环磷酰胺治疗儿童肾病综合征随机对照试验的系统评价

Cyclophosphamide for primary nephrotic syndrome of children: a systematic review

目的评价环磷酰胺(CTX)联合激素治疗儿童原发性肾病综合征(INS)的有效性与安全性,探讨最佳治疗方案。方法检索PubMed、EMBASE、Ovid、Springer、中国期刊全文数据库等,获得CTX治疗儿童INS的临床文献。使用国际 Cochrane中心推荐的方法进行质量评价后,用Review Manager 4．2软件对主要结果进行合并统计分析。结果共检索出1 351篇文献,14篇随机对照试验(RCT)文献纳入研究。分析显示儿童INS以CTX联合激素治疗与单用激素治疗比较:治疗后6个月复发率RR=0．31,95％CI:0．18-0．53;治疗后1年复发率RR=0．29,95％CI:0．17-0．50;治疗后2年复发率 RR=0．39,95％CI:0．27-0．56。最差情况演示分析,结果均不变。敏感度检验:排除低质量的文献后结果无变化。对于局灶阶段性肾小球硬化(FSGS)肾病综合征,CTX联合激素治疗效果不明显。CTX静脉给药和口服给药治疗后完全缓解率比较:治疗后6个月RR=2．50,95％CI:1．18～5．32,治疗后1年RR=2．55,95％CI:1．45-4．47,治疗后2年RR=1．01,95％ CI:0．31-3．29。静脉给药比口服给药的不良反应小。CTX累积剂量<200 mg·kg-1性腺损害发生的危险性较小。CTX 口服治疗不同疗程比较:2周与8周治疗后6个月的复发率,RR=9．00,95％CI:1．29-63．02;治疗后15个月的复发率,RR =2．50,95％CI:0．67-9．31。12周与8周治疗比较:治疗后5年的复发率RR=1．01,95％CI:0．77-1．31。治疗后200 d 缓解率比较:RR=0．78,95％CI:0．47-1．31。400 d缓解率比较,RR=1．01,95％CI:0．51-2．01,800 d缓解率比较:RR= 1．07,95％CI:0．49～2．35。CTX口服治疗每日低剂量(2．5 mg·kg-1)与每日高剂量(5．0 mg·kg-1)比较(总剂量一致): 治疗后6、12和18个月完全缓解率均为RR=0．88,95％CI:0．67-1．14。结论 CTX联合激素治疗与单用激素治疗相比, 治疗后2年内患儿复发率降低。对于FSGS肾病综合征患儿效果不明显,尚需大样本RCT进一步证实。CTX静脉给药与口服给药比较,有提高激素依赖和激素抵抗患儿完全缓解率的趋势,累计剂量更少,不良反应更小。考虑到使用更多的免疫抑制剂会导致更多不良反应的发生,口服CTX治疗疗程以8周较适宜。对于CTX的远期疗效评价仍需更多设计严密的、科学的大样本RCT进一步证实。

Objective To perform a sysmetic review on the efficiency and safety of cyclophosphamide applied in treating primary nephrotic syndrome of children and to find the best regime of cyclophosphamide therapy. Methods PubMed, EMBASE, Ovid, Springer, CNKI database were searched by using the terms Cyclophosphamide and Nephrotic Syndrome for human clinical trials, including unpublished documents from scientific meetings and thesis, and the similar documents listed in the references of above documents were also included. All of the randomized controlled trials were included by comparing cyclophosphamide with general medicine or comparing different dasage, duration and different methods of cyclophoaphamide medication for the treatment of primary nephrotic syndrome of children. Two reviewers independently performed data extraction and appraised using Juni instrument ; disagreements were resolved by consensus. Double data were input and analyzed by software of Review Manager 4. 2, recommended by Cochrane Collaboration. Results 14 RCTs involving 655 children were included. Compared to prednisone alone Cyclophosphamide combined with prednisone could significantly reduce the relapse risk in 6 months [ 4 trials; RR = 0. 31,95% CI：0. 18 to 0.53], ofl year [4 trials; RR= 0. 29,95%CI： 0. 17 to 0. 50], and in 2 years [4 trials; RR =0.39,95%CI： 0.27 to 0. 56 ] except for focal segmental glomerulosclerosis （FSGS）. Worst-case scenario analysis and sensitivity analysis did not change the results. Compared with oral cyclophosphamide intravenous cyclophosphamide could raise the complete remission rate at 6 months （ RR = 2. 50,95% CI ： 1.18 to 5.32）, at 1 year （ RR = 1.76,95% CI： 1.03 to 2. 98 ）. and at 2 years （ RR = 1.01,95% CI ： 0. 31 to 3.29）. Intravenous cyclophosphamide had less side effects while oral cyclophosphamide was cheaper. The toxicity was higher if the total dosage was more than 200 mg. kg^- 1. d^-1. Comparing to two weeks therapy eight weeks cyclophosphamide could reduce the relapse risk in 6 months （ RR = 9.00,95% CI： 1.29 to 63.02） and in 15 months （ RR = 2. 50,95% CI： 0. 67 to 9. 31 ）. Comparing twelve weeks and eight weeks cyclophoaphamide therapy, there was no difference on relapse risk at five years （ RR = 1.01,95% CI： 0. 77 to 1.31 ） and no difference on remission rate at 200 days （ RR = 0. 78,95% CI： 0. 47 to 1.31 ）, 400 days （ RR = 1.01,95% CI 0. 51 to 2. 01 ） and 800 days （ RR = 1.07,95% CI： 0.49 to 2. 35 ）. Low dosage treatment appeared to be just as effctive in sustained remission as the same total amount of a higher daily dosage. The side effects would be more when high-dosage treatment was given. Conclusions Cyclophosphamide combined with prednisone can significantly reduce the relapse risk in 2 years compared with prednisone alone. Considering more unpleasant events when the dosage is raised, eight weeks cyclophosphamide therapy is more suitable. Intravenous cyclophosphamide appears to be more effective in raising the remission rate with a favorable trend, and has less accumulative dosage so that it is safer than oral cyclophosphamide. Further adequately powered and well-designed RCTs are needed to confirm the long-term effect of cyclophoaphamide.