Title: Defatting of donor transplant livers during normothermic perfusion – a randomised clinical trial
Funder: Medical Research Council

Abstract: Liver disease is the third leading cause of premature death in the UK. Liver transplantation is the only successful treatment for end-stage liver disease but is limited by a shortage of suitable donor organs. As a result, up to 20% of patients on the NHS liver transplant waiting list die before receiving a life-saving transplant. _x000D_ _x000D_ However, a third of donated livers cannot be used for transplants. A frequent reason for this is the presence of fat within the liver cells (known as non-alcoholic fatty liver disease). This affects a third of the UK population and is commonest with obesity. As the incidence of obesity in the general population increases, donated organs are more likely to be fatty. _x000D_ _x000D_ Transplanting a fatty liver carries a much greater risk to the patient compared to a normal liver. This is because fatty livers do not tolerate being cooled down, and we currently store organs in an ice-box before the transplant. An alternative new technology (normothermic machine perfusion; NMP) stores the liver in very similar conditions to those in the body: it maintains the liver at body temperature and provides oxygen and nutrition. We know that this preserves it in better condition, with less damage to liver cells: it also allows the surgeon to test how well the organ is working before deciding whether to carry out the transplant. However, whilst beneficial, NMP technology does not completely resolve the problem of fatty livers, because fat remains in the liver cells._x000D_ _x000D_ We have been using fatty human livers, which were declined for transplants, in order to test a new way to remove fat from the liver during NMP. We added a combination of (currently available) drugs to release fat from liver cells, and we then removed the fat using a filter. This reduced the amount of fat in the liver and improved its function. None of the livers treated in this experimental study were actually transplanted: if used for patients, we believe that this might increase the number of livers that could be transplanted safely._x000D_ _x000D_ In the proposed trial, we will randomly assign 60 livers from donors with a high risk of fatty liver disease to either NMP alone or NMP with fat removal treatment. We will assess how many of these livers are safe to transplant and, in those that are transplanted, follow the outcomes after the operation. The main objective is to show whether this treatment is safe; it will also help us to design a future, larger study which will test the extent to which fat removal actually leads to additional transplants._x000D_ _x000D_ Patients and their families have contributed in the design of the study and will be members of the committee that run it. They believe that the study is addressing an important issue, particularly in the context of the global obesity crisis and its consequent implications for liver transplantation. They have concluded that this area of research is of great significance in order to reduce waiting list deaths._x000D_ _x000D_ We plan to present the results of this 3-year project at national and international conferences and publish this research in high-impact journals. This will ensure that transplant teams around the world become aware of this treatment.

Lay abstract: Scientific Abstract_x000D_ _x000D_ Liver disease is the third leading cause of premature death in the UK. Transplantation is the only successful treatment for end-stage liver disease but is limited by a shortage of suitable donor organs. As a result, up to 20% of patients on the liver transplant waiting list die before receiving a transplant. A third of donated livers are not suitable for transplant, often due to steatosis. Hepatic steatosis affects 33% of the UK population and is strongly associated with obesity, an increasing problem in the potential donor pool._x000D_ _x000D_ We have recently tested defatting interventions during normothermic machine perfusion (NMP) in discarded steatotic human livers that were not transplanted. A combination of therapies including forskolin and L-carnitine to defat liver cells and lipoprotein apheresis filtration were investigated. These interventions resulted in functional improvement during perfusion and reduced the intrahepatocellular triglyceride (IHTG) content. We hypothesise that defatting during NMP will allow more steatotic livers to be transplanted with improved outcomes._x000D_ _x000D_ In the proposed multi-centre pilot clinical trial, we will randomly assign 60 livers from donors with a high-risk of hepatic steatosis to either NMP alone or NMP with defatting interventions. We aim to test the safety and feasibility of the defatting intervention, and will explore efficacy by comparing ex-situ and post-reperfusion liver function between the groups._x000D_ _x000D_ The primary endpoint will be the proportion of livers that achieve predefined functional criteria during perfusion which indicate potential suitability for transplantation. These criteria reflect hepatic metabolism and injury and include: lactate clearance; perfusate pH; glucose metabolism; bile composition; vascular flows; transaminase levels._x000D_ _x000D_ Clinical secondary endpoints will include: proportion of livers transplanted in the 2 arms, graft function; cell-free DNA (cfDNA) at follow-up visits (cfDNA has been correlated with allograft injury, rejection and formation of de novo donor specific antibodies); patient and graft survival; hospital and ITU stay; evidence of ischemia-reperfusion injury (IRI); ischaemic cholangiopathy; recurrence of steatosis (determined on MRI at 6 months)._x000D_ _x000D_ Mechanistic secondary endpoints will include histological quantification of steatosis sequentially during perfusion and following reperfusion (in recipients). We will measure markers of hepatic lipid metabolism, allograft injury (cfDNA) and cytokines implicated in ischaemia-reperfusion injury (IRI) during ex-situ perfusion and peri-operatively (prior to and following reperfusion in the recipient). RNA sequencing, proteomic and glycomic analysis will investigate the effect of defatting on the expression of genes and proteins associated with post-transplant outcome, testing proposed viability markers for use in future studies and/or clinical practice._x000D_ _x000D_ Following completion of set-up tasks, the proposed duration of recruitment is 18 months, followed by 6 month clinic follow-up (one year follow-up data will be obtained from the NHSBT registry), 6 months analysis/dissemination._x000D_ _x000D_ To our knowledge, this will be the first study to deliver an ex-situ intervention during NMP with subsequent transplantation. If the intervention proves effective, it will allow the safe transplantation of livers that are currently very likely to be discarded, thereby reducing waiting list deaths. The results of the trial will be disseminated via high-impact publications, presentation at conference presentations and press releases. We will work with patient groups to ensure efficient dissemination of our results to patients, carers and the general public. These will also be shared with NHS bodies and decision makers including NICE, NHSBT and NHS England.

Research activity codes: 5.4 SURGERY;6.4 SURGERY
Health categories: ORAL AND GASTROINTESTINAL