槐杞黄颗粒联合糖皮质激素治疗儿童原发性肾病综合征Meta分析
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摘要
目的通过Meta分析评估槐杞黄颗粒联合糖皮质激素治疗儿童原发性肾病综合征(nephroticsyndrome,NS)的有效性和安全性。方法检索主要的中英文数据库,收集槐杞黄颗粒联合糖皮质激素治疗儿童NS的随机临床对照试验(RCT),采用Cochrane handbook 5. 1. 0中的偏倚风险评估工具对纳入文献进行风险评估,用STATA12. 0和RevMan 5. 3软件进行Meta分析,并按照GRADE标准进行证据质量评价。结果 (1) Meta分析共纳入12个RCT,结果显示:槐杞黄颗粒联合糖皮质激素等西医常规疗法与单一西医疗法在缩短尿蛋白转阴时间、升高免疫球蛋白G(IgG)、免疫球蛋白A(IgA)、CD3、CD4、CD4/CD8、NK细胞、降低复发率和感染率等方面疗效差异有统计学意义(P <0. 05),在降低免疫球蛋白M(IgM)、CD8方面疗效差异无统计学意义(P> 0. 05)。(2)共有7项研究阐述不良反应,试验组218例中有6例出现不良反应,不良反应发生率为3%。(3)漏斗图与Egger's检验结果提示无明显发表偏倚。(4)根据GRADE方法评价证据质量,结果显示在感染率和IgG方面质量为中级,其他方面为低级或极低。结论槐杞黄颗粒联合糖皮质激素疗法可以调节NS患儿免疫功能,降低复发率和感染率,且不良反应较小;但因纳入研究的质量较低,证据质量级别较低,临床使用该证据时尚需谨慎。
Objective To evaluate the efficacy and safety of the combination therapy of Huaiqihuang Granule and glucocorticoid in the treatment of children with primary nephrotic syndrome( NS) by Meta-analysis. Methods All randomized controlled trials( RCTs) of the combination therapy of Huaiqihuang Granule and glucocorticoid in the treatment of children with NS were collected by searching the main Chinese and English medical databases. Risk assessments were conducted for the screened articles by the bias risk assessment tool in Cochrane handbook 5. 1. 0,meta-analysis was performed by using STATA12. 0 and Rev Man 5. 3 software,and the quality of evidence was evaluated according to the GRADE criteria. Results( 1) The meta-analysis including a total of 12 RCTs showed that there were significant differences between the combination therapy and monotherapies of modern Western medicine in shortening the course of proteinuria,increasing immunoglobulin G( Ig G),immunoglobulin A( Ig A),CD3,CD4,CD4/CD8,NK cells,and reducing recurrence rate and infection rate(P <0. 05). And there were no differences in reducing the immune globulin M( Ig M),CD8(P > 0. 05).( 2) A total of 7 studies described adverse reactions,of which there had been 6 patients with adverse reactions in 218 cases of the combined group,and the incidence of adverse reactions was 3%.( 3) There was no obvious publication bias based on funnel plot and Egger's test.( 4) The quality of evidence which evaluated by GRADE system showed the middle quality in infection rate and Ig G,and low or very low quality in other aspects. Conclusions The combination therapy of Huaiqihuang Granule and glucocorticoid in the treatment of children with NS could regulate the immunity of children with NS,reduce the recurrence and infection rate and with less adverse reactions. However,due to the low quality of included studies and the low level of evidence quality,clinical use of this evidence should be cautious.
