环孢素A治疗儿童难治性肾病综合征随机对照试验的系统评价

Efficacy and safety of cyclosporine A in treatment of refractory nephrotic syndrome in children： a systematic review of randomized controlled trials

目的评价环孢素A（CsA）治疗儿童难治性肾病综合征（RNS）的疗效和安全性。方法按系统评价的要求全面检索了Cochrane图书馆、PubMed、EMBASE、中国生物医学文献光盘数据库（CBMdisk）、中国期刊全文数据库（CNKI）和中国维普数据库（VIP），对符合纳入标准的文献按临床类型及干预措施分亚组进行Meta分析。结果共纳入9篇文献（n=293），6篇g～7分，3篇1～3分。（1）在激素（GC）效应组中，CsA联合GC的近期疗效优于单用GC[OR值0．14，95％CI（0．03，0．71）]，但与环磷酰胺、麦考酚酸酯的差异无统计学意义，比苯丁酸氮芥疗效差且易复发[OR值和95％c，分别为6．93（1．53，31．38）、0．06（0，01，0．58）]，维持治疗期间保持CsA血药浓度在60～80斗∥L能降低远期复发率[OR值6．43，95％CI（1．21，34．19）]，两组终末期。肾病（ESRD）的发生率和病死率均为0。（2）在激素耐药组中，CsA的近期疗效优于安慰剂或支持治疗及环磷酰胺[OR值和95％c，分别为0．15（0．02，0．96）、0．41（0．03，5．00）]，但复发率、ESRD的发生率和病死率的差异均无统计学意义。（3）CsA的安全性：CsA组的肾毒性、多毛和牙龈增生的发生率均高于对照组[OR值和95％C1分别为0．19（0．05，0．79）、0．06（0．02，0．19）、0．05（0．02，0．18）]，但两组间高血压和肝毒性发生率的差异无统计学意义。结论已有证据提示CsA能提高儿童RNS的近期疗效，但不能提高其远期和终点疗效，是治疗儿童RNS较理想的二线药物，其安全性较好，从总体趋势上看，CsA对儿童激素效应NS的疗效优于激素耐药NS。此外，在维持治疗期问，保持CsA的血药浓度在60～80ug/L能减少远期的复发率。

Objective To evaluate the efficacy and safety of cyclosporine A（CsA） in the treatment of refractory nephrotie syndrome （RNS） in children. Methods The Cochrane library, PubMed, EMBASE, CBMdisk, CNKI and VIP were searched from the time when the databases were established to December 31, 2008. Reports on RCTs on treating RNS in children with CsA were collected. Data were extracted and assessed independently by three reviewers. The methodological quality of included RCTs was assessed by the revised Jadad-seale （including randomization, allocation concealment, blinding method and withdrawal ）. Meta-analysis of homogenous RCTs was managed by using RevMan4. 2. 3. Result Nine RCTs involving 293 participants were included. Six RCTs were assessed as high-quality studies with scores from 4 to 7 and 3 RCTs were assessed as low-quality studies with scores from 1 to 3. Sub-category recta-analysis was based on different clinical types and interventions of RNS in children. Meta-analysis based on included RCTs showed the following results. （ 1 ） in children with steroid-dependent or frequent relapse nephrotic syndrome ： the short-term efficacy of CsA plus prednisone was better than that of prednisone alone [ OR O. 14, 95% CI （0. 03, 0. 71 ） ] ; the short-term efficacy of CsA, cyclophosphamide （CTX） and mycophenolate mofetil had no significant differences, but compared with chlorambueil, CsA had a worse short-term efficacy [ OR 6. 93, 95% CI（ 1.53,3 1. 38 ） ] and a higher relapse rate [ OR O. 06, 95% CI（0. 01,0. 58 ） ] ; maintaining a blood level of CsA between 60 and 80 ug/L during remission period could reduce the long term relapse rate [ OR 6. 45, 95% CI（ 1.21,34. 19） ] ; the incidence of end-stage renal disease （ESRD） or mortality was zero in both groups. （2） In children with steroid-resistant nephrotic syndrome, the short-term efficacy of CsA was better than that of placebo or supportive treatment and CTX, OR and 95% CI were 0. 15 （0. 02,0. 96） and 0.41 （0. 03, 5.00 ）, respectively, but no significant differences were found in the relapse rate and the incidence of ESRD or mortality. （3） Side effects of CsA ： the incidence of nephrotoxicity, hypertrichosis and gum hypertrophy was higher in the CsA group than in that of control group, OR and 95% CI were 0. 19 （0. 05,0. 79） , 0. 06 （0. 02,0. 19）, 0. 05（0. 02,0. 18）, respectively, but no significant differences were found in the incidence of hypertension and liver toxicity. Conclusions Available evidence showed that CsA could improve short term efficacy in RNS in children, but could not improve long term and endpoint efficacy, therefore CsA could be one of the ideal second-line drugs for RNS in children. There was a trend that the effect of CsA on steroid-dependent or frequent relapse nephrotic syndrome was superior to that on steroid- resistant nephrotic syndrome.