Cardiovascular risk in individuals with type 1 diabetes mellitus and advanced renal disease following simultaneous pancreas and kidney transplantation

Abstract

Background: The survival of individuals with type 1 diabetes mellitus and chronic kidney disease is limited by cardiovascular disease (CVD), which is often asymptomatic. Diabetes and renal impairment are associated with diffuse interstitial myocardial fibrosis, which is challenging to identify and monitor. Simultaneous pancreas and kidney transplantation (SPKT) improves survival in this cohort, however CVD remains a concern, limiting both recipient and allograft survival. SPKT is associated with significant surgical morbidity and mortality risk hence cardiovascular evaluation of recipients that includes assessment for interstitial myocardial fibrosis is paramount to improve short and long-term outcomes. The degree to which a pancreas or kidney allograft contribute to improvements in cardiovascular structure and function is poorly understood. The primary aims of this study were to investigate cardiovascular risk in a cohort of SPKT recipients and to validate diffusion weighted (dw) cardiovascular magnetic resonance (CMR) imaging methods for myocardial fibrosis which could be further developed for use in the pre-transplant cardiovascular evaluation of candidates for SPKT. A secondary aim was to investigate survival following SPKT and living donor kidney transplantation (LDKT) in individuals with type 1 diabetes. Methods: The risk factors for Major Adverse Cardiovascular Events (MACE) were assessed in recipients of SPKT in the United Kingdom (UK) over a 15-year period. A cardiovascular risk score was calculated using pre-transplant variables and related to post transplant MACE in a subgroup of the national cohort. Cardiovascular events in SPKT recipients following failure of either the pancreas or kidney allografts were also assessed. To compare recipient and kidney allograft survival in SPKT and LDKT recipients, a meta-analysis of observational studies was undertaken. For the CMR study, three sheep underwent insertion of a ventricular pacemaker and received six weeks of ventricular tachypacing to induce heart failure and diffuse myocardial fibrosis, a further three sheep were used as controls. Diffusion weighted CMR methods were investigated ex-vivo for their ability to detect changes in collagen volume. Results: The epidemiological investigations demonstrate a high rate of MACE in SPKT recipients and highlight that non-fatal cardiovascular events increase the risk of subsequent allograft failure, while isolated allograft failure is associated with higher MACE risk. The recipient and donor factors associated with MACE are reported and a pretransplant cardiovascular risk score is related to post transplant MACE. The meta-analysis of studies comparing survival following SPKT and LDKT shows that LDKT is associated with better short-term outcomes while SPKT is associated with better survival ten or more years after transplantation. The results of the CMR investigations include the first report of relationships between diffusion orientated complexity and collagen, and diffusion imaging biomarkers and collagen subtype. Conclusions: This thesis provides a comprehensive assessment of CVD risk in UK SPKT recipients in the short, medium and long-term following transplantation. The large animal CMR studies provide histological validation of diffusion markers for fibrosis and introduce diffusion orientated complexity as a novel analytical method that is sensitive to changes in cardiac microstructure. The meta-analysis generates hypotheses that will be tested in the future work stemming from this thesis.

Date of Award	1 Aug 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Angela Summers (Supervisor), Christopher Miller (Supervisor), Josephine Naish (Supervisor), Martin Rutter (Supervisor) & David Vandellen (Supervisor)