The impact of eplet mismatches and de novo donor specific antibodies in kidney and simultaneous pancreas-kidney transplantation

Improving kidney transplant graft survival is of critical importance to patients, caregivers and health professionals. Advances in immunosuppression regimens have mitigated the risk and injurious effects of T-cell mediated rejection resulting in increased graft survival rates, particularly in the first year after transplantation. The leading cause of graft attrition is now antibody mediated rejection (AMR), implicated in up to two thirds of graft loss after one year. Donor specific antibodies (DSA) are central to the pathogenesis of AMR, with the presence of pre-transplant DSA (or sensitisation) reducing access to transplantation due to the risk of hyper-acute or acute AMR. Children with end-stage kidney disease (ESKD) are particularly disadvantaged by sensitisation due to their expected need for re-transplantation, yet strategies to avoid sensitisation and overcome this antibody barrier are poorly defined. Chapter 2 of this thesis provides an overview of sensitisation and desensitisation therapies in children with ESKD. Similar to pre-transplant DSA, de novo DSA (dnDSA) may form after transplantation and are implicated in AMR. The incidence and magnitude of effects of dnDSA on graft and patient outcomes is however variably reported in the literature. Chapter 3 of this thesis provides a systematic review and meta-analysis of the association between dnDSA and graft and patient outcomes. Greater understanding of the harmful effects of dnDSA has increased interest in developing strategies to avoid their development. Current assessment of histocompatibility considers whole HLA antigen mismatches, the precision of which may be improved by accounting for differences in the surface antibody accessible amino acid sequences (eplets) on donor and recipient HLA. Previous studies have demonstrated that increasing number of eplet mismatches are associated with dnDSA development, acute rejection and transplant glomerulopathy. This relationship is particularly evident for HLA class II eplet mismatches and is modified by immunosuppression. The longitudinal relationship between eplet mismatches, dnDSA and acute rejection outcomes has however been poorly defined in children and is addressed by Chapter 4 of this thesis. Apart from requiring a greater understanding of the causal pathways between eplet mismatches and graft outcomes, a further challenge to utilising eplet mismatch information in organ allocation is the large number and complexity of mismatches which require consideration. Eplet mismatches are recognised to have innate properties such as electrostatic potential which confer their ability to induce an immune response (immunogenicity) or produce subsequent alloantibody recognition (antigenicity). Differentiating between the specific eplet mismatches which are predictive of adverse graft outcomes and those which are less likely to produce an immune response may allow assignment of unacceptable mismatches and permissible mismatches, thus simplifying implementation into organ allocation. Chapters 5 and 6 of this thesis identify specific eplet mismatches which predict dnDSA and acute rejection outcomes. The studies within this thesis collectively detail the relationship between eplet mismatches, dnDSA and acute rejection in kidney transplantation and identify specific eplet mismatches which are predictive of adverse graft outcomes