中医分期辨治提高糖尿病肾病达标水平及改善肾小管损害的临床研究
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摘要
[研究背景]
糖尿病肾病(DN)是糖尿病最严重和最常见的慢性微血管并发症之一,已逐渐成为终末期肾病(ESRD)的首位病因,DN患者一旦进入ESRD,必将给个人、家庭、社会带来沉重的经济负担,生活质量亦严重下降。现代医学治疗该病多采取合理饮食、降糖、降压、调脂、应用ACEI、ARB等方法,虽有一定疗效,但不能有效阻止本病发展及恶化,因此,如何有效防治DN的发生、发展,是当前医学界亟需解决的问题。中医药在治疗早期DN、阻断病情的进展,保护肾功能等方面取得了一定进展,并显示出其独特优势。目前人们对DN的防治,观念从“重医疗”向“重预防”开始转变。DN属于慢性病范畴,慢病管理可满足慢性病患者防治过程中的多样化需求,有利于增强健康意识和健康理念。中医““治未病”思想与目前所提倡的对慢性病健康管理在本质上目标是一致的。糖尿病肾病属于中医“消渴病肾病”范畴,本虚标实是基本病机,本虚证以气阴两虚为主,随着病程的进展,逐渐阴损及阳,发展为脾肾阳虚之证；所兼挟的标实证因病程阶段不同和个体差异而表现各异,但血瘀证为贯穿DN病程始终的重要兼证。辨证论治是中医学的精华所在,结合DN病机特点,当分期辨治。但目前对该病中医证候的客观依据和中医“证”的实质缺乏系统研究,没有将中医辨证论治与慢病管理有机结合起来。随着对DN研究的深入,人们认识到DN的发展和预后不仅与肾小球的损害有关,更取决于肾小管间质病变的有无及程度的轻重,尿视黄醇结合蛋白(RBP)、N-乙酰-β-D-氨基葡萄糖苷酶(NAG)与早期肾小管间质损害程度明显相关。本课题是北京市中医管理局中医药特色优势病种的预防和重大疾病中医药科技攻关专题“慢病管理模式下中医分期辨治糖尿病肾病远期疗效多中心临床研究”(课题编号JJ2011-73)及北京市科委首都临床特色应用研究“中医分期辨治结合慢病管理提高糖尿病肾病远期疗效的临床研究”(课题编号Z121107001012012)的一部分,从主要疗效指标达标水平、肾小管损害指标等方面系统评价中医药防治DN的效果,为建立具有中医特色的DN慢病管理防治方案提供依据。
[研究目的]
1、为更好的体现防治结合的卫生方针及中医药的优势,把中医分期辨治引入DN慢病管理模式中,通过多中心、前瞻性、开放式研究,观察中医分期辨治DN方案干预效果,从主要疗效指标、控制达标水平、肾小管损害指标等方面系统观察分期辨治在提高疗效、改善肾小管损害、延缓DN病程进展的作用；
2、对糖尿病及DN患者的肾小管损害指标URBP及UNAG进行对比研究,为DN的早期诊断寻找敏感指标；
3、对DN中医证候和肾小管损害指标的相关性进行分析,从而为DN的分期辨治提供客观依据。
[研究方法]
第一部分
1、研究对象：2012年9月～2012年12月间在望京医院、平谷中医院、大兴区医院、将台社区服务中心、垡头社区服务中心住院或者门诊治疗的糖尿病肾病Ⅲ、Ⅳ期患者。
2、干预措施：采用前瞻性研究,中央随机分组方法分为两组,60例患者为治疗组,接受中医分期辨治+慢病管理+常规西医治疗,60例患者为对照组,接受常规西医治疗。
3、观察指标：蛋白尿、肾功能,糖化血红蛋白、血脂、肾小管损害指标URBP、UNAG,临床症状疗效,终点事件。
第二部分
1、研究对象：2012年10月～2013年3月中国中医科学院望京医院内分泌肾病科住院患者,2型糖尿病患者及2型糖尿病肾病Ⅲ、Ⅳ期患者各30例、体检中心健康人30例,
2、研究方法：采用免疫透射比浊法测定URBP;采用4HP-NAG底物法测定UNAG。
3、观察指标：URBP、UNAG。
第三部分
1、研究对象：2012年9月～2012年12月间望京医院、平谷中医院门诊或住院治疗的2型糖尿病肾病Ⅲ、Ⅳ期60例患者。
2、研究方法：记录中医证候积分；采用免疫透射比浊法测定URBP;采用4HP-NAG底物法测定UNAG;对中医证候与URBP、UNAG进行相关分析
3、观察指标：中医证候,URBP、UNAG,相关系数
[研究结果]
第一部分
本研究共纳入病例120例,其中治疗组60例,对照组60例,两组基线资料经比较具有可比性。
1、治疗组尿蛋白显效率33.3%,有效率31.7%,总有效率65.0%；对照组显效率13.3%,有效率21.7%,总有效率35.0%。两组总有效率经X2检验,P<0.05,差异有统计学意义。
2、治疗组肾功能疗效显效率26.7%,有效率40.0%,总有效率66.7%；对照组显效率8.3%,有效率15.0%,总有效率23.3%。两组总有效率经X2检验,P<0.05,差异有统计学意义。
3、治疗组糖化血红蛋白达标率78.3%,；对照组达标率31.7%。两组达标率经X2检验,P<0.01,差异有明显统计学意义。治疗组HDL、LDL、TG达标率分别为75.0%、78.3%、75.0%,；对照组HDL、LDL、TG达标率分别为28.3%、31.6%、33.3%。两组达标率经X2检验,P<0.01,差异有明显统计学意义。
4、治疗组临床主要症状显效率45.0%,有效率35.0%,总有效率80.0%；对照组显效率11.7%,有效率18.3%,总有效率30.0%。两组总有效率经X2检验,P<0.01,有显著统计学差异。
5、治疗组治疗后URBP与对照组相比,有明显下降,两组比较,P<0.05,差异有统计学意义；治疗组URBP治疗前后结果有显著性差异,P<0.05；治疗组UNAG治疗前后结果有显著性差异,P<0.05；治疗组治疗后UNAG与对照组相比,有下降趋势,但两组比较,P>0.05,无统计学差异。
6、早期DN蛋白尿终点事件治疗组发生率为3.1%；对照组发生率为6.4%。临床期DN蛋白尿终点事件发生率为7.1%；对照组发生率为13.8%。各期DN蛋白尿终点事件治疗组总发生率为5.0%；对照组总发生率为10.0%。各期DN肾功能终点事件治疗组总发生率为6.7%；对照组发生率为15.0%。以上数据两组比较,P>0.05,差异无统计学意义。两组均无死亡病例。
第二部分
1、尿RBP正常对照组与DM组及DN组比较均有显著性差异(P<0.01),DM组与DN组比较有显著性差异(P<0.05)。
2、尿NAG正常对照组与DM组及DN组比较均有显著性差异(P<0.05,P<0.01),DM组与DN组比较有显著性差异(P<0.05)。
第三部分
1、糖尿病肾病Ⅲ期患者中医证候特点：发生概率在前十位的中医证候依次为：腰酸软、双目干涩、口干、腰痛、疲倦懒动、口渴欲饮、手足麻木、健忘、尿频、下肢水肿。糖尿病肾病Ⅳ期发生概率在前十位的中医证候依次为：腰痛喜温、腰酸软、手足麻木、下肢水肿、疲倦懒动、健忘、手足不温、皮肤瘙痒、双目干涩、畏寒。
2、糖尿病肾病Ⅲ、Ⅳ期患者URBP检测结果两组具有显著性差异(P<0.05),Ⅲ、Ⅳ期患者UNAG检测结果两组具有显著性差异(P<0.05)。
3、糖尿病肾病Ⅲ期中医证候尿频分别与URBP、UNAG呈正相关,(r=0.869,P<0.01),(r=0.726,P<0.01)；糖尿病肾病Ⅳ期中医证候下肢水肿与URBP、UNAG呈正相关,(r=0.857,P<0.01),(r=0.821,P<0.01)。
[结论]
1、中医分期辨治结合慢病管理是防治糖尿病肾病的一种新模式,中医分期辨治DN可有效改善临床症状、降低蛋白尿、延缓肾功能进展、提高血糖及血脂达标水平、改善肾小管损害指标。中医慢病管理体现了中医的辨证论治及整体性原则,充分发挥了中医药防治糖尿病肾病、延缓病情进展的优势。
2、2型糖尿病患者在尿蛋白阴性时,URBP和UNAG已有所升高,提示这两项肾小管损害指标可作为早期诊断DN的敏感指标。
3、DN Ⅲ期中医证型多以气阴两虚为主,Ⅳ期出现脾肾阳虚,瘀血阻络贯穿始终。糖尿病肾病Ⅲ期中医证候中,尿频分别与URBP、UNAG呈正相关；糖尿病肾病Ⅳ期中医证候中,下肢水肿与URBP、UNAG呈正相关,中医证候与肾小管损害相关指标的连接点在于“水”这一病理要素。
[创新性]
1、中医慢病管理具有创新性：本研究将中医分期辨治引入慢性病管理模式,符合当代防治结合、促进健康、延缓慢病进展的医学新理念。
2、研究设计思路具有创新性：运用多中心、大样本、随机平行对照的临床前瞻性研究,思路具有创新性。
3、研究内容具有创新性：对中医分期辨治糖尿病肾病从提高达标水平、改善肾小管损害指标等方面进行研究,对比研究糖尿病和DN患者的肾小管损害标记物,并进行DN中医证侯与肾小管损伤指标的相关性研究,发现中医证候与肾小管损害相关指标的连接点在于“水”这一病理要素。
Background
Diabetic nephropathy(DN) is one of the most common and serious chronic microvascular complications of Diabetes Mellitus (DM). DN has gradually become the first cause of end-stage renal disease (ESRD), which is bound to bring a heavy personal, family, social economic burden, meanwhile the quality of life is in serious declining. The modern medical treatment of DN includes taking a more reasonable diet, hypoglycemic, antihypertensive, lipid-lowering, the application of ACEI, ARB, etc., although there is certain effect, but it is hardly to prevent the development and progression of the disease effectively. Therefore, how to prevent and treat DN effectively is the problem to solve in medical field. Chinese medicine has made some progress in the treatment of early DN by blocking the progress of the disease and protecting renal function, and showed its unique advantages. At present, the concept of people about DN control have changed from treatment to prevention.DN belongs to the category of chronic diseases, chronic disease management can meet the diverse needs of patients with chronic disease prevention and control process, and help enhance health awareness and healthy concept. In essence the preventive treatment of disease thinking in Chinese medicine has the same objective with the current advocated management of chronic health. Diabetic nephropathy belongs to Chinese "Diabetes kidney disease" category, the basic pathogenesis is the deficiency in the "root" and excess in the "branch". With the progression of the disease, the deficiency of Qiyin will transfer to Yang deficiency of the spleen and kidney. The symptoms are different in different stages and individual, but blood stasis throughout the DN course of the disease is always important syndrome. Diagnosis and treatment is the essence of TCM. Based on the characteristics of DN pathogenesis,TCM staging diagnosis and treatment is a must. At present it is lack of systematic research on the essence of the disease TCM climate objective basis and TCM symptom element, as well as organic combination of TCM diagnosis and treatment and chronic disease management. With the deepening of the DN research, it is recognized that the development and prognosis of DN is not only associated with glomerular damage, but also depends on the presence and degree of severity of the renal tubulointerstitial lesion. Urinary retinol binding protein (RBP) and N-acetyl-beta-D-glucosaminidase (NAG) are related with the extent of early renal tubulointerstitial damage. The thesis is one part of the research based on the Beijing Municipal Administration of Traditional Chinese Medicine Chinese medicine characteristics and advantages of the disease prevention and major diseases in medicine science and technology research topics, that is a multi-center clinical study on the long-term efficacy of TCM installments Treating diabetic nephropathy under chronic disease management model(project number JJ2011-73). It is also a part of the research supported by Beijing Municipal Science and Technology Commission, the capital of the clinical characteristics of applied research, named "installment Diagnosis and Treatment of traditional Chinese medicine combined with chronic disease management to improve the long-term efficacy of diabetic nephropathy clinical research" part of the (project number Z121107001012012). In order to provide the basis for the establishment of prevention and treatment programs of DN chronic disease management with Chinese characteristics, the research evaluates the effect of Chinese herbal to prevent and treat DN from the primary efficacy endpoint compliance level, renal tubular damage markers and so on.
