糖尿病肾病中医证候分布特点及中药干预糖尿病肾病的临床研究
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摘要
糖尿病,作为一种终生进展性疾病,在其晚期阶段,因常常伴发多种并发症,而给患者及其家庭、医疗机构和国家带来了巨大的挑战和经济负担。据预计,全球糖尿病的患病率在2030年将达到7.7%。而中国糖尿病的患病率则从2001年的5.5%进展至2008年的9.7%,糖尿病患病总人数已达到92.400.000。糖尿病肾病(diabetic nephropathy, DN),作为糖尿病最常见的微血管并发症,在中国已成为导致终末期肾脏疾病的第二位病因。虽然有部分研究表明,良好的血糖、血压、血脂管理和使用血管紧张素转化酶抑制剂(Angiotensin-converting enzyme inhibitors, ACEI)或血管紧张素受体拮抗剂(Angiotensin Receptor blockers, ARB)可以延缓其进展。但到目前为止,仍未有公认的可以防治糖尿病肾病的有效方法。中医治疗,尤其是中药方剂在中国被广泛地用于治疗糖尿病肾病。当前一些研究也表明中医药疗法能改善糖尿病肾病患者临床症状、减少尿蛋白排泄、改善肾功能、提高生存质量。但是,这些研究往往存在一些质量缺陷,例如：研究样本量过小、缺乏安慰剂对照、临床研究质量管理缺如等等,导致了其研究结果可信度不足。本研究旨在通过对横断面回顾性病例调查和专家意见问卷调查,探讨糖尿病肾病的中医证候分布规律。并在此研究基础上,遵循循证医学研究原则,设计并实施中药配方颗粒干预糖尿病肾病的临床研究,进一步探讨中药治疗糖尿病肾病的疗效和安全性。
目的：探讨糖尿病肾病不同阶段的中医证候分布规律,并探讨中医复方——糖肾方辨证加味干预糖尿病肾病的疗效和安全性。
方法：首先,回顾性统计分析北京地区213例因糖尿病肾病入院患者的中医症状,并借助聚类分析等数理统计方法,探讨糖尿病肾病的中医证候分布规律。同时,采用德尔菲法,通过三轮问卷调查,总结专家对糖尿病肾病的诊治经验,探索糖尿病肾病的中医证候规律。在此基础上,纳入180例2型糖尿病,糖尿病肾病Ⅲ期和大量蛋白尿期患者,开展多中心(六个中心参与)、随机、双盲、安慰剂对照临床研究,观察中药配方颗粒——糖肾方辨证加味干预2型糖尿病肾病的有效性和安全性。在本研究中,采用分层区组随机的方法,按2：1的比率将患者随机分为治疗组(糖肾方辨证加减)和对照组(安慰剂),治疗24周后观察疗效。微量蛋白尿组的主要疗效指标为尿微量白蛋白排泄率；大量蛋白尿组的主要疗效指标为24小时尿蛋白定量。次要疗效指标为肾功能(Scr. eGFR)、血脂(TC、 TG、 HDL-C、 LDL-C)、血糖、中医症状积分和安全性指标。并试验开始前设立标准化操作流程和质量控制方法,以保证研究的可行性和可靠性。
结果：糖尿病肾病的中医证候特点为本虚标实,气阴两虚夹瘀为Ⅲ、Ⅳ期的主要证候,可因个体差异而兼挟热盛、湿热证；V期逐渐发展至气血阴阳俱虚,兼见湿浊、瘀血夹杂的重症。随机对照研究结果显示,对于已经应用ACEI/ARB作为基础治疗的2型糖尿病肾病患者,应用以糖肾方为基础的加味中药复方治疗,可使大量蛋白尿期患者24小时尿蛋白定量进一步减少0.40±0.91g(安慰剂组增加0.31±0.95g,p<0.05),eGrR增加1.96±22.57ml／min(安慰剂组下降7.05±12.31ml／min,P=0.026)。经混合效应模型分析,两组患者中医症状积分均随治疗时间的延长而下降,在24周时试验组下降幅度显著大于对照组。两组患者治疗前后血清肌酐、血脂(TC、TG、HDL-C、LDL-C)、血糖、血压水平改变组间比较,无统计学差异(P>0.1)。两组不良事件发生率、安全性指标(血常规、ALT、AST)治疗前后改变组间比较无统计学差异。本研究采用的中药复方颗粒耐受性良好。在24周随访期结束后,治疗组仍坚持服药的受试者为80.33%,高于安慰剂组(75.86%)。
结论：以糖肾方为基础的中药复方可减少糖尿病肾病大量蛋白尿期患者的尿蛋白漏出,延缓肾小球滤过率的减退,从而延缓糖尿病肾病患者疾病进展至终末期肾功能衰竭。无明显药物不良反应,安全性良好,值得临床推广应用。
Diabetic mellitus (DM) is a lifelong progressive disease, usually associated with various complications in its late stage, which could cause great challenges and burdens to patients, their families, health care system and national economics. The prevalence of DM all over the world was predicts to reach7.7%by2030. The prevalence of DM in China was5.5%in2001and reached to9.7%in2008with totally92.4million diabetics. Diabetic nephropathy is one of the most common microvascular complications of diabetes mellitus, and it has become the second cause of end-stage renal disease (ESRD) in China.Up to now, there is no proved therapy to cure or prevent the progression of DKD, though some reports showed that good management of blood glucose, blood pressure and blood lipid and medicine application of Angiotensin-converting enzyme inhibitors (ACEI) or Angiotensin Receptor blockers (ARB) might postpone the disease' progression. Traditional Chinese medicine (TCM) has been applied to treat DKD for a long history, and recently several studies have reported some advantages of TCM in ameliorating clinical symptoms, improving quality of life, decreasing urinary protein excretion and improving renal function. Nevertheless, these trials of either small sample size or lack of placebo-controlled arm or low quality monitoring and management of study process take high risk bias to these evidences to support, the effects of TCM. Therefore we undertook a prospective, multicenter, double-blind, randomized controlled study to evaluate the efficacy and safety of Chinese herbal formula (Tangshen Formula and individualized prescription based on syndrome differentiation) in treating diabetic nephropathy, which based on the investigation of the characteristics of TCM syndrome of diabetic nephropathy by means of retrospective cross-sectional survey and questionnaire survey.
