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

Autor: Abbas SH; Nuffield Department of Surgical Sciences, University of Oxford, The Churchill Hospital, Oxford, OX3 7LJ, UK. hussain.abbas@nds.ox.ac.uk., Ceresa CDL; Royal Free London NHS Foundation Trust, The Royal Free Hospital, Pond St, Hampstead, London, NW3 2QG, UK., Hodson L; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, The Churchill Hospital, Oxford, OX3 7LJ, UK., Nasralla D; Royal Free London NHS Foundation Trust, The Royal Free Hospital, Pond St, Hampstead, London, NW3 2QG, UK., Watson CJE; Department of Surgery, Addenbrooke's Hospital, Hills Road, University of Cambridge, Box 202, Cambridge, CB2 2QQ, UK., Mergental H; Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Mindelsohn Way, Birmingham, B15 2TH, UK.; TransMedics Inc, 200 Minuteman Road, Andover, MA, 01810, USA., Coussios C; Institute of Biomedical Engineering, Old Road Campus Research Building, University of Oxford, Oxford, OX3 7DQ, UK., Kaloyirou F; NHSBT CTU, Long Road, Cambridge, CB2 0PT, UK., Brusby K; NHSBT CTU, Long Road, Cambridge, CB2 0PT, UK., Mora A; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0BB, UK., Thomas H; NHS Blood and Transplant Clinical Trials Unit, Fox Den Road, Stoke Gifford, Bristol, BS34 8RR, UK., Kounali D; Oxford 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., Keen K; NHSBT CTU, Long Road, Cambridge, CB2 0PT, UK., Pollok JM; Royal Free London NHS Foundation Trust, The Royal Free Hospital, Pond St, Hampstead, London, NW3 2QG, UK., Gaurav R; Department of Surgery, Addenbrooke's Hospital, Hills Road, University of Cambridge, Box 202, Cambridge, CB2 2QQ, UK., Iype S; Royal Free London NHS Foundation Trust, The Royal Free Hospital, Pond St, Hampstead, London, NW3 2QG, UK., Jassem W; Kings College Hospital, King's College Hospital NHS Foundation Trust, Denmark Hill, London, SE5 9RS, UK., Perera MTP; Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Mindelsohn Way, Birmingham, B15 2TH, UK., Hakeem AR; Kings College Hospital, King's College Hospital NHS Foundation Trust, Denmark Hill, London, SE5 9RS, UK.; St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Beckett Street, Leeds, LS9 7TF, UK., Knight S; Nuffield Department of Surgical Sciences, University of Oxford, The Churchill Hospital, Oxford, OX3 7LJ, UK., Friend PJ; Nuffield Department of Surgical Sciences, University of Oxford, The Churchill Hospital, Oxford, OX3 7LJ, UK.
Jazyk: angličtina
Zdroj: Trials [Trials] 2024 Jun 17; Vol. 25 (1), pp. 386. Date of Electronic Publication: 2024 Jun 17.
DOI: 10.1186/s13063-024-08189-4
Abstrakt: Background: 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 liver transplant waiting lists die before receiving a transplant. A third of donated livers are not suitable for transplant, often due to steatosis. Hepatic steatosis, which affects 33% of the UK population, 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 (NKH477) 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.
Methods: In the proposed multi-centre 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 and transaminase levels. Clinical secondary endpoints will include proportion of livers transplanted in the two arms, graft function; cell-free DNA (cfDNA) at follow-up visits; patient and graft survival; hospital and ITU stay; evidence of ischemia-reperfusion injury (IRI); non-anastomotic biliary strictures and recurrence of steatosis (determined on MRI at 6 months).
Discussion: This study explores ex-situ pharmacological optimisation of steatotic donor livers during NMP. 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.
Trial Registration: ISRCTN ISRCTN14957538. Registered in October 2022.
(© 2024. The Author(s).)
Databáze: MEDLINE
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