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Title: The significance of antibody in the steroid-free era of kidney transplantation
Author: Lawrence, Christopher
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Kidney transplantation provides the best hope of normalised quantity and quality of life for patients with end stage renal failure. It is a cliché to state that organs for transplantation are a scarce resource; however it is true to say that demand for transplantation continues to grow. One reason for this growth in the waiting list is the return of transplanted patients to the waiting list for a subsequent transplant. Whilst short term graft survival has improved over the decades since kidney transplantation was first performed in 1954, long term graft attrition rates remain a problem. Over the last decade we have become increasingly aware, some would say we have become aware again, of the importance of the humoral immune response in the causation of long term graft loss. This thesis examines the issue of antibody in transplantation in a comprehensive manner. Firstly, the thesis deals with the issue of improving access to transplantation by reporting the results of a blood group-incompatible transplant programme and an HLA-incompatible transplant programme (HLAi - T cell flow cross match positive) conducted in West London during the last decade. Reasons for success in these programmes are explored by an examination of the characteristics of the antibody barrier being crossed. Secondly, when this research was devised the transplant community did not apportion high risk status to a kidney transplant which proceeded with negative CDC and flow crossmatch, but in the presence of a low level pre-formed donor-specific antibody (DSA). Using stored serum samples to test the complement-activating characteristics of DSA we are able to predict the impact of such low level DSAs on outcomes. Thirdly, the significance of de novo DSA has been debated. In this thesis we explore the characteristics of the patients and the antibody in 70 patients (15% of those transplanted) who develop a de novo DSA. Two methods of detecting complement-activation in vitro using microbeads are directly compared. An attempt was made to bypass the expensive consumables by directly measuring serum levels of the anaphylatoxin, C5a, and DNA analysis of common complement inhibitors was performed to identify whether the recipient complement system phenotype, or 'complotype', influenced transplant outcomes. The study concludes that a close examination of the property of donor-specific antibody both before and after transplantation allows immunological risk stratification and should be used to make better decisions relating to which transplants should go ahead and which should not, at least directly. The study concludes that there is currently no substitute to Luminex technology and that recipient complement gene polymorphisms do not have a material influence on allograft survival. There is need for further work to establish the role of complement inhibitors in transplantation and to explore alternative strategies for the prevention of allosensitization in the first instance and subsequently for the prevention of alloimmune injury to the graft.
Supervisor: Lightstone, Liz; Warrens, Anthony Sponsor: Imperial College Healthcare NHS Trust
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available