the ischa emic and bosentan groups and were higher than in the non-ischaemic group. T hroughout the follow-up, serum creatinine was significantly higher in the i schaemic group than in the bosentan group. Moreover, creatinine decreased r apidly in the bosentan group after nephrectomy, whereas it continued to inc rease for 48h in the ischaemic group. Kidneys from the ischaemic group show ed a higher degree of tubular-cell necrosis and epithelial-cell detachment than kidneys from the bosentan group. Conclusions. We conclude that cold ischaemia and preservation damage induce s an increase in renal ET mRNA and irET expression in the reperfusion phase , contributing both to the deterioration of renal function and to tubular n ecrosis. Bosentan is effective in protecting kidneys from this cold ischaem ia-reperfusion damage. Non-selective ETA/ETB receptor antagonists might be potentially useful in clinical renal transplantation.