Objective
1.Combine TCM staging diagnosis and Treatment with chronic disease management model in DN, evaluate the efficacy of staging diagnosis and Treatment by multi-center, prospective, open-label study from the aspects such as the primary efficacy endpoint. Controlled level of compliance, renal tubular damage markers, et al. Observe the role of staging diagnosis and Treatment on improving efficacy and renal damage, delaying the progression of DN, to better reflect the prevention and treatment of health policy and the advantages of Chinese medicine.
2.Look for sensitive markers for the early diagnosis of DN by comparing study tubular damage indicators URBP and UNAG between diabetes patients and DN ones.
3.Make a correlation analysis between TCM symptoms of DN and renal tubular damage indicators to provide an objective basis for DN staging diagnosis and treatment.
Methods
Part one
1. Object:patients with DN Ⅲ, Ⅳ stages from Wangjing Hospital, Hospital of Pinggu, Daxing District Hospital, Jiangtai community service centers, the Fatou Community Service in-patient or out-patient. September2012to December2012.
2.Interventions:A prospective study of central randomization method. Subjects are divided into two groups,60patients for the treatment group, to accept staging diagnosis and treatment, chronic disease management, conventional Western medicine treatment as well, the other60patients as the control group, treated with conventional Western.
3. Observation indexes:Albuminuria, renal function, glycosylated hemoglobin, lipids, tubular damage indicators URBP and UNAG, the efficacy of clinical symptoms, endpoint events.
Part two
1. Object:patients from China Academy of Traditional Chinese Medicine, Wangjing Hospital, hospitalized patients with type2diabetes and type2diabetic nephropathy III and stage IV patients of the30cases, medical centers30cases of healthy people, October2012to March2013.
2. Methods:by immune transmission turbidimetric method URBP; the4HP-NAG substrate method for determination of UNAG.
3. Observation indexes:URBP, UNAG.
Part three
1. Object:patients with DN Ⅲ, Ⅳ stages from Wangjing Hospital, Hospital of Pinggu, in-patient or out-patient, September2012to December2012.
2. Methods:record TCM symptoms scores, by immune transmission turbidimetric method URBP; the4HP-NAG substrate method for determination of UNAG. make person correlation analysis between TCM syndromes and URBP, UNAG
3. Observation indexes:TCM syndromes,URBP, UNAG Correlativity.
Results
Part one
120cases were enrolled in the study, including60cases in treatment group and60cases in control group. Baseline data were compared with the comparable.
1. In treatment group markedly effective rate of proteinuria decreasing was33.3%, efficiency was31.7%and Total efficiency was65.0%. In control group, markedly effective rate of proteinuria decreasing was13.3%, efficiency was21.7%and Total efficiency was35.0%. Total efficiency by X2test, P<0.05, the difference was statistically significant.
