Cellular senescence and renal transplantation

Gingell-Littlejohn, Marc (2014) Cellular senescence and renal transplantation. MD thesis, University of Glasgow.

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Abstract

With the current crisis of organ shortage and an increasing number of dialysis patients,studies directed at ameliorating such a substantial organ discrepancy are of considerable importance to the transplant community. The use of extended criteria donation has helped to compensate the disparity of organs however, we are still a long way from achieving satisfactory targets. Still there are many organs from older donors that are discarded primarily on the basis of chronological age. It is here that biological age may display a crucial role in allowing the transplant team to characterize donor organs with greater accuracy. Indeed both biological and chronological age are very closely related and ECD criteria are based very much on the latter, albeit with other clinical variables. However the biomarker of ageing CDKN2A which is suitably represented by Baker and Sprott’s criteria, displays closer variabilities with post-operative transplant function, at least up to one year. Telomere length known as the “Gold standard” biomarker of ageing does not display as robust a role in predicting organ function as CDKN2A. The classification of organs represented in this text from category I-IV serves merely as a guide to future studies and is yet to be validated in larger clinical trials. It is however a simple and rapid assessment tool (Gingell-Littlejohn et al PLOS One 2013). Relatively advanced cellular senescence was displayed in the mutant AS/AGU rat kidney when compared to the parent AS strain. This was exploited in a unique animal model to study the effects of ischaemia reperfusion injury on the mutant kidney, hence mimicking to a certain degree the transplant related injuries in ECD kidneys. Although ischaemic times in the model were moderate in nature, there was nonetheless a difference in the tolerance to IR injury between parent and mutant strain as evidenced by increased p16 and p21 staining in AS/AGU rats. Such a model therefore is exclusive in that interventions to improve ECD renal function post-transplantation can accurately and conveniently be represented and studied at a pre-clinical level. Anti-ischaemic compounds have been the subject of much debate over the years, however a single “Holy Grail” compound able to completely abolish the injurious effects of IR injury has never been elicited. mTOR inhibitors however, display several cellular effects and act as potent immunosuppressants. They (AZ-6) have also been shown to partially mediate the detrimental effects of IR injury on the native kidneys of AS rats in a specifically designed animal model as shown. Further studies encompassing transplanted kidneys from mutant AS/AGU rats exposed to such a promising agent would be of undoubted importance to the clinical field of transplantation, potentially leading to immeasurable economic and patient benefits.

Item Type: Thesis (MD)
Qualification Level: Postdoctoral
Keywords: Transplantation, Senescence, Ischaemia-Reperfusion Injury, Kidney, CDKN2A, Telomere, AS/AGU rat
Subjects: Q Science > Q Science (General)
Q Science > QP Physiology
R Medicine > R Medicine (General)
R Medicine > RB Pathology
R Medicine > RD Surgery
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Funder's Name: UNSPECIFIED
Supervisor's Name: Shiels, Professor Paul G. and Clancy, Mr. Marc J.
Date of Award: 2014
Depositing User: Mr Marc Gingell-Littlejohn
Unique ID: glathesis:2014-4986
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 10 Apr 2014 09:07
Last Modified: 10 Apr 2014 09:18
URI: http://theses.gla.ac.uk/id/eprint/4986
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