A Randomized, Prospective, Multicenter Trial to Compare the Effect on Chronic Allograft Nephropathy Prevention of Mycophenolate Mofetil Versus Azathioprine as the Sole Immunosuppressive Therapy for Kidney Transplant Recipients

INTRODUCTION The introduction of triple-therapy regimens that include a calcineurin inhibitor, steroids, and azathioprine (AZA) or mycophenolate mofetil (MMF) greatly reduced the risk of acute rejection in renal transplantation. However, the long-term use of both calcineurin inhibitors and steroids is associated with serious toxicities that ultimately impact patient and graft survival. Minimisation of chronic immunosuppression is therefore of paramount importance to improve patient and graft survival. Thus, the quest for strategies inducing specific immune hyporesponsiveness or even tolerance - ideally via short-term interventions that would target only the pathogenic immune response and leave the protective host immune response unimpaired - has provided a "holy grail" for transplant immunologists.

We recently found that induction therapy with basiliximab and lower (about one fourth) than conventional doses of Rabbit Anti-human Thymocyte Globulin (RATG), combined to low-dose CsA and MMF maintenance therapy, allowed ineffective prevention of acute rejection without steroids. Of note, unlike induction protocols with "standard" RATG doses, the above regimen was extremely well tolerated, avoided the risk of acute cytolysis reactions, reduced the incidence of immuno-hemolytic anemia and the need for red blood cell transfusions. Moreover, this approach did not increase the risk of CMV reactivations or lymphoproliferative disorders, even as compared to standard triple immunosuppressive regimens without induction therapy.

The doses of CsA employed in the above protocol were about half the doses currently used in clinical practice. However, even these very low doses have been reported to have a significant toxicity that, in the long-term, may adversely affect the graft function and survival. Thus, implementing innovative immunosuppressive strategies allowing to early and safely withdraw calcineurin inhibitor therapy might have major clinical implications in term of improved kidney function and long term survival. This would also avoid the adverse effects of chronic CsA therapy on arterial blood pressure, lipid profile and blood glucose that, altogether, remarkably increase the overall cardiovascular risk in these patients.

To this purpose, induction therapy with basiliximab plus low-dose RATG might help inducing a condition of reduced immuno-responsiveness that might allow to sequentially withdraw steroids and CsA without adversely affect the outcome of the graft.

Evidence that MMF suppresses the production of anti-HLA antibodies, inhibits the recruitment of mononuclear cells into the allograft, as well as the proliferation of arterial smooth muscle cells, has been taken to suggest that MMF might play an important protective effect against the development and progression of CAN. Thus, an immunosuppressive regimen based on low-dose MMF as sole antirejection drug not only would avoid chronic toxicity of steroids, and calcineurin inhibitors, but would also limit the risk of CAN, the main cause of allograft loss in the long-term. On the other hand, however, the Mycophenolate Steroid Sparing (MYSS) trial found that AZA was as effective as MMF in preventing acute allograft rejection in CsA-treated kidney transplant recipients, even after steroid withdrawal. Since acute allograft rejection is one of the strongest predictor of CAN, these findings can be taken to suggest that, in the long-term, AZA might share with MMF also a similar protective effect against the development of CAN. Moreover, it must be emphasized that chronic CsA nephrotoxicity is a major component of CAN. Thus, the prevalence and severity of CAN may be reduced in patients on CsA-free immunosuppressive regimens. In this clinical setting, the benefits of MMF against the development of CAN might not appreciably exceed those of AZA. Should this be the case, AZA might confer the same benefits of MMF, but at remarkably lower costs since, at equivalent doses, AZA is about 15 times less expensive than MMF.