Molecular signals of tissue (and organ) dysfunction in disease and ageing. Matching the transplant organs potential to the individual recipients’ needs

Shapter, Oliver (2020) Molecular signals of tissue (and organ) dysfunction in disease and ageing. Matching the transplant organs potential to the individual recipients’ needs. MD thesis, University of Glasgow.

Due to Embargo and/or Third Party Copyright restrictions, this thesis is not available in this service.

Abstract

Background:
The mismatch between organ supply and demand has resulted in the use of organs from more extreme donors. Recent evidence has indicated that donor biological age and pre-existing physiological stressors are the most important single negative predictors of long-term outcome after renal transplantation.
Thus, biomarkers of ageing are key to the cellular assessment of donor organs in the pre-transplant setting. In this study we have sought to test the MTR in a retrospectively analysed pre-implantation and post-perfusion renal transplant biopsies as sources of tissue undergoing normative ageing.
Specifically, we have assayed for biomarkers associated with natural ageing and with human premature ageing syndromes, to determine if they were related to post-transplant function and outcomes. Additionally, under the tenets of the Mitochondrial-Telomere-Ribosome (MTR) hypothesis, we have sought to determine if age related regulation of cellular metabolism is reflected in longitudinal organ function and if its dysregulation manifests in poor post-transplant performance characteristics.

Methods and material:
Quantitative polymerase chain reaction (qPCR) was undertaken on biopsies from renal allograft in pre- and post- perfusion states. Markers of cellular senescence including mitochondrial DNA (mtDNA) copy number, CDKN2 transcripts, Lamin-A (LMNA), Bloom (BLM) protein, Werner (WRN) Protein and Surtuin (SIRT) 1-7 were analysed and compared to donor and recipient characteristics and transplant outcomes.

Results:
Pre-perfusion mtDNA copy number correlated with short term renal function in the first 12 months post-transplant with organs surpassing an average energy threshold performing better in the first-year post-transplant. Elevated LMNA expression in the pre-perfusion state was associated with a rapid functioning renal allograft where as a lower expression was linked to delayed graft function (DGF). Pre-perfusion WRN protein expression correlated with post-transplant renal function at 6 months and pre-perfusion LMNA expression. Strong positive association was seen with SIRT 6 and WRN expression pre-transplant.

Conclusion:
The pre-transplant expressions of markers of related to premature and normal ageing, cellular senescence, inflammation and DNA damage have significant relationship to post-transplant outcomes. Furthermore, this has demonstrated that pre-transplant assessment of all potential donor organs under the terms of the MTR postulate offers an accurate and biologically proven method of graft assessment. Additional studies are required to analyse the impact of these elements further, which may allow the mainstream use of these markers in the selection of organ donors. Clinically, this would allow for a more robust pre-transplant assessment of any potential donor organ by providing an accurate cellular evaluation of donor health and bio-age compared to the use of chronological age. This would allow for the appropriate use of organs by assigning those organs with the greatest functional capacity and longevity to the most appropriate recipients. However, significant clinical work is required in parallel to laboratory studies to allow the transition of these biomarkers from bench to bedside.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Keywords: Ageing, chronic kidney disease, end-stage renal function, kidney failure, renal transplantation, delayed graft function.
Subjects: R Medicine > RC Internal medicine
R Medicine > RZ Other systems of medicine
Colleges/Schools: College of Medical Veterinary and Life Sciences
Supervisor's Name: Shiels, Professor Paul and Kingsmore, Professor David
Date of Award: 2020
Embargo Date: 4 June 2023
Depositing User: mr Oliver Shapter
Unique ID: glathesis:2020-81417
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 04 Jun 2020 15:23
Last Modified: 04 Jun 2020 15:23
URI: http://theses.gla.ac.uk/id/eprint/81417

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