Genetics of acute rejection after kidney transplantation

Abstract

SUMMARY Treatment of acute rejection (AR) following kidney transplantation has improved in recent years, but there are still limitations to successful outcomes. This review article covers literature in regard to recipient and donor genetics of AR kidney and secondarily of liver allografts. Many candidate gene and some genome-wide association studies (GWASs) have been conducted for AR in kidney transplantation. Genetic associations with AR in kidney and liver are mostly weak, and in most cases, the associations have not been reproducible. A limitation in the study of AR is the lack of sufficiently large populations that account for population stratification to study the AR phenotype which in this era occurs in <10% of transplants. Furthermore, the AR phenotype has been difficult to define and the definitions of classifications have evolved over time. Literature related to the pharmacogenomics of tacrolimus is robust and has been validated in many studies. Associations between gene expression and AR are emerging as markers of outcomes and AR classification. In the future, combinations of pretransplant genotype for AR risk prediction, genotype-based immune suppressant dosing, and pharmacogenomic markers to select AR maintenance or treatment and expression markers from biopsies may provide valuable clinical tools for guiding treatment.

Association between epidermal growth factor (EGF) and EGF receptor gene polymorphisms and end-stage renal disease and acute renal allograft rejection in a Korean population

“…Acute renal allograft rejection (AR) is the single most important risk factor for developing chronic renal allograft rejection [4,5]. Numerous genetic polymorphisms have been determined to be associated with AR, including those in human leukocyte antigens (HLA) [6]. Despite the advances made in immunosuppression and technical care of renal transplant recipients, leading to an improvement in the first-year allograft survival, chronic renal allograft rejection continues to be a major impediment over the decades [7][8][9].…”

Precision Sub-phenotyping of Histologically Stable Kidney Transplants by a Composite Molecular and Cellular Instability Score

“…In this study we identified discrepancies in the current histological recognition of stable allografts and demonstrated a new Instability Score (or InstaScore), a linear combination of selected features based on the input from tissue gene expression and inferred cell type biopsy molecular data modeled on AR biology, that provides precise (sub-)phenotyping and early recognition of molecular and cellular rejection of otherwise functionally and histologically stable allografts on protocol biopsies. Unlike other published studies by others [61][62][63][64][65] and our group [2,54,66,67] that have only studied gene expression transcriptional perturbation in AR, this is the first development and application of a combined genes and cell types into Instability Score in tissue that can rapidly reclassify samples into molecularly and even more importantly, functionally relevant, diverse groups: those most similar to the normal kidneys (hSTA/mSTA) and those most similar to the rejected kidneys (hSTA/mAR).…”

Joint testing of donor and recipient genetic matching scores and recipient genotype has robust power for finding genes associated with transplant outcomes

“…Genetic association studies for transplant outcomes tend to look at the recipient genome only (Dorr, Oetting, Jacobson, & Israni, 2018). Individual recipient single nucleotide polymorphisms (SNPs) have been found to be associated with acute rejection outcomes for kidney, liver, and heart transplants (Almoguera et al, 2014; Green et al, 2017; Morris et al, 2015).…”

“…Individual recipient single nucleotide polymorphisms (SNPs) have been found to be associated with acute rejection outcomes for kidney, liver, and heart transplants (Almoguera et al, 2014; Green et al, 2017; Morris et al, 2015). Recipient's genes have also been found to affect pharmacogenetic outcomes, such as immunosuppressant concentration in transplant recipients (Almoguera et al, 2014; Dorr et al, 2018; Oetting et al, 2016). Multiple studies have examined how differences in transplant outcomes that seem to be based on self‐reported race may be because of underlying genetic differences between different ethnic groups (Green et al, 2017; Morris et al, 2015).…”