【作者】 李绍钦；

【导师】 李顺民；

【作者基本信息】 广州中医药大学 ， 肾内科， 2009， 博士

【摘要】 本论文从临床角度出发,以早期糖尿病肾病(diabetic nephropathy,DN)为切入点,以中医络病理论为指导原则,研究络病的共同表现—络脉瘀阻与早期糖尿病肾病的病理相关性,并以符合随机对照(randomized controlled trial,RCT)标准的临床研究文献提供的证据为基础,进行了Meta分析的初步尝试,探讨中医药治疗本病的利弊和中医的临床治疗决策。糖尿病肾病(DN)是常见的糖尿病(DM)微血管严重并发症之一。随着近年糖尿病(尤其是2型)发生率的逐渐上升,DN的发病人数也相应增加。DN是个渐进性的肾脏疾病且代表了糖尿病严重的晚期并发症。早期糖尿病肾病发生隐蔽,夹杂因素多,往往出现在糖尿病5—15年期间,但临床一旦发生持续蛋白尿,则肾脏损害发展迅速,很快就出现高血压、水肿及肾功能全,此时肾病已属不可逆转。因该病的发病机制目前仍未完全阐明,也缺乏有效的治疗手段,多数患者都在较短的时间内进入终末期肾病(end-stage renal disease,ESRD)。所以揭示本病的病理机制并在早期就给予针对性的防治,对控制和缓肾脏病的进一步发展具有积极意义。中医络病理论是中医基础理论重要的组成部分,随着现代科学的发展,多学科的相互渗透、融合,给络病理论的发展赋予新的内容。络病理论认为络病是由各种因素而导致络脉瘀阻、气血津液运行不畅的一类病变。作为沟通机体内外的功能性网络系统,络脉既是气血津液运行的通道,也是病邪传变的通道,而肾脏又具有极其丰富的肾络,由于肾络细窄迂曲的生理结构和血流缓慢运行的功能特点,这就决定了毒邪伤及络脉时容易出现络脉瘀阻、络毒蕴结的病理变化。从中医的角度看,糖尿病肾病是消渴日久,导致气阴两虚,气虚则血运不,阴虚则血稠而滞,均可致瘀血阻络;瘀血,是脾肾亏损,人体津液失调后的病理产物,这些病理产物既源于正虚,又阻碍气血的生成和脾肾的功能而导致正虚加重,造成恶性循环。可以说,瘀血阻络是糖尿病肾病的主要病机,这既符合于中医“久病必瘀”“久病入络”的学术观点,也与现代医学认识的糖尿病肾病患者血液动力学和肾脏微血管病理学实验中,血液流变学的指数普遍升高、血浆粘度增加、血脂增高、肾血流量减少,血小板聚集、血管硬化,肾微循环障碍,甚至出现高凝状态的研究相当吻合。而活血通络中药治疗可改善肾小球的血液动力学、减少蛋白尿、减轻血尿、保护肾功能的实验研究也佐证了络脉瘀阻的病机。为进一步探讨络脉瘀阻与早期糖尿病肾病的病理相关性和中医药治疗糖尿病肾病的利弊,从而为中医的临床治疗决策提供建议,本研究从近10年(1998.1—2007.12)治疗早期糖尿病肾病的临床研究文献中,试图按现代循证医学(evidence-basedmedicine,EBM)的原则和方法进行综合评估。通过电子检索和手工检索共检出糖尿病肾病研究6711篇,其中对符合纳入标准的27个随机对照试验(endomized controlled trial,RCT)进行Meta分析(Meta-analysis)。所有纳入的各研究试验期1-6个月不等;所有研究地点均在国内医科大学附属医院或国家三级医院进行。各研究所纳入的患者数量从28人-80人,共1341人。年龄由28岁-76岁,平均年龄55.2岁,平均病程8.9年。27个研究均在饮食控制、适量运动和西药控制血糖的基础上,结合中药治疗与西药的对照,其中1个研究为中西药结合与中药治疗的对照。本研究主要评估内容包括:控制血糖(FBG、HbAlc)、血脂(TC、TG、HDC—C)的评价,改善肾功能(Scr、BUN)、尿微量蛋白排泄率(UAER)及血液流变参数的评价,以及早期糖尿病肾病证型分布特点、中医方药应用和症状积分及生存质量标准分析评价等。测量结果显示:1)本研究涉及的27篇随机对照文献,对于早期糖尿病肾病,在西医基础治疗上若配合中医药辨证施治,能有效减少蛋白尿,减轻水肿并有降低血糖、调节脂代谢、改善微循环、纠正肾功能的作用。疗效明显优于单纯西药,其防治早期糖尿病肾病方面的良好疗效及其低不良反应的优势,可能成为一种重要的干预手段。2)通过对人体脏腑功能的调理治疗,改善患者的临床症状,提高患者生存质量,是中医药防治糖尿病肾病独特优势。3)早期糖尿病肾病出现率最高的中医证型是气阴两虚证(占68.6%),其后为阴虚热盛证(占19.2%)而阴阳两虚证只占12.2%。各证型分布显著差异。中医兼证分布特点显示瘀血证出现频次居首,发生率为70.54%,其次为湿热、湿浊证,发生率28.49%,外感证仅占0.97%。且湿浊、外感为主的各证中还兼挟着不同程度的瘀血证,可见早期糖尿病肾病兼证出现率最高的是瘀血证。也由此印证早期糖尿病肾病与络脉瘀阻存在着明显的相关性。4)研究显示早期糖尿病肾病的病位以脾肾为根本。糖尿病肾病虽累及五脏,但从方药分析,主要责之脾肾。从用药30%以上的药物分析,主要是由补肾阴的六味地黄丸、左归丸化裁。进一步分析常用药物中都有参、芪、术、苓等健脾药。本研究涉及的27条处方中,健脾益肾贯穿始终,可见脾肾虚是本病的特点。5)研究显示益气养阴、活血通络是早期糖尿病肾病的治疗特色。糖尿病的主要病机是阴虚燥热,阴虚为本,燥热为标。病程日久,发展到糖尿病肾病时,由于热盛伤阴耗气而致气阴两虚,故初期治疗仍以益气养阴为主,从用药次数最多的是黄芪、参类、地黄可知。实乃瘀湿浊毒,多因虚而致实,又因实而致虚,形成恶性循环。其中瘀浊内停为本病的病理产物,瘀阻肾络可见于本病的全过程,从丹参用药占51.8%显而易见,且用药最多的前22种药物中,活血化瘀通络之药竞占11种。由此可见,对于早期糖尿病肾病,益气养阴,散瘀通络为主要治则。通过以上的Meta分析,本文试图从循证医学的角度探讨早期糖尿病肾病的中医治疗决策,从循证医学的角度看,如何确定糖尿病肾病基本证型,正确把握其基本病机及不同时期的变化,创立有针对性的中药系列方药进行治疗,以获得最佳的诊治方案,达到最佳治疗效果和使患者获得最佳预后,这是循证医学的基本要求。由此,本研究提出利用中西医各自的优势互补,提高临床疗效;借助现代医学的检测技术确立诊断;着重益气养阴、健脾益肾;善用活血通络,佐以利湿化浊,收敛固涩;结合尿蛋白辨证论治以体现中医个体治疗特色;结合现代药理加入适当降糖作用的中药等建议。结合中医的络病理论、现代医学对早期糖尿病肾病的病理认识及本研27个随机对照试验的Meta分析,本研究最后作出三点结论:(一)肾络瘀阻与糖尿病肾病的发生、发展呈明显的相关性,并贯穿于早期糖尿病肾病的全过程。(二)早期糖尿病肾病的主要中医证型是气阴两虚证;益气养阴,活血通络是治疗原则。(三)中医药治疗早期糖尿病肾病的优势,是在血糖控制稳定的基础上体现,在延缓早期糖尿病肾病进展方面,可能是一种有前景的治疗手段;但中医药的临床试验方法学质量尚有待提高和完善。本研究也指出,循证医学((evidence-based medicine,EBM)的问世标志着以经验和推论为基础的、传统的经验医学,已开始转变为主要以大型临床试验提供的证据为基础的循证医学,是现代临床医学实践和临床基础研究的新模式。本研究以早期糖尿病肾病的临床研究文献提供的证据为基础,进行了Meta分析的初步尝试。然则,在研究中也发现中医的临床研究文献仍存在不少问题,临床研究常缺乏严谨合理的设计和严格的操作规范;RCT资料较少,随机质量不能让人满意;盲法应用极少;中医的临床分期、分型及疗效判定标准尚不统一,多数论文套用西医诊疗标准,缺少中医特色;临床资料的样本含量偏小,缺乏大宗的前瞻性研究;对中药治疗DN复发率和不良反应发生率观察不足,远期疗效及跟踪随访少;多数以症状、体征及实验室指标为疗效的评价标准,少考虑对患者生存质量的影响等等。如何规范化地建立既与现代医学相通又具有中医特色的糖尿病肾病统一诊断依据、中医辨证分期标准和疗效评价标准?如何按照多中心、随机、对照、盲法的原则,加强中医药防治糖尿病肾病的基础研究和临床研究?如何在中药的具体应用上既体现量化标准又发挥其多中心、多靶点的灵活治疗优势?这是循证中医学科学发展必须面临的课题。更多还原

