Genomic Donor-Recipient Mismatches in Kidney Transplantation: A Focus on the Techniques and Approaches

In solid organ transplantation, HLA matching between donor and recipient is an important factor in maintaining graft survival. For this reason, national and international transplantation programmes include HLA matching into their algorithms for deceased donor organ allocation and are used in centres as guidance for maintenance immunosuppression. However, HLA matching explains only a short fraction of long term-outcomes. It is likely that assessing genome-wide compatibility could be the next step towards longer graft survival. Hence in this review, when a donor allele is not present in the recipient, we define this as a genomic mismatch. We describe how the context around a genomic mismatch (i.e. protein expression, surface accessibility, immune recognition, etc.) contributes to an alloimmune risk, which we define as an effective genomic mismatch. As a review focused on the technical aspects, we outline the core components one should consider in analysing the transplant pair through a genome-wide approach, and review current literature based on these core components, contrasting with HLA matching tools. While several studies have explored the role of the genomic mismatches between a donor and recipient, the biological and immunological context of this mismatch is required. Further advancements in this field will benefit greatly from established guidelines and tools. Concluding this review, we evaluate the clinical relevance of these sequencing-based approaches, and whether this increase in scope is valuable for further insights in alloimmunity.