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糖尿病肾病辨证方案研究
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摘要
中医药防治DN的作用和优势日益受到国内外的关注,有关DN的既往研究由于缺少严格的科研设计和统一的中医辨证标准,疗效评价方面又缺少既能突出中医优势又能与国际医学接轨的疗效评价方法,得出的结论科学性较差,严重制约了中医药科研成果的推广应用和走向世界。因此,总结DN中医诊治规律,开展DN诊疗标准化、规范化工作势在必行。辨证是诊疗的起点和关键,开展辨证方案研究是首要工作之一。
     1目的
     遵照循证医学精神,结合中医特点,开展DN文献调研、专家经验征集、地区性诊疗方案分析、多中心大样本中医证候流行病学调查、中医病机理论研究等方面研究,从中分析和把握DN中医证候类型和分布规律,为DN的辨证工作提供循证医学证据,以期建立较为合理DN的辨证方案。
     2方法
     文献调研采用定性、定量研究方法对近20年有关DN辨证分型文献进行评价;专家经验征集采用国外广泛应用德尔菲(Delphi)法;地区性诊疗方案分析采用定性研究方法;中医证候流行病学调查采用量表进行测量,运用统计描述、主成分分析等多元统计学方法对证候特点及分布规律进行分析;理论研究采用传统文献梳理与现代文献分析的方法对DN病机进行归纳和总结。
     3结果
     3.1文献调研
     通过文献定性研究表明DN辨证方案多达60余种,临床辨证方法有分型辨证、分期辨证、分型分期辨证、分期分型辨证等不同;辨证模式有气血阴阳辨证、脏腑辨证、标本虚实辨证等不同;还有一些辨证方法和模式相互重叠、交叉的情况。这些皆来源于实践,具有一定合理性,各具特征,各有规律,各有侧重。
     文献定量评价研究借鉴Meta分析原理,收集到DN病例2182例,涉及DN证型种类多达40余种。中医证型的构成比排在前5位的依次是:气阴两虚型(33.91%)、阴阳两虚型(20.90%)、阳虚型(12.56%)、阴虚型(11.32%)、阴虚热盛型(5.32%)。
     3.2基于德尔菲(Delphi)法的DN辨证专家问卷调查分析
     中医是经验医学,专家经验在大多数情况下被认为是金标准,Delph法可合理科学地征集专家意见。本研究就DN辨证模式、辨证方法、病变脏腑、常见证素等条目进行了两轮问卷咨询。
     第一轮汇总结果,中医证候、病变脏腑部分专家意见高度集中,且变异系数较低,专家的协调程度较高,认为DN中医证候以复合证、虚实夹杂形式存在,病变脏腑以两脏或多脏多见;有些指标专家集中程度较低,变异系数在1.0以上,在第二轮问卷中对咨询条目进行了调整,删除了六经辨证及其他辨证模式等条目,增加了一项条目。
     第二轮专家问卷评价结果来看,大多数指标变异系数在0.5左右,调查专家观点趋于一致,意见较为集中。专家在DN病性、病机、病位等认识取得一致意见,认为DN乃本虚标实之证,本虚有气虚、阴虚、阳虚、血虚之分,标实有血瘀、湿浊、痰湿、气滞之别,其中气(阴)两虚、血瘀、湿浊在DN发展中占了较大比率。DN病变具有以肾虚为中心,脾肾、肝肾乃至心、肺、脾胃等多脏腑阴阳气血复合虚损的特点。
     3.3“十一五”重点专科建设项目DN辨证方案定性研究
     国家中医药管理局“十一五”肾病重点专科13份DN诊疗方案代表了国内当今DN治疗水平,可作为循证医学证据来进行研究。通过定性分析得出结论:虽然DN辨证方案多样化,但对DN病性、病位、病机等认识基本一致,气阴两虚、气虚、阴阳两虚、血瘀、湿浊在DN方案中占了较大比率,病位以肾为中心,涉及脾肾、肝肾,以脾肾气(阳)虚、肝肾阴虚、肝肾气阴两虚型多见。DN作为一种复杂而不断变化的疾病,有着明确阶段性,早期DN多以气阴两虚、气虚为多,晚期肾病以阳虚、阴阳两虚、湿浊比率高,血瘀证则贯穿于病程始终。分期辨证已成趋势,分期辨证体现了DN动态变化,便于临床操作,又便于中西医沟通。
     3.4糖尿病肾病中医证候学调查
     经全国10个中心308例DN中医证候流行病学调查,发现DN证候分布及演变呈一定规律。
     DNⅢ期证候因子发生率依次为:气虚>血瘀>阴虚>阳虚>痰湿>湿浊>血虚,提示本虚证以气虚、阴虚为主要表现,标实证中以血瘀、痰湿为主要表现;Ⅳ期为:气虚>血瘀>阴虚>阳虚>湿浊>痰湿>血虚,提示本虚证以气虚、阴虚、阳虚为主要表现,标实证中以血瘀、湿浊为主要表现;Ⅴ期为:气虚>阳虚>湿浊>血虚>血瘀>痰湿>阴虚,提示本虚证以气虚、阳虚、血虚为主要表现,标实证中以湿浊、血瘀为主要表现。
     DN证候以虚实夹杂为主,Ⅲ期患者单纯虚证占9.43%,实证占3.77%,虚实夹杂占86.79%。Ⅳ期患者单纯虚证占4.52%,虚实夹杂占95.48%。Ⅴ期单纯虚证占2.12%,虚实夹杂占98.87%。可以看出随病程的发展,虚实夹杂呈上升趋势。
     从证素组合结果来看,每期证素组合多达几十种。Ⅲ期单一证占总数的6.6%,两证组合占15.1%,三证组合占29.3%,四证组合占20.8%,五证组合占16.9%,六证组合占8.5%,七证组合占总数2.3%;Ⅳ期单一证占1.3%,两证组合占9.7%,三证组合占24.5%,四证组合占26.5%,五证组合占20.0%,六证组合占12.9%,七证组合占5.2%;Ⅴ期单一证、两证组合0例,三证组合占6.4%,四证组合占25.5%,五证组合占14.9%,六证组合占总数31.9%,七证组合数21.3%。
     将DN七个证素经主成分分析法(PCA)法分析,根据贡献率和专业知识,选取了三个主成分,得到三个主成分表达式为:
     Z_1=0.315X_1+0.267X_2-0.213X_3+0.431X_4+0.275X_5+0.435X_6+0.431X_7
     Z_2=0.304X_1+0.172X_2+0.712X_3-0.418X_4+0.351X_5+0.248X_6-0.112X_7
     Z_3=-0.424X_1+0.242X_2+0.442X_3+0.381X_4-0.629X_5+0.144X_6+0.342X_7
     运用专业知识对三个主成分进行分析,第一主成分Z_1与气虚、阳虚、痰湿、湿浊关系密切;第二主成分Z_2与气虚、阴虚、阳虚、血瘀、痰湿关系密切;第三主成分Z_3与气虚、阴虚、阳虚、血瘀、湿浊关系密切。三个主成分集中了七个证素原始信息,组合相对稳定,且出现机率较高,三个主成分实际上将DN划分为三个类型(即中医证型),所以,运用主成分分析等降维统计学方法对DN辨证分型进行探索具有一定意义。
     3.5理论研究
     通过传统文献梳理与现代文献分析,DM“内热伤阴耗气”(简称热伤气阴)基本病机和DN“微型(?)瘕”病理假说可全面地反映了DN发生、发展、变化的机理,对DN临床辨证有指导意义。
     DN是在“内热伤阴耗气”基本病机基础上发展而来,内热是“壮火”,“壮火食气”,不仅可伤阴,又可耗气,形成气阴两虚结热之局,进一步传变,阴损及阳,乃至阴阳俱虚;久病入络,热结、气滞、血瘀、痰湿互相影响,混处络脉,日久在肾之络脉形成“微型(?)瘕”,可致肾体受损,肾用失司,导致DN的发生。
     4结论
     (1) DN辨证方案具有多样化、复杂性特点。
     (2)德尔菲(Delphi)法是科学合理地获得专家经验一种途径。
     (3) DN分期辨证已成趋势。
     (4) DN证候分布及演变具有一定规律。
     (5)采用主成分分析等降维统计学方法可对DN证型进行探索。
     (6)“热伤气阴”基本病机和“微型(?)瘕”病理假说理论对DN辨证具有指导意义。
Effect of traditional Chinese medicine (TCM) on diabetic nephropathy (DN) is getting more and more concerns in the world. But the previous studies on DN was always deficient in the rigorous experimental design and uniform standard of syndrome differentiation, so the conclusion of the study was always not authentic and it had become a major for the application of the TCM treatment to the world. It is necessary to sum up experience of treatment on DN and get the progress on the standardization and normalization of the DN treatment. At the first, different types of syndrome is one of the most important works to investigate.
     Objective
     The study follows the rule of evidence-based medicine and combined with the characteristics of TCM, and based on DN clinical date and TCM theoretical research, experiences was collected from experts, According the analysis of regional treating program of DN, and the research of multi-center epidemiological clinical syndrome types of DN with large sample, distribution rule and clinical syndrome types of DN was investigated. Then the program of syndrome types research in DN will be set up for clinical treatment.
     Methods
     The literature research in the past 20 years on the DN was used with qualitative and quantitative methods; Experiences from experts collected by Delphi method; Analysis of regional clinics program was used by qualitative research methods; The program of syndrome type research in DN used by multivariate statistical analysis, such as descriptive statistics, principal component analysis statistical methods and so on; Traditional and modern literature about DN was summarized for theoretical research.
     Results
     1 Literature research
     Qualitative study of the literature showed that DN syndrome types up to more than 60 species. Syndrome types were classified by different stages or other ways. Patterns of differentiation syndrome were classified by qi blood yin yang, by organs, or by xu shi. They were derived from practice, and had some rationality. Each had its characteristics, different laws, and different emphases.
     The study on quantitative evaluation of literature was made use of meta analysis of principle. 2182 cases of DN was collected, DN Syndromes were up to 40 kinds of types. The top five TCM syndromes were: qi-yin deficiency type (33.91%), yin-yang deficiency type (20.90%), Yang deficiency type (12.56%), yin deficiency type (11.32%), extreme heat with yin deficiency type (5.32%).
     2 The experiences of DN syndromes from experts collected with Delphi method
     TCM is a medicine based on experiences, the experiences from experts in most cases can be considered the gold standard. The opinions of experts may be reasonably collected by Delphi method.
     From the summary of first round results, Experts achieved highly consensus in TCM syndromes and disease location. Many entries had lower coefficient of variation and a higher degree of coordination. Experts agree on that TCM syndromes appear with compound symptomes and multiple zang-fu diseases.
     From the results of the second round questionnaire, we found that the variation coefficient of major entries were about 0.5. We got a conclusion: experts' opinions tended to be uniform. Experts agreed to opinions of the disease location, nature of disease, disease pathogenesis. DN was primary deficiency-secondary excess syndrome, the primary deficiency syndromes involved qi deficiency, blood deficiency, yin deficiency, yang deficiency; the secondary excess syndrome involved blood stasis, qi stagnation, phlegm turbid, turbid dampness. Qi-yin deficiency, blood stasis, turbid dampness accounted for a larger proportion of the DN syndromes.
     3 DN regional clinics programs analysis with qualitative research method
     13 DN clinic programs from kidney specialist of National Administration of Traditional Chinese Medicine, represent the domestic level of DN treatment. They can be used as evidences to evidence-based medicine research. By qualitative analysis we concluded that: although the DN syndrome programs diversification, opinions of the disease location, nature of disease, disease pathogenesis were the same. The DN syndromes were made up a larger proportion of qi-yin deficiency, qi deficiency, yin-yang deficiency, blood stasis, turbid dampness. Blood stasis existed in the whole development of DN syndromes. Different treatment by stage had become a trend, it could reflect the dynamic changes of DN, and easy to be accepted in the exchanges between Chinese and Western medicine.
