【作者】 孙晓泽；

【导师】 范冠杰；

【作者基本信息】 广州中医药大学 ， 中医内科学， 2011， 博士

【摘要】 研究背景及意义本课题研究是国家“十一五”科技支撑计划“中医全程干预糖尿病肾病进程综合方案研究”的一部分,作为本次研究的其中一个分中心,我们按照试验方案,观察了止消通脉宁等干预糖尿病肾病的临床疗效,以期对中医药干预糖尿病肾病进程的作用进行科学评价,并为最终建立具有中医特色的糖尿病肾病综合防治方案提供依据。糖尿病肾病(DN)是糖尿病最典型的微血管并发症,在糖尿病肾病早期,尚可通过正确的治疗使之逆转,随着病情进展,患者一旦出现尿微量白蛋白排泄率增加,病情就将持续加重,进一步可表现为蛋白尿、水肿等,直至发生终末期肾衰尿毒症。在全世界范围内已经成为日益增长的家庭和社会的巨大经济负担。因此糖尿病肾病的早期诊断和防治是其治疗的关键。目前被循证医学证明有效的治疗糖尿病肾病的途径主要是降糖、降压,限制蛋白质摄入,纠正脂代谢紊乱,抗氧化应激等对症措施,尚缺少更有效的延缓糖尿病肾病病程进展的防治方案。糖尿病肾病属于中医“消渴病”继发“尿浊”、“水肿”、“关格”等病证范畴。吕仁和教授提出“微型癥瘕”病理假说,认为糖尿病肾病是消渴病日久伤阴耗气、阴损及阳,致气阴两虚、阴阳两虚,久病入络,痰浊、邪热、血瘀、气郁互相胶结,形成“微型癥瘕”,使肾体受损,肾用失司所致。肾元虚损,湿浊邪毒内生,变生关格危候。并在多年研究糖尿病及其并发症的经验基础上,研制出了止消通脉宁等适合糖尿病肾病不同阶段的中药系列方,取得了良好疗效。目前中医药对糖尿病肾病的防治存在着巨大的潜力和前景,研究中医药疗法早期防治、延缓糖尿病肾病的发生、发展具有重要临床及科研意义。目的通过糖尿病肾病的相关文献研究,了解目前中西医治疗糖尿病肾病的现状以及止消通脉宁等干预糖尿病肾病的临床与实验研究概况,了解1995～2010年中医药治疗糖尿病肾病临床对照试验文献发表数量及变化趋势；并通过随机、对照、单盲的前瞻性临床研究,观察止消通脉宁对早期和临床期糖尿病肾病病人中医证候变化的干预作用及对尿白蛋白排泄率、24小时尿蛋白定量、肾功能等指标的影响,同时进行生存质量评估及作出安全性评价,综合评价止消通脉宁等系列药物辩证治疗糖尿病肾病的临床疗效,为建立中医药全程干预糖尿病肾病综合防治方案提供依据。方法1文献研究方法对近年来糖尿病肾病中西医文献和研究药物止消通脉宁等的相关文献进行综述；通过电子计算机检索及手工检索维普《中文科技期刊数据库》(1995-2010.12),检索中医药治疗糖尿病肾病临床对照试验文献并进行计量分析。2临床研究方法2.1选择明确诊断并符合入选标准的早期糖尿病肾病和临床糖尿病肾病患者32例,随机分为治疗组、对照组各16例,并进行临床观察准备。2.2观察方法：在饮食治疗、西药降糖、降压、调节血脂等基础治疗基础上,治疗组给予中医药辨证治疗,根据辨证分别给予止消通脉宁、止消温肾宁及止消保肾宁颗粒剂,每次1袋,每日2次口服；对照组给予厄贝沙坦(安博维,赛诺菲安万特民生制药有限公司,150mg/片),1片,每日1次口服。3个月随访1次,共随访9个月。2.3观察指标：疗效性指标包括：中医症状,尿微量白蛋白排泄率,24h尿蛋白,血清肌酐、肾小球滤过率、空腹及餐后血糖、糖化血红蛋白、血脂等,并进行生存质量评估；安全性指标包括：血、尿、大便常规及肝功能、心电图检查等。2.4数据统计：建立数据库进行数据的录入和审核,全部数据采用SPSS18.0统计分析软件包进行统计分析。结果1文献计量分析结果中医药治疗糖尿病肾病的临床对照试验数量从1995年开始逐年递增,其中临床随机对照试验文献数量从1999开始呈显著上升趋势,非随机的临床随机对照试验数量虽然也是从1999年开始增多,但上升速度从2000年开始放缓,并于2000年开始少于随机对照试验。从逐年发表篇数构成比走向来看,临床随机对照试验文献所占比例亦呈逐步上升趋势。中医药治疗糖尿病肾病临床对照试验中随机与非随机的比值在1995-1998年接近于0,以后几乎逐年递增,到2010年增至远大于4,临床随机对照试验文献较非随机的呈上升趋势相对明显。2临床研究结果2.1基线情况：两组患者性别、婚姻、文化、职业、年龄、体重、病情分级、中医证型分类和过敏史等基本情况,以及主要疗效观察指标、次要疗效观察指标和生存质量评价差异均无显著性(P>0.05)。2.2临床疗效的意向性分析：治疗3、6、9个月,治疗组主要疗效观察指标、次要疗效观察指标和生存质量评价与对照组相比差异均无显著性(P>0.05)；两组各时段主要观察指标的总体变化趋势平稳(P>0.05),肾小球滤过率与分组之间有交互效应,治疗组肾小球滤过率升高趋势较对照组明显(P<0.05)2.3符合方案数据临床疗效分析：治疗3个月,治疗组主要观察指标、次要观察指标和生存质量评价与对照组相比,差异无显著性(P>0.05)；治疗6个月,治疗组血清肌酐、肾小球滤过率改善优于对照组(P<0.05)；治疗9个月,治疗组主要观察指标、次要观察指标与对照组相比,差异无显著性(P>0.05)；两组患者各时段主要指标总体变化趋势平稳(P>0.05)；治疗3个月与治疗前相比,患者血清肌酐、中医症状总分、肾小球滤过率明显改善(P<0.05),且治疗组血清肌酐、中医症状总分下降趋势优于对照组(P<0.05)；治疗6个月与3个月相比,治疗组肾小球滤过率升高趋势较对照组明显(P<0.05)。2.4中医症状疗效评分,治疗3、6、9个月,治疗组临床效果构成比与对照组相比均无统计学差异(P>0.05)2.5安全性评价为1级；出现1例不良事件,认为该不良事件与研究药物的关系为“不太可能有关”。结论1近年来,中医药干预糖尿病肾病取得了较大进展；近15年,中医药治疗糖尿病肾病临床随机对照试验数量无论在绝对数还是相对数上均呈逐渐上升趋势。2中医药辨证综合治疗方案对防治早期和临床期糖尿病肾病有积极的临床效应,且安全性良好。中药辨证治疗组在3个月短疗程和6个月、9个月疗程的总体疗效与对照组厄贝沙坦相当；对肾小球滤过率、血清肌酐指标的改善程度在3个月、6个月时段优于厄贝沙坦。3止消通脉宁等系列方对早期和临床期糖尿病肾病患者的治疗作用进一步证实了糖尿病肾病是消渴病日久伤阴耗气、阴损及阳,致气阴两虚、阴阳两虚,久病入络,痰浊、邪热、血瘀、气郁互相胶结,形成“微型瘤瘕”,使肾体受损,肾用失司这一病机演变。4本研究中药辨证综合治疗方案对早期和临床期糖尿病肾病患者中医证候和生存质量无明显改善,可能与本分中心的样本量偏少有关,尚待“十一五”科技支撑计划“中医全程干预糖尿病肾病进程综合方案研究”多中心、大样本的全部结果揭示。更多还原