2. In treatment group markedly effective rate of renal function was26.7%, efficiency was40.0%and Total efficiency was66.7%. In control group, markedly effective rate of renal function was8.3%, efficiency was15.0%and Total efficiency was23.3%. Total efficiency by X2test, P<0.05, the difference was statistically significant.
3.The compliance rate of glycosylated hemoglobin of treatment group was78.3%, while31.7%of control group. The compliance rate by X2test, P<0.01, the difference was statistically significant between two groups. The compliance rate of HDL、LDL、TG of treatment group was separately75.0%,78.3%,75.0%,while28.3%,31.6%,33.3%of control group. The compliance rate by X2test, P<0.01, the difference was statistically significant between two groups.
4. In treatment group markedly effective rate of clinical main symptoms was45.0%, efficiency was35.0%and Total efficiency was80.0%. In control group, markedly effective rate of clinical main symptoms was11.7%, efficiency was18.3%and Total efficiency was30.0%. Total efficiency by X2test, P<0.01, the difference was statistically significant.
5. After treatment URBP of treatment group decreased significantly compared with that of control group, P<0.05, the difference was statistically significant between the two groups. There was a statistically significance about URBP of treatment group between before treatment and after treatment P<0.05. There was a statistically significance about UNAG of treatment group between before treatment and after treatment P<0.05. compared with control group, after treatment UNAG had downward trend, but no significant difference P>0.05between two groups.
6. The early DN proteinuria endpoint event rate was3.1%in treatment group and6.4%in control group. Clinical stage DN proteinuria endpoint event rate was7.1%and the control group was13.8%. the overall incidence rate of proteinuria endpoint event rate was5.0%in treatment group,10.0%in control group. The total incidence of periods DN renal function endpoint event was6.7%in treatment group,15.0%in control group. From above data between the two groups, there was no statistically significant difference P>0.05. There were no deaths in two groups.
Part two
1. There was statistically significant difference of URBP among normal control group, DM group and DN group (P<0.01). URBP of DM group had statistically significant difference compared with that of DN group (P<0.05).
2. There was statistically significant difference of UNAG among normal control group, DM group and DN group (P<0.05,P<0.01). UNAG of DM group had statistically significant difference compared with that of DN group(P<0.05).
Part three
1. Diabetic nephropathy in patients with stage Ⅲ TCM syndromes:the occurrence probability of the top ten Chinese medicine syndrome are as follows: soreness and weakness in lower back, the foreign body sensation of eyes, dry mouth, lumbago, tired or fatigue, thirst, numbness, forgetfulness, urinary frequency, lower extremity edema. Diabetic nephropathy stage IV probability of occurrence of the top ten Chinese medicine syndrome:lumbago like warm, soreness and weakness in lower back, numbness in the hands and feet, lower extremity edema, fatigue, forgetfulness, hand-foot no warm, itchy skin, the foreign body sensation of eyes, intolerance of cold.
2.There was statistically significant difference of URBP and UNAG respectively between Diabetic nephropathy with stage Ⅲ and stage Ⅳ.(P<0.05).
3. TCM syndrome urinary frequency with diabetic nephropathy stage Ⅲ was positive related respectively to URBP and UNAG.(r=0.869, P<0.01)(r=0.726, P <0.01); TCM syndrome lower extremity edema with diabetic nephropathy stage Ⅳ was positive related respectively to URBP and UNAG.(r=0.857, P<0.01),(r=0.821, P<0.01).
Conclusions
1.It is a new model to integrate TCM staging diagnosis and treatment and chronic disease management. TCM staging diagnosis and treatment can improve clinical symptoms, decrease proteinuria, protect renal function, improve the level of compliance about blood glucose and lipid, and improve the indicators of renal tubular damage as well. Chinese medicine chronic disease management reflects the diagnosis and treatment of traditional Chinese medicine and holistic principles, giving full play to the prevention and treatment of diabetic nephropathy of Traditional Chinese Medicine and the advantages of delaying the progress of the disease.
2. URBP and UNAG has been increased when the urine protein is negative in patients with type2diabetes. That suggests these two tubular damage indicators can be used as sensitive makers of early diagnosis of DN.
3. Qiyinliangxu is the common TCM syndrome type in diabetic nephropathy stage Ⅲ, and Pishenyangxu is the common type in stage IV with blood stasis throughout the course of disease. TCM syndrome urinary frequency with diabetic nephropathy stage Ⅲ was positive related respectively to URBP and UNAG. TCM syndrome lower extremity edema with diabetic nephropathy stage IV was positive related respectively to URBP and UNAG. The connection point between TCM syndromes and renal tubular damage related indicator is the "water" pathological elements.
Innovations
1. Chinese medicine chronic disease management model is an innovation:In this study, TCM staging diagnosis and treatment integrates with chronic disease management mode, which is in line with the new contemporary medical concept of combining prevention with control, Promoting health and slowing progress of the chronic disease.
2. Innovative research and design ideas:to use a multi-center, large sample, randomized controlled clinical prospective study is innovative idea.
3. Innovative research:to research the efficiency of TCM staging diagnosis and treatment from improving the level of compliance and renal tubular damage indicators. to compare tubular damage indicators URBP and UNAG between diabetes patients and DN ones. To make a correlation analysis between TCM symptoms of DN and renal tubular damage indicators and find the "water" pathological elements is the connection point of them.
