利妥昔单抗在小儿频复发肾病综合征中的应用

Rituximab in treatment of children with frequently relapsed nephrotic syndrome

目的探讨利妥昔单抗（rituximab，RTX）在儿童频复发肾病综合征中的疗效和安全性。方法选取频复发肾病综合征患儿（激素减至隔日1．5-2．0mg／kg时复发，用多种免疫抑制剂效果欠佳）12例，其中男8例，女4例。患儿停用原免疫抑制药物；激素改为足量应用，尿蛋白转阴后5d开始改为隔日2mg／kg，以后每2周减5mg，减至小剂量（隔日〈0．5mg／kg）或停药；同时予RTX375mg／（m^2·次），每周1次，共3次。结果患儿尿蛋白在使用RTX第1剂后1-14d转阴；共随访4-19个月，平均（7．79±3．00）个月，随访结束时激素用量明显减少[治疗前为（1．83±1．02）mg／kg，隔日1次，治疗后（0．34±0．16）mg／kg，隔日1次，t=3．78，P=0．002]；患儿齿龈增生、柯兴貌均有明显改善，激素性青光眼消失，身高增长幅度较用药前明显增加[治疗前（2．21±1．40）cm／年，治疗后（8．27±2．10）cm／年]；6例未出现复发，另6例在5．5-19．0个月时复发；外周血CD19＋B淋巴细胞在RTX治疗后均下降到0，在5．5～12．0个月开始回升，免疫球蛋白水平无明显变化。RTX输注过程中未见任何不良反应。结论RTX可使频复发患儿在停用其他免疫抑制药的情况下，激素用量明显减少，甚至停药，维持患儿缓解（7．79±3．00）个月，明显改善激素和免疫抑制的不良反应，对于频繁复发肾病综合征，如果常用免疫抑制治疗无效，可以考虑应用RTX治疗。

Objective To explore the effect and safety of rituximab （RTX） in children with frequently re- lapsed nephrotic syndrome. Methods Twelve children （ 8 male and 4 female） with frequently relapse nephrotic syn- drome were treated with RTX. They all showed resistance to various immunosuppressive agents and relapsed when ste- roid was reduced at 1.5 - 2.0 mg/kg. All immunosuppressive agents were stopped. Steroid was prescribed at doses of 2 rag/（ kg·d） ,followed by alternate-day dosing （2 mg/kg） after proteinuria was negative for 5 days, and then tapered by 5 mg every 2 weeks until to low dose （ 〈 0.5 mg/kg on ahemate day ） or discontinued. RTX was administered at a dose of 375 mg/m2 once every week for 3 weeks. Results The patients were followed up for 4 - 19 months [ median （7.79 ±3.00） months]. Proteinuria turned negative on 1 - 14 d after first RTX treatment. Mean steroid dosages were significantly reduced than before treatment [ alternate-day dosing （ 1. 83 ±1. 02 ） mg/kg vs alternate-day dosing （ 0.34 ± 0.16 ） mg/kg ,t = 3.78 ,P = 0. 002 ]. Gingival hyperplasia and Cushing appearance were significantly improved and steroid-induced glaucoma disappeared. The height was significantly increased compared with before treatment [ （2.21± 1.40） cm/year vs （8.27 ± 2.10） cm/year]. Six cases had no relapse during follow-up. Another 6 cases re- lapsed in 5.5 - 19.0 months. All patients showed CD19 ＋ B lymphocytes depletion after RTX treatment. However, CD19＋ recovery could be seen in 5.5 - 12.0 months. Serum immunoglobulin did not significantly change. None of the patients was found with adverse events. Conclusions RTX can significantly reduce the dosage of steroid or even stop medica- tion in children free of immunosuppressive agents, maintain remission for （7.79 ± 3.00 ） months, significantly improve the adverse reaction induced by steroid and immune-suppression. Thus, for children with frequently relapsed nephritic syndrome/steroid-dependent nephrotic syndrome who show resistance to immunosuppressive therapies, RTX treatment may be considered.