【Abstract】 BackgroundThe study is a part of the research that making a synthesis Plant for Chinese medicine in whole range treatment of patients with diabetic nephro-pathy (DN).The research is supported by Science and Technology program for the "11th Five Years" Plan. As a research subcenter, we observed the clinical effect on zhixiaotongmaining series granule in the treatment of DN, follow the experiment program. We wish to scientifically evaluate the effect of Chinese medicine in whole range treatment of patients with DN and finally to provide the evidence for making a TCM characteristics plant for preventing and curing DN.The exemplary diabetic microvascular complication is DN.In the early of DN, the condition can be reversed thought right treatment. But, as the development of the disease, when UAER increased, the condition would continually exacerbate to CKD v, and the Clinical manifes-tation is proteinuria, edema and so on. The grouting cost of DN has be the great economic burden of familiy and society. So, the early diagnosis and treatment for diabetic nephropathy is more important. Presently, the effect therapie of DN that has be proved by evidence-based medicine is symptomatic treatment, thatcontain hypoglycemia, hypotension, limiting protein, correcting dyslipidemia, anti-oxidation and so on. There is not some prevention and cure methods that can effectively delay the process of DN.DN is the one of "the dispersion-thirst disease", secondary "niaozhuo" "shuizhong" and "guange". Pro. LV Ren-he proposals the histology hypothesis of "mini-abdominal mass".In the long time of diabetic, yin and qi were damaged by the dispersion-thirst disease.It caused the deficient of both Yin and Yang that the deficient yin affected yang. As Chronic Diseases Transforming to Collaterals, "mini-abdominal mass" was formed by phlegm, heat pathogen, blood stasis, and qi stagnations interpenetrating.So the kidney was damages and llosed its function. Conception of nephron caused endogenous damp pathogen and toxin, and grow into guange. On the base of studying diabetic microvascular complication, professor. LV researched zhixiaotongmaining series granule that fits every step of DN, and get noticeable effect. Chinese medicine has great prospect and potential in prevention and cure methods of diabetic. The research that about the effect of preventing and delaying the process of DN has important clinical and scientific significance.ObjectivesThrough literature research of DN, to comprehend the current treatment of DN in the status of western and TCM, and the clinical and experimental research of Zhixiaotongmaining ect. To comprehend the quantity and trends of literatures about clinical controlled trials of Traditional Chinese Medicine from 1995 to 2010. The clinical reach was random, contrast, single-blind and prospective.It observes the different of TCM symptom change, UAER,24hrUprV and renal functiong in the patients of early and clinical periods of diabetic nephropathy. Then,it evaluates the quality of life and safety, and comprehensively evaluate the clinical effect of zhixiao