糖尿病肾病(DN)是糖尿病最严重和最常见的慢性微血管并发症之一,已逐渐成为终末期肾病(ESRD)的首位病因,DN患者一旦进入ESRD,必将给个人、家庭、社会带来沉重的经济负担,生活质量亦严重下降。现代医学治疗该病多采取合理饮食、降糖、降压、调脂、应用ACEI、ARB等方法,虽有一定疗效,但不能有效阻止本病发展及恶化,因此,如何有效防治DN的发生、发展,是当前医学界亟需解决的问题。中医药在治疗早期DN、阻断病情的进展,保护肾功能等方面取得了一定进展,并显示出其独特优势。目前人们对DN的防治,观念从“重医疗”向“重预防”开始转变。DN属于慢性病范畴,慢病管理可满足慢性病患者防治过程中的多样化需求,有利于增强健康意识和健康理念。中医““治未病”思想与目前所提倡的对慢性病健康管理在本质上目标是一致的。糖尿病肾病属于中医“消渴病肾病”范畴,本虚标实是基本病机,本虚证以气阴两虚为主,随着病程的进展,逐渐阴损及阳,发展为脾肾阳虚之证；所兼挟的标实证因病程阶段不同和个体差异而表现各异,但血瘀证为贯穿DN病程始终的重要兼证。辨证论治是中医学的精华所在,结合DN病机特点,当分期辨治。但目前对该病中医证候的客观依据和中医“证”的实质缺乏系统研究,没有将中医辨证论治与慢病管理有机结合起来。随着对DN研究的深入,人们认识到DN的发展和预后不仅与肾小球的损害有关,更取决于肾小管间质病变的有无及程度的轻重,尿视黄醇结合蛋白(RBP)、N-乙酰-β-D-氨基葡萄糖苷酶(NAG)与早期肾小管间质损害程度明显相关。本课题是北京市中医管理局中医药特色优势病种的预防和重大疾病中医药科技攻关专题“慢病管理模式下中医分期辨治糖尿病肾病远期疗效多中心临床研究”(课题编号JJ2011-73)及北京市科委首都临床特色应用研究“中医分期辨治结合慢病管理提高糖尿病肾病远期疗效的临床研究”(课题编号Z121107001012012)的一部分,从主要疗效指标达标水平、肾小管损害指标等方面系统评价中医药防治DN的效果,为建立具有中医特色的DN慢病管理防治方案提供依据。
[研究目的]
1、为更好的体现防治结合的卫生方针及中医药的优势,把中医分期辨治引入DN慢病管理模式中,通过多中心、前瞻性、开放式研究,观察中医分期辨治DN方案干预效果,从主要疗效指标、控制达标水平、肾小管损害指标等方面系统观察分期辨治在提高疗效、改善肾小管损害、延缓DN病程进展的作用；
2、对糖尿病及DN患者的肾小管损害指标URBP及UNAG进行对比研究,为DN的早期诊断寻找敏感指标；
3、对DN中医证候和肾小管损害指标的相关性进行分析,从而为DN的分期辨治提供客观依据。
[研究方法]
第一部分
1、研究对象：2012年9月～2012年12月间在望京医院、平谷中医院、大兴区医院、将台社区服务中心、垡头社区服务中心住院或者门诊治疗的糖尿病肾病Ⅲ、Ⅳ期患者。
2、干预措施：采用前瞻性研究,中央随机分组方法分为两组,60例患者为治疗组,接受中医分期辨治+慢病管理+常规西医治疗,60例患者为对照组,接受常规西医治疗。
3、观察指标：蛋白尿、肾功能,糖化血红蛋白、血脂、肾小管损害指标URBP、UNAG,临床症状疗效,终点事件。
第二部分
1、研究对象：2012年10月～2013年3月中国中医科学院望京医院内分泌肾病科住院患者,2型糖尿病患者及2型糖尿病肾病Ⅲ、Ⅳ期患者各30例、体检中心健康人30例,
2、研究方法：采用免疫透射比浊法测定URBP;采用4HP-NAG底物法测定UNAG。
3、观察指标：URBP、UNAG。
第三部分
1、研究对象：2012年9月～2012年12月间望京医院、平谷中医院门诊或住院治疗的2型糖尿病肾病Ⅲ、Ⅳ期60例患者。
2、研究方法：记录中医证候积分；采用免疫透射比浊法测定URBP;采用4HP-NAG底物法测定UNAG;对中医证候与URBP、UNAG进行相关分析
3、观察指标：中医证候,URBP、UNAG,相关系数
[研究结果]
第一部分
本研究共纳入病例120例,其中治疗组60例,对照组60例,两组基线资料经比较具有可比性。
1、治疗组尿蛋白显效率33.3%,有效率31.7%,总有效率65.0%；对照组显效率13.3%,有效率21.7%,总有效率35.0%。两组总有效率经X2检验,P<0.05,差异有统计学意义。
2、治疗组肾功能疗效显效率26.7%,有效率40.0%,总有效率66.7%；对照组显效率8.3%,有效率15.0%,总有效率23.3%。两组总有效率经X2检验,P<0.05,差异有统计学意义。
3、治疗组糖化血红蛋白达标率78.3%,；对照组达标率31.7%。两组达标率经X2检验,P<0.01,差异有明显统计学意义。治疗组HDL、LDL、TG达标率分别为75.0%、78.3%、75.0%,；对照组HDL、LDL、TG达标率分别为28.3%、31.6%、33.3%。两组达标率经X2检验,P<0.01,差异有明显统计学意义。
4、治疗组临床主要症状显效率45.0%,有效率35.0%,总有效率80.0%；对照组显效率11.7%,有效率18.3%,总有效率30.0%。两组总有效率经X2检验,P<0.01,有显著统计学差异。
5、治疗组治疗后URBP与对照组相比,有明显下降,两组比较,P<0.05,差异有统计学意义；治疗组URBP治疗前后结果有显著性差异,P<0.05；治疗组UNAG治疗前后结果有显著性差异,P<0.05；治疗组治疗后UNAG与对照组相比,有下降趋势,但两组比较,P>0.05,无统计学差异。
6、早期DN蛋白尿终点事件治疗组发生率为3.1%；对照组发生率为6.4%。临床期DN蛋白尿终点事件发生率为7.1%；对照组发生率为13.8%。各期DN蛋白尿终点事件治疗组总发生率为5.0%；对照组总发生率为10.0%。各期DN肾功能终点事件治疗组总发生率为6.7%；对照组发生率为15.0%。以上数据两组比较,P>0.05,差异无统计学意义。两组均无死亡病例。
第二部分
1、尿RBP正常对照组与DM组及DN组比较均有显著性差异(P<0.01),DM组与DN组比较有显著性差异(P<0.05)。
2、尿NAG正常对照组与DM组及DN组比较均有显著性差异(P<0.05,P<0.01),DM组与DN组比较有显著性差异(P<0.05)。
第三部分
1、糖尿病肾病Ⅲ期患者中医证候特点：发生概率在前十位的中医证候依次为：腰酸软、双目干涩、口干、腰痛、疲倦懒动、口渴欲饮、手足麻木、健忘、尿频、下肢水肿。糖尿病肾病Ⅳ期发生概率在前十位的中医证候依次为：腰痛喜温、腰酸软、手足麻木、下肢水肿、疲倦懒动、健忘、手足不温、皮肤瘙痒、双目干涩、畏寒。
2、糖尿病肾病Ⅲ、Ⅳ期患者URBP检测结果两组具有显著性差异(P<0.05),Ⅲ、Ⅳ期患者UNAG检测结果两组具有显著性差异(P<0.05)。
3、糖尿病肾病Ⅲ期中医证候尿频分别与URBP、UNAG呈正相关,(r=0.869,P<0.01),(r=0.726,P<0.01)；糖尿病肾病Ⅳ期中医证候下肢水肿与URBP、UNAG呈正相关,(r=0.857,P<0.01),(r=0.821,P<0.01)。
[结论]
1、中医分期辨治结合慢病管理是防治糖尿病肾病的一种新模式,中医分期辨治DN可有效改善临床症状、降低蛋白尿、延缓肾功能进展、提高血糖及血脂达标水平、改善肾小管损害指标。中医慢病管理体现了中医的辨证论治及整体性原则,充分发挥了中医药防治糖尿病肾病、延缓病情进展的优势。
2、2型糖尿病患者在尿蛋白阴性时,URBP和UNAG已有所升高,提示这两项肾小管损害指标可作为早期诊断DN的敏感指标。
3、DN Ⅲ期中医证型多以气阴两虚为主,Ⅳ期出现脾肾阳虚,瘀血阻络贯穿始终。糖尿病肾病Ⅲ期中医证候中,尿频分别与URBP、UNAG呈正相关；糖尿病肾病Ⅳ期中医证候中,下肢水肿与URBP、UNAG呈正相关,中医证候与肾小管损害相关指标的连接点在于“水”这一病理要素。
[创新性]
1、中医慢病管理具有创新性：本研究将中医分期辨治引入慢性病管理模式,符合当代防治结合、促进健康、延缓慢病进展的医学新理念。
2、研究设计思路具有创新性：运用多中心、大样本、随机平行对照的临床前瞻性研究,思路具有创新性。
3、研究内容具有创新性：对中医分期辨治糖尿病肾病从提高达标水平、改善肾小管损害指标等方面进行研究,对比研究糖尿病和DN患者的肾小管损害标记物,并进行DN中医证侯与肾小管损伤指标的相关性研究,发现中医证候与肾小管损害相关指标的连接点在于“水”这一病理要素。
