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HLA matching; Kidney transplantation; Graft survival; Genetic polymorphisms; Non-HLA antigens; Immunogenetics; Allograft rejection; Donor-recipient compatibility; Long-term outcomes; Precision transplantation

Introduction

Kidney transplantation remains the preferred therapeutic option for patients with end-stage renal disease, offering improved quality of life and survival compared to dialysis. A critical determinant of transplant success is the degree of immunological compatibility between donor and recipient, traditionally assessed through human leukocyte antigen (HLA) matching [1-5]. While HLA compatibility—especially at loci HLA-A, HLA-B, and HLA-DR—has long been associated with reduced rates of acute rejection and improved long-term graft function, it does not fully account for the variability in outcomes observed among recipients. Increasing evidence suggests that non-HLA genetic factors, including polymorphisms in cytokine genes, complement system components, and innate immune receptors, also play a significant role in allograft survival. This review evaluates the combined influence of HLA and non-HLA genetic factors on long-term kidney graft survival and their potential applications in personalized transplant medicine [6-10].

Discussion

The role of HLA matching in transplantation is well established. Better-matched grafts—especially those with zero or minimal mismatches at HLA-A, -B, and -DR—are associated with reduced alloimmune responses and fewer rejection episodes. In living donor transplants, particularly from related donors, full HLA matches contribute to superior long-term outcomes. However, even perfectly HLA-matched grafts can fail due to other immunological and non-immunological causes, pointing to the importance of non-HLA factors.

Recent advances in genomic technologies have enabled researchers to identify non-HLA genetic variants that influence graft outcomes. For example, polymorphisms in the cytokine genes IL-10, TNF-α, and TGF-β have been linked to differential immune responses. High-producer genotypes for pro-inflammatory cytokines like TNF-α may predispose recipients to heightened immune activation and rejection risk. Similarly, variants in the complement system, such as those in the CFH (complement factor H) gene, have been implicated in complement-mediated injury and transplant glomerulopathy.

One of the most promising areas of non-HLA immunogenetics is the study of MICA (MHC class I chain-related gene A) antigens. Although not part of the classical HLA system, MICA molecules are polymorphic and expressed on endothelial cells. Anti-MICA antibodies have been associated with chronic rejection and worse graft survival. Moreover, killer-cell immunoglobulin-like receptors (KIRs), present on natural killer (NK) cells, interact with HLA class I molecules, and mismatches in KIR-HLA combinations can influence the risk of rejection through NK cell-mediated cytotoxicity.

Beyond immune-related genes, certain donor-recipient genetic mismatches in minor histocompatibility antigens (mHAgs), metabolic enzymes, and drug-metabolizing genes like CYP3A5 also influence transplant outcomes by modulating immune recognition or affecting immunosuppressant efficacy.

Large-scale cohort studies such as the DeKAF (The Deterioration of Kidney Allograft Function) and GEN03 have explored associations between genetic variants and graft outcomes, revealing that an integrated model combining HLA and non-HLA genetics offers better predictive power for graft survival than HLA typing alone.

Despite these advances, practical challenges remain in implementing full-scale genomic screening in clinical practice. The complexity of gene-gene and gene-environment interactions, the lack of consensus on which non-HLA markers are most predictive, and the need for cost-effective genotyping platforms have limited widespread adoption.

Conclusion

While HLA compatibility continues to be a cornerstone of kidney transplant success, it is increasingly clear that non-HLA genetic factors also significantly impact long-term graft survival. Polymorphisms in immune regulation, complement pathways, and endothelial antigen expression contribute to graft injury and rejection risk. A deeper understanding of these factors enables a more precise donor-recipient matching strategy, ultimately leading to personalized immunosuppression protocols and improved transplant outcomes. As next-generation sequencing becomes more accessible and integrated into transplant registries, the future of kidney transplantation lies in comprehensive immunogenetic profiling, offering a new era of precision transplant medicine.

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