tongmaining series granule in the treatment of DN, in order to provide the evidence for making a TCM characteristics plant for preventing and curing DN.Methods1 literature researchReviewed the literature of Diabetic nephropathy and Zhixiaotongmai-ning;Searched VIP(1995 to 2010.12) by computer search and manual search. Search the quantity of clinical controlled trials of Diabetic nephropathy of Traditional Chinese Medicine published every year, and then try to analyse it quantitatively.2 clinical research2.1 32 cases of DN were randomly divided into two groups. Those patients were early and clinical periods of diabetic nephropathy.2.2 In the basic treatment of diet therapy, hypoglycemia, hypotension and correcting dyslipidemia, the treatment group were treated by Zhixiao tongmaining, zhixiao wenshenning or zhixiao baoshenning,1 packet bid po; the control group were treated by Irbesartan, 1grain qd po. They were followed up every 3 months, and still 9 months.2.3 Their therapeutic effects include TCM symptoms, UAER,24hrUprV, SCr, GFR, FBG, PBG, HbAlc, blood lipids. Those were be evaluated;The safety effects include Blood routine, urine routine test, stool for routine, Liver function and ECG.2.4 After inputing and audit the data into database, all data was statistically analysied by SPSS18.0.Result1 Quantitative analysis of the literatureClinical controlled trials of DN treated by TCM from the beginning of a gradual increase in 1995, of which the number of randomized controlled trials from the beginning of 1999 was a significant upward trend in non-randomized clinical randomized controlled trials from 1999 the number increased, but increased the speed of the slowdown since 2000, and in 2000 less on randomized controlled trials. Articles published from year to year than to look at composition, clinical randomized controlled trials was also the proportion of the gradual upward trend. Clinical controlled trials of Chinese medicine in the random and the ratio of non-random in 1995-1998 from close to 0, to increase in 2010 is much larger than 4.2 clinical research2.1 Baseline:no significant(P>0.05)between two groups in sex, marriage, culture, occupation, age, weight, disease classification, syndromes classification of TCM and allergies, as well as main outcome measures, secondary outcome measures and quality of life evaluation were found. And no significant (P>0.05)were found in main outcome measures between patients in stage III, IV of two groups.2.2 Intention-to-treat of clinical efficacy:treatment after 3,6,9 months, there was no significant (P>0.05) between two groups in main outcome measures, secondary outcome measures and quality of life evaluation after treatment 3 months.The general Change Trend of main outcome measures of two groups was found stable(P>0.05), there was interaction between glomerular filtration rate and grouping, and the rising trends of treatment group was found more obvious than the control group (P<0.05). 