Expanding the Liver Transplant Organ Pool through Ex Vivo Liver Perfusion

通过离体肝脏灌注扩大肝移植器官库

• 批准号: 9310237
• 负责人: JAMES FRANCIS MARKMANN
• 金额: $ 55.17万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-10 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9310237
• 关键词: Adult; Bile fluid; Biliary; Biological Preservation; Cause of Death; Cell Respiration; Cessation of life; Cirrhosis; Clinical; Clinical Trials; Cryopreservation; Data; Deterioration; Development; Diagnosis; Effectiveness; Flushing; Fostering; Future; Health; Histology; Human; Ice; Individual; Injury; Ischemia; Kinetics; Lead; Life; Literature; Liver; Liver Cirrhosis; Liver diseases; Metabolic; Metabolism; Methods; Mitochondria; Modality; Modeling; Normalcy; Nutrient; Organ; Organ Donor; Organ Preservation; Organ Transplantation; Outcome Measure; Oxidative Stress; Oxygen; Oxygen Consumption; Pathway interactions; Patients; Perfusion; Phenotype; Production; Protocols documentation; Public Health; Randomized; Recovery; Reperfusion Therapy; Reporting; Resuscitation; Savings; Selection Criteria; Survival Rate; Technology; Temperature; Therapeutic Intervention; Time; Transplantation; United Network for Organ Sharing; University of Wisconsin-lactobionate solution; Waiting Lists; Warm Ischemia; Whole Blood; attributable mortality; base; chronic liver disease; clinical application; cost; design; ex vivo respiration; exhaustion; experience; graft failure; head-to-head comparison; high risk; improved; inflammatory marker; injured; innovation; liver injury; liver preservation; liver transplantation; metabolic profile; metabolome; metabolomics; mortality; reconstitution; repaired; response to injury; standard of care; success

PROJECT SUMMARY / ABSTRACT Liver transplantation provides life saving treatment for patients with end-stage liver disease. However, the potential of this therapy is limited by an inadequate supply of deceased donor livers to treat all those who could benefit. This has resulted in narrow indications for liver transplantation, high waiting list mortality, and increased use of marginal organs that worsen post transplant survival rates and increase costs. We believe that pretransplant ex vivo donor liver perfusion (EVLP) has unparalled potential to alter this paradigm. Unlike the current standard liver preservation by static cold storage (SCS) in which incompletely arrested metabolic activity under anoxic conditions leads to gradual exhaustion of cellular energy stores and progressive deterioration of graft quality, under EVLP, cellular aerobic respiration is restored by oxygenated perfusion allowing normal metabolic processes to ensue ex vivo. This will permit pretransplant recovery for grafts injured by warm ischemia (such as those from DCD donors), diagnosis of grafts suitable from those nonsuitable for transplant and a marked net expansion of the organ pool for transplantation. In this proposed project, we seek to define the most appropriate and effective application of EVLP to liver transplants. We will investigate the boundaries of organ injury that allows recovery by EVLP and will delineate the ideal parameters of liver perfusion. These studies will also provide a wealth of data to inform future designed to identify multi parameter discriminators of organ suitability for transplantation. In the final aim of of this project, we utilize the information gained in Aims I and II to conduct a randomized comparison of SCS and EVLP using DCD livers as a prelude to a clinical trial. Collectively, these studies will generate data critically necessary in optimal development of the field of ex vivo liver perfusion.

项目摘要/摘要 肝移植为终末期肝病患者提供了挽救生命的治疗方法。然而， 这种疗法的潜力受到已故供肝供应不足的限制，无法治疗所有有能力治疗的人 利益。这导致了肝移植适应症的狭窄，等待名单上的高死亡率，并增加了 使用边缘器官会恶化移植后的存活率并增加成本。我们相信 移植前体外供肝灌流(EVLP)具有改变这一模式的无与伦比的潜力。 与目前标准的静态冷藏(SCS)保存肝脏不完全停滞不同 缺氧条件下的代谢活动导致细胞储能的逐渐耗尽和进行性 移植物质量恶化，在EVLP下，细胞的有氧呼吸通过充氧灌流恢复 从而使正常的新陈代谢过程在体外得以进行。这将允许移植前对受伤的移植物进行恢复 通过热缺血(例如来自DCD供者的移植物)，诊断适合的移植物与不适合于 移植和移植器官池的显著净扩大。 在这个拟议的项目中，我们试图定义最合适和最有效的EVLP在肝脏的应用 移植。我们将调查允许EVLP恢复的器官损伤的边界，并将划定 肝血流灌注的理想参数。这些研究还将提供丰富的数据，为未来设计 确定器官移植适宜性的多参数判别因子。在这个项目的最终目标中， 我们利用在AIMS I和II中获得的信息来进行SCS和EVLP的随机比较，使用 DCD肝脏作为临床试验的前奏。总的来说，这些研究将在#年产生至关重要的数据 体外肝脏灌流领域的优化发展。