Objective To evaluate the efficacy and safety of the combination therapy of Huaiqihuang Granule and glucocorticoid in the treatment of children with primary nephrotic syndrome( NS) by Meta-analysis. Methods All randomized controlled trials( RCTs) of the combination therapy of Huaiqihuang Granule and glucocorticoid in the treatment of children with NS were collected by searching the main Chinese and English medical databases. Risk assessments were conducted for the screened articles by the bias risk assessment tool in Cochrane handbook 5. 1. 0,meta-analysis was performed by using STATA12. 0 and Rev Man 5. 3 software,and the quality of evidence was evaluated according to the GRADE criteria. Results( 1) The meta-analysis including a total of 12 RCTs showed that there were significant differences between the combination therapy and monotherapies of modern Western medicine in shortening the course of proteinuria,increasing immunoglobulin G( Ig G),immunoglobulin A( Ig A),CD3,CD4,CD4/CD8,NK cells,and reducing recurrence rate and infection rate(P <0. 05). And there were no differences in reducing the immune globulin M( Ig M),CD8(P > 0. 05).( 2) A total of 7 studies described adverse reactions,of which there had been 6 patients with adverse reactions in 218 cases of the combined group,and the incidence of adverse reactions was 3%.( 3) There was no obvious publication bias based on funnel plot and Egger's test.( 4) The quality of evidence which evaluated by GRADE system showed the middle quality in infection rate and Ig G,and low or very low quality in other aspects. Conclusions The combination therapy of Huaiqihuang Granule and glucocorticoid in the treatment of children with NS could regulate the immunity of children with NS,reduce the recurrence and infection rate and with less adverse reactions. However,due to the low quality of included studies and the low level of evidence quality,clinical use of this evidence should be cautious.
引文
[1]Certikova-Chabova V,Tesar V.Recent insights into the pathogenesis of nephrotic syndrome[J].Minerva Med,2013,104(3):333-347.
[2]Ulinski T,Aoun B.New treatment strategies in idiopathic nephrotic syndrome[J].Minerva Pediatr,2012,64(2):135-143.
[3]Eddy AA,Symons JM.Nephrotic syndrome in childhood[J].Lancet,2003,362(9384):629-639.
[4]McKinney PA,Feltbower RG,Brocklebank JT,et al.Time trends and ethnic patterns of childhood nephrotic syndrome in Yorkshire,UK[J].Pediatr Nephrol,2001,16(12):1040-1044.
[5]Koskimies O,Vilska J,Rapola J,et al.Long-term outcome of primary nephrotic syndrome[J].Arch Dis Child,1982,57(7):544-548.
[6]Tarshish P,Tobin JN,Bernstein J,et al.Prognostic significance of the early course of minimal change nephrotic syndrome:report of the International Study of Kidney Disease in Children[J].J Am Soc Nephrol,1997,8(5):769-776.
[7]Lombel RM,Gipson DS,Hodson EM,et al.Treatment of steroid-sensitive nephrotic syndrome:new guidelines from KDIGO[J].Pediatr Nephrol,2013,28(3):415-426.
[8]Pravitsitthikul N,Willis NS,Hodson EM,et al.Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children[J].Cochrane Database Syst Rev,2013,29(10):CD002290.
[9]Hogan J,Radhakrishnan J.The treatment of idiopathic focal segmental glomerulosclerosis in adults[J].Adv Chronic Kidney Dis,2014,21(5):434-441.
[10]Van den Berg JG,Weening JJ.Role of the immune system in the pathogenesis of idiopathic nephrotic syndrome[J].Clin Sci(Lond),2004,107(2):125-136.
[11]Abeyagunawardena AS,Sebire NJ,Risdon RA,et al.Predictors of long-term outcome of children with idiopathic focal segmental glomerulosclerosis[J].Pediatr Nephrol,2007,22(2):215-221.
[12]Prasad N,Gulati S,Sharma RK,et al.Pulse cyclophosphamide therapy in steroid-dependent nephrotic syndrome[J].Pediatr Nephrol,2004,19(5):494-498.
[13]Ueda N,Takahashi K,Akioka Y,et al.Beneficial effect of chlorambucil in steroid-dependent and cyclophosphamide-resistant minimal change nephrotic syndrome[J].JNephrol,2009,22(5):610-615.
[14]Gellermann J,Ehrich JH,Querfeld U.Sequential maintenance therapy with cyclosporin A and mycophenolate mofetil for sustained remission of childhood steroid-resistant nephrotic syndrome[J].Nephrol Dial Transplant,2012,27(5):1970-1978.
[15]Al-Saran K,Mirza K,Al-Ghanam G,et al.Experience with levamisole in frequently relapsing,steroid-dependent nephrotic syndrome[J].Pediatr Nephrol,2006,21(2):201-205.
[16]Sinha A,Bagga A.Rituximab therapy in nephrotic syndrome:implications for patients'management[J].Nat Rev Nephrol,2013,9(3):154-169.
[17]汪卫,于健宁,刘小贤.槐杞黄颗粒对MRL/Lpr狼疮小鼠肾损伤治疗作用的影响[J].中国中西医结合杂志,2018,38(4):478-483.
