Initial Mycophenolate Dosing in De Novo Kidney Transplant Recipients Taking Tacrolimus - 1.5 or 2 Grams Daily?

Abstract

Aim: Currently mycophenolate mofetil (MMF) and tacrolimus (tac) are the most commonly used combination of maintenance immunosuppressants, yet the optimal dose of MMF is not known. This study aimed to determine if the initial MMF dose influences the risk of biopsy proven acute rejection episodes (BPAR), leukopaenia or poorer renal function in the first 12 months after transplant in kidney transplant recipients (KTR). Methods: Our unit changed the routine initial MMF dose from 1.5gm to 2gm daily in late 2009 for all de novo KTR commenced on tacrolimus. Consecutive KTRs for 16 months either side of this change were included to form 2 cohorts. Cox regression was used to assess the association of MMF dose with BPARs and leukopaenia. Serum creatinine at 12 months was compared. All KTR received maintenance prednisolone and infection prophylaxis with Trimethoprim-Sulfamethoxazole and Valganciclovir/Valaciclovir. Results: There were no significant baseline differences between groups in terms of age, gender, peak or current Complement Dependent Cytotoxicity Panel Reactive Assay, HLA mismatch, transplant number or type nor CMV serology. After adjusting for recipient age, gender, cmvd+/r-, cmv viraemia and rejection, MMF 2gm/day was associated with a doubling of the risk of leukopaenia (HR 1.99, 95%CI 1.1-3.6, p=0.02) relative to 1.5gm/day. A 45% reduction in the risk of BPARs (HR 0.55, 95%CI 0.31-0.99, p=0.047) was also observed in the group on MMF 2g/day after adjustment for recipient age, gender, leukopaenia, transplant number and peak CDC PRA. CMV viraemia and transplant number were also significantly associated with leukopaenia and BPAR respectively in the above models. Despite these associations there were no significant differences in mean serum creatinine levels at 12 months, infections episodes or infection related hospitalisations between the two groups. Conclusion: The MMF dose chosen for KTR on tacrolimus maintenance influences the rate of BPARs and leukopaenia in the initial 12 months. A randomised controlled trial is warranted to establish the degree of this effect as well as the long-term impact of MMF dose on graft function and patient safety.