     4 Epidemiological investigation on DN TCM syndromes
     308 cases were collected from 10 national centers for the epidemiological investigation on DN TCM syndromes. We discovered that the law of the distribution and evolution of DN syndromes showed some regularity.
     The incidences of syndrome factors in DNⅢstage were as follows: qi deficiency>blood stasis>yin deficiency>yang deficiency>phlegm>turbid dampness>blood deficiency. The incidences of syndrome factor in DNⅣstage were as follows: qi deficiency>blood stasis>yin deficiency>yang deficiency>turbid dampness>phlegm>blood deficiency. The incidences of syndrome factor in DNⅤstage were as follows: qi deficiency>yang deficiency>turbid dampness>blood deficiency>blood stasis>phlegm>yin deficiency.
     From the results combination of syndromes, each stage had many combinations. In DNⅢ, a single syndrome is the total 6.6%, combination of two syndromes is 15.1%, combination of three syndromea is the total 29.3%, combination of four syndromes is the total 20.8%, combination of five syndromes is the total 16.9%, combination of six syndromes is the total 8.5%, combination of seven syndromes is the total 2.3%. In DNⅣ, a single syndrome is the total 1.3%, combination of two syndromes is 9.7%, combination of three syndromes is the total 24.5%, combination of four syndromes is the total 26.5%, combination of five syndromes is the total 20.0 %, combination of six syndromes is the total 12.9%, combination of seven syndromes is the total 5.2%. In DN V, combination of three syndromes is the total 6.4%, combination of four syndromes is the total 25.5%, combination of five syndromes is the total 14.9%, combination of six syndromes is the total 31.9%, combination of seven syndromes is the total 21.3 %.
     The seven symptom factors were statistically analyzed by principal component analysis, we selected the three principal components according to the contribution rate and professional knowledge. The formula of the three principal components is:
     Z_1=0.315X_1+0.267X_2-0.213X_3+0.431X_4+0.275X_5+0.435X_6 +0.431X_7
     Z_2=0.304X_1+0.172X_2+0.712X_3-0.418X_4+0.351X_5+0.248X_6-0.112X_7
     Z_3=-0.424X_1+0.242X_2+0.442X_3+0.381X_4-0.629X_5+0.144X_6+0.342X_7
     We use our professional knowledge to analysis the three principal components. The first principal component was close relationship with qi deficiency, yang deficiency, phlegm, turbid dampness. The second principal component was close relationship with qi deficiency, yin deficiency, yang deficiency, blood stasis, phlegm. The third principal component was close relationship with qi deficiency, yin deficiency, yang deficiency, blood stasis, turbid dampness.
     5 Theoretical research
     According to the analysis of traditional and modern literatures, we got a conclusion: the happening, development, and changing of DN could be explained by DM basic pathological mechanism of "hot hurt qi and yin" and DN pathological hypothesis of "micro-Zhengjia". This theory could be directional for the differentiation of DN syndrome types.
     The onset and development of DN is the delay and the improper treatment of DM, which leaded the injury of the yin and qi, even the yin and yang. The cementation of the sputum, qi stagnation, heat, and blood stasis in the kidney collaterals which called"micro-Zhengjia" was formed.
     Conclusions:
     ①Syndrome types in DN showed diversification and complication.
     ②Experiences from experts can be reasonable collected by Delphi method.
     ③Syndromes differentiation for different stage of DN has become a trend.
     ④The distribution and evolution of DN syndromes had some regularity.
     ⑤The statistical methods such as principal component analysis can be used in the investigation of syndrome types of DN.
     ⑥DM basic pathological mechanism of "hot hurt qi and yin" and DN pathological hypothesis of "micro-Zhengjia" has showed significance for the differentiation of DN syndrome types.
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