Research Group

  • Dr. Debra Hullett, Principal Investigator
  • Alexander Pietsch, Research Associate
  • Dr. Bryan Becker, Collaborator

Location

  • University of Wisconsin, Madison, USA

Title

  • Effect of Vitamin D on Renal Allograft Function
Graft failure following transplantation results from either acute or chronic rejection

Graft failure following transplantation results from either acute or chronic rejection. There are currently many immunosuppressive agents that are effective at preventing acute rejection. There are no such reagents for the prevention of chronic rejection. In the kidney, chronic rejection is characterized by the development of fibrotic changes, which include interstitial fibrosis, tubular atrophy, glomerulosclerosis, and concentric intimal hyperplasia. This process has been termed chronic allograft nephropathy (CAN).

1,25-Dihyroxyvitamin D3 [1,25-(OH)2D3] is the active metabolite of vitamin D. Its long-known function is to regulate calcium metabolism. Recent evidence suggests that 1,25-(OH)2D3 also regulates the growth and differentiation of many cell types, and in particular that 1,25-(OH)2D3 regulates immune responses. We have shown that 1,25-(OH)2D3 treatment prolongs allograft survival. Importantly, we have shown in a retrospective study that renal transplant patients who received 1,25-(OH)2D3 supplementation because of renal insufficiency had stabilized graft function.

The mechanisms that lead to the development of CAN are unknown, but are thought to involve both immune and non-immune factors. The cytokine transforming growth factor beta (TGF) has been implicated in the pathogenesis of the fibrotic changes in CAN. We and others have shown an interaction between the TGF and 1,25-(OH)2D3 signal transduction pathways. Thus, we hypothesize that 1,25-(OH)2D3 will be an effective agent in preventing CAN and that 1,25-(OH)2D3 may regulate TGF-mediated fibrosis. We intend to determine whether 1,25-(OH)2D3, when used in combination with low-dose standard immunosuppression, is effective in preventing CAN, and to determine the effect of 1,25-(OH)2D3 treatment on the expression of genes for proteins that regulate fibrotic changes, namely the matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases.

The experiments proposed in this application should lead to a greater understanding of the mechanisms underlying CAN and may identify new targets for therapy.