Defatting of donor transplant livers during normothermic perfusion – a randomised clinical trial

Scientific Abstract

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.

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.

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.

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.

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).

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.

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.

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.