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Title: Donor specific HLA antibodies and renal transplant outcomes
Author: Willicombe, Michelle
ISNI:       0000 0004 2728 2124
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Despite the use of potent modern immunosuppressive agents chronic rejection remains the leading cause of allograft failure after renal transplant. Historically T cells were considered to be the main pivot of rejection mechanisms; however, over the past decade the key role of B cells in allograft rejection has been much more fully described. Antibody mediated rejection [AMR] was first classified as a distinct entity in the Banff histological classification of allograft pathology as late as 2001. This was a consequence of the demonstration of the complement split product C4d in renal allografts giving indirect evidence of humoral injury, along with the development of newer assays to detect circulating HLA donor specific antibodies [DSAs]; both of which were subsequently shown to be associated with reduced allograft survival. The development of solid phase technologies, in particular single antigen beads has introduced a readily available assay which can detect HLA DSA with high sensitivity and specificity. The benefit of routine application of such assays in renal transplantation is not known and is the principal question of this thesis; that is to establish if the detection of HLA DSAs will help in predicting rejection and allograft loss. Patients transplanted at Imperial College Renal and Transplant Centre were recruited into the studies. The underlying hypothesis is that donor specific antibodies identified by the more recently developed techniques are associated with inferior allograft survival, addressed in several related studies as follows: 1. Is C4d staining with no morphological features of rejection associated with risk of subsequent AMR and allograft loss? 2. Are preformed DSA detected by single antigen beads in the setting of a negative crossmatch associated with inferior allograft survival? 3. What is the relevance of de novo DSAs after renal transplantation? 4. What is the clinical significance of DQ DSA and should consideration be given to DQ mismatching in deceased organ allocation? 5. Do outcomes in patients with ACR with a humoral component differ when compared to those with pure ACR when treated in a uniform manner? A summary of the results is as follows: 1. C4d in the absence of histological features is not associated with AMR. However, patients with acute tubular injury who have DSA are at risk of subsequent AMR. 2. Patients with preformed DSA are at significant risk of AMR and allograft loss and as such antibodies detected by single antigen beads alone pre-transplant should be considered a relative contraindication to transplantation. 3. Patients who develop de novo DSA are at risk of AMR, transplant glomerulopathy [TG] and allograft failure. Routine testing for the detection of DSA may allow the potential to augment immunosuppression in order to improve outcomes. 4. DQ DSA are the most common DSA detected after transplant and are associated with inferior allograft outcomes. Patients mismatched at both DR and DQ alleles are at risk of developing DQ DSA. Algorithms incorporating the level of DQ mismatch might reduce DQ DSA formation and therefore improve long term allograft survival. 5. Patients with ACR with a humoral element are at risk of subsequent AMR, TG and graft failure. Such patients might benefit from more aggressive therapies than those targeted at ACR alone.
Supervisor: Cairns, Thomas ; Pusey, Charles Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral