Background: Recent studies have demonstrated that complete conversion from cyclosporine A (CsA) to mycophenolate mofetil (MMF) prolongs graft survival in patients undergoing clinical organ transplantation. We investigated the effects of conversion from CsA to MMF on recipient kidneys and transplant arteriosclerosis in a rat aortic allograft model as a high responder combination.
Methods: DA (MHC haplotype, RT1a) rat abdominal aortic grafts were orthotopically transplanted into Lewis (RT1l) rats. The recipients were divided into four oral treatment groups: (1) vehicle group, (2) CsA group (15 mg/kg/day), (3) CsA/MMF40 group (conversion from CsA 15 mg/kg/day to MMF 40 mg/kg/day on day 14), and (4) CsA/MMF20 group (conversion from CsA 15 mg/kg/day to MMF 20 mg/kg/day on day 14). On day 28 after transplantation, the rats were sacrificed and the hematoserological parameters were analyzed. The grafted aortas and recipient kidneys also were evaluated histologically and immunohistochemically.
Results: The CsA group developed serological renal dysfunction, arteriolar hyalinosis, and apoptosis in the recipient kidneys, whereas the CsA/MMF40 and CsA/MMF20 groups did not. In the vehicle group, we observed remarkable intimal hyperplasia and marked inflammatory cell infiltration including macrophages and T cells. In the CsA group, intimal hyperplasia was evident without infiltration of macrophages or T cells. In the CsA/MMF40 and CsA/MMF20 groups, intimal hyperplasia was abrogated, while adventitial infiltration of and adhesion to the endothelium by macrophages and T cells occurred.
Conclusions: Conversion from CsA to MMF protected recipient kidneys and prevented transplant arteriosclerosis. However, insufficient immunosuppression by MMF might reactivate immune cells. This conversion therapy has preventive potential in transplant patients with CsA-associated nephrotoxicity and transplant arteriosclerosis.