Combined treatment with mycophenolate mofetil and an angiotensin II receptor antagonist fully protects from chronic rejection in a rat model of renalallograft

Antigen-dependent and antigen-independent factors have been implicated in t he pathophysiology of chronic allograft rejection, but their relative role is not well established. In the Fisher 344 --> Lewis rat kidney transplant model, we sought (1) to compare the relative efficacy of the novel immunosu ppressant. mycophenolate mofetil (MMF), with that of the AT1 receptor block er, losartan, in preventing the development of chronic graft rejection when given for 52 wk; (2) to examine whether combining MMF with losartan afford s better protection than each of the drugs alone. For comparison, the effec t of cyclosporine (CsA) to control chronic graft rejection was also assesse d. Administration of MMF alone or losartan alone to the kidney allografted rats resulted in a partial decrease in the amount of proteinuria, preservat ion of glomerular and tubulointerstitial graft structure, limitation of int ragraft cell infiltration, and improvement of graft survival compared with corresponding parameters in untreated. transplanted control rats. Combined treatment with MMF and losartan completely prevented the development of pro teinuria, largely reduced glomerular and tubulointerstitial injury, and sup pressed intragraft cell infiltration, and all animals survived at the end o f the followup. Similarly, CsA treatment largely prevented graft injury but failed to achieve 100% animal survival. We have shown that MMF synergizes with the angiotensin II receptor antagonist, losartan, in simultaneously ta rgeting complementary pathways of chronic allograft rejection. Combining MM F and angiotensin II receptor blocker offers superior long-term renoprotect ion as compared with CsA. Together, these findings provide the basis to pre vent chronic injury and progressive dysfunction after renal transplantation .