[18]孙雯,朱智,俞建,等.槐杞黄颗粒对阿霉素肾病大鼠肾组织nephrin和podocin表达的影响[J].中西医结合学报,2011,9(5):546-552.
[19]Moher D,Liberati A,Tetzlaff J,et al.Preferred reporting items for systematic reviews and meta-analyses:the PRIS-MA statement[J],PLo S Med,2009,6(7):e1000097.
[20]曾宪涛,包翠萍,曹世义,等.Meta分析系列之三:随机对照试验的质量评价工具[J].中国循证心血管医学杂志,2012,4(3):183-185.
[21]曾宪涛,冷卫东,李胜,等.如何正确理解及使用GRADE系统[J].中国循证医学杂志,2011,11(9):985-990.
[22]文进,李幼平.Meta分析中效应尺度指标的选择[J].中国循证医学杂志,2007,7(8):606-613.
[23]Higgins JP,Thompson SG,Deeks JJ,et al.Measuring inconsistency in meta-analyses[J].BMJ,2003,327(7414):557-560.
[24]Deeks JJ,Higgins JP,Altman DG.Analysing data and undertaking meta-analyses[A].Higgins JP,Green S,Eds.Cochrane handbook for systematic reviews of interventions[M].New Jersey:Wiley-Blackwell,2008:243-296.
[25]石修权,王增珍.Egger's test与Begg's test的功效差异比较与原因分析[J].华中科技大学学报(医学版),2009,38(1):91-93,102.
[26]张天嵩,钟文昭,李博主编.实用循证医学方法学[M].第2版.长沙:中南大学出版社,2014:275.
[27]郑铠军.槐杞黄颗粒对原发性肾病综合征患儿免疫功能的影响[J].中国中西医结合儿科学,2015,7(5):435-437.
[28]赵波,唐学兵,李红云,等.槐杞黄颗粒联合强的松治疗儿童原发性肾病综合征21例疗效观察[J].云南中医中药杂志,2009,30(11):40-41.
[29]张波,倪宁,吴玉斌.原发性肾病综合征患儿槐杞黄颗粒治疗前后血清细胞因子变化的研究[J].中国实用儿科杂志,2010,25(1):33-36.
[30]夏科君,张琦,孙建新,等.槐杞黄颗粒对儿童肾病综合征免疫功能的影响[J].现代实用医学,2015,27(7):855-857.
[31]汪春华,刘萍.槐杞黄颗粒调节肾病综合征患儿免疫功能的临床研究[J].中外健康文摘,2011,8(38):87-88.
[32]沙志勇,刘文婷.槐杞黄颗粒对原发性肾病综合征儿童血清炎性细胞因子的变化影响[J].中国医药科学,2016,6(12):49-51.
[33]钱古柃,赵镭,刘爱民.槐杞黄颗粒辅助治疗儿童肾病综合征的疗效观察[J].中草药,2014,45(16):2375-2377.
[34]耿海云,曹力,王薇,等.槐杞黄颗粒治疗儿童原发性肾病综合征的前瞻性随机对照临床研究[J].中国当代儿科杂志,2015,17(1):31-34.
[35]冯仕品,谢敏,王莉,等.槐杞黄颗粒联合糖皮质激素治疗小儿原发性肾病综合征的临床研究[J].四川医学,2011,32(12):1870-1872.
[36]戴路露,吴玉斌,吴惠颖.槐杞黄颗粒对原发性肾病综合征患儿免疫状态调节作用研究[J].中国实用儿科杂志,2012,27(6):446-448.
[37]曹广海,刘翠华,云鹰.槐杞黄颗粒对肾病综合征患儿体液免疫及细胞免疫的影响[J].世界中西医结合杂志,2013,8(6):585-587.
[38]刘运广,曹珊,林娜,等.槐杞黄颗粒联合泼尼松治疗儿童原发性肾病综合征疗效及对免疫功能影响的前瞻性随机对照研究[J].右江民族医学院学报,2017,39(3):163-167.
[39]Li T,Mao J,Huang L,et al.Huaiqihuang may protect from proteinuria by resisting MPC5 podocyte damage via targeting pERK/CHOP pathway[J].Bosn J Basic Med Sci,2016,16(3):193-200.