Background
Diabetic nephropathy(DN) is one of the most common and serious chronic microvascular complications of Diabetes Mellitus (DM). DN has gradually become the first cause of end-stage renal disease (ESRD), which is bound to bring a heavy personal, family, social economic burden, meanwhile the quality of life is in serious declining. The modern medical treatment of DN includes taking a more reasonable diet, hypoglycemic, antihypertensive, lipid-lowering, the application of ACEI, ARB, etc., although there is certain effect, but it is hardly to prevent the development and progression of the disease effectively. Therefore, how to prevent and treat DN effectively is the problem to solve in medical field. Chinese medicine has made some progress in the treatment of early DN by blocking the progress of the disease and protecting renal function, and showed its unique advantages. At present, the concept of people about DN control have changed from treatment to prevention.DN belongs to the category of chronic diseases, chronic disease management can meet the diverse needs of patients with chronic disease prevention and control process, and help enhance health awareness and healthy concept. In essence the preventive treatment of disease thinking in Chinese medicine has the same objective with the current advocated management of chronic health. Diabetic nephropathy belongs to Chinese "Diabetes kidney disease" category, the basic pathogenesis is the deficiency in the "root" and excess in the "branch". With the progression of the disease, the deficiency of Qiyin will transfer to Yang deficiency of the spleen and kidney. The symptoms are different in different stages and individual, but blood stasis throughout the DN course of the disease is always important syndrome. Diagnosis and treatment is the essence of TCM. Based on the characteristics of DN pathogenesis,TCM staging diagnosis and treatment is a must. At present it is lack of systematic research on the essence of the disease TCM climate objective basis and TCM symptom element, as well as organic combination of TCM diagnosis and treatment and chronic disease management. With the deepening of the DN research, it is recognized that the development and prognosis of DN is not only associated with glomerular damage, but also depends on the presence and degree of severity of the renal tubulointerstitial lesion. Urinary retinol binding protein (RBP) and N-acetyl-beta-D-glucosaminidase (NAG) are related with the extent of early renal tubulointerstitial damage. The thesis is one part of the research based on the Beijing Municipal Administration of Traditional Chinese Medicine Chinese medicine characteristics and advantages of the disease prevention and major diseases in medicine science and technology research topics, that is a multi-center clinical study on the long-term efficacy of TCM installments Treating diabetic nephropathy under chronic disease management model(project number JJ2011-73). It is also a part of the research supported by Beijing Municipal Science and Technology Commission, the capital of the clinical characteristics of applied research, named "installment Diagnosis and Treatment of traditional Chinese medicine combined with chronic disease management to improve the long-term efficacy of diabetic nephropathy clinical research" part of the (project number Z121107001012012). In order to provide the basis for the establishment of prevention and treatment programs of DN chronic disease management with Chinese characteristics, the research evaluates the effect of Chinese herbal to prevent and treat DN from the primary efficacy endpoint compliance level, renal tubular damage markers and so on.
