Identification of the complement C4d fragment in peritubular capillaries as a specific marker for antibody mediated rejection in renal transplantation revealed the critical role of antibodies in graft survival. In this thesis, I document the design and findings of studies performed to investigate the clinical impact of anti-HLA antibodies present before and/or after transplantation. Over time, the detection techniques for anti-HLA antibodies has evolved from the less sensitive complement-dependent lymphocytotoxicity (CDC) crossmatching (XM) to more sensitive solid phase assays such as Luminex®. Studies have been conducted to compare the predictive value of different antibody detection techniques. The first result chapter presents antibody specificity in positive CDC B-cell crossmatch (BXM), analysed with highly specific Luminex® assays. The study also investigates the predictive value of BXM in the general transplant population. I found that donor-specific anti-HLA antibodies (DSA) are only present in one third of positive BXM and are associated with poor outcomes. The novel finding is that >80% of the DSA detected by BXM are complement-fixing IgG₁ and IgG₃ subclasses. Transplant glomerulopathy (TG) is type of chronic renal graft rejection. The pathogenesis of TG is unclear. In the second result chapter, I report risk factors and involvement of anti-HLA antibodies in the development of TG. This study shows that glomerular rejection, delayed graft function, HLA presensitization and DSA have a univariate effect on TG development. Multivariate analysis revealed that DSA are an independent predictor of TG, after adjustment for other risk factors. I have further investigated the role of BXM in a unique, well-matched, highly sensitized patient group transplanted under the national renal exchange programme. I compared Luminex® antibody analysis with BXM in predicting transplant outcomes. In highly sensitized patients, DSA are found in two thirds of positive BXM. In univariate analyses, BXM is associated with humoral rejection whereas DSA defined by Luminex® are associated with total and all rejection types. The major finding is that, by multivariate analysis, DSA defined by Luminex® are an independent predictor of total and humoral rejection, but BXM are not. These interesting findings are reported in the third result chapter. Studies reported in this thesis define the clinical significance of anti-HLA antibodies in renal transplant outcomes. Method comparison studies provide useful information on antibody specificity and their impact on graft survival. Collectively, a better understanding of alloantibodies associated with graft rejection and limitation of antibody detection methods may facilitate donor selection and choice of immunosuppressants, and consequently improve transplant outcomes. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1379925 / Thesis (Ph.D.) - University of Adelaide, School of Medicine, 2010
| Identifer | oai:union.ndltd.org:ADTP/287575 |
| Date | January 2010 |
| Creators | Eng, Hooi Sian |
| Source Sets | Australiasian Digital Theses Program |
| Detected Language | English |
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