[40]Manganelli R,Iannaccone S,Ferbo U,et al.Diagnostic pathway of an unusual case of nephrotic syndrome:immunotactoid glomerulopathy[J].G Ital Nefrol,2010,27(6):668-673.
[41]江从海,王英,段朝晖,等.儿童肾病综合征患者免疫球蛋白的检测及其临床意义[J].中国实用医药,2008,3(24):25-26.
[42]于力,卓美瑛,杨小苏,等.肾病综合征患儿细胞免疫和细胞因子的变化及其意义[J].中国实用儿科杂志,2001,16(8):483-485.
[2]Ulinski T,Aoun B.New treatment strategies in idiopathic nephrotic syndrome[J].Minerva Pediatr,2012,64(2):135-143.
[3]Eddy AA,Symons JM.Nephrotic syndrome in childhood[J].Lancet,2003,362(9384):629-639.
[4]McKinney PA,Feltbower RG,Brocklebank JT,et al.Time trends and ethnic patterns of childhood nephrotic syndrome in Yorkshire,UK[J].Pediatr Nephrol,2001,16(12):1040-1044.
[5]Koskimies O,Vilska J,Rapola J,et al.Long-term outcome of primary nephrotic syndrome[J].Arch Dis Child,1982,57(7):544-548.
[6]Tarshish P,Tobin JN,Bernstein J,et al.Prognostic significance of the early course of minimal change nephrotic syndrome:report of the International Study of Kidney Disease in Children[J].J Am Soc Nephrol,1997,8(5):769-776.
[7]Lombel RM,Gipson DS,Hodson EM,et al.Treatment of steroid-sensitive nephrotic syndrome:new guidelines from KDIGO[J].Pediatr Nephrol,2013,28(3):415-426.
[8]Pravitsitthikul N,Willis NS,Hodson EM,et al.Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children[J].Cochrane Database Syst Rev,2013,29(10):CD002290.
[9]Hogan J,Radhakrishnan J.The treatment of idiopathic focal segmental glomerulosclerosis in adults[J].Adv Chronic Kidney Dis,2014,21(5):434-441.
[10]Van den Berg JG,Weening JJ.Role of the immune system in the pathogenesis of idiopathic nephrotic syndrome[J].Clin Sci(Lond),2004,107(2):125-136.
[11]Abeyagunawardena AS,Sebire NJ,Risdon RA,et al.Predictors of long-term outcome of children with idiopathic focal segmental glomerulosclerosis[J].Pediatr Nephrol,2007,22(2):215-221.
[12]Prasad N,Gulati S,Sharma RK,et al.Pulse cyclophosphamide therapy in steroid-dependent nephrotic syndrome[J].Pediatr Nephrol,2004,19(5):494-498.
[13]Ueda N,Takahashi K,Akioka Y,et al.Beneficial effect of chlorambucil in steroid-dependent and cyclophosphamide-resistant minimal change nephrotic syndrome[J].JNephrol,2009,22(5):610-615.
[14]Gellermann J,Ehrich JH,Querfeld U.Sequential maintenance therapy with cyclosporin A and mycophenolate mofetil for sustained remission of childhood steroid-resistant nephrotic syndrome[J].Nephrol Dial Transplant,2012,27(5):1970-1978.
[15]Al-Saran K,Mirza K,Al-Ghanam G,et al.Experience with levamisole in frequently relapsing,steroid-dependent nephrotic syndrome[J].Pediatr Nephrol,2006,21(2):201-205.
[16]Sinha A,Bagga A.Rituximab therapy in nephrotic syndrome:implications for patients'management[J].Nat Rev Nephrol,2013,9(3):154-169.
[17]汪卫,于健宁,刘小贤.槐杞黄颗粒对MRL/Lpr狼疮小鼠肾损伤治疗作用的影响[J].中国中西医结合杂志,2018,38(4):478-483.
[18]孙雯,朱智,俞建,等.槐杞黄颗粒对阿霉素肾病大鼠肾组织nephrin和podocin表达的影响[J].中西医结合学报,2011,9(5):546-552.
[19]Moher D,Liberati A,Tetzlaff J,et al.Preferred reporting items for systematic reviews and meta-analyses:the PRIS-MA statement[J],PLo S Med,2009,6(7):e1000097.
[20]曾宪涛,包翠萍,曹世义,等.Meta分析系列之三:随机对照试验的质量评价工具[J].中国循证心血管医学杂志,2012,4(3):183-185.
