Controlled Rewarming after Hypothermia: Adding a New Principle to Renal Preservation

Early graft dysfunction due to preservation/reperfusion injury still represents a notable issue after kidney transplantation, affecting long term prognosis of graft viability. One trigger of postischemic cell dysfunction could be recognized in the abrupt temperature shift from hypo- to normothermia, leading to mitochondrial dysfunction and proapoptotic signal transduction. Here we propose a technique to cope with this "rewarming injury" by interposing a period of gentle warming up by hypo- to subnormothermic machine perfusion of the isolated graft prior to warm reperfusion. Porcine kidneys were subjected either to 18 hours of hypothermic machine preservation (HMP) or 18 hours static cold storage + 3 hours of gentle, machine controlled oxygenated rewarming (COR). Functional integrity was evaluated in both groups by subsequent normothermic reperfusion in vitro. The functional benefit of COR was documented by an approximately twofold increase in renal clearances of creatinine as well as urea upon warm reperfusion, compared to controls. This was accompanied with a notable mitigation of postischemic mitochondrial dys-homeostasis. COR significantly improved renal oxygen consumption and maintained total NAD tissue content upon reperfusion. Mitochondrial initiation of cellular apoptosis, as evidenced by activation of caspase 9 was also largely prevented after COR but not in controls. The concept of gentle regenerative graft rewarming could become a valuable adjunct in renal transplantation.