LAUSR

Since the 1970s, cyclophosphamide (CPM) has been the most commonly used first-line steroid-sparing agents (SPA) in the treatment of frequent-relapsing and steroid-dependent nephrotic syndrome (FR/SDNS) among pediatric nephrologist across the world. In a recent study on 46 children with FR/SDNS and had received either CPM or rituximab (RTX) [1], however, Kari et al. observed that significantly more number of patients in the RTX group had a complete withdrawal of prednisolone after 3 month of therapy than those in the CPM group (73.7% vs. 29.6%). Although the observation period was relatively short (12 months), they concluded that RTX was effective and safe as a first-line SPA in this cohort. In another study on 102 children with FR/SDNS who received a first course of CPM and/or RTX [2], Webb et al. found that the median time to first relapse after the therapy was significantly longer in the RTX group than in the CPM group (14 vs. 7 months). Although there was no significant difference in the proportion of patients in the 2 groups who achieved long-term remission after the therapy, the authors also concluded that RTX could be a superior first-line SPA in FR/SDNS patients. Although cyclosporine has been used as a second-line SPA for children with FR/SDNS, many reports have demonstrated that the therapy was not necessarily associated with improved long-term outcomes. We reported that mizoribine (MZR) maintenance therapy after CPM may have positive effects on preventing NS relapse compared to CPM monotherapy [3]. In our study (median observation period, 5.9 years) on 54 young children (mean age, 5.8 years) with SDNS who had received a first course of 12-week CPM, 36 patients had received single daily MZR from 2008 as maintenance therapy after CPM (MZR group), while 18 patients had received CPM monotherapy between 2001 and 2007 (CPM group). For 2 years after CPM, 21 of the 36 in the MZR group were in sustained remission, while only 4 of the 18 in the CPM group maintained remission (58% vs. 22%, p < 0.05). During MZR therapy, no severe adverse events, such as severe infections that required hospitalization and drug discontinuation, were observed in any patient. At the final follow-up, 27 of the 36 patients in the MZR group (75%) had not received any SPA after the discontinuation of MZR (median, 30 months). In contrast, in our other study (mean observation period, 5.4 years) on 43 SDNS patients who first received RTX, SPA was still used in 33 of the 43 patients (77%) at the final follow-up, and treatment-free remission (> 12 months) was achieved in only 5 patients (12%) [4]. Furthermore, RTXassociated late-onset severe neutropenia (< 500/mm3) developed in 3 patients, one of whom needed to be hospitalized because of acute infection. Therefore, we believe that MZR should be selected as the remission maintenance agent after the first course of CPM before initiating RTX administration, even in young children with SDNS. As emphasized in previous reports, we must consider that children with FR/SDNS are not essentially cured by RTX but shift from dependence on prednisolone or cyclosporine to that on RTX in the long term; this could lead to late-onset adverse events, such as severe neutropenia and persistent hypogammaglobulinemia, owing to repeated RTX administrations [5].