Objective
1.Combine TCM staging diagnosis and Treatment with chronic disease management model in DN, evaluate the efficacy of staging diagnosis and Treatment by multi-center, prospective, open-label study from the aspects such as the primary efficacy endpoint. Controlled level of compliance, renal tubular damage markers, et al. Observe the role of staging diagnosis and Treatment on improving efficacy and renal damage, delaying the progression of DN, to better reflect the prevention and treatment of health policy and the advantages of Chinese medicine.
2.Look for sensitive markers for the early diagnosis of DN by comparing study tubular damage indicators URBP and UNAG between diabetes patients and DN ones.
3.Make a correlation analysis between TCM symptoms of DN and renal tubular damage indicators to provide an objective basis for DN staging diagnosis and treatment.
Methods
Part one
1. Object:patients with DN Ⅲ, Ⅳ stages from Wangjing Hospital, Hospital of Pinggu, Daxing District Hospital, Jiangtai community service centers, the Fatou Community Service in-patient or out-patient. September2012to December2012.
2.Interventions:A prospective study of central randomization method. Subjects are divided into two groups,60patients for the treatment group, to accept staging diagnosis and treatment, chronic disease management, conventional Western medicine treatment as well, the other60patients as the control group, treated with conventional Western.
3. Observation indexes:Albuminuria, renal function, glycosylated hemoglobin, lipids, tubular damage indicators URBP and UNAG, the efficacy of clinical symptoms, endpoint events.
Part two
1. Object:patients from China Academy of Traditional Chinese Medicine, Wangjing Hospital, hospitalized patients with type2diabetes and type2diabetic nephropathy III and stage IV patients of the30cases, medical centers30cases of healthy people, October2012to March2013.
2. Methods:by immune transmission turbidimetric method URBP; the4HP-NAG substrate method for determination of UNAG.
3. Observation indexes:URBP, UNAG.
Part three
1. Object:patients with DN Ⅲ, Ⅳ stages from Wangjing Hospital, Hospital of Pinggu, in-patient or out-patient, September2012to December2012.
2. Methods:record TCM symptoms scores, by immune transmission turbidimetric method URBP; the4HP-NAG substrate method for determination of UNAG. make person correlation analysis between TCM syndromes and URBP, UNAG
3. Observation indexes:TCM syndromes,URBP, UNAG Correlativity.
Results
Part one
120cases were enrolled in the study, including60cases in treatment group and60cases in control group. Baseline data were compared with the comparable.
1. In treatment group markedly effective rate of proteinuria decreasing was33.3%, efficiency was31.7%and Total efficiency was65.0%. In control group, markedly effective rate of proteinuria decreasing was13.3%, efficiency was21.7%and Total efficiency was35.0%. Total efficiency by X2test, P<0.05, the difference was statistically significant.
2. In treatment group markedly effective rate of renal function was26.7%, efficiency was40.0%and Total efficiency was66.7%. In control group, markedly effective rate of renal function was8.3%, efficiency was15.0%and Total efficiency was23.3%. Total efficiency by X2test, P<0.05, the difference was statistically significant.
