Ischemic Training and Immunosuppressive Agents Reduce the Intensity of Ischemic Reperfusion Injury after Kidney Transplantation

摘要

Objectives: Ischemia-reperfusion injury affects posttransplant renal function, directly increases the probability of acute rejection, and is associated with chronic rejection and impaired long-term function. Animal studies suggest that ischemic preconditioning enhances resistance to ischemia and may be augmented by treating donors using immunosuppressant agents. This study sought to confirm the hypothesis that a combination of ischemic training and immunosuppression prior to renal harvest would maximize a transplanted kidney’s resistance to ischemia-reperfusion injury. Materials and Methods: Landrace pigs underwent either preharvest immunosuppression plus left kidney ischemic training (group 1, n = 6) or ischemic training alone (group 2, n = 6). Immunosuppression was composed of mycophenolate mofetil (20 mg/kg) and tacrolimus (0.1 mg/kg) administered intravenously 30 minutes before training. Training comprised 2 cycles of left renal pedicle occlusion for 5 minutes followed by release (reperfusion) for 10 minutes. Warm renal ischemia was then induced by clamping the left renal pedicle for 30 minutes, followed by heterotopic left kidney transplantation. Blood from the transplanted kidney renal vein was sampled directly at 0, 10, 20, 40, and 60 minutes posttransplantation for malondialdehyde (a reactive oxygen species marker), tumor necrosis factor-alpha (TNFα), interleukins 6 and 8 (inflammatory cytokines), and erythrocyte-reduced glutathione (an antioxidant). Renal histology was graded on a 3-point scale. Results: Reperfusion levels of malondialdehyde, TNFα, and interleukin 6 were significantly lower in group 1 at both 40 and 60 minutes. None of the animals in group 1 (0/6) that received preharvest immunosuppression showed severe interstitial inflammation, compared with 4 of 6 animals in group 2 that did ( P < .03). Conclusions: Preharvest immunosuppression with mycophenolate mofetil and tacrolimus significantly decreases immediate posttransplant reactive oxygen species and inflammatory cytokine production, enhances the protective effect of ischemic training, and should not only reduce ischemia-reperfusion injury in transplanted kidneys but also should enhance immediate and long-term graft function while preventing acute rejection.