Objective:This study investigated the characteristics of TCM syndrome of diabetic nephropathy, and to evaluate the efficacy and safety of Chinese herbal formula (Tangshen Formula and individualized prescription based on syndrome differentiation) in treating diabetic nephropathy.
Methods:Firstly, this study analyzed the characteristics of TCM syndromes of213cases of in-patients with diabetic nephropathy by using data mining methods such as cluster analysis. Secondly, this study summed up the clinic TCM experts' experiences of the basic characteristic syndromes and symptoms of diabetic nephropathy through three series interview by questionnaires based on Delphi methods.Then,a six-center,semi-standardizedized,randomjzed,double-blind. placebo-controll ed trial was conducted to evaluate the efficacy and safety of Chinese herbal formula(Tangshen Formula and individualized prescription based on syndrome differentiation)in treating diabetie nephropathy secondary to type2diabetes mellitus.A total of180Chinese patients with DN in microalbuminuria stage and macroa]buminuria stage were randomly assigned to the Chinese herbal formula treatment group(Tangshen formula and individualized formulas based on syndrome differentiation) or the placebo group sa the ratio of2∶1,according to the method of stratified area of random,Patients were followed up for24weeks.The primary outcomes were UAER for DN patients in the microalbuminuria stage,24-hour urinary protein excretion amount for DN patients in the macroalbuminuria stage.The secondary outcomes were renal function (Scr and eGFR estimated by G/C equation);blood lipid (TG,TC,HDL-C,LDL-C);blood glycemia: seore of TCM symptoms and safety index.Standing Operating Procedure (SOP) and quality control methods were set up to guarantee quality of the process.
Results:The essential characteristies of TCM syndrome of diabetic Rephropathy is deficiency in root and excess in branch.Qi and yin defieiency with blood stasis is the basic characteristies of DN in Ⅲ and Ⅳ stages sometimes accompanied with interior heat or damp-heat.with the progress of the disease,the characteristies of TCM syndrome hsa changed to deficiency of qi, blood,yin and yang;accompanied with blood stasis and damp-turbidity in stage Ⅴ.
The clinie trial shows that after24weeks intervention (TSF and individualized formulas based on syndrome differentiation,along with ACEI/ARB applied sa primary drug treatment),the24h urinary protein in the treatment group was decreased(week24VS baseline,p<0.05)while the UP in the placebo group was increased (week24VS baseline,p-0.233).The change of UP between the two groups was significant (0.40±0.91g/24hr of the treatment group VS0.31±0.95g/24hr of the placebo group,p<0.05).The eGFR in the placebo group was decreased(week24VS baseline,p<0.05)while eGFR in the treatment group was improved (week24vs baseline,p=0.586).The change of eGFR between the two groups was signifieant (1.96±22.57ml/min of the treatment group VS-7.05±12.31ml/min of the placebo group,P=0.026).As lineat mised-effects model was applied to the TCm scores,the main effect of time is significant,The TCM scores of two groups were both decresaed over time,and the TCM scores of the treatment group declined significantly more than the placebo group in the24th week.There were no significant differences in partieipants Scr,blood lipid (TG、CHO、 HDL-C、 LDL-C), blood glucose (FBG), BP between the treatment group and placebo group(P>0.1). There was no significant difference of the side effects between the two groups. The herbal compound particles used in this study was well tolerated. After the end of the24weeks follow-up,80.33%subjects in the treatment group insisted on taking the medication, compared with75.86%in the placebo group.
