Using Genetic Variation to Predict and Extend Long-term Kidney Transplant Function

Abstract

Renal transplantation has transformed the life of patients with end-stage renal disease and other chronic kidney disorders by returning endogenous kidney function and enabling patients to cease dialysis. Several clinical indicators of graft outcome and long-term function have been established. Although rising creatinine levels and graft biopsy can be used to determine graft loss, identifying early predictors of graft function will not only improve our ability to predict long-term graft outcome but importantly provide a window of opportunity to therapeutically intervene to preserve graft function before graft failure has occurred. Since understanding the importance of matching genetic variation at the HLA region between donors and recipients and translating this into clinical practise to improve transplant outcome, much focus has been placed on trying to identify additional genetic predictors of transplant outcome/function. This review will focus on how candidate gene studies have identified variants within immunosuppression, immune response, fibrotic pathways, and specific ethnic groups, which correlate with graft outcome. We will also discuss the challenges faced by candidate gene studies, such as differences in donor and recipient selection criteria and use of small data sets, which have led to many genes failing to be consistently associated with transplant outcome. This review will also look at how recent advances in our understanding of and ability to screen the genome are starting to provide new insights into the mechanisms behind long-term graft loss and with it the opportunity to target these pathways therapeutically to ultimately increase graft lifespan and the associated benefits to patients.

The 1-year Renal Biopsy Index: a scoring system to drive biopsy indication at 1-year post-kidney transplantation

“…In contrast, we could not propose a decision rule to convince transplantation centers usually performing a 1‐year surveillance biopsy to avoid biopsies for patients on the basis of 1‐RBI calculation as only 1% of patients presented a high chance of normal or mild IFTA for a NPV of 80%, and a corresponding threshold of 1‐RBI of 0.43. The 1‐RBI seems to not be a surrogate for avoiding a surveillance biopsy, but instead a simple clinical tool to help indication for a 1‐year biopsy when there is a good likelihood of observing potential actionable histological lesions despite bleeding risk after a biopsy and despite being aware that there is no clear therapeutic consensus according to the identification of most histological lesions . Note that we did not observe abnormal bleeding rate compared to the literature with 1% of hematoma and serious bleeding and 0.05% isolated and rapidly recovering hematuria since 2006 in our whole cohort .…”

“…Thus, the inclusion of such a marker in the 1‐RBI could lead to achieving a diagnostic tool that is more accurate in terms of NPV. There is also an increasing interest in other markers that could predict histological lesions, such as acute rejection . Secondly, the definition of both AH and NSH groups can be discussed.…”

Single Nucleotide Polymorphisms and Long-Term Clinical Outcome in Renal Transplant Patients: A Validation Study

“…A genetic profile is a nonmodifiable risk factor, but risk stratification based on susceptibility loci might allow for more tailored immunosuppressive drug regimens . In addition to the benefit for the individual patients, there is hope that research based on “‐omics” techniques will provide valuable insight into the mechanisms responsible for long‐term graft loss . Genome‐wide association studies (GWAS) allow for screening of a large proportion of the genome in search for genetic variants that can confer higher risk of disease or higher rate of disease progression.…”

Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study

“…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.…”