Defatting of donor transplant livers during normothermic perfusion-a randomised clinical trial: study protocol for the DeFat study

Syed Hussain Abbas ¹, Carlo D L Ceresa ², Leanne Hodson ³

¹Nuffield Department of Surgical Sciences, University of Oxford, The Churchill Hospital, Oxford, OX3 7LJ, UK. hussain.abbas@nds.ox.ac.uk.
²Royal Free London NHS Foundation Trust, The Royal Free Hospital, Pond St, Hampstead, London, NW3 2QG, UK.
³Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, The Churchill Hospital, Oxford, OX3 7LJ, UK.
⁴Department of Surgery, Addenbrooke's Hospital, Hills Road, University of Cambridge, Box 202, Cambridge, CB2 2QQ, UK.
⁵Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Mindelsohn Way, Birmingham, B15 2TH, UK.
⁶TransMedics Inc, 200 Minuteman Road, Andover, MA, 01810, USA.
⁷Institute of Biomedical Engineering, Old Road Campus Research Building, University of Oxford, Oxford, OX3 7DQ, UK.
⁸NHSBT CTU, Long Road, Cambridge, CB2 0PT, UK.
⁹Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0BB, UK.
¹⁰NHS Blood and Transplant Clinical Trials Unit, Fox Den Road, Stoke Gifford, Bristol, BS34 8RR, UK.
¹¹Oxford Clinical Trials Research Unit (OCTRU), Centre for Statistics in Medicine (CSM), Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), Medical Sciences Division, The Botnar Research Centre, University of Oxford, Windmill Road, Oxford, OX3 7LD, UK.
¹²Kings College Hospital, King's College Hospital NHS Foundation Trust, Denmark Hill, London, SE5 9RS, UK.
¹³St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Beckett Street, Leeds, LS9 7TF, UK.
¹⁴Nuffield Department of Surgical Sciences, University of Oxford, The Churchill Hospital, Oxford, OX3 7LJ, UK.

⁰Nuffield Department of Surgical Sciences, University of Oxford, The Churchill Hospital, Oxford, OX3 7LJ, UK. hussain.abbas@nds.ox.ac.uk.

Trials +

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June 17, 2024

View abstract on PubMed

Summary

This study investigates defatting interventions during normothermic machine perfusion (NMP) to improve the viability of steatotic donor livers for transplantation, aiming to reduce waiting list deaths.

Area Of Science

Hepatology
Transplantation immunology
Organ preservation

Background

Liver disease is a leading cause of premature death in the UK, with transplantation limited by donor organ shortage.
Hepatic steatosis, prevalent in 33% of the UK population and linked to obesity, renders many donor livers unsuitable for transplant.
Current interventions during normothermic machine perfusion (NMP) have shown promise in reducing intrahepatocellular triglyceride (IHTG) content and improving function in steatotic livers.

Purpose Of The Study

To evaluate the safety and feasibility of defatting interventions during NMP for steatotic donor livers.
To explore the efficacy of these interventions by comparing ex-situ and post-reperfusion liver function.
To increase the number of transplantable steatotic livers and improve patient outcomes.

Main Methods

A multi-centre clinical trial will randomly assign 60 high-risk steatotic livers to NMP alone or NMP with defatting interventions.
Primary endpoint: proportion of livers meeting predefined functional criteria (lactate clearance, pH, glucose metabolism, bile composition, vascular flows, transaminase levels) indicating transplant suitability.
Secondary endpoints include transplant rates, graft function, patient/graft survival, and complications like ischemia-reperfusion injury (IRI) and biliary strictures.

Main Results

Preliminary tests showed functional improvement and reduced IHTG content in discarded steatotic livers using defatting interventions (forskolin, L-carnitine, lipoprotein apheresis).
The clinical trial aims to confirm these findings and assess transplant suitability based on key functional parameters.
Exploration of clinical outcomes including graft function, survival, and complications post-transplant.

Conclusions

Pharmacological optimization of steatotic donor livers during NMP offers a potential solution to increase organ utilization.
Successful implementation could significantly reduce liver transplant waiting list mortality.
This approach may enable the safe transplantation of currently discarded steatotic livers.

Keywords:

Defatting Functional assessment Hepatic steatosis Liver transplantation Non-alcoholic fatty liver disease (NAFLD) Normothermic machine perfusion (NMP)