Open Randomized Trial Comparing Early Withdrawal of either Cyclosporine or Mycophenolate Mofetil in Stable Renal Transplant Recipients Initially Treated with a Triple Drug Regimen

Abstract

ABSTRACT. Cyclosporine (CsA) is the current primary immunosuppressant for the prevention of renal allograft rejection. Its chronic use is associated with various adverse effects like hypertension, hyperlipidemia, and nephrotoxicity, which in turn may contribute to chronic allograft nephropathy and cardiovascular mortality. This study compares a CsA-free maintenance regimen of mycophenolate mofetil (MMF) and corticosteroids with CsA and corticosteroids after early conversion from triple drug therapy. Eighty-four renal transplant recipients who had stable graft function on triple drug therapy with MMF, CsA, and steroids were randomly assigned to be withdrawn from either CsA (n = 44) or MMF (n = 40) at 3 mo posttransplantation. Kidney function at 1 yr was the primary endpoint. Secondary parameters of efficacy were patient and graft survival, incidence of acute rejection episodes, BP, and lipids. At study entry, the alternative treatment groups were similar with respect to demographics, renal function, dosage of CsA, BP, and concomitant medication. Both the creatinine clearance (71.7 versus 60.9 ml/min) and calculated GFR (73.2 versus 61.9 ml/min) were significantly better in MMF-treated patients at 1 yr. Conversion to MMF was associated with a decline of systolic and diastolic BP (128/76 versus 139/82 mmHg) and with a more favorable lipid profile. There was no difference in patient survival (100%) and graft survival (97.7% versus 100%). Acute rejection episodes occurred more frequently after withdrawal of CsA (11.3% versus 5.0%), but the difference was NS. Early tapering of CsA can safely be accomplished in renal transplant recipients who are stable on a triple drug regimen with MMF, thereby resulting in improved renal function, a more favorable lipid profile, and beneficial effects on posttransplant hypertension.

Is the failure of recent trials on withdrawal of calcineurin inhibitors due to inadequate mycophenolic acid dosing?

“…They also found more biopsy-proven chronic rejection in the CsA withdrawal arm by 2 years post-transplant. Schnuelle et al randomized 84 patients to either CsA or MMF withdrawal after 3 months (6). Those who underwent CsA withdrawal remained on 2 g/d MMF as prednisolone was temporarily increased to 25 mg/d and slowly tapered thereafter.…”

“…Despite the disappointing results of these first studies in terms of the rejection risk, they showed that patients in whom CsA withdrawal was successful had better renal function, blood pressure, and lipid profile than those remaining on CsA (5)(6)(7)9,10). This encouraged researchers not to abandon the goal of CNI withdrawal, but to better identify predictors of AR and to find a way to optimize the maintenance dose of MMF and steroids.…”