2.3 Per-Protocll population of clinical efficacy:treatment for 3 months, There were no significant (P>0.05) in main outcome measures, secondary outcome measures and quality of life evaluation of two groups;treatment for 6 months, the serum creatinine and glomerular filtration rate of the treatment group were better than that in the control group(P<0.05);9 months after treatment, the main outcome measures, secondary outcome measures of treatment group compared with the control group, the difference was not significant(P> 0.05);Change Trend of main outcome measures of two groups in different periods of time were stable (P>0.05); treatment for 3 months, serum creatinine, scores of TCM symptoms, glomerular filtration rate were improved significantly (P <0.05) compared with before treatment;the downward trend of treatment group in serum creatinine, scores of TCM symptoms were more obvious than in the control group(P<0.05);compared the glomerular filtration rate in treatment for 6 months with in treatment for 3months, the treatment group rised more obviously than the control group(P<0.05).2.4 Efficacy score of TCM symptoms:treatment for 3,6,9 months, there was no significant(P>0.05)in the composition of clinical efficacy between the treatment group and the control group.2.5 The safety was evaluated as 1 level;adverse events occurred in 1 case which was regarded "unlikely related" to the study drugs.Conclusion1 These years, we have made grate progress on the research of DN by the treatment of TCM;Over the past 15 years, the quantity of randomized controlled trials of Traditional Chinese Medicine in terms of both absolute number or proportion of the rising trend year by year.2 Comprehensive Treatment project of TCM differentiation and Treatment have Positive clinical effects and good safety in treatment for early and clinical periods of diabetic nephropathy.There was the same general efficacy betweenTCM differential treatment group and control group at 3 months,6 months and 9 months;the degree of improvement on the glomerular filtration rate, serum creatinine, in the periods of 3-month and 6-month better than irbesartan.3 The therapeutic effects of series prescriptions as Zhixiaotongmaining in the early and the clinical periods of diabetic nephropathy further confirmed the pathogenesis rule what is Diabetes injured the qi and yin,also injure the yin and yang, and lead to the deficiency of qi and yin, as well as yin and yang, Chronic Diseases Transforming to Collaterals, the interaction of turbid phlegm, pathogenic heat, Blood Stasis, Qi depression lead to the formation of mini-abdominal mass, damage to the renal, then Renal dysfunction in the course of time.4 Comprehensive Treatment project of TCM differentiation and Treatment in the subject can’t improve obviously the TCM symptoms and quality of life in early and clinical periods, and the reason was needed to further discussion.更多还原