Long term graft survival following a kidney allograft remains a leading limitation to transplantation, despite the low levels of acute rejection seen over the past decade. The leading cause of late graft loss is chronic allograft nephropathy (CAN). This disease is manifested by proteinuria, hypertension and renal failure associated with a progressive fibrosis of the graft. While the etiology of this disorder is not certain, both immunologic and non-immunologic factors are implicated in the pathogenesis. Furthermore, there is no specific therapy for this disease. The goal of this project is to identify new targets for the treatment of CAN, and importantly, to identify biomarkers of disease. Our hypothesis is that CAN is mediated by growth factor(s) that are induced either by TGFbeta or via other signals following transplantation. Furthermore, disruption of the matrix deposition cascade, via inhibition of these factors or by blocking matrix production, may ameliorate the development of CAN. We have accomplished the following over the past year: 1. In our established clinical protocol, 03-DK-0132, The Expression of Connective Tissue Growth Factor and Other Mediators in the Pathogenesis of Chronic Allograft Nephropathy, and we have enrolled 105 patients. A manuscript has been submitted for review characterizing CTGF in mouse kidney allograft rejection. 2. As the potency of immunosuppression has risen over the decade, so has graft loss due to BK polyomavirus nephropathy. We have identified the transcriptional profile of BK PVN and determined that while it is remarkably similar to acute rejection, markers of T cell cytotoxicity are dramatically elevated out of proportion to rejection. Moreover, more so than acute rejection which is tightly linked to CAN, PVN biopsies show transcriptional evidence of fibrogenesis. We are the first group to report transcriptional events in PVN and the presence of a pro-fibrotic milieu is also novel. This manuscript has been accepted for publication in the American Journal of Transplantation. 3. We are prospectively monitoring for BK polyomavirus in the urine in all transplant recipients in this program. We have demonstrated that the presence of viruria indicates over-immunosuppression and with monitored reductions, can safely avoid PVN in the majority of cases. Additional subjects and observations are needed and a manuscript is in preparation. 4. Using our real time PCR low density array as a platform, we have been investigating, at a molecular level, the gene transcript profile of fibrogenesis. The first version of this card was utilized in the published studies noted in #3. We have added additional targets based on both observations in the literature using gene arrays in kidney grafts, as well as molecules derived in other fibrotic kidney diseases. 5. Our collaborative trial with NHGRI 04-DK-0057 (Renal transplantation in recipients with nephropathic cystinosis) has now enrolled 8 patients. We have transplanted two patients, and the remaining are being followed with progressive chronic kidney disease. Based on these patients and others in Branch protocols, we continue to demonstrate the relative safety and efficacy of steroid free immunosuppression in a young adult and pediatric population that is not sensitized. We have also contributed to a position statement on the management of patients with cystinosis. 6. We have provided our collaborators Dr. Pedro Jose and Dr. David Sibley with 15 kidney transplants in mutant mice lacking the dopamine D5 receptor. These studies appear to indicate that there are non-renal mechanisms of blood pressure regulation.
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