Babu, Adarsh (2021) The role of the complement system in the presence of donor-specific antibodies and antibody incompatible renal transplantation. PhD thesis, University of Warwick.

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Abstract

Patients with advanced chronic kidney disease have a survival advantage if they get an organ transplant. The need for organs outstrips supply. Direct transplantation with pre-conditioning is the last, and sometimes the sole solution for highly sensitised patients against the shared donor pool of tissue antigens (HLA antigens).

The numbers of antibody-incompatible renal transplants have been increasing globally, as there is lower mortality with transplantation than remaining on dialysis. However, antibody-incompatible transplants carry the burden of increased long-term immunosuppression.

Current antibody assays have limitations in risk stratification of patients undergoing Human Leucocyte Antigen incompatible transplantation. Functional characteristics of anti-HLA antibodies may be helpful to predict graft outcomes.

In this thesis, I have investigated the role of IgM donor specific antibodies, and complement activating IgG donor specific antibodies in the context of HLAi renal transplantation.

Pre-treatment IgM donor-specific antibodies were not associated with early AMR or worse renal allograft survival, however post-transplant IgM donor specific antibodies were associated with worse graft survival, suggesting a role for testing IgM donor specific antibodies in early post-transplant period.

Pre-treatment, and post-transplant complement activating donor specific antibodies, as detected by C3d assay were associated with significantly worse renal allograft survival compared to patients with no C3d positive donor specific antibodies. In a single centre study, hazard ratio for graft failure was 2.85 (95% CI 1.018 – 8.01) in the presence of pre-treatment C3d-positive DSA. In multicentre centre study, hazard ratio for graft failure in pre-treatment C3d-positive DSA cases were 2.73 (95% CI 1.16 – 6.42). Patients with persistent C3d-positive donor specific antibodies had the lowest five-year graft survival of 46.5%, hazard ratio of 4.02 (95% CI 1.55 – 10.41). The finding from this thesis has shown benefit of testing for C3d donor specific antibodies to stratify patients before transplantation in the context of highly sensitized patients.

In this thesis, I also examined the effects of complement regulatory protein expression on the endothelial cells in the presence of anti-HLA antibodies. Surface expression levels of CD46, CD55 and CD59 were similar after stimulation for 24 and 48 hours. No modulation of membrane bound complement regulators implies that basal expression of proteins may vary between individuals and the difference in graft outcomes observed after episode of rejection.

Item Type:	Thesis (PhD)
Subjects:	Q Science > QP Physiology Q Science > QR Microbiology > QR180 Immunology R Medicine > RD Surgery R Medicine > RM Therapeutics. Pharmacology
Library of Congress Subject Headings (LCSH):	Kidneys -- Transplantation -- Complications, Immunoglobulins -- Therapeutic use, Antibody-dependent cell cytotoxicity, Tissue-specific antibodies, Graft rejection
Official Date:	13 October 2021
Dates:	Date Event 13 October 2021 UNSPECIFIED
Institution:	University of Warwick
Theses Department:	Warwick Medical School
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Mitchell, Daniel A. ; Daga, Sunil
Format of File:	pdf
Extent:	396 pages : illustrations (colour), charts
Language:	eng

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