Molecular fingerprints linked to graft viability in extended criteria donor livers during normothermic machine perfusion
Abstract Background Donor organ shortage has led to increased reliance on extended-criteria donor (ECD) livers for transplantation. Normothermic machine perfusion (NMP) has led to a paradigm shift in organ preservation from cold storage to full ex-situ metabolic support. This study investigated ECD liver metabolic profiling to elucidate NMP molecular signatures and whether signatures were predictive of graft viability and clinical outcome. Methods Thirty-one livers underwent NMP for a minimum of four hours and 23 livers fulfilled NMP viability criteria. Perfusate from graft perfusion commencement to 4-h time point were collected at 0.25, 2 and 4 h. Samples underwent untargeted metabolomics analysis using Ultra High Performance Liquid Chromatography-Mass Spectrometry. Univariate statistical analyses revealed dynamic changes in metabolic profiles across the perfusion period and differences in water-soluble and lipid-based metabolites between viable and non-viable livers. Results Pathway enrichment analysis highlights pathways relating to amino acid and energy metabolism differing between viable and non-viable livers. Metabolic changes are not observed for ECD livers based on post-transplant clinical outcome. Conclusions This study revealed metabolic signatures of ECD livers that may define metabolic differences related to graft viability which can be targeted for improved viability.
Authors
- Darius F. Mirza (ORCID: https://orcid.org/0000-0002-7531-9089)
- Hentie Cilliers
- John Isaac (ORCID: https://orcid.org/0000-0002-5520-0734)
- Paolo Muiesan (ORCID: https://orcid.org/0000-0002-7389-6691)
- Lukáš Najdekr (ORCID: https://orcid.org/0000-0001-9559-5454)
- Gavin Rhys Lloyd (ORCID: https://orcid.org/0000-0001-7989-6695)
- Hynek Mergental (ORCID: https://orcid.org/0000-0001-5480-9380)
- Joseph Anthony Attard (ORCID: https://orcid.org/0000-0001-5770-2896)
- Peter John Friend (ORCID: https://orcid.org/0000-0003-0841-9685)
- Manpreet Wilkhu (ORCID: https://orcid.org/0000-0002-7520-0336)
- Darren Barton (ORCID: https://orcid.org/0000-0003-0106-5861)
- Andris Jankevics (ORCID: https://orcid.org/0000-0003-2095-6846)
- YURI LONGATTO BOTEON (ORCID: https://orcid.org/0000-0002-1709-9284)
- Chris G. Morris (ORCID: https://orcid.org/0000-0001-9102-6668)
- Simon C. Afford (ORCID: https://orcid.org/0000-0003-2858-3319)
- Desley Neil (ORCID: https://orcid.org/0000-0001-9800-6811)
- Warwick B. Dunn (ORCID: https://orcid.org/0000-0001-6924-0027)
- Amanda Kirkham
- Lorraine Wallace
- Andrea Schlegel
- Stuart Curbishley
- Christina Yap
- Richard Laing
- M. Thamara P. R. Perera
- Keith J. Roberts
- James Ferguson
- Manuel Abradelo
Institutions
- University Hospitals Birmingham NHS Foundation Trust (GB)
- Cleveland Clinic (US)
- Institute of Cancer Research (GB)
- University of Liverpool (GB)
- Cleveland Clinic Lerner College of Medicine (US)
- University of Oxford (GB)
- Cancer Research UK Clinical Trials Unit (GB)
- OrganOx (United Kingdom) (GB)
- NIHR Birmingham Biomedical Research Centre (GB)
- University of Birmingham (GB)
Publication Details
- Journal
- Communications Medicine
- Published
- 2026-10-13
- DOI
- https://doi.org/10.1038/s43856-025-00737-6
- Primary Topic
- Organ Transplantation Techniques and Outcomes
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- NHS Blood and Transplant
- Wellcome Trust
- University Hospitals Birmingham NHS Foundation Trust
- Queen Elizabeth Hospital Birmingham Charity
- Cancer Research UK
- National Institute for Health and Care Research
- Department of Health and Social Care