Redefining the limits of tolerable warm ischemia in deceased donor kidneys

项目总结 尽管为扩大器官捐赠者的人才库作出了重大努力，但在器官捐赠者和器官捐赠者之间仍然存在严重的差距。 器官的数量和需要挽救生命的移植的患者数量。坚持不懈和纯粹的规模 这一问题表明，需要一种颠覆性的新方法，从根本上改变 器官捐献。我们建议通过开发新的器官灌流技术来实现这一范式转变 可以改变捐赠者的资格标准，允许在不受控制的情况下在死亡后进行捐赠 医院。目前，在某一年去世的器官捐赠者中，只有0.7%的人能真正找到他们的器官。 造成这一低比例的一个主要因素是捐献者必须死在受控医院的要求 设置以促进器官快速恢复，确保&lt；1小时热缺血。如果这种可耐受的热缺血 时间可以延长到~3小时或更长时间，这将使允许死后捐赠在后勤上是可行的 在不受控制的情况下，比如去医院的路上心脏骤停。这可能会显著增加 可获得的捐赠器官数量，特别是在心脏骤停后。我们最近展示了两个 人肾和猪脑的独立研究表明，体外器官灌流具有适当的治疗作用 灌流液可以获得以前未被认识到的对缺血损伤的弹性。在此基础上，我们假设 一个适当设计的灌流系统将能够在体外恢复稳定的肾功能。 至少~3小时热缺血后的肾脏。为此，我们开发了一种新的灌流方法。 它结合了无细胞的细胞保护灌流液和定制的灌流系统，能够 持续的生理监测和实时综合器官支持。而不是红血球，我们的 灌流液使用聚合血红蛋白在一定的灌流温度范围内实现氧气输送 避免溶血并发症。在这项提议中，我们将改进和测试我们的新方法的能力 减轻热缺血3小时后的两种严重衰竭模式：1)严重的ATP耗竭和相关的 电子传递链(ETC)的中断；以及2)由调节性坏死引起的功能障碍炎症 再灌流后。该项目的成功完成将建立新的技术，具有潜在的 改变我们对合格器官捐赠者的定义。

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.