【作者】 黄学民；

【导师】 赵进喜；

【作者基本信息】 北京中医药大学 ， 中医内科学， 2012， 博士

【摘要】 目的：研究早期和临床期糖尿病肾病(diabetic nephropathy, DN)证候动态变化与重要的肾功能指标和生存质量的关系,以及不同干预方案对糖尿病肾病各证素(证候要素)中每个症状动态变化的影响,为揭示糖尿病肾病中医证候内涵提供依据,为糖尿病肾病中医证候变化及规范化研究提供更多比较可靠的数据。方法：依托国家“十一五”科技支撑计划--《中医药全程干预糖尿病肾病进程综合方案研究》,病例来源自北京中医药大学东直门医院、北京大学第一医院等10家研究单位,按照严格制定的调查表对早期和临床DN患者的一般情况、合并症、0时点和中西医干预后8个时点(共2年)的中医四诊信息、生化指标等及生存质量评分进行收集,录入数据库,并审核无误。研究一：研究两种不同干预后早期和临床期DN7个证素的34个症状在9个时点的变化趋势；包括积分差值(开始入组时得分与每个时点得分的差值)检验和秩和检验。研究二：对早期和临床期DN证候9个时点的动态变化与生存质量评分变化的关系进行研究,生存质量量表用糖尿病特异性生存质量量表修订版(Adjusted Diabetes of Life Measure, A-DQOL),并用线性混合效应模型对多次重复测量的纵向数据进行回归分析,在考虑的变量中,除了中医证候积分之外,也加入了年龄、性别、并发症等变量,一起进行了分析研究三：对早期和临床期DN证候9个时点的动态变化与主要肾功能指标变化之间的关系进行研究,用线性混合效应模型对多次重复测量的纵向数据进行回归分析,变量中加入了年龄、性别、并发症等可能影响肾功能指标的变量,一起进行了分析。结果：研究一：1在9个时点,两种不同干预对早期和临床期糖尿病肾病34个症状(7个证素)积分的变化对比显示,中医治疗组和西药厄贝沙坦组均能改善中医症状积分,而在不少时点,中医药组的改善程度优于厄贝沙坦组,两组比较有显著差异；而在其他时点(进行治疗后),两组比较无显著差异。在观察结束时点(8时点),有18个症状的积分改善中药组优于厄贝沙坦组,两组比较有显著差异。2对一些症状积分的改善,中药组明显优于厄贝沙坦组。症状积分差值研究中,在治疗后所有8个时点,中药组对痰湿4(全身困倦)的改善均优于厄贝沙坦组,两组比较有显著差异；在第5个疗程结束之外的7个时点中药组对血瘀2(口唇舌紫,或紫暗、瘀斑、舌下络脉色紫怒张)的改善均优于厄贝沙坦组,两组比较有显著差异3在第2、3、4疗程期间,只有6个症状在共6个时点,中药组的改善程度优于厄贝沙坦组,在各时点两组比较有显著差异；而在第6、7、8疗程期间,有24个症状在共47个时点,中药组的改善程度优于厄贝沙坦组,在各时点两组比较有显著差异研究二：1DN证候总积分变化与DQOL量表总评分变化的相关性：DN证候总积分变化与DQOL量表总评分的变化呈正相关,患有高脂血症与DQOL量表总评分变化呈负相关2DN证候总积分变化与DQOL量表四个分功能评分变化的相关性：(1)DN证候总积分变化与DQOL量表生理功能影响评分变化呈正相关。(2)DN证候总积分变化与DQOL量表心理/精神影响评分变化呈正相关,年龄、患有高脂血症与心理/精神影响评分变化呈负相关。(3)DN证候总积分变化与DQOL量表社会关系影响评分变化呈正相关,患有冠心病、高脂血症与社会关系影响评分变化呈负相关。(4)DN证候总积分变化与DQOL量表治疗对患者的影响评分变化呈正相关研究三：1DN证候总积分变化与肾功能指标变化的相关性：(1)年龄、患有高血压与GFR的变化呈负相关。DN证候总积分变化与GFR的变化关系密切度不足(2)证候总积分变化、年龄与BUN的变化呈正相关。(3)年龄、患有高血压与Scr的变化呈正相关。性别与Scr变化呈负相关。DN证候总积分变化与Scr变化关系密切度不足。(4)DN证候总积分变化、患有高血压与UAER的变化呈正相关2DN各证素总积分变化与肾功能指标变化的相关性：(1)阳虚证素的总积分变化、年龄、患有高血压与GFR的变化呈负相关。(2)气虚证素、血虚证素、阳虚证素、痰湿证素、湿浊证素的总积分变化、年龄与BUN的变化呈正相关。(3)气虚证素与阳虚证素的总积分变化、年龄、患有高血压与Scr的变化呈正相关,性别与Scr的变化呈负相关。(4)患有高血压与UAER的变化呈正相关,所有各证素总积分变化与UAER的变化关系密切度不足结论：1在9个时点,对比了两种不同干预方案对糖尿病肾病34个症状的积分变化,在症状积分研究层面证实了饮食治疗、现代医学对症治疗基础上的中医药治疗比厄贝沙坦治疗组有优势,与证候疗效结果相符合。另外,症状动态变化研究显示,中医药治疗并非在所有时点,对所有症状的改善均优于厄贝沙坦组,而对某些症状的改善程度更突出,值得进一步深入研究。分析中医药组改善更加突出的时间分布,在后半疗程明显多见,提示应该重视中医药的长疗程治疗。2本研究提示,DN证候总积分变化与DQOL量表评分变化相关,表明了中医证候的改善能体现患者生存质量的改善,说明相关生存质量研究可以作为中医证候研究的重要补充,有助于中医药疗效的客观评价以及中医证候的规范化。3DN证候变化与肾功能指标变化的相关性研究提示,BUN、Scr等代谢产物与气虚证素与阳虚证素等正虚证候也可能相关,与把代谢产物更多与痰湿、湿浊相关的传统认识不同。说明在糖尿病肾病的后期可能因虚致实的病机比较突出,治疗中不仅要重视泄浊解毒,而且也要强调固护正气,以达到扶正祛邪的目的；也说明了在重视扶助正气的基础上泄浊解毒、化瘀散结的治疗组处方组方思想的合理性和科学性。本研究也有助于糖尿病肾病中医证候本质的进一步的探索。更多还原

【Abstract】 Objective:To investigate the relationship between dynamic changes of syndromes in the early and clinical stages of diabetic nephropathy (DN) and important parameters of renal function and quality of life, and the effects of different intervention protocols on dynamic changes of each symptom in the elements of syndromes of DN, in order to provide evidence for the understanding of the nature of traditional Chinese medicine (TCM) syndromes in DN, and provide more reliable evidence for the study on standardization and changes of TCM syndromes in DN.Methods:With the support from "11th five-year" National KeyTechnology Research and Development Program-the Study on the Comprehensive Protocol of Whole-course TCM Intervention for the Development of DN, the cases were enrolled from10institutions (Dongzhimen Hospital of Beijing University of Chinese Traditional Medicine and Peking University First Hospital etc.); according to survey forms established strictly, the general condition, comorbidities, the information of four TCM diagnostic methods at zero time point and8time points after interventions of TCM and western med i c ine(a total of2years), biochemical indexes and scores of quality of life in patients at early and clinical stages of DN were collected, input into the database, and examined and verified unmistakably.First study:The change trend of34symptoms of7syndrome elements at the early and clinical stages of DN after two different kinds of intervention at9time points was examined, including score differences (the difference between the score at the enrollment and that at each time point) and rank sum test.Second study:the relationship between dynamic changes of syndromes in early and clinical stages of DN at9time points and score changes of quality of life were examined. The ad justed diabetes of life measure (A-DQOL) was used as the scale for quality of life, and linear mixed effects model was used for regression analysis of longitudinal data being measured repeatedly; in terms of variables being considered, besides score of TCM syndromes, other variables, such as age, sex and complications, were also analyzed together.Third study:the relationship between dynamic changes of syndromes in early and clinical stages of DN at9time points and changes of major parameters of renal function was examined. Linear mixed effects model was used for regression analysis of longitudinal data being measured repeatedly, and variables that may affect the parameters of renal function, such as age, sex and complications, were also analyzed together.ResultsFirst study:1At9time points, the comparison of score changes of34symptoms at early and clinical stages of DN (7syndrome elements) by two different interventions showed that, the symptom scores of TCM were improved in both groups, but at some time points, the improvement was greater in TCM group than that in the irbesartan group with significant differences between the two groups; but at other time points (after treatment), there was no significant difference between these two groups. At the time point of the end of observation (time point of8), the improvement of scores of18symptoms in TCM group was greater than that in irbesartan group, with significant difference.2The score improvement of some symptoms in TCM group was greater than that in irbesartan group. In terms of score difference of symptoms, the improvement of phlegm-dampness4(fatigue of whole body) in TCM group was greater than that in irbesartan group, with significant difference, at all of8time points after treatment; at7time points after the end of the fifth course of treatment, the improvement of blood stasis(purple or dark purple lips and tongue, petechia, purple and engorged sublingual collaterals) in TCM group was greater than that in irbesartan group, with significant difference.3During the2nd, third and fourth course of treatment, the improvement of only6symptoms in TCM group was greater than that in irbesartan group at6time points, with significant differences at each time point; however, during the6th,7th and8th course of treatment, the improvement of24symptoms in TCM group was greater than that in irbesartan group at47time points, with significant differences at each time point.Second Study:1The correlation between the change of total score of DN syndromes and that of DQOL:The change of total score of DN syndromes was positively correlated with that of DQOL, and hyper1ipidemia in patients was negatively correlated with the change of total score of DQOL.2The correlation between the change of total score of DN syndromes and the score changes of four sub-functions of DQOL:1.The change of total score of DN syndrome was positively correlated with the score change of effects of physiologic function in DQOL.2. The change of total score of DN syndromes was positively correlated with the score change of psychological/mental effects in DQOL, and age, hyper1ipidemia in patients were negatively correlated with the score change of psychological/mental effects.3. The change of total score of DN syndromes was positively correlated with the score change of effects of social relationship in DQOL, and age, hyperlipidemia and coronary heart disease in patients were negatively correlated with the score change of effects of social relationship.4. The change of total score of DN syndromes was positively correlated with the effects of treatment on patients in DQOLThird Study:1The correlation