The Role of Connective Tissue Growth Factor in the Development of Kidney Disease After Organ Transplantation

Following transplantation, recipients of organ allografts are placed on immunosuppression indefinitely. Despite dramatic improvements in acute rejection rates and short-term graft survival, long term graft survival has not changed appreciably over the past 20 years. In kidney transplantation, the leading cause of late graft loss is chronic allograft nephropathy (CAN). This disorder is clinically characterized by a progressive decline in kidney function, associated with the characteristic histologic features of interstitial fibrosis and inflammation, arteriosclerosis, glomerulosclerosis, and tubular atrophy. Both immunologic and non-immunologic factors have been implicated in the development of CAN. However, the etiology of this disorder has not been clearly defined nor is there specific therapy for treating CAN.

Implicated in the development of CAN in rodents and humans is transforming growth factor beta (TGF-beta), a pleiotropic cytokine which is elevated in CAN recipients, and stimulates matrix deposition within the graft. A downstream effector of TGF-b is connective tissue growth factor (CTGF), which has been recently associated with other fibrotic renal diseases. In preliminary studies in a mouse model of CAN, CTGF gene expression is increased in kidney transplants with CAN. However, its role in human CAN is unknown.

The aim of this investigation is to identify whether CTGF may play a role in the pathogenesis of CAN in humans. Our long-term objective is to determine whether CTGF and other cytokine mediators may be novel targets for the therapy of CAN. Our goals are to: 1. Determine the level of CTGF expressed in the urine and serum CTGF of recipients of kidney transplants; 2. Identify whether urinary or serum CTGF might be a marker of CAN and be utilized as a predictor for those at risk to develop the disease; 3. Identify other molecular messages and proteins that may identify the development of CAN, as potential future targets of treatment.

In this prospective study, serial urine and serum samples will be obtained in recipients, before, during, and after transplantation of a kidney allograft. The graft will be monitored in the context of standard measures of renal function, which include serum creatinine and creatinine clearance. These results will be correlated with other clinically descriptive information regarding the recipient s transplant.