Immunometabolic impact of machine perfusion strategies in liver transplantation

肝移植的数量不能满足现有的需求，全世界仍有成千上万的患者在等待移植，许多人在等待救命的器官时死亡。器官短缺的一个关键因素是，由于担心器官在移植后可能出现缺血再灌注损伤（IRI）现象，而丢弃来自被认为是高风险的捐赠者的可存活器官。大多数被丢弃的肝脏是在循环性死亡（DCD）后捐赠的，目前在英国只有27%的肝脏被使用。通过在机器中灌注肝脏（机器灌注或MP）的策略取代冷冻箱（静态冷藏或SCS），可以提高DCD器官的质量，这仍然是取出肝脏后保存肝脏的主要方法。目前临床上采用的MP策略有3种：供者的肝脏在37℃下灌注供者的血液，采用常温区域灌注（NRP），体外获取的肝脏采用常温（NMP）或低温（HOPE）灌注（分别使用温灌注液或冷灌注液）。到目前为止，还没有对这些不同的MP策略进行控制的客观比较，我们对它们的作用机制也没有很好的了解。我们的假设是，MP的益处将取决于它们是否能够改善肝细胞线粒体的损伤，这是在移植时引发IRI的第一个事件。为了确定这一点，我们建议进行一项随机临床试验，将36个DCD人肝脏分配到3个治疗组中的1个：1)SCS；(二)NRP;iii)希望。随后将在NMP中进行一段时间，以研究IRI反应，并确定肝脏质量是否足够好，可以进行移植。我们的建议将包括三个关键目标：1)研究线粒体损伤在DCD肝脏移植时发生的IRI中的作用。2)确定不同MP策略影响DCD肝移植IRI的机制。3)建立标志物，评估肝脏在NMP灌注后移植患者体内的质量。我们的研究将使我们能够以比迄今为止更好的方式破译人类肝脏IRI的机制。此外，它将为使用MP技术的最佳方式提供指导，并可能导致确定新的治疗方法。最终，我们的建议将有助于提高DCD肝脏的质量，并增加可以安全接受肝移植的患者数量。

Liver transplant numbers do not meet the existing needs, thousands of patients remain on transplant waiting lists worldwide and many die while awaiting a life-saving organ. A key contributor to organ shortage is the discarding of viable organs coming from donors considered high-risk, for fear that they might malfunction after transplantation as a result of a phenomenon called ischaemia reperfusion injury (IRI). Most of the discarded livers are those donated after circulatory death (DCD), only 27% of which are currently utilised in the UK. The quality of DCD organs can be improved by replacing the icebox (static cold storage or SCS), which remains the main approach to preserve the livers after having been retrieved, by strategies that perfuse the livers in a machine (machine perfusion or MP). There are currently 3 MP strategies employed in the clinic: normothermic regional perfusion (NRP) is used in the donors by perfusing the liver with the donor's blood at 37 degrees Celsius, and normothermic (NMP) or hypothermic (HOPE) perfusion are used in the procured livers out of the body (using warm or cold perfusion fluids, respectively). To date, no controlled objective comparisons of these different MP strategies have been undertaken and we do not have a good understanding of their mechanisms of action. Our hypothesis is that the benefits of MP will depend on whether they are capable of improving the damage to the liver cell mitochondria, which constitutes the first event that elicits IRI at the time of transplantation. To determine this, we propose to conduct a randomised clinical trial in which 36 DCD human livers will be allocated to 1 of 3 treatment arms: : i) SCS; ii) NRP; and iii) HOPE. This will be followed by a period of time in NMP in order to study the IRI response and determine if the quality of the livers is good enough to proceed to transplantation. Our proposal will include three key Objectives:1) To investigate the role of mitochondrial damage in the IRI that takes place when DCD livers are transplanted.2) To determine the mechanisms through which the different MP strategies influence IRI in DCD liver transplantation.3) To develop markers to assess the quality of the livers while they are being perfused using NMP before being transplanted into patients. Our study will allow us to decipher the mechanisms of liver IRI in humans in a much better way than what has been achieved to date. Furthermore, it will provide guidelines as to the best way of employing the MP technologies and may result in the identification of new treatments. Ultimately, our proposal will serve to improve the quality of DCD livers and increase the number of patients who can safely receive a liver transplant.