【Abstract】 With the entry point of early stage diabetic nephropathy and theory of Chinese medicine collateral disease.as guiding principle,the paper is about the associated relationship between collateral stagnation and the early stage diabetic nephropathy(DN) pathology.It initially attempt to do Meta analysis on the basis of clinical research literature which comply with the randomized controlled trial(RCT) standard and explore the pros and cons of Chinese treatment of DN as well as Chinese medicine clinical decision-making.Diabetic nephropathy is one of the common serious diabetic capillary complications.Along with the gradual increase of incidence,recently diabetic patients become more and more.Early stage diabetic nephropathy occurs hidden.Once it begins,the kidney damage grows rapidly.Persistent albuminuria,hypertension,edema and renal failure will rapidly appear and the kidney disease will be irreversible.As the pathogenesis of the disease has not been completely clear and there are no effective treatment measures,most patients enter end-stage renal disease (ESRD) in short period of time.Therefore,revealing the pathology of the disease and giving specific prevention at early stage make positive significance to control and delay the further development of renal disease.Collateral theory is an important component of Traditional Chinese Medicine basic theory.With the development of modern science, multidisciplinary integration and infiltration apply collateral theory with new content.As a functional network system of communication both inside and outside the body,collateral vessel is not only the running channel of both qi and blood,but also the pathway of pathogen.While kidney is rich of capillaries and renal collateral is thin and tortuous as well as slow blood flow determines the pathological changes of evil injury and collateral stagnation.From the perspective of Chinese medicine,DN is due to the deficiency of qi and yin in a long time.Deficiency of qi makes the blood flow unsmooth and deficiency of yin make high blood viscosity and leading to blood stagnation. Blood stasis,as the pathological products of body fluid imbalance,is due to deficiency of spleen and kidney.Vital qi deficiency causes the generation of pathological products,whereas the products inhibit the production of qi and blood and the splenorenal function leading to a vicious cycle.It can be said thatblood stasis is the main pathology of DN,which is in line with Chinese medicine in "invalidism must accompany with blood stagnation" "invalidism develop into collaterals" The view of blood stasis also match the modern medical point of hemodynamics changes and capillaries disease in patients with DN,such as increased hemorheology general index,blood viscosity and lipids, reduced kidney blood flow,platelet aggregation,sclerosis of blood vessels, renal microcirculation disturbance,even hypercoagulability.Furthermore, herbs which could promote blood circulation to remove meridian obstruction, improve glomerular hemodynamics,reduce albuminuria and hematuria and protect renal function.These researches also prove the theory of collateral stasis pathology.In order to explore the further relationship between collateral stagnation and early stage diabetic nephropathy and pros and cons of Chinese medical treatment,the research comprehensively assess clinical early stage diabetic nephropathy literatures from 1998.1 to 2007.12,with the principle and methods of evidence-based medicine(EBM).There are 6711 papers about DN research,according electronic and manual search.27 randomized controlled trials(RCT) are adapted for Meta analysis