Ischemia/reperfusion injury in kidney transplantation: mechanisms and prevention

Abstract

Ischemia has been an inevitable event accompanying kidney transplantation. Ischemic changes start with brain death, which is associated with severe hemodynamic disturbances: increasing intracranial pressure results in bradycardia and decreased cardiac output; the Cushing reflex causes tachycardia and increased blood pressure; and after a short period of stabilization, systemic vascular resistance declines with hypotension leading to cardiac arrest. Free radical-mediated injury releases proinflammatory cytokines and activates innate immunity. It has been suggested that all of these changes-the early innate response and the ischemic tissue damage-play roles in the development of adaptive responses, which in turn may lead to an acute font of kidney rejection. Hypothermic kidney storage of various durations before transplantation add to ischemic tissue damage. The final stage of ischemic injury occurs during reperfusion. Reperfusion injury, the effector phase of ischemic injury, develops hours or days after the initial insult. Repair and regeneration processes occur together with cellular apoptosis, autophagy, and necrosis; the fate of the organ depends on whether cell death or regeneration prevails. The whole process has been described as the ischemia-reperfusion (I-R) injury. It has a profound influence on not only the early but also the late function of a transplanted kidney. Prevention of I-R injury should be started before organ recovery by donor pretreatment. The organ shortage has become one of the most important factors limiting extension of deceased donor kidney transplantation worldwide. It has caused increasing use of suboptimal deceased donors (high risk, extended criteria [ECD], marginal donors) and uncontrolled non-heart-beating (NHBD) donors. Kidneys from such donors are exposed to much greater ischemic damage before recovery and show reduced chances for proper early as well as long-term function. Storage of kidneys, especially those recovered from ECD (or NHBD) donors, should use machine perfusion.