Anti-Angiotensin II Type 1 Receptor Antibodies and Kidney Transplant Outcomes

Overview

Incompatibility between non-genetically identical donors and recipients has been increasingly recognized as the main contributing factor to solid allograft rejection and failure, through the triggering of donor-specific responses mediated by T- and B-lymphocytes. The Human Leucocyte Antigen (HLA) system has been identified as the main target of donor-specific responses, especially through the production by the recipient of antibodies directed toward non-self donor HLA molecules expressed on the allograft endothelium. As a consequence, in organ transplantation, the current approach to immunological risk stratification, patient monitoring and rejection diagnosis is based on biomarkers derived from the HLA system. However, this approach does not provide a sufficient accuracy for the risk stratification and the diagnosis of immunological complications in solid organ transplantation, which still remain the dominant cause of allograft failure. A recent body of evidence supports that specific non-HLA antigens expressed on the allograft endothelium may be relevant to allograft rejection, suggesting that a new strategy to transplant diagnostic testing at a non-HLA level would help to overcome the limitations of the current HLA-based approach to immunological assessment of transplant recipients. Among antibodies to non-HLA endothelial antigens, angiotensin II type 1 receptor activating antibodies have been the most widely reported antibodies to associate with the occurrence of allograft rejection, dysfunction and loss, even if their independent role, with respect to the presence of concomitant anti-HLA antibodies, has not been demonstrated.

The aims of this study are: 1. To assess the incidence of post-transplant anti-angiotensin II type 1 receptor antibodies within the first year after transplantation in an unselected population of kidney transplant recipients. 2. To investigate the incidence of biopsy-proven kidney allograft rejection according to the presence of post-transplant anti-angiotensin II type 1 receptor antibodies and of post-transplant concomitant donor-specific anti-HLA antibodies within the first year after transplantation, and to evaluate the incidence of rejection cases associated with anti-angiotensin II type 1-receptor antibodies that are not recognized by the current diagnostic approach based on HLA testing. 3. To investigate the allograft injury phenotype associated with post-transplant anti-angiotensin II type 1 receptor, using histopathology, immunochemistry and measurement of endothelial-associated transcript (ENDAT) expression level in allograft. 4. To evaluate the impact of post-transplant anti-angiotensin II type 1 receptor antibodies on kidney allograft survival up to 7 years after inclusion, in univariate and multivariable survival models including clinical, histological and immunological risk factors for allograft loss. This study includes kidney recipients transplanted between January 1, 2008 and December 31, 2012 at Necker and Saint-Louis Hospitals (Paris, France), who undergo screening for post-transplant anti-angiotensin II type 1 receptor antibodies and simultaneous kidney allograft biopsy within the first year after transplantation, either at the time of an episode of rejection in the first year after transplantation or at 1 year after transplantation in the absence of previous rejection episode.