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 a total of 123 patients. We are finding that serum CTGF levels are elevated in kidney transplant recipients compared to healthy individuals. Moreover, urine levels are similarly elevated, compared to normal individuals and correlate to biopsy pathology. The results of these studies were published in the Am Journal of Transplantation 2006.? 2. In a mouse model of kidney transplantation in which CAN develops over a 6 week period, CTGF protein and mRNA are highly expressed. Protein expression is associated with the development of fibrosis. In vitro studies by our group have demonstrated that CTGF mediates epithelial-mesenchymal transformation in renal tubular epithelial cells. The results of these human and rodent studies are in press in the American Journal of Transplantation 2006.? 3. 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. With collaboration with both NIH IC and extramural investigators, we are identifying whether the profibrotic impact of infection is related to the immune response to virus or to an intrinsic response of tubular epithelial cells infected by virus.? 4. Using our real time PCR low density array as a platform, we continue to investigate, 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. We are also exploring these molecules and other immune factors in transplant glomerulopathy, a pathologic entity associated with rapid rate of graft loss and high levels of proteinuria. We are also investigating T cell activation in peripheral blood using RT-PCR and ATP production with specific interest in homeostatic changes occuring following clinical T cell depletion.? 5. Our collaborative trial with NHGRI 04-DK-0057 (Renal transplantation in recipients with nephropathic cystinosis) has now enrolled 10 patients. We have transplanted four 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. ? 6. We have provided our collaborators Dr. Pedro Jose and Dr. David Sibley with 30 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.? 7. We collaborated with a multi-center study to prospectively monitor PHA-stimulated ATP production in peripheral lymphocytes of kidney transplant recipients. The results of this study were published in Transplantation 2006 and provide some general indication of the risk of rejection or infection in immunosuppressed recipients.
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