[21]曾宪涛,冷卫东,李胜,等.如何正确理解及使用GRADE系统[J].中国循证医学杂志,2011,11(9):985-990.
[22]文进,李幼平.Meta分析中效应尺度指标的选择[J].中国循证医学杂志,2007,7(8):606-613.
[23]Higgins JP,Thompson SG,Deeks JJ,et al.Measuring inconsistency in meta-analyses[J].BMJ,2003,327(7414):557-560.
[24]Deeks JJ,Higgins JP,Altman DG.Analysing data and undertaking meta-analyses[A].Higgins JP,Green S,Eds.Cochrane handbook for systematic reviews of interventions[M].New Jersey:Wiley-Blackwell,2008:243-296.
[25]石修权,王增珍.Egger's test与Begg's test的功效差异比较与原因分析[J].华中科技大学学报(医学版),2009,38(1):91-93,102.
[26]张天嵩,钟文昭,李博主编.实用循证医学方法学[M].第2版.长沙:中南大学出版社,2014:275.
[27]郑铠军.槐杞黄颗粒对原发性肾病综合征患儿免疫功能的影响[J].中国中西医结合儿科学,2015,7(5):435-437.
[28]赵波,唐学兵,李红云,等.槐杞黄颗粒联合强的松治疗儿童原发性肾病综合征21例疗效观察[J].云南中医中药杂志,2009,30(11):40-41.
[29]张波,倪宁,吴玉斌.原发性肾病综合征患儿槐杞黄颗粒治疗前后血清细胞因子变化的研究[J].中国实用儿科杂志,2010,25(1):33-36.
[30]夏科君,张琦,孙建新,等.槐杞黄颗粒对儿童肾病综合征免疫功能的影响[J].现代实用医学,2015,27(7):855-857.
[31]汪春华,刘萍.槐杞黄颗粒调节肾病综合征患儿免疫功能的临床研究[J].中外健康文摘,2011,8(38):87-88.
[32]沙志勇,刘文婷.槐杞黄颗粒对原发性肾病综合征儿童血清炎性细胞因子的变化影响[J].中国医药科学,2016,6(12):49-51.
[33]钱古柃,赵镭,刘爱民.槐杞黄颗粒辅助治疗儿童肾病综合征的疗效观察[J].中草药,2014,45(16):2375-2377.
[34]耿海云,曹力,王薇,等.槐杞黄颗粒治疗儿童原发性肾病综合征的前瞻性随机对照临床研究[J].中国当代儿科杂志,2015,17(1):31-34.
[35]冯仕品,谢敏,王莉,等.槐杞黄颗粒联合糖皮质激素治疗小儿原发性肾病综合征的临床研究[J].四川医学,2011,32(12):1870-1872.
[36]戴路露,吴玉斌,吴惠颖.槐杞黄颗粒对原发性肾病综合征患儿免疫状态调节作用研究[J].中国实用儿科杂志,2012,27(6):446-448.
[37]曹广海,刘翠华,云鹰.槐杞黄颗粒对肾病综合征患儿体液免疫及细胞免疫的影响[J].世界中西医结合杂志,2013,8(6):585-587.
[38]刘运广,曹珊,林娜,等.槐杞黄颗粒联合泼尼松治疗儿童原发性肾病综合征疗效及对免疫功能影响的前瞻性随机对照研究[J].右江民族医学院学报,2017,39(3):163-167.
[39]Li T,Mao J,Huang L,et al.Huaiqihuang may protect from proteinuria by resisting MPC5 podocyte damage via targeting pERK/CHOP pathway[J].Bosn J Basic Med Sci,2016,16(3):193-200.
[40]Manganelli R,Iannaccone S,Ferbo U,et al.Diagnostic pathway of an unusual case of nephrotic syndrome:immunotactoid glomerulopathy[J].G Ital Nefrol,2010,27(6):668-673.
[41]江从海,王英,段朝晖,等.儿童肾病综合征患者免疫球蛋白的检测及其临床意义[J].中国实用医药,2008,3(24):25-26.
[42]于力,卓美瑛,杨小苏,等.肾病综合征患儿细胞免疫和细胞因子的变化及其意义[J].中国实用儿科杂志,2001,16(8):483-485.