滋补肝肾颗粒联合口服激素治疗肝肾阴虚型、重症IgA肾病的随机、双盲、对照的多中心研究

Treatment of Zibuganshen Granules Plus Prednisone on Patients with Severe IgA Nephropathy( Ying- deficiency of the Liver and Kidney pattern) : a Randomized,Double- blind,Placebo- controlled Multicentre Clinical Trial

目的：明确中药滋补肝肾颗粒配合口服激素在治疗病理表现为LEEⅢ级及以上、肝肾阴虚型IgAN患者中的有效性及安全性。方法：本研究为多中心、随机、双盲、对照的临床试验。研究对象来自2011年1月～2012年2月期间,上海4所三级甲等医院就诊的病理表现为LEEⅢ级及以上、中医辨证为肝肾阴虚证的原发性重症IgAN患者,共80例。病例随机分为中西结合组（中药滋补肝肾颗粒配合口服泼尼松）及单纯西药组（中药安慰颗粒剂联合口服泼尼松）,两组比例为1∶1。根据患者的体重、肾功能状况,予以口服泼尼松的起始剂量为40～60 mg/d,共服用8～12周;其后每2周减5 mg,减至30 mg/d;再改为每月减5 mg,至停服。滋补肝肾颗粒由地黄、制黄精等成分组成。疗程共48周。分别在第0、4、12、24、36、48周观察主要指标：肾小球滤过率（e GFR）,血肌酐、中医证候积分、24 h尿蛋白等次要指标,同时观察不良事件的发生情况。采用SAS9.3统计软件,主要运用mixed model进行重复测量资料的分析,比较各疗效指标变化趋势的差别。结果：最终共完成病例为67例,试验组34例,对照组33例。48周时,主要疗效指标e GFR,试验组相较于基线有明显升高（t=4.80,P〈0.05）,对照组的改善则不明显（t=0.95,P〉0.05）。试验组的上升速度快于对照组（F=11.87,P〈0.05）。试验组中医证候有效率为75.00%,对照组43.59%,两组差异有统计学意义（χ^2=10.17,P〈0.05）。次要疗效指标对比基线情况,试验组血肌酐有所下降（t=-3.47,P〈0.05）,对照组则保持稳定（t=1.04,P〉0.05）;两组的中医证候积分均有明显下降（t=-7.24,t=-5.66;P〈0.05）、24 h尿蛋白明显减少（t=-3.71,t=-5.36;P〈0.05）。在组间比较方面,试验组血肌酐及中医证候积分的疗效优于对照组（F=6.63,F=41.82;P〈0.05）。研究中,试验组出现不良事件4例,对照组3例,两组比较差异无统计学意义（χ^2=0.514,P〉0.05）。结论：在病理表现为LEEⅢ级及以上、中医辨证为肝肾阴虚证的原发性重症IgAN患者中,中药配方滋补肝肾颗粒配合口服激素治疗方案,在改善肾功能及减轻临床症状方面的疗效更优。

Objective： To confirm the safety and efficacy of the Zibuganshen granules plus oral prednisone in the severe Immunoglobulin A Nephropathy（ IgAN） patients（ Ying- deficiency of the Liver and Kidney pattern） with pathological classifications on LEEⅢ level and above. Methods： A randomized,double- blind,placebo- controlled multi- centre clinical trial was conducted.From Janurary 2011 to Feburary 2012,a total of 80 pathologically- diagnosed IgAN patients with the serious pathological classifications（ LEEⅢ level and above） were recruited. All of the patients were presented Ying- deficiency of the Liver and Kidney pattern.They are from 4 hospitals in Shanghai. Participants were divided randomly and equally into two groups of Integrative Medicine（ Zibuganshen Granules with oral prednisone） and Control（ TCM placebo granules with oral prednisone）. According to the patient＇s weight and renal function,the starting dose of oral prednisone was 40- 60 mg / d for a total of 8- 12 weeks. Thereafter,the oral prednisone dose was reduced by 5 mg every two weeks,and by 5 mg every mouth until the dose reached 30 mg / d. The Zibuganshen granules were made from Rehmannia,Polygonatum sibiricum and etc. The treatment lasted 48 weeks. TCM symptoms,serum creatinine,24-hour urine protein excretion and e GFR（ MDRD method） were monitored at different time points（ 0,4,12,24,36,48 week） in both groups of patients. Statistical analyses were carried out using SAS,version 9. 3. Mixed model was used for analyze of repeated measuring data to compare efficacy difference between the two groups. Results： 67 patients（ 34 Integrative Medicine group,33 Control group） completed the study. e GFR（ MDRD method） level increased significantly than baseline in the Integrative Medicine group（ t =4. 80,P〈0. 05）,but not in the Control group（ t = 0. 95,P〉0. 05）. The e GFR（ MDRD method） lever increased more from the baseline in Integrative Medicine group than in Control group（ F = 11. 87,P〈0. 05） at 48- week. The total effective rate of TCM syndromes was higher in the Integrative Medicine group（ 75. 00%） than in Control group（ 43. 59%）（ χ^2= 10. 17,P〈0. 05）. Serum creatinine level decreased significantly in the Integrative Medicine group（ t =- 3. 47,P〈0. 05）,but not in the Control group（ t =1. 04,P〈0. 05）. TCM syndrome score and urinary protein excretion were lower than baseline in both groups（ P〈0. 05）. The downward trend of serum creatinine and TCM syndrome score in Integrative Medicine group were more obvious（ F = 6. 63,F = 41. 82; P〈0. 05）. Seven adverse events（ 4 Integrative Medicine group,Control group） were observed（ χ^2= 0. 514,P〉0. 05）. Conclusion：Compared with the prednisone alone therapy,dual therapy of TCM granules（ Zibuganshen Granules） with oral prednisone was more effective in relieving TCM syndromes and improving renal functions in IgA nephropathy（ IgAN） patients（ Ying- deficiency of the Liver and Kidney pattern） with serious pathological classifications（ LEEIII level and above）.