between the change of total score of DN syndromes and changes of parameters of renal function:1. Age, and hypertension in patients were negatively correlated with the change of GFR. The change of total score of DN syndromes was not closely related with the change of GFR.2. The change of total score of syndromes and age were positively correlated with the change of BUN.3. Age and hypertension in patients were positively correlated with the change of Scr. Sex was negatively correlated with the change of Scr. The change of total score of DN syndromes was not closely related with the change of Scr.4. The change of total score of DN syndromes and hypertension in patients were positively correlated with the change of urinary albumin excretion rate (UAER).2The correlation between the changes of total scores of DN syndrome elements and the changes of parameters of renal function:1. The change of total score of yang-deficiency syndrome elements, age and hypertension in patients were negatively correlated with the change of GFR.2. The total score changes of syndrome elements of qi-deficiency, blood-deficiency, yang-deficiency, phlegm-dampness and damp-turbidity, sex, and hypertension in patients were positively correlated with the change of BUN.3. The total score change of syndrome elements of qi-deficiency and yang-deficiency, age and hypertension in patients were positively correlated with the change of Scr, and sex was negatively correlated with the change of Scr.4. Hypertension in patients was positively correlated with the change of UAER, and the change of total score of all syndrome elements was not closely related with the change of UAER.Conclus ion:1In terms of symptom score, the comparison of score changes of34DN symptoms by two different intervention protocols at9time points demonstrated that TCM treatment was better than irbesartanon the basis of diet therapy and symptomatic treatment of modern medicine, which was in accordance with the results of syndrome efficacy. In addition, the study on the dynamic changes of symptoms showed that the improvement of all symptoms by TCM was not greater than that by irbesartan at all time points, but the improvement of some symptoms by TCM was more prominent, which should be further investigated. In terms of the temporal distribution of the improvement by TCM, it was more often significant during the latter half of treatment course, which indicated that the long-term treatment of TCM should be emphasized.2The study indicated that the change of total score of DN syndromes was correlated with the score change of DQOL, which demonstrated that the improvement of TCM syndromes could reflect that of quality of life in patients and related study on quality of life could be used as important supplement for the study of TCM syndrome and be helpful for the objective evaluation of TCM efficacy and standardization of TCM syndrome.3The correlational study between the change of DN syndromes and the change of parameters of renal function indicated that, the metabolites, such as BUN and Scr may also be related with syndromes of healthy energy deficiency, such as qi-deficiency and yang-deficiency, which was different from the traditional concept that the metabolites were more related with phlegm-dampness and damp-turbidity. This showed that the pathogenesis of excess due to deficiency was more prominent in the late stage of DN, so during the treatment not only dispelling turbidity and detoxification should be emphasized, but also strengthening healthy-qi should be stressed, in order to strengthen vital qi to eliminate pathogenic factors; it also demonstrated the rationality and scientificness of the concept of prescription that the treatment of dissolving stasis and softening lump should be established with the emphasis on the strengthening of health-qi. The study is also helpful for further investigation into the nature of TCM syndromes of DN.更多还原