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Introduction:
Calcineurin inhibitors such as cyclosporine are associated with efficacy
limiting adverse events such as nephrotoxicity, which may impact adversely upon
long term renal function and graft survival. Switching of patients from a CsA
regimen and maintainence on azathioprine(aza) and steroids has been tried in
the past but not passed into clinical practice due to a high late acute
rejection rate (up to 30 %). Mycophenolate Mofetil (MMF) is a potent inhibitor
of purine synthesis approved for prophylaxis of acute rejection and could
possibly permit the withdrawal of CsA without paying this heavy price. This
study investigates the effects of switching patients from aza to MMF or adding
in MMF to dual therapy to facilitate the withdrawal of Neoral in patients with
stable renal function at least one year post transplant.
Methods: 159 patients received triple therapy with 2g MMF replacing previous azathioprine or added to Neoral and corticosteroids dosed as per centre practice for at least three months. Following randomisation half the patients had Neoral withdrawn slowly over a period of 12 weeks, at the end of which they were cyclosporine free and maintained on MMF and steroids alone. They were then followed for a period of 6 months to determine the effect on renal function, late rejection episodes and other parameters. The other half of the patients remained on their original therapy.
Results:
Data on patients varying between 58 and 379 days post randomisation (median 183
days) are included in this report. The groups were comparable for type of
transplant (mostly first cadaveric ), mean ischaemic time (20 hrs), degree of
HLA mismatch and previous rejections (most none or one). To date 6 patients in
the Neoral withdrawal arm experienced a biopsy proven rejection episode
compared to 2 remaining on triple therapy(p=NS). One patient in the triple
therapy arm experienced acute cyclosporine toxicity. Renal function in both
groups was the same at baseline (Creatinine Clearance 65.7 ml/min in the
withdrawal group and 65.6 ml/min in the CsA group) and improved in the CsA
withdrawal group only (73.3 vs. 61.4 ml/min) by 6 months following complete
elimination.
Conclusion: CsA withdrawal under MMF therapy appears safe and associated with an apparent improvement in renal function.
This research was funded in part by Hoffmann-La Roche, Basel/Switzerland.