Despite more potent immunosuppressive therapies resulting in improved early graft survival, long term graft survival remains a leading limitation to transplantation. In kidney transplantation, 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. The etiology of this disorder includes both immunologic and non-immunologic insults. There is no specific therapy for this disease, and renal function fails over a period of months to years The goal of this project is to identify new targets for the treatment of CAN, and importantly, to identify biomarkers of disease. Over the past year, we have established that connective tissue growth factor (CTGF), a downstream effector of TGFbeta, is upregulated in a mouse model of CAN. Moreover, enhanced expression occurs in human kidney grafts preceding the histologic development of CAN, and is also induced following ischemic injury. 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 a mouse model of kidney transplantation, both TGFbeta and CTGF mRNA expression rise rapidly within the first weeks of transplantation. Associated with this increase is expression of alpha-SMA, a marker of epithelial-mesenchymal transformation, and this is the first time this has been demonstrated in CAN. 2. We have enrolled more than 80 patients in our clinical protocol, 03-DK-0132, The Expression of Connective Tissue Growth Factor and Other Mediators in the Pathogenesis of Chronic Allograft Nephropathy. To date, we have determined that urine and serum levels are highly elevated in transplant recipients, and highest in patients with CAN. Furthermore, CTGF mRNA expression is dramatically elevated in kidney biopsies with CAN, as well as following reperfusion of the transplant. 3. Hypoxia is a robust inducer of CTGF mRNA expression and protein production in mouse kidney cell lines. This appears to be independent of TGFbeta signaling. Moreover, we have determined that after ischemic injury, CTGF mRNA expression is increased within human kidney grafts and the level of mRNA expression appears to be predictive of future graft outcome. 4. We have prospectively characterized the presence of polyoma virus in all transplant recipients in this program to analyze the natural history and to assess whether chronic viral infection may contribute to CAN. Transcriptional profiles demonstrate similarity to acute rejection. We are also retrospectively studying our recipient population to identify risk factors for the development of polyomavirus nephropathy, in collaboration with investigators in NINDS. 5. In collaboration with NHGRI, we have established a clinical protocol (04-DK-0057 Renal transplantation in recipients with nephropathic cystinosis) to provide steroid free immunosuppressive therapy to recipients with cystinosis, a rare genetic disorder that if left untreated results in renal failure and multi-organ failure. Incorporated into this protocol is sample collection to study CTGF expression in this patient population. Four patients have been enrolled to date.
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