Conclusions:This study shows that TSF and individualized formulas based on syndrome differentiation, along with ACEI/ARB applied as primary drug treatment, can reduce the level of24-hour urinary protein excretion, delaying eGFR decline and improving TCM symptoms with low side effects in DN patients in the macroalbuminuria stage. Due to favorable safety, efficacy and well-tolerated, TSF would provide a candidate for treating DKD with macroabluminuria.
目的：探讨糖尿病肾病不同阶段的中医证候分布规律,并探讨中医复方——糖肾方辨证加味干预糖尿病肾病的疗效和安全性。
方法：首先,回顾性统计分析北京地区213例因糖尿病肾病入院患者的中医症状,并借助聚类分析等数理统计方法,探讨糖尿病肾病的中医证候分布规律。同时,采用德尔菲法,通过三轮问卷调查,总结专家对糖尿病肾病的诊治经验,探索糖尿病肾病的中医证候规律。在此基础上,纳入180例2型糖尿病,糖尿病肾病Ⅲ期和大量蛋白尿期患者,开展多中心(六个中心参与)、随机、双盲、安慰剂对照临床研究,观察中药配方颗粒——糖肾方辨证加味干预2型糖尿病肾病的有效性和安全性。在本研究中,采用分层区组随机的方法,按2：1的比率将患者随机分为治疗组(糖肾方辨证加减)和对照组(安慰剂),治疗24周后观察疗效。微量蛋白尿组的主要疗效指标为尿微量白蛋白排泄率；大量蛋白尿组的主要疗效指标为24小时尿蛋白定量。次要疗效指标为肾功能(Scr. eGFR)、血脂(TC、 TG、 HDL-C、 LDL-C)、血糖、中医症状积分和安全性指标。并试验开始前设立标准化操作流程和质量控制方法,以保证研究的可行性和可靠性。
结果：糖尿病肾病的中医证候特点为本虚标实,气阴两虚夹瘀为Ⅲ、Ⅳ期的主要证候,可因个体差异而兼挟热盛、湿热证；V期逐渐发展至气血阴阳俱虚,兼见湿浊、瘀血夹杂的重症。随机对照研究结果显示,对于已经应用ACEI/ARB作为基础治疗的2型糖尿病肾病患者,应用以糖肾方为基础的加味中药复方治疗,可使大量蛋白尿期患者24小时尿蛋白定量进一步减少0.40±0.91g(安慰剂组增加0.31±0.95g,p<0.05),eGrR增加1.96±22.57ml／min(安慰剂组下降7.05±12.31ml／min,P=0.026)。经混合效应模型分析,两组患者中医症状积分均随治疗时间的延长而下降,在24周时试验组下降幅度显著大于对照组。两组患者治疗前后血清肌酐、血脂(TC、TG、HDL-C、LDL-C)、血糖、血压水平改变组间比较,无统计学差异(P>0.1)。两组不良事件发生率、安全性指标(血常规、ALT、AST)治疗前后改变组间比较无统计学差异。本研究采用的中药复方颗粒耐受性良好。在24周随访期结束后,治疗组仍坚持服药的受试者为80.33%,高于安慰剂组(75.86%)。
结论：以糖肾方为基础的中药复方可减少糖尿病肾病大量蛋白尿期患者的尿蛋白漏出,延缓肾小球滤过率的减退,从而延缓糖尿病肾病患者疾病进展至终末期肾功能衰竭。无明显药物不良反应,安全性良好,值得临床推广应用。
Diabetic mellitus (DM) is a lifelong progressive disease, usually associated with various complications in its late stage, which could cause great challenges and burdens to patients, their families, health care system and national economics. The prevalence of DM all over the world was predicts to reach7.7%by2030. The prevalence of DM in China was5.5%in2001and reached to9.7%in2008with totally92.4million diabetics. Diabetic nephropathy is one of the most common microvascular complications of diabetes mellitus, and it has become the second cause of end-stage renal disease (ESRD) in China.Up to now, there is no proved therapy to cure or prevent the progression of DKD, though some reports showed that good management of blood glucose, blood pressure and blood lipid and medicine application of Angiotensin-converting enzyme inhibitors (ACEI) or Angiotensin Receptor blockers (ARB) might postpone the disease' progression. Traditional Chinese medicine (TCM) has been applied to treat DKD for a long history, and recently several studies have reported some advantages of TCM in ameliorating clinical symptoms, improving quality of life, decreasing urinary protein excretion and improving renal function. Nevertheless, these trials of either small sample size or lack of placebo-controlled arm or low quality monitoring and management of study process take high risk bias to these evidences to support, the effects of TCM. Therefore we undertook a prospective, multicenter, double-blind, randomized controlled study to evaluate the efficacy and safety of Chinese herbal formula (Tangshen Formula and individualized prescription based on syndrome differentiation) in treating diabetic nephropathy, which based on the investigation of the characteristics of TCM syndrome of diabetic nephropathy by means of retrospective cross-sectional survey and questionnaire survey.
