Genome-wide donor-recipient non-HLA mismatch and graft loss

HLA-matching between donor (D) and recipient (R) is routinely performed in kidney allocation to optimize allograft survival but explains only a moderate variability of these outcomes. Recent findings suggest that donor-to-recipient mismatches outside the HLA region contribute to alloimmunity and graft loss, but the extent varies in different publications. We therefore conducted a systematic review of publications on this subject using a broad search string in our literature review in accordance with current guidelines for systematic reviews. The effect sizes were analyzed by a meta-analysis. A total of 1890 publications from 2019-25 within three different repositories (465 Medline, 1408 Embase, 17 Central) were systematically screened using the PICOTS (Population, Intervention, Comparator, Outcome, Time and Setting) system, which resulted in 12 eligible papers that met the inclusion criteria. Cohort studies that investigated the association of D-R non-HLA SNP mismatch and graft rejection/loss in renal transplant patients were included. We found that overall SNP mismatch between D-R pairs outside the HLA region was independently numerically associated with rejection hazard ratio (HR) 1.26 [95% confidence interval (CI) 0.97-1.65] and graft loss HR 1.35 (95% CI 0.86-2.12). Furthermore, loss of function mutation of the gene LIMS1 in the recipient who received a transplant organ with at least one functioning copy (collision genotype) was numerically associated with rejection HR 1.23 (95% CI 0.68-2.23) and graft loss HR 1.43 (95% CI 0.61-3.36). The exact quantification of the effect size of these mismatches varied by publication and needs further investigation. Based on these data, the strength of immunosuppression may be guided by the load of D-R mismatches in the future.