Alexander Maxwell

Factors influencing survival after kidney transplant failure

BackgroundThe failure of a kidney transplant is now a common reason for initiation of dialysis therapy. Kidney transplant recipients commencing dialysis have greater morbidity and mortality than transplant-naïve, incident dialysis patients. This study aimed to identify variables associated with survival after graft failure.MethodsAll recipients of first, deceased donor kidney transplants performed in Northern Ireland between 1986 and 2005 who had a functioning graft at 12xa0months were included (nu2009=u2009585). Clinical and blood-derived variables (age, gender, primary renal disease, diabetic status, smoking status, human leukocyte antigen (HLA) mismatch, acute rejection episodes, immunosuppression, cardiovascular disease, graft survival, haemoglobin, albumin, phosphate, C reactive protein, estimated glomerular filtration rate (eGFR), rate of eGFR decline, dialysis modality, and access) were collected prospectively and investigated for association with re-transplantation and survival. The association between re-transplantation and survival was explored by modelling re-transplantation as a time-dependent covariate.ResultsMedian follow-up time was 12.1xa0years. Recipients with a failing graft (158/585) demonstrated rapid loss of eGFR prior to graft failure, reducing the time available to plan for alternative renal replacement therapy. Median survival after graft failure was 3.0xa0years. In multivariate analysis, age and re-transplantation were associated with survival after graft failure. Re-transplantation was associated with an 88% reduction in mortality.ConclusionsOptimal management of kidney transplant recipients with failing grafts requires early recognition of declining function and proactive preparation for re-transplantation given the substantial survival benefit this confers. The survival benefit associated with re-transplantation persists after prolonged exposure to immunosuppressive therapy.

AbstractsNew onset diabetes after transplantation: unravelling the pathophysiological process

Abstract Background Kidney transplantation is a procedure that transforms recipients lives, and 1-year transplant and patient survival are now excellent. However, improvements in long-term outcomes after kidney transplantation have been disappointing. New onset diabetes after transplantation (NODAT) is a common complication that reduces recipient survival. The aim of this study was to investigate clinical, genetic, and epigenetic risk factors for NODAT. Methods We included all adult recipients of first, deceased-donor kidney transplants in Northern Ireland between 1986 and 2005 who had a functioning transplant at 12 months. NODAT was defined as diabetes developing after transplantation that required pharmacotherapy. Clinical data were recorded prospectively and variables associated with NODAT were identified in multivariate analysis. A genome-wide association study (GWAS) was done in a subset of NODAT cases and controls (Illumina 660K array). Single nucleotide polymorphisms (SNPs) associated with NODAT and SNPs previously reported to be associated with NODAT in a white population were subsequently genotyped in all NODAT cases and controls. Epigenome wide DNA methylation analysis was performed (Infinium Methylation 450K array) on blood-derived DNA acquired immediately before transplantation. Findings Of 529 patients receiving kidney transplants, 57 developed NODAT. In multivariate analysis, recipient age (odds ratio [OR] 1·4 per decade, 95% CI 1·1–1·8), female gender (2·2, 1·2–4·3), weight at transplantation (1·03 per kg, 1·01–1·05), and percentage weight gain in the first year (2·0, 1·3–3·1) were associated with NODAT. There were 561u2008233 SNPs genotyped in the subset of 26 NODAT cases and 230 controls; 26 SNPs were associated with NODAT (p −5 ). De-novo genotyping was undertaken in 57 NODAT cases and 383 controls. In multivariate analysis, eight novel SNPs remained associated with NODAT (rs10484821, rs7533125, rs2861484, rs11580170, rs2020902, rs1836882, rs198372, rs4394754). In gene enrichment analysis, the response to stimulus gene set had the highest enrichment score (p=0·006). DNA methylation was analysed at 485u2008577 CpG sites. After quality control, differential methylation at 14 CpG sites remained associated with NODAT (ANOVA p −5 ). These associations did not persist after adjustment for multiple testing. Interpretation This is the first genome and epigenome wide association study, to our knowledge, to investigate variants for association with NODAT. Eight novel SNPs remained associated with NODAT after adjustment for potentially confounding clinical variables. Seven of these SNPs are implicated in β-cell apoptosis. Our results corroborate recent reports suggesting that β-cell stress due to post-transplant hyperglycaemia could be crucial in the pathogenesis of NODAT. There was no association between DNA methylation before transplantation and NODAT. However, it is plausible that hyperglycemia post-transplantation alters DNA methylation in key genes and might contribute to NODAT pathogenesis in this manner. This hypothesis requires further investigation. Funding Funding Kidney Research UK, Northern Ireland Kidney Research Fund.