Protocol development for donor liver function assessment during end-ischaemic normothermic machine perfusion as a platform for transplant viability testing and therapeutics evaluation

Attard, Joseph ORCID: 0000-0001-5770-2896 (2023). Protocol development for donor liver function assessment during end-ischaemic normothermic machine perfusion as a platform for transplant viability testing and therapeutics evaluation. University of Birmingham. M.D.

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Abstract

Donor organ shortage has increased reliance on extended criteria donor livers for transplantation. Simultaneously, the development of machine perfusion technology has caused a paradigm shift in organ preservation practices from cold storage metabolic suppression to dynamic organ functional support. This platform has provided opportunities to assess the transplant viability of these extended criteria organs based on functional parameters rather than static donor variables. Machine perfusion has therefore been shown to provide superior organ preservation than static cold storage. This has in turn led to an increase in basic science and clinical research with the development of perfusion protocols designed to optimise liver function in various ways. However, this research is dominated by small series of liver perfusions due to the scarcity of donor organs for research. This, coupled with the singularity of individual livers, has restricted translation into clinical medicine. The VITTAL clinical trial indicated that the viability assessment potential of normothermic machine perfusion increases the utilisation of extended criteria grafts. Using high throughput analytical technologies, a metabolomic study was conducted in tandem with the clinical trial to elucidate the molecular pathways that influence extended criteria donor metabolic behaviour and organ viability during perfusion. Key metabolic pathways were discovered, relating lipid pathways, fatty acid metabolism and amino acid metabolism with links to anti-inflammatory and gluconeogenic pathways. A second study was a proof-of-concept experiment which sought to tackle the aforementioned issues surrounding research perfusions by exploring the basic science implications of normothermic split liver perfusion. In addition to doubling the number of perfusion experiments; metabolic, perfusion and histological characteristics were comparable between split lobes from the same liver. This demonstrated the perfusion protocol’s potential in providing internal controls for the assessment of therapeutics, perfusion techniques and optimisation protocols.

Type of Work:

Thesis (Doctorates > M.D.)

Award Type:

Doctorates > M.D.

Supervisor(s):