Led by Professor Menna Clatworthy (Cambridge) this cross-cutting theme will measure proteins and RNA transcripts at scale in tissues and biological fluids. The information obtained will be used to find biomarker signatures that delineate donor organ quality, to understand the molecular processes occurring during machine perfusion across organs, and to determine how perfusion conditions can be optimised to improve outcomes. These technologies will support multiple studies across the main research themes, producing benchmarking data that will be used to select the best interventions for study in large clinical trials.
Major workstreams under this theme include:
Prediction of transplant outcomes: Using RNA sequencing of QUOD kidney biopsies we have identified gene signatures present at the time of retrieval that are associated with delayed graft function (DGF) and poor 1-year graft function. We will apply the same methodology to pre-implantation biopsies from transplanted organs (liver, kidney, heart, lung) to generate gene signatures that help to predict outcome. Ultimately, these molecular biomarkers will be combined with donor demographics and standard histological scoring to assist clinicians making decision on whether to use an organ, enabling more organs to be used and increasing the number of transplants available for all patient groups. Our pilot study of dual-hypothermic oxygenated machine perfusion (D-HOPE) identified a 6-protein perfusate signature that differentiates good and poor outcomes after liver transplantation. This will be further investigated in a large prospective cohort study.
Identification of the best therapeutics during NMP: We have demonstrated that RNA sequencing of organs undergoing normothermic machine perfusion (NMP) reveals how different therapeutic interventions affect the molecular processes in the graft. Using paired kidneys from the same donor, with the same genetics, co-morbidities and ischaemic injury, we demonstrated the effectiveness of cytokine adsorption in reducing inflammation during NMP whilst preserving energy generation by oxidative phosphorylation. We will use human organs declined for transplantation to generate high-impact benchmarking data to create a hierarchy of interventions that identify the most promising therapeutics to study in multicentre trials. This model will be applied to liver, kidney, heart and lung to assess the interventions in Theme 1.
Patient impact
- Increasing the number of organs available for transplantation
- Improving the quality of organs through pre-transplant interventions
The identification of biomarkers that assist with the assessment of organ quality and pre-transplant organ repair will improve organ utilisation and reduce transplant waiting lists and may impact long-term outcomes for patients. Identification of the underlying pathways and mechanisms involved in adverse outcomes for marginal organs will facilitate the development of novel therapeutic strategies so that ultimately we can improve and use these organs.
