Long– and Short–term Outcomes in Renal Allografts With Deceased Donors

A Large Recipient and Donor Genome-Wide Association Study

Maria P. Hernandez-Fuentes; Christopher Franklin; Irene Rebollo-Mesa; Jennifer Mollon; Florence Delaney; Esperanza Perucha; Caragh Stapleton; Richard Borrows; Catherine Byrne; Gianpiero Cavalleri; Brendan Clarke; Menna Clatworthy; John Feehally; Susan Fuggle; Sarah A. Gagliano; Sian Griffin; Abdul Hammad; Robert Higgins; Alan Jardine; Mary Keogan; Timothy Leach; Iain MacPhee; Patrick B. Mark; James Marsh; Peter Maxwell; William McKane; Adam McLean; Charles Newstead; Titus Augustine; Paul Phelan; Steve Powis; Peter Rowe; Neil Sheerin; Ellen Solomon; Henry Stephens; Raj Thuraisingham; Richard Trembath; Peter Topham; Robert Vaughan; Steven H. Sacks; Peter Conlon; Gerhard Opelz; Nicole Soranzo; Michael E. Weale; Graham M. Lord

Disclosures

American Journal of Transplantation. 2018;18(6):1370-1379. 

In This Article

Abstract and Introduction

Abstract

Improvements in immunosuppression have modified short–term survival of deceased–donor allografts, but not their rate of long–term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short– and long–term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large–scale genome–wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant–pairs with replication in 5866 complete pairs. We studied deceased–donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long– or short–term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application.

Introduction

Kidney transplantation is a highly successful treatment for end–stage renal failure, with significant benefits for recipients both in survival and quality of life. Early outcomes have steadily improved over the last 10 years,[1] with risk–adjusted and death–censored, 1–year renal graft survival rates of 94% and 97% for deceased and living donor transplants, respectively.[2] However, both late allograft loss and increased mortality among transplant recipients remain key challenges for the transplant community. There are a wide number of factors that are known to influence long–term transplant outcome, including donor factors such as age and comorbidity, recipient factors such as comorbidity and response to immunosuppression, as well as allograft ischemic time, the degree of HLA mismatch, and the development of donor–specific antibodies.[3,4,5] However, a comprehensive understanding of the pathophysiology of graft failure has remained elusive, with the observed variation in patient outcomes still inadequately explained by our current understanding of risk factors. An improved understanding of the determinants of transplantation outcome would allow the development of truly personalized approaches to the management of transplant recipients.

The importance of genetic factors in transplantation has been clear since the inception of the technique, with the first successful kidney transplant having been performed between identical twins in 1954. Renal transplantation between identical twins continues to show excellent long–term outcomes,[6,7] and HLA matching has a large impact on graft survival even in the modern era of immunosuppression.[8]

HLA genes are highly polymorphic, and demonstrate the importance of genetic variation in donor–recipient pairing that impacts on long–term outcomes. However, over recent decades, our ability to assay human genetic variation beyond the HLA region has increased considerably.

A number of studies have been published over recent years exploring the association between genotypes of interest and renal transplant outcomes.[9,10] A large proportion of these studies have concentrated on immune–related genes, based on the hypothesis that the risk of acute rejection or late allograft loss may be modulated by genetic variation in the immune response. As summarized in Table S1, associations have been described between various transplant phenotypes and single nucleotide polymorphisms (SNPs) in a number of genes including those encoding tumor necrosis factor–α, interleukins–1, −6, and −10, and interferon–γ. Of note, many of these studies have reported inconsistent findings. For example, analysis of DNA from donor–recipient pairs in the Collaborative Transplant Study failed to replicate an earlier finding that particular combinations of C3 genotypes in the donor and recipient were associated with reduced graft survival.[11,12] While some of this discrepancy might be explained by methodological or populational differences between these studies, it is difficult to draw firm conclusions about the role of these genetic variations.[13]

More recently, attention has also focused on non–immune–related genetic risk variants. Donor genetic variation in CAV1 (caveolin–1),[14]APOL1 (apolipoprotein–L1),[15,16] or ABCB1 (ATP–binding cassette, subfamily–B, member–1, expressed in the kidney) genes [17,18] has been reported to be associated with increased risk of allograft failure or poorer recipient survival. Recipient genetic variation effects on graft and patient survival have only been reported in 1 cohort for CAV1.[14] In addition to effects of donor genetic variants, it might be expected that recipient genotypes in other pharmacometabolic pathways might also impact on transplant outcomes such as increased risk of acute rejection.[19]

In general, candidate gene studies in renal transplantation have so far failed to provide consistent and reproducible results. Some of the reasons for this may include small sample sizes, variations in genotyping methodology and strategy, and, perhaps most importantly, a lack of consistency in clinical phenotyping.[20] Genome–wide association studies (GWAS) have contributed greatly to an increased understanding of complex common conditions such as inflammatory bowel disease, hypertension, type 2 diabetes, and schizophrenia.[21] A small number of GWAS have been reported in the field of renal transplantation, describing SNPs associated with cardiovascular adverse events in recipients taking calcineurin inhibitor immunosuppression,[22] 2 SNPs associated with serum creatinine levels at 5 years posttransplant,[23] and a number of SNPs associated with the development of new–onset diabetes after transplantation.[24] Recently, a GWAS using pooled DNA of recipient–only origin found variation in 2 new loci associated with acute rejection in both univariate and multivariate analysis.[25] However, these studies were underpowered for discovery of genetic variants with small effect sizes.

The Wellcome Trust Case Control Consortium (www.wtccc.org.uk/ccc3) has led the deployment of GWAS in a wide range of conditions. As part of WTCCC–3, all renal transplant centers in the United Kingdom and Ireland formed the United Kingdom and Ireland Renal Transplant Consortium (UKIRTC; www.ukirtc.org). Collaborative initiatives such as these are essential for the collection of adequate sample numbers, for the sharing of expertise, standardization of techniques, and building consensus on accurate phenotyping of clinical data. Through this consortium, 3936 samples comprising 2094 complete donor–recipient pairs were tested in the GWAS discovery phase, and an additional 5866 complete donor–recipient pairs in the replication phase, making this the largest GWAS conducted to date in renal transplantation outcomes.

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