Combined treatment with mycophenolate mofetil and an angiotensin II receptor antagonist fully protects from chronic rejection in a rat model of renal allograft.
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.
Noris
Marina
M
Department of Immunology and Clinics of Organ Transplantation Ospedali Riuniti Bergamo, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Azzollini
Nadia
N
Department of Immunology and Clinics of Organ Transplantation Ospedali Riuniti Bergamo, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Pezzotta
Angela
A
Department of Immunology and Clinics of Organ Transplantation Ospedali Riuniti Bergamo, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Mister
Marilena
M
Department of Immunology and Clinics of Organ Transplantation Ospedali Riuniti Bergamo, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Benigni
Ariela
A
Department of Immunology and Clinics of Organ Transplantation Ospedali Riuniti Bergamo, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Marchetti
Gianfranco
G
Department of Immunology and Clinics of Organ Transplantation Ospedali Riuniti Bergamo, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Gagliardini
Elena
E
Department of Immunology and Clinics of Organ Transplantation Ospedali Riuniti Bergamo, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Perico
Norberto
N
Department of Immunology and Clinics of Organ Transplantation Ospedali Riuniti Bergamo, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Remuzzi
Giuseppe
G
Department of Immunology and Clinics of Organ Transplantation Ospedali Riuniti Bergamo, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001794:Blood Pressure; D002908:Chronic Disease; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000517:prevention & control* / Q000652:urine; D006085:Graft Survival / Q000187:drug effects; D006439:Hemodynamics; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation; D019808:Losartan / Q000627:therapeutic use*; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D011507:Proteinuria / Q000517:prevention & control; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D044140:Receptor, Angiotensin, Type 1; D012079:Renal Circulation; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D057911:Angiotensin Receptor Antagonists; D007166:Immunosuppressive Agents; D044140:Receptor, Angiotensin, Type 1; D016572:Cyclosporine; D003404:Creatinine; D009173:Mycophenolic Acid; D019808:Losartan