according to the standard.The trial periods are from 1 to 6 months,and studies all proceed in Chinese Medical University Affiliated Hospitals or the three-level hospitals.The number of patients in all studies varies from 28 to 80,a total of 1341.Age of patient changes from 28 to 76,and the average age 55.2,average course 8.9 years.All the 27 studies are on the basis of controlling diet,proper sports, and stable blood glucose with western medicine.Compare the treatment of combination of Chinese medicine to single intervention with western medicine.The main index of this assessment include:blood glucose(FBG, HbAlc),lipids(TC,TG,HDL-C),renal function(Scr,Bun),urine protein excretion rate(UAER) and hemorheology indices as well as the Early stage diabetic nephropathy syndrome distribution,Chinese medical recipes and herbs application,symptom score and life quality standard evaluation.The findings indicate:1) Chinese medical differentiation syndromes are combined with western medical basic treatment to cure early stage diabetic nephropathy in the 27 randomized controlled literatures.It could effectively reduce albuminuria, edema,and blood glucose,regulate lipid metabolism,improve microcirculation and rectify renal function.The effect is much better than western medicine alone.The good result and low side effect make it an important means of intervention.2) It is the unique advantage of Chinese medicine that improving patients’ clinical symptoms and quality of life through regulating viscera function.3) Deficiency of qi and yin is the highest syndrome in early stage diabetic nephropathy(68.6%),followed by deficiency of yin and excessive of heat syndrome(19.2%),and the latter is deficiency of yin and yang(12.2%).The distribution differentiates obviously.While the distribution characteristics of the accompanied symptoms show that blood stasis is number 1,with a incidence rate of 70.54%,followed by damp heat and muddy syndrome (28.49%),and exogenous syndrome only account for 0.97%.Moreover blood stasis syndrome also accompany with damp heat and muddy syndrome.So,blood stasis syndrome has the highest rate of emergence in early stage diabetic nephropathy. This also confirms the relevant relationship between early stage diabetic nephropathy and collateral blood stasis.4) Studies show spleen and kidney are the basement of early stage diabetic nephropathy.Although the five viscera are involved in DN,spleen and kidney are the key organs according analysis of the herbs.More than 30%prescriptions make by Liuwei Dihuang pills and Zuogui pills.The commonly used herbs are reinforcing spleen medicine,such as:shen,qi,zhu,ling.In the 27 prescriptions,invigorating spleen and kidney penetrate all along.Therefore, deficiency of spleen and kidney is the characteristics of the disease.5) Studies show reinforcing qi and yin,activating blood and removing stasis are the treatment characteristics of early stage diabetic nephropathy. The main pathology of diabetes is yin deficiency and dryness-heat.Yin deficiency is the basement and dryness-heat is the surface.After long period, it develops into DN.As excessive heat consume qi and yin,leading to deficiency of qi and blood.Therefore,reinforcing qi and yin is the main measure in early stage,and this can be speculated from the most common herbs,such as huangqi, shen,dihuang.The sthenia syndrome means blood stasis,dampness,muddy and poison.Deficiency could lead to sthenia syndrome,whereas sthenia syndrome also causes deficiency,generating a vicious circulation.Muddy