Abstract
BackgroundIdiopathic nephrotic syndrome (INS) is the most common chronic glomerular disease in children. Approximately 80–90% of patients with childhood INS have steroid-sensitive nephrotic syndrome (SSNS), and can obtain remission with steroid therapy, while the remainder have steroid-resistant nephrotic syndrome (SRNS). Furthermore, approximately 50% of children with SSNS develop frequently-relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS). Children with FRNS/SDNS are usually treated with immunosuppressive agents such as cyclosporine, cyclophosphamide, or mizoribine in Japan. However, 10–20% of children receiving immunosuppressive agents still show frequent relapse and/or steroid dependence during or after treatment, which is defined as complicated FRNS/SDNS. Furthermore, 30% of SRNS patients who obtain remission after additional treatments such as cyclosporine also turn out to be complicated FRNS/SDNS. For such complicated FRNS/SDNS patients, rituximab (RTX) is currently used; however, recurrence after RTX treatment also remains an open issue. Because long-term use of existing immunosuppressive drugs has limitations, development of a novel treatment for maintenance therapy after RTX is desirable. Mycophenolate mofetil (MMF) is an immunosuppressive drug with fewer side effects than cyclosporine or cyclophosphamide. Importantly, recent studies have reported the efficacy of MMF in children with nephrotic syndrome.MethodsWe conduct a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of MMF after RTX therapy in children with complicated FRNS/SDNS. Patients are allocated to either RTX plus MMF treatment group, or RTX plus placebo treatment group. For the former group, MMF is administered at a dose of 1000–1200 mg/m2/day (maximum 2 g/day) twice daily for 17 months after RTX treatment. The primary endpoint is time-to-treatment failure (development of frequent relapses, steroid dependence or steroid resistance).DiscussionThe results will provide important data on the use of MMF as maintenance therapy after RTX to prevent complicated FRNS/SDNS patients from declining into treatment failure. In future, MMF in conjunction with RTX treatment may permit increased duration of remission in ‘complicated’ FRNS/SDNS cases.Trial registrationThis trial was prospectively registered to UMIN Clinical Trials Registry on June 23, 2014 (UMIN Trial ID: UMIN000014347).
Highlights
Idiopathic nephrotic syndrome (INS) is the most common chronic glomerular disease in children
Most children with frequently-relapsing nephrotic syndrome (FRNS)/steroid-dependent nephrotic syndrome (SDNS) are effectively treated with these recommended immunosuppressant drugs; at least 10–20% of children receiving immunosuppressive agents still show frequent relapses or steroid dependence after treatment
Statistical analyses The primary aim of this study is to examine the superiority of RTX plus Mycophenolate mofetil (MMF) combination therapy compared with RTX monotherapy in extending the duration to treatment failure
Summary
Idiopathic nephrotic syndrome (INS) is the most common chronic glomerular disease in children. 10–20% of children receiving immunosuppressive agents still show frequent relapse and/or steroid dependence during or after treatment, which is defined as complicated FRNS/SDNS. A total of 50–60% of children with FRNS develop two consecutive relapses during tapering or within 14 days of stopping steroid therapy, this is termed steroid-dependent nephrotic syndrome (SDNS) (Table 2) [3, 6]. The clinical practice guidelines for pediatric idiopathic nephrotic syndrome (2013) recommend cyclosporine, cyclophosphamide, and mizoribine as immunosuppressive drugs for FRNS/SDNS [6]. Some patients with SRNS develop steroid-sensitive frequent relapses or steroid dependence after achievement of complete remission by immunosuppressive therapies including calcineurin inhibitors (complicated FRNS/ SDNS). A 5-year follow-up study of cyclosporine treatment in children with SRNS showed that 7 of 31 (23%) patients developed frequent relapses under immunosuppressive therapy after achievement of complete remission [8]. Body temperature ○○○ ○ ○ Pregnancy test HIV, HCV, HBVa
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