Improving renal graft survival

a characterization of antibodies and complement regulatory proteins

Laura Michielsen

Promoter:
Prof.dr. M.C. (Marianne) Verhaar
Co-promoter:
Dr. A.D. (Arjan) van Zuilen & dr. H.G. (Henny) Otten
Date:
January 24, 2019
Time:
14:30 h

Summary

The most common cause of graft failure in kidney transplant recipients, apart from death with a functioning graft, is antibody-mediated rejection (AMR). The presence of donor-specific HLA antibodies (DSA) is a well-established risk marker for AMR, whereas the relevance of non-donor specific HLA antibodies (nDSA) and non-HLA antibodies is less well understood. In addition, not all patients with DSA experience AMR. One of the potential explanations for this observation is that some allografts may be more capable to protect themselves against antibody-mediated injury by enhanced complement regulatory capacities. A better understanding of the impact of antibodies and complement regulation on rejection and graft loss can help to identify patient groups at increased risk and guide monitoring and immunosuppressive therapy.

We studied the impact of pretransplant DSA and nDSA on graft survival in a paired kidney design. The results confirmed that the presence of pre-transplant DSA in deceased donor transplantations is a risk marker for graft loss, whereas nDSA in general were not associated with a lower graft survival. Given the increased incidence of acute rejection and graft loss in patients with pretransplant DSA, this group probably requires an intensified immunosuppressive therapy compared to patients at immunological low-risk. Covariate adjusted analyses suggested that in immunological low-risk patients excellent long-term graft survival can be achieved irrespective of the type of initial immunosuppressive therapy (cyclosporine or tacrolimus; with or without MMF), despite a higher incidence of acute rejection in the patients treated with a cyclosporine-based regime.

As a protection mechanism against complement activation, donor endothelial cells express complement regulatory proteins (CD46, CD55 and CD59). Genetic polymorphisms may affect protein levels and function. In kidney donors, CD46 and CD59 promoter polymorphisms were associated with 1-year rejection free survival. When combining two polymorphisms in CD46 and CD59, we observed that none of the patients receiving a kidney with both protective genotypes suffered from acute rejection within the first year nor lost their graft within five years. Further studies on complement regulation in this thesis revealed amongst others that the expression of CD59 on leukocytes is reduced posttransplantation, which could result in decreased resistance against complement and enhanced T-cell activation.

Integration of the pretransplant antibody profile, complement polymorphisms, with other traditional and novel risk markers may result in a more complement immunologic risk profile. This risk profile can then be used for personalized immunosuppressive strategies but also posttransplant surveillance to assess immunosuppression adequacy.