National Institute of Diabetes and Digestive and Kidney Diseases 5K08DK134762-04

Implementation of Eplet Mismatch Analysis in Pediatric Kidney Transplantation

This award funds research to analyze high-risk eplet mismatches in pediatric kidney transplantation to improve organ allocation and long-term graft survival by developing an adaptive allocation model incorporating molecular mismatch analysis.

Description

Donor specific HLA antibodies (DSA) develop against short amino acid sequences (eplets) within the HLA antigen and lead to early graft loss in kidney transplant recipients. Identifying which mismatched eplets are most high-risk for DSA formation can help to avoid these in upcoming transplants and improve long-term allograft survival. This research will inform the development of a novel and adaptive allocation model aimed at reducing immunological burden, minimizing health disparities, and ensuring optimal organ utilization. Kidney transplant (KT) offers a significant survival and morbidity benefit over dialysis, making it the preferred treatment modality for end-stage kidney disease. While late allograft failure has a multifactorial etiology, one of the largest contributors is the development of donor specific HLA antibodies (dnDSA), leading to allograft loss at a median 3-5 years post detection of antibodies. Donor specific HLA antibodies develop against short amino acid sequences within the HLA antigen. Each HLA antigen has multiple epitopes that can interact with the recipient immune system, and antibody-verified epitopes are termed “eplets”. Mismatched epitopes can be identified and enumerated using various molecular mismatch software packages. However, not all epitopes are equally likely to induce an antibody response in the recipient, as specific “high-risk” eplet mismatches were found to be disproportionally associated with dnDSA formation. Avoidance of high-risk mismatches between donor and recipient at the time of organ allocation is one way to improve long-term allograft survival because it would reduce the number of potential dnDSA targets. Variable immunogenicity is an accepted concept; however, details about which mismatches are high risk have not been well established. The project proposes to establish a multi-site pediatric kidney transplant (KT) cohort with full HLA genotyping on recipients and donors to perform such an analysis. This will inform the development of an adaptive allocation model that can better account for the entangled and dynamic nature of allocation systems. The Organ Procurement and Transplant Network (OPTN) has mandated the development of a new allocation model, to develop a composite allocation scoring system that can account for dynamic changes in multiple recipient and donor characteristics. There is insufficient data to inform such a model on how to handle HLA mismatch on an epitope-level. The work with the multi-site cohort will inform how to best incorporate molecular mismatch analysis and high-resolution tissue typing data into an adaptive allocation model.

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