Despite advances in medical science, dialysis treatment for end stage renal disease remains fraught with complications and severely limits the quality and longevity of life in these patients. Renal transplantation allows for an enhanced length and quality of life. Unfortunately the demand for kidneys outstrips the supply and nephrologists have taken to performing transplantation in conditions that were previously thought impossible. Human leucocyte antigen (HLA) antibody incompatible transplantation, a process of transplanting kidneys into recipients who have antibodies against HLA antigen on the donor kidney, has recently become an acceptable mode of transplanting patients who would have previously died whilst on dialysis. Although increasingly successful, the Achilles’ heel of this form of transplantation remains acute antibody mediated rejection (AMR), a particularly severe form of rejection. It is generally accepted that the complement system is intricately involved in the process of acute AMR and, indeed, C4d, a split product of complement factor C4, when detected on renal biopsies in the correct context, is considered by the BANFF classification (an internationally accepted method of classifying renal transplant rejection) to be a hallmark feature of acute AMR. The sensitivity and specificity of this test, however, is increasingly debated and requires an interventional diagnostic test that is not without risk. A “blood” test to detect or predict the onset of acute AMR is not available. In addition, although the complement system is known to be involved in acute AMR, characterisation of the three complement pathways and the degree of their systemic activation has not been fully described. Although the liver is the main source of complement factors in the body, other organs such as the kidney, are capable of synthesizing complement. It is unknown whether the complement factors involved in acute AMR following renal transplantation are of systemic or local origin. It is also not known which renal cell, if any, is responsible for this. Importantly, the first cells to encounter antibodies against antigen on their surfaces, the renal microvascular endothelial cells, have not so far been shown to be able to produce complement factors. This thesis briefly examines changes in antibody levels during the process of HLA antibody incompatible transplantation, histological features associated with subsequent graft dysfunction and possible serum markers (soluble CD27 and Cd30) that could indicate onset of AMR. Whilst anti-HLA antibody monitoring was found to be useful in the management of patients it was not possible to use levels to predict rejection or accommodation of the graft. No correlation was found between soluble factors CD27 and CD30 and AMR. The thesis then examines the effect of HLA antibody incompatible renal transplantation on the complement pathways and on the levels of complement factors C3a and C4a. There was no systemic pathway activation in the presence of rejection. Systemic levels of C3a and C4a did not rise with a simultaneous increased level of HLA antibodies or with rejection episodes. Indeed, in patients who did not have an episode of rejection and in those with rejection but no evidence of C4d on renal biopsy, mean C4a levels were significantly lower at 4-6 weeks when compared to those who did have C4d-postive AMR. This points to a role for inhibitory mechanisms in these patients. The thesis also demonstrates the ability of microvascular endothelial cells (including of glomerular origin for the first time) to produce complement C4 on stimulation with gamma interferon and with antibodies against the cell HLA type. Finally, the thesis briefly examines the possible use of a complement inhibitor in the treatment of AMR.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:560425 |
| Date | January 2012 |
| Creators | Hamer, Rizwan |
| Publisher | University of Warwick |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://wrap.warwick.ac.uk/51636/ |
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