MICA: Novel approaches in optimising steatotic livers for transplantation

MICA：优化脂肪肝移植的新方法

• 批准号: MR/P001734/1
• 负责人: Carlo Ceresa
• 金额: $ 18.21万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP001734%2F1
• 关键词: MICA; Novel; approaches; optimising; steatotic

Liver disease is the only major cause of death still increasing year-on-year and the number of people dying from liver disease has doubled in the last 20 years. Liver transplantation is a successful treatment for end-stage liver disease but is limited by donor organ availability. As a result of this donor shortage, 20% of patients are removed from, or die whilst on the UK waiting list every 2 years. It is therefore of great importance to identify ways of making more organs available for transplantation. One way of achieving this is through the utilisation of more "marginal" or suboptimal livers, accepting the potential risk of poorer outcomes. Fatty livers derive poor outcomes when transplanted and as a result, a large number are discarded. It is believed that fatty livers are particularly susceptible to the damage associated with cooling the organ for storage prior to transplantation. Obesity levels in the UK and worldwide are increasing at an alarming rate. With this, comes an increasing incidence of fatty liver disease and it is estimated that 33% of the UK population suffer from non-alcoholic fatty liver disease. An increase of fatty livers in the donor pool is therefore inevitable and identifying methods of optimising and salvaging these livers for transplantation is essential. The key to successful transplantation of fatty livers may lie in organ preservation. Current practice involves cooling the organ with ice and a specialised preservation solution, termed static cold storage (SCS). New technology involves maintaining the liver on a machine that provides oxygen and nutrition to the liver at normal body temperature, known as normothermic machine perfusion (NMP). We believe that NMP will allow the safe transplantation of fatty livers by: 1) avoiding the deleterious effects of cooling; and, 2) enabling the delivery of de-fatting agents to the perfusion circuit to remove the fat from the liver before it is transplanted. At present the University of Oxford are leading a multi-centre randomised controlled trial comparing SCS and NMP as a preservation technique. Several fatty livers have been transplanted as part of the study and they provide a unique opportunity to compare outcomes from fatty livers transplanted via the two preservation techniques and compare them to normal, non-fatty livers. As part of the study protocol, liver biopsies are obtained prior to and at the end of the preservation period and following implantation of the liver in the recipient. I will analyse these biopsies and compare the fat content at the three time points in each group. I will also be able to assess the degree of damage associated with cooling after transplantation and compare this for fatty livers in the SCS and NMP groups. Post-transplant patient and organ outcomes will be compared in each group. The results obtained will provide a unique insight into the effects of NMP on fatty human livers, data which has not been reported to date.I also plan to obtain 20 livers which have not been transplanted and discarded due to a high fat content. Tissue samples will be obtained and de-fatting agents which have previously shown to reduce the fat content of fatty rat liver cells will be validated and refined for human cells in a laboratory setting. Once the agents have been optimised, I plan to apply them to whole livers through the NMP circuit. By examining biopsy and perfusate samples from the circuit for fat content at specific time points during perfusion I will be able to establish the effect on NMP +/- de-fatting agents on fatty livers. I aim to gain an understanding of the process by which de-fatting occurs in the liver by investigating key processes of fat breakdown in the liver.Through the above experiments I plan to demonstrate that a combination of NMP and de-fatting agents will allow the safe and reliable transplantation of fatty livers. This will result in more livers being transplanted and ultimately, lives saved.

肝病是唯一的主要死亡原因，仍在逐年增加，死于肝病的人数在过去20年中翻了一番。肝移植是终末期肝病的成功治疗方法，但受供体器官可用性的限制。由于供体短缺，每两年有20%的患者在英国等待名单上被移除或死亡。因此，确定使更多器官可用于移植的方法非常重要。实现这一目标的一种方法是通过利用更多的“边缘”或次优肝脏，接受更差结果的潜在风险。脂肪肝在移植时效果不佳，因此大量脂肪肝被丢弃。据信，脂肪肝特别容易受到与移植前冷却器官储存相关的损害。英国和世界各地的肥胖水平正在以惊人的速度增长。与此同时，脂肪肝的发病率也在增加，据估计，33%的英国人口患有非酒精性脂肪肝。因此，供体库中脂肪肝的增加是不可避免的，并且确定优化和挽救这些肝脏用于移植的方法是必不可少的。脂肪肝移植成功的关键可能在于器官的保存。目前的做法包括用冰和专门的保存溶液冷却器官，称为静态冷藏（SCS）。新技术涉及将肝脏维持在一台机器上，在正常体温下为肝脏提供氧气和营养，称为常温机器灌注（NMP）。我们相信，NMP将通过以下方式实现脂肪肝的安全移植：1）避免冷却的有害影响; 2）能够将脱脂剂输送到灌注回路，以在移植之前去除肝脏中的脂肪。目前，牛津大学正在进行一项多中心随机对照试验，比较SCS和NMP作为一种保存技术。作为研究的一部分，已经移植了几个脂肪肝，它们提供了一个独特的机会来比较通过两种保存技术移植的脂肪肝的结果，并将其与正常的非脂肪肝进行比较。作为研究方案的一部分，在保存期之前和结束时以及在将肝脏植入受体之后获得肝脏活组织检查。我将分析这些活组织检查，并比较每组三个时间点的脂肪含量。我还将能够评估移植后与冷却相关的损伤程度，并比较SCS和NMP组中脂肪肝的损伤程度。将比较各组的移植后患者和器官结局。获得的结果将提供一个独特的洞察NMP对脂肪人类肝脏的影响，数据尚未报告日期。我还计划获得20个肝脏没有被移植和丢弃，由于高脂肪含量。将获得组织样本，并将在实验室环境中验证和改进先前显示可降低脂肪大鼠肝细胞脂肪含量的脱脂剂用于人体细胞。一旦试剂被优化，我计划通过NMP回路将它们应用于整个肝脏。通过在灌注期间的特定时间点检查来自回路的活检和灌注液样本的脂肪含量，我将能够确定NMP +/-脱脂剂对脂肪肝的影响。我的目标是通过调查肝脏中脂肪分解的关键过程来了解肝脏中发生脱脂的过程。通过上述实验，我计划证明NMP和脱脂剂的组合将允许脂肪肝移植的安全性和可靠性。这将导致更多的肝脏被移植，并最终挽救生命。

项目成果

A Back-to-Base Experience of Human Normothermic Ex Situ Liver Perfusion: Does the Chill Kill?

• DOI: 10.1002/lt.25464
• 发表时间: 2019-06-01
• 期刊: LIVER TRANSPLANTATION
• 影响因子: 4.6
• 作者: Bral, Mariusz;Dajani, Khaled;Shapiro, A. M. James
• 通讯作者: Shapiro, A. M. James

Normothermic Machine Preservation of the Liver: State of the Art.

• DOI: 10.1007/s40472-018-0186-9
• 发表时间: 2018
• 期刊: Current transplantation reports
• 影响因子: 2.1
• 作者: Ceresa CDL;Nasralla D;Jassem W
• 通讯作者: Jassem W