Objective:This study investigated the characteristics of TCM syndrome of diabetic nephropathy, and to evaluate the efficacy and safety of Chinese herbal formula (Tangshen Formula and individualized prescription based on syndrome differentiation) in treating diabetic nephropathy.
Methods:Firstly, this study analyzed the characteristics of TCM syndromes of213cases of in-patients with diabetic nephropathy by using data mining methods such as cluster analysis. Secondly, this study summed up the clinic TCM experts' experiences of the basic characteristic syndromes and symptoms of diabetic nephropathy through three series interview by questionnaires based on Delphi methods.Then,a six-center,semi-standardizedized,randomjzed,double-blind. placebo-controll ed trial was conducted to evaluate the efficacy and safety of Chinese herbal formula(Tangshen Formula and individualized prescription based on syndrome differentiation)in treating diabetie nephropathy secondary to type2diabetes mellitus.A total of180Chinese patients with DN in microalbuminuria stage and macroa]buminuria stage were randomly assigned to the Chinese herbal formula treatment group(Tangshen formula and individualized formulas based on syndrome differentiation) or the placebo group sa the ratio of2∶1,according to the method of stratified area of random,Patients were followed up for24weeks.The primary outcomes were UAER for DN patients in the microalbuminuria stage,24-hour urinary protein excretion amount for DN patients in the macroalbuminuria stage.The secondary outcomes were renal function (Scr and eGFR estimated by G/C equation);blood lipid (TG,TC,HDL-C,LDL-C);blood glycemia: seore of TCM symptoms and safety index.Standing Operating Procedure (SOP) and quality control methods were set up to guarantee quality of the process.
Results:The essential characteristies of TCM syndrome of diabetic Rephropathy is deficiency in root and excess in branch.Qi and yin defieiency with blood stasis is the basic characteristies of DN in Ⅲ and Ⅳ stages sometimes accompanied with interior heat or damp-heat.with the progress of the disease,the characteristies of TCM syndrome hsa changed to deficiency of qi, blood,yin and yang;accompanied with blood stasis and damp-turbidity in stage Ⅴ.
The clinie trial shows that after24weeks intervention (TSF and individualized formulas based on syndrome differentiation,along with ACEI/ARB applied sa primary drug treatment),the24h urinary protein in the treatment group was decreased(week24VS baseline,p<0.05)while the UP in the placebo group was increased (week24VS baseline,p-0.233).The change of UP between the two groups was significant (0.40±0.91g/24hr of the treatment group VS0.31±0.95g/24hr of the placebo group,p<0.05).The eGFR in the placebo group was decreased(week24VS baseline,p<0.05)while eGFR in the treatment group was improved (week24vs baseline,p=0.586).The change of eGFR between the two groups was signifieant (1.96±22.57ml/min of the treatment group VS-7.05±12.31ml/min of the placebo group,P=0.026).As lineat mised-effects model was applied to the TCm scores,the main effect of time is significant,The TCM scores of two groups were both decresaed over time,and the TCM scores of the treatment group declined significantly more than the placebo group in the24th week.There were no significant differences in partieipants Scr,blood lipid (TG、CHO、 HDL-C、 LDL-C), blood glucose (FBG), BP between the treatment group and placebo group(P>0.1). There was no significant difference of the side effects between the two groups. The herbal compound particles used in this study was well tolerated. After the end of the24weeks follow-up,80.33%subjects in the treatment group insisted on taking the medication, compared with75.86%in the placebo group.
Conclusions:This study shows that TSF and individualized formulas based on syndrome differentiation, along with ACEI/ARB applied as primary drug treatment, can reduce the level of24-hour urinary protein excretion, delaying eGFR decline and improving TCM symptoms with low side effects in DN patients in the macroalbuminuria stage. Due to favorable safety, efficacy and well-tolerated, TSF would provide a candidate for treating DKD with macroabluminuria.
引文
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