Transplantation of Discarded Livers Following Normothermic Machine Perfusion: A Multicenter RESTORE Trial

修改后的项目摘要/摘要 肝移植是终末期肝病患者的最终治疗方法，包括一些肝癌。然而，很大一部分患者，特别是那些终末期肝病模型(MELD)评分为？24和衰弱的肝脏疾病，如肝细胞癌、肝内胆管细胞癌和结直肠癌肝转移的患者，由于供体肝脏短缺，没有接受这种挽救生命的手术。延迟肝移植不仅影响患者的死亡率、风险和生活质量，还会增加医疗费用。目前的捐赠者利用做法将加剧现有的器官短缺。许多肝脏被拒绝移植，因为外科医生根据他/她对器官的主观评估怀疑其生存能力。此外，由于类似的担忧，许多额外的肝脏甚至从未恢复。在移植前对边缘肝进行可靠和客观的检测将有助于外科医生对边缘供肝的可用性做出明智的决定。我们团队和其他人积累的证据支持常温机器灌流(NMP)是一种安全可行的修复边缘肝脏的方法，它在正常体温下用营养物质和药物泵入含氧血液，以维持器官的正常代谢活动。此外，NMP为移植团队提供了一个独特的机会，通过评估肝移植的血流动力学状态和代谢功能来测试肝脏的生存能力。在我们的单中心1期试验(NCT04483102)的基础上，我们建议进行2期单臂多中心试验(MRESTORE)，该试验将在客观生存测试后移植经NMP治疗的先前衰退的孤儿肝脏。这项研究将在研究资助期内(长达4年)评估患者和移植物的存活率以及二次移植的结果，包括胆道并发症，进行机制研究，并评估原本会被丢弃的NMP治疗的肝脏移植的成本效益。九个肝脏移植中心及其服务于种族/民族不同患者的OPO将参与这项研究。在规划阶段，我们将最终确定研究设计和方案，获得监管部门的批准，并建立业务基础设施(例如，病例报告表、方案监测计划)，以及时实施mRESTORE。在过渡到全面研究之后，我们将把NMP治疗过的先前下降的边缘肝移植到患者身上，并研究他们的移植结果。此外，我们将研究NMP对先前下降的边缘供者肝脏的肝细胞损伤机制，确定NMP的肝功能障碍表型与相关的移植结果，并评估NMP治疗的肝移植的成本效益。我们的研究结果将为增加可移植肝脏的数量提供实用策略，这将改变目前供体利用做法的范式，并最终改善获得肝脏移植的机会，拯救生命。

MODIFIED PROJECT SUMMARY/ABSTRACT Liver transplantation is the definitive treatment for patients with end-stage liver disease, including some liver cancers. However, a significant proportion of patients, particularly those with the Model for End-stage Liver Disease (MELD) score ??24 and debilitating liver diseases, such as hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and colorectal liver metastases, do not receive this life-saving surgery due to a shortage in donor livers. Delayed liver transplantation not only affects the mortality risk and quality of life but also increases health care costs. The current donor utilization practice will exacerbate the existing organ shortage. Many livers are declined for transplantation because a surgeon doubts its viability based on his/her subjective assessment of the organ. Also, many additional livers are never even recovered because of similar concerns. A reliable and objective testing to assess the viability of marginal livers before transplant will help surgeons make informed decisions on the usability of marginal donor livers. Accumulating evidence from our group and others supports that normothermic machine perfusion (NMP) that pumps oxygenated blood with nutrients and medications at normal body temperature to maintain normal metabolic activity of the organ is a safe and feasible means of reconditioning marginal livers. In addition, NMP provides a unique opportunity for the transplant team to test viability of livers by assessing hemodynamic state and metabolic function of the liver graft. Building upon our single center phase 1 trial (NCT04483102), we propose to conduct a phase 2 single-arm multicenter trial (mRESTORE) that will transplant NMP-treated previously declined orphan livers after objective viability testing. The study will evaluate patient and graft survival and secondary transplant outcomes, including biliary complications, for the duration of the study funding period (up to 4 years), conduct mechanistic studies, and evaluate the cost-effectiveness of transplantation of NMP-treated livers that would otherwise have been discarded. Nine liver transplant centers and their OPOs that serve race/ethnically diverse patients will participate in this study. During the planning phase, we will finalize the study design and protocol, obtain regulatory approvals and build the operational infrastructure (e.g., case report forms, protocol monitoring plan) to enable timely implementation of the mRESTORE. After the transition to the full study, we will transplant NMP-treated previously declined marginal livers to patients and study their transplant outcomes. In addition, we will investigate hepatocellular injury mechanisms that are affected by NMP of previously declined marginal donor livers, identify liver dysfunction phenotypes of NMP with associated transplant outcomes, and evaluate the cost-effectiveness of the utilization of NMP-treated liver transplantation. Our study findings will inform a practical strategy to increase the number of transplantable livers, which will shift the paradigm of current donor utilization practices and ultimately improve access to liver transplants and save lives.