stasis as the pathologic products,obstruct in renal collateral throughout the whole disease course.In the study,Danshen’ s using rate is 51.8%.Moreover,during the former 22 kinds of herbs,activating blood herbs occupy 11 kinds.Therefore, reinforcing qi and yin,activating blood and removing stasis are the main therapeutic principle in early stage diabetic nephropathy.From respective of evidence-based medicine(EBM),this study attempt to explore Chinese medical treatment decision in early stage diabetic nephropathy, with the above Meta analysis.Decide the basic DN syndrome,grasp the general pathology and changes of different of periods,and crate targeted formula and herbs.Make optimal diagnostic and therapeutic scheme,reach satisfactory effect and make a best prognosis for patients.These are the basic demands of EBM.Therefore,the study propose suggestions,such as:make best use of individual advantage of Chinese and Western medicine,and improve clinical effect;establish diagnosis assisted by modern medical testing technology; reinforce qi and yin,invigorate spleen and tonify kidney;activate blood and remove the stasis,combining with eliminating muddy dampness and astringing; syndrome differs on albuminuria to manifest individual characteristics of TCM; according to modern pharmacology,add proper hypoglycemic effect herbs and soon.According to theory of Chinese medical collateral disease,pathology of early stage diabetic nephropathy in modern medicine and the Meta analysis of 27 RCT in this study,three conclusions are made.1 There is obvious correlation between renal collateral blood stasis and incidence and development of DN.It runs through the whole process of early stage diabetic nephropathy.2 The main Chinese medical syndrome is deficiency of qi and yin in early stage diabetic nephropathy,and the therapeutic principle is reinforcing qi and yin,activating blood and removing stasis.3 The advantage of TCM in treating early stage diabetic nephropathy base on stable blood glucose.It is a promising method for delaying early stage diabetic nephropathy development.While quality of TCM clinical trial still need to improve and develop.Evidence-based medicine(EBM) marks the transformation from traditional empirical medicine to the new form of modern clinical medical practice and clinical basic research,EBM,with the basis of large-scale clinical trial proof.With the basis of Clinical researching literature proof of early stage diabetic nephropathy,the study initially attempt to do Meta analysis.While, many problems of TCM clinical literature are discovered in this research, such as lacking rigorous reasonable design and operational specification;Few RCT materials and unsatisfactory quality of randomizing;Rarely application of blind;lacking unified standard of TCM clinical stage,syndrome and efficiency;small sample size of clinical data,lacking of large prospective studies;insufficiency of observation of recurrence and side effect in TCM treatment;deficiency of long-term effect and little follow-up;inadequacy of quality of life evaluation and so on.How to establish standardized modern TCM characteristic diagnostic evidence,syndrome and effect standards? With the principle of multi-centre, randomized,controlled,blind,how to improve the basic and clinical research of TCM in treating DN? How does Chinese medicine application not only show the quantitative criteria,but also play multi-centre,multi-target flexible advantage? This is an issue scientific development evidence TCM must be faced.更多还原