Redefining the limits of tolerable warm ischemia in deceased donor kidneys

项目摘要 尽管为扩大器官捐献者的数量做出了巨大努力， 器官数量和需要移植挽救生命的病人数量。它的持久性和巨大性 这一问题表明，需要一种破坏性的新方法，从根本上改变 器官捐献我们建议通过开发新的器官灌注技术来实现这种范式转变， 可以改变捐赠者的资格标准，允许在不受控制的情况下， 医院目前，在特定年份死亡的器官捐献者中，只有0.7%的人会得到器官。 造成这一低比例的一个主要因素是要求捐赠者必须在受控医院死亡 设置为促进快速器官恢复，确保<1小时的热缺血。如果这种可耐受的热缺血 时间可以延长到3小时或更长，这将使死后捐赠在逻辑上可行 在不受控制的情况下，例如在去医院的路上心脏骤停。这可能会大大增加 可供捐赠的器官数量，特别是在心脏骤停后。我们最近在两个 对人肾和猪脑进行独立研究， 灌注液可以获得以前未被重视的对缺血性损伤的恢复力。基于此，我们假设 适当设计的灌注系统将能够在体外恢复稳定的肾功能， 热缺血至少~3小时后的肾脏。为此，我们开发了一种新的灌注方法， 其将脱细胞细胞保护灌注液与能够 持续的生理监测和实时集成的器官支持。而不是红细胞，我们的 灌注液使用聚合血红蛋白以在灌注温度范围内实现氧气输送， 避免溶血并发症。在本提案中，我们将完善和测试我们的新方法的能力 以减轻3小时热缺血后的两种关键失效模式：1）严重的ATP耗竭， 电子传递链（ETC）的破坏;和2）由调节性坏死诱导的功能障碍性炎症 再灌注后。该项目的成功完成将建立新的技术， 改变我们对合格器官捐献者的定义

PROJECT SUMMARY In spite of significant effort to expand the pool of organ donors, there remains a severe gap between the supply of organs and the number patients in need of a living saving transplant. The persistence and sheer magnitude of this issue suggests the need for a disruptive new approach that can fundamentally change the paradigm of organ donation. We propose to achieve this paradigm shift by developing new organ perfusion technology that can transform donor eligibility criteria to allow for donation after death in an uncontrolled setting outside of the hospital. At current, only 0.7% of organ donors that die in a given year will have their organs actually recovered. A major contributing factor to this low percentage is the requirement that donors must die in a controlled hospital setting to facilitate rapid organ recovery that ensures <1 hr of warm ischemia. If this tolerable warm ischemic time could be expanded to ~3 hrs or more, this would make it logistically feasible to allow for donation after death in uncontrolled settings such as cardiac arrest on the way to the hospital. This could dramatically increase the number of donor organs available, particularly following sudden cardiac arrest. We have recently shown in two independent studies of human kidney and pig brain, that ex vivo organ perfusion with the appropriate therapeutic perfusate can access a previously unappreciated resilience to ischemic injury. Based on this, we hypothesize that an appropriately designed perfusion system will be capable of restoring stable renal function ex vivo in kidneys after at least ~3 hrs of warm ischemia. To this end, we have developed a novel perfusion approach which combines an acellular cytoprotective perfusate paired with a custom perfusion system capable of continuous physiologic monitoring and real-time integrated organ support. Instead of red blood cells, our perfusate uses polymerized hemoglobin to enable oxygen delivery under a range of perfusion temperatures and avoid the complications of hemolysis. In this proposal, we will refine and test the capacity of our novel approach to mitigate two critical modes of failure following 3 hrs of warm ischemia: 1) Severe ATP depletion with related disruption of the electron transport chain (ETC); and 2) Dysfunctional inflammation induced by regulated necrosis after reperfusion. Successful completion of this project will establish new technology with the potential to transform our definition of what constitutes an eligible organ donor.