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Abstract . Antigen-dependent and antigen-independent factors have  been implicated in the 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 immunosuppressant, mycophenolate mofetil (MMF), with  that of the AT1 receptor blocker, losartan, in preventing the development of  chronic graft rejection when given for 52 wk; ( 2 ) to examine whether  combining MMF with losartan affords better protection than each of the drugs  alone. For comparison, the effect of cyclosporine (CsA) to control chronic  graft rejection was also assessed. Administration of MMF alone or losartan  alone to the kidney allografted rats resulted in a partial decrease in the  amount of proteinuria, preservation of glomerular and tubulo-interstitial  graft structure, limitation of intragraft 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 proteinuria, largely reduced glomerular and  tubulointerstitial injury, and suppressed intragraft cell infiltration, and  all animals survived at the end of the follow-up. 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 targeting complementary pathways of chronic  allograft rejection. Combining MMF and angiotensin II receptor blocker offers  superior long-term renoprotection as compared with CsA. Together, these  findings provide the basis to prevent chronic injury and progressive  dysfunction after renal transplantation.

journal of the american society of nephrology

Combined Treatment with Mycophenolate Mofetil and an Angiotensin II Receptor Antagonist Fully Protects from Chronic Rejection in a Rat Model of Renal Allograft