3.The compliance rate of glycosylated hemoglobin of treatment group was78.3%, while31.7%of control group. The compliance rate by X2test, P<0.01, the difference was statistically significant between two groups. The compliance rate of HDL、LDL、TG of treatment group was separately75.0%,78.3%,75.0%,while28.3%,31.6%,33.3%of control group. The compliance rate by X2test, P<0.01, the difference was statistically significant between two groups.
4. In treatment group markedly effective rate of clinical main symptoms was45.0%, efficiency was35.0%and Total efficiency was80.0%. In control group, markedly effective rate of clinical main symptoms was11.7%, efficiency was18.3%and Total efficiency was30.0%. Total efficiency by X2test, P<0.01, the difference was statistically significant.
5. After treatment URBP of treatment group decreased significantly compared with that of control group, P<0.05, the difference was statistically significant between the two groups. There was a statistically significance about URBP of treatment group between before treatment and after treatment P<0.05. There was a statistically significance about UNAG of treatment group between before treatment and after treatment P<0.05. compared with control group, after treatment UNAG had downward trend, but no significant difference P>0.05between two groups.
6. The early DN proteinuria endpoint event rate was3.1%in treatment group and6.4%in control group. Clinical stage DN proteinuria endpoint event rate was7.1%and the control group was13.8%. the overall incidence rate of proteinuria endpoint event rate was5.0%in treatment group,10.0%in control group. The total incidence of periods DN renal function endpoint event was6.7%in treatment group,15.0%in control group. From above data between the two groups, there was no statistically significant difference P>0.05. There were no deaths in two groups.
Part two
1. There was statistically significant difference of URBP among normal control group, DM group and DN group (P<0.01). URBP of DM group had statistically significant difference compared with that of DN group (P<0.05).
2. There was statistically significant difference of UNAG among normal control group, DM group and DN group (P<0.05,P<0.01). UNAG of DM group had statistically significant difference compared with that of DN group(P<0.05).
Part three
1. Diabetic nephropathy in patients with stage Ⅲ TCM syndromes:the occurrence probability of the top ten Chinese medicine syndrome are as follows: soreness and weakness in lower back, the foreign body sensation of eyes, dry mouth, lumbago, tired or fatigue, thirst, numbness, forgetfulness, urinary frequency, lower extremity edema. Diabetic nephropathy stage IV probability of occurrence of the top ten Chinese medicine syndrome:lumbago like warm, soreness and weakness in lower back, numbness in the hands and feet, lower extremity edema, fatigue, forgetfulness, hand-foot no warm, itchy skin, the foreign body sensation of eyes, intolerance of cold.
2.There was statistically significant difference of URBP and UNAG respectively between Diabetic nephropathy with stage Ⅲ and stage Ⅳ.(P<0.05).
3. TCM syndrome urinary frequency with diabetic nephropathy stage Ⅲ was positive related respectively to URBP and UNAG.(r=0.869, P<0.01)(r=0.726, P <0.01); TCM syndrome lower extremity edema with diabetic nephropathy stage Ⅳ was positive related respectively to URBP and UNAG.(r=0.857, P<0.01),(r=0.821, P<0.01).
Conclusions
1.It is a new model to integrate TCM staging diagnosis and treatment and chronic disease management. TCM staging diagnosis and treatment can improve clinical symptoms, decrease proteinuria, protect renal function, improve the level of compliance about blood glucose and lipid, and improve the indicators of renal tubular damage as well. Chinese medicine chronic disease management reflects the diagnosis and treatment of traditional Chinese medicine and holistic principles, giving full play to the prevention and treatment of diabetic nephropathy of Traditional Chinese Medicine and the advantages of delaying the progress of the disease.
2. URBP and UNAG has been increased when the urine protein is negative in patients with type2diabetes. That suggests these two tubular damage indicators can be used as sensitive makers of early diagnosis of DN.
3. Qiyinliangxu is the common TCM syndrome type in diabetic nephropathy stage Ⅲ, and Pishenyangxu is the common type in stage IV with blood stasis throughout the course of disease. TCM syndrome urinary frequency with diabetic nephropathy stage Ⅲ was positive related respectively to URBP and UNAG. TCM syndrome lower extremity edema with diabetic nephropathy stage IV was positive related respectively to URBP and UNAG. The connection point between TCM syndromes and renal tubular damage related indicator is the "water" pathological elements.
Innovations
1. Chinese medicine chronic disease management model is an innovation:In this study, TCM staging diagnosis and treatment integrates with chronic disease management mode, which is in line with the new contemporary medical concept of combining prevention with control, Promoting health and slowing progress of the chronic disease.
2. Innovative research and design ideas:to use a multi-center, large sample, randomized controlled clinical prospective study is innovative idea.
3. Innovative research:to research the efficiency of TCM staging diagnosis and treatment from improving the level of compliance and renal tubular damage indicators. to compare tubular damage indicators URBP and UNAG between diabetes patients and DN ones. To make a correlation analysis between TCM symptoms of DN and renal tubular damage indicators and find the "water" pathological elements is the connection point of them.
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