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

Area of Science:

• Nephrology
• Immunology
• Transplantation

Background:

• Human Leukocyte Antigen (HLA) matching optimizes kidney transplant outcomes but explains limited variability.
• Emerging evidence suggests non-HLA genetic mismatches contribute to alloimmunity and graft loss.

Purpose of the Study:

• To systematically review and meta-analyze the association between donor-recipient (D-R) non-HLA single nucleotide polymorphism (SNP) mismatches and kidney transplant outcomes.
• To evaluate the impact of specific genetic variations, like LIMS1 mutations, on transplant success.

Main Methods:

• Systematic literature review of 1890 publications (Medline, Embase, Central) from 2019-2025.
• Meta-analysis of 12 eligible cohort studies investigating D-R non-HLA SNP mismatches and graft rejection/loss.
• PICOTS system used for study screening and inclusion criteria adherence.

Main Results:

• Overall D-R non-HLA SNP mismatch was numerically associated with increased rejection (HR 1.26) and graft loss (HR 1.35).
• Recipient LIMS1 loss-of-function mutations showed numerical associations with rejection (HR 1.23) and graft loss (HR 1.43).
• Effect sizes varied across publications, indicating a need for further research.

Conclusions:

• Non-HLA genetic mismatches represent a significant factor in kidney transplant outcomes.
• Quantifying the precise impact of these mismatches requires further investigation.
• Future immunosuppression protocols may benefit from incorporating D-R mismatch load assessments.