A prospective clinical trial of immunosuppression reduction in recipients of low eplet mismatched renal allografts: the kidney for life initiative

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PROJECT SUMMARY Kidney transplantation is the best available treatment for end stage renal disease as it improves both survival and quality of life and is more cost effective than dialysis. However, the lifespan of transplanted kidneys is shortened due to chronic immune-driven injury and the direct nephrotoxicity of immunosuppressive drugs. Premature graft loss and the need for re-transplantation worsens an already dire organ shortage. Prolonging graft survival may hinge on optimizing immunologic matching of donors with recipients, to minimize targets of immunologic attack and decrease the need for aggressive immunosuppression. HLA matching has historically relied upon comparison of donor and recipient HLA genotypes determined either by serologic analysis or two- dimensional gene sequences. With newer high-resolution genotyping, the physical structures of HLA antigens can be predicted, enabling comparisons of donor/recipient HLA genotypes at the molecular level. In brief, with high-resolution genotype data, a computer algorithm called HLAMatchmaker can distill gene sequences into strings of polymorphic amino acids termed ‘eplets’ that are located on the HLA molecule surface and are thus accessible to the host immune system. When donor and recipient HLA genotypes are translated into their corresponding eplets, we can tally the immunologically recognizable differences between them as the number of eplet mismatches. Retrospective data indicate that patients who, by chance, received deceaseddonorkidneys with a low eplet mismatch (MM) load have lower rates of de novo donor specific antibody (dnDSA) formation, superior graft survival, and may require less immunosuppression. With living donation, there is opportunity to evaluate multiple potential donors for a given recipient and compare their degree of eplet MM before choosing which donor to proceed with to transplant. Thus, living donor kidney transplant (LKDT) recipients are the optimal patient population in which to test whether optimizing eplet matching indeed yields transplants that are at lower alloimmune risk. In collaboration with the largest paired kidney exchange, the National Kidney Registry (NKR), we have begun combining eplet MM analysis with its existing donor-recipient matching algorithms in order to generate high volumes of low eplet MM living donor kidney transplants. These transplants are now being performed at centers across the country as part of this pilot program. Preliminary data indicate that dnDSA formation is rare occurred in these recipients, however the degree to which low eplet MM LDKT permits immunosuppression reduction is not known. This R34 grant will enable us to design a multi-center randomized trial to prospectively test immunosuppression reduction in recipients of low eplet MM LDKT, as well as to compare the safety and efficacy of low eplet MM LKDT to high eplet MM LDKT. If our hypothesis is correct, we will establish a pathway by which donor/recipient matching can be optimized to maximize graft longevity and ultimately improve both patient survival and quality of life.