【作者】 王庆华；

【导师】 彭万年；

【作者基本信息】 广州中医药大学 ， 中医临床基础， 2008， 博士

【摘要】 糖尿病肾病(Diabetic Nephropathy,DN)是糖尿病(Diabetes Mellitus,DM)患者临床常见而难治的微血管并发症之一。随着人们生活方式的改变、寿命的延长,现代疾病谱发生了根本性转变,DM发病率在全球迅速上升,DN的发病率也在不断上升,DN已成为导致终末期肾病患者死亡的主要原因。由于DN的发生率和病死率水平高,目前国内外尚无治疗、延缓DN发展的理想药物和方法,故提高DN病人的生存质量、降低其死亡率,有效防治DN如今己成为医学界共同关注的热点。而中医药对防治DN、保护肾脏、控制病变等方面有其独特的优势,在治疗上取得了良好的临床效果。中医药是一个伟大的宝库。古今中医药文献中就包含有诊治本病的宝贵经验。很值得我们去挖掘。本文从古今文献整理和方药应用分析等理论研究入手,总结DN古今文献研究概况及古今方药证治规律等,以期对科研及临床用药提供有益的参考。一、糖尿病肾病中医相关文献考辨这是引古鉴今,探流寻源的关键点。虽然中医古籍中并无糖尿病肾病之名,但其症状与中医的“肾消”、“尿浊”、“水肿”、“肾劳”、“关格”等病证相合。糖尿病肾病还可涉及很多古病名,但有的似是而非,有的争议较大。如关于“肺消与糖尿病无涉”、“食亦、食夜即中消”“鬲消是否消渴病肾病?”等的争议。弄清这些古病名的准确含义,对糖尿病肾病的研究是很重要的。通过对古代医籍有关DN资料的收集、整理,并经认真考辨分析,我们对此已有较客观的认识。以下病名与DN有较密切的联系:①消瘅,可以是DM并发症期(包括DN),也可能是甲亢等其它疾病。②三消,DN属于此范畴。三消病久,可出现尿浊、水肿、痈疽等各种并发症,这与现代DN有很大的相关性。③下消、消肾,DN属于下消的范畴,消肾属于下消中较严重的情况,病位主要在肾,也可继发水肿、尿浊、胀满、关格等。下消、消肾与DN有密切的关系。④内消、急消,多为古代有些医家对类似下消、消肾等证的一种称谓。⑤渴利、食亦与DM及DN有一定的相关。因此,DN与消瘅、肾消(消肾)、下消、三消存在着密切的联系,其中以肾消(消肾)、下消关系最为密切。此外,经认真考辨分析,上述有争议的“肺消”不仅不能完全排除糖尿病,还可以包括消渴病肾病的相关病证;食亦、食夜、中消,义近而词异;“鬲消”即“隔消”,与消渴病肾病关系不太大。这些古病名含义的准确界定,对糖尿病肾病的研究可起正本清源的重要作用。二、方药证治规律研究通过对古今方药进行统计学方法的分析,总结治疗DN主要证治方药的运用情况和证治特点,以探讨DN辨证论治及遣药组方的规律,为临床用药提供参考,以对本病相关文献研究和理论完善有所裨益。(一)古代方药证治规律研究1研究方法古代方药的选择以《中医方剂大辞典》为主要检索目标,筛选了上至东汉,下至清末民国期间的有关治疗消渴病肾病的方药文献资料。以历朝历代消渴病合并症从,肾论治的方药为主要研究范围,采取辨证、从症、从药、以方测证等手段,收集了历朝历代“下消”“消肾”“肾消”“消渴小便白浊”等病症的方药。然后规范数据,建立方药数据库,运用统计学方法,进行三消分型、用药频数、聚类等分析,总结其方药证治规律。2研究结果(1)宋代以前方药统计分析结果中,三消分型以下消为主症者占80%;用药以茯苓、人参、熟地黄等药物使用频数较高;以补益药(37.22%)、清热药(15.74%)、收涩药(12.56%)、利水渗湿药(10.08%)所占比例较大,累积频率达75.60%。用药偏于温平,以甘味为主;药物归经主入肾(22.80%)、肝(16.07%)、心(15.57%);聚类分析药物组合中,以治疗三消(气虚、心肾不交之证)、消渴肾虚、渴后下虚、消肾、下消为主,多见小便滑数、白浊,虚乏,烦渴等症状。(2)金元时期方药统计分析结果中,三消分型以下消为主症者占77.36%;用药以茯苓、甘草、人参等药物使用频数较高;以补益药(29.55%)、清热药(20.90%)、利水渗湿药(11.59%)、收涩药(7.27%)、解表药(6.14%)所占比例较大,累积频率达75.45%,用药偏于寒凉,以温、寒性为主,药味以甘为主;药物归经主入肺(18.59%)、脾(15.28%)、胃(15.20%);聚类分析药物组合中,以治疗下消、三消(气阴两虚、火热内盛、阴液亏损)为主,多见小便淋浊、渴饮、燥热等症状。(3)明代方药统计分析结果中,三消分型以下消为主症者占96.67%:用药以茯苓、熟地黄、山茱萸等药物使用频数较高;以补益药(43.07%)、利水渗湿药(13.63%)、收涩药(12.90%)、清热药(10.46%)所占比例较大,累积频率达80.05%,用药偏于温,以甘味为主;药物归经主入肾(26.25%)、肝(16.89%)、脾(16.17%);聚类分析药物组合中,以治疗三消(阳虚、肾虚)、消肾、渴后下虚为主,多见小便频数、白浊,烦渴、燥热等症状。(4)清代方药统计分析结果中,三消分型以下消为主症者占95.50%;用药以茯苓、熟地黄、山药等药物使用频数较高;以补益药(42.29%)、清热药(18.89%)、利水渗湿药(11.70%)、收涩药(11.12%)所占比例较大,累积频率高达84.01%;用药偏于温平,以甘苦之味为主;药物归经主入肾(27.29%)、肝(15.85%)、心(15.23%);聚类分析药物组合中,以治疗下消或三消之证为主,多见渴饮,小便频数,小便如膏脂的症状。3结论从历代三消分型证治方药分布分析可知,宋金元(包括宋代以前)为三消分型的初期,明清时期为三消分型的完善发展期。由古代方药频数分析可知,以补益药为主,另外清热药、利水渗湿药、收涩药的使用比例和频率较高,药性以温平为主,药味以甘为主,主归肾经;方药聚类组合体中,常常涉及补益、清热、固涩及利水渗湿等四大类药,具有补肾固肾、清热养阴、生津止渴、收敛固涩及利尿通淋等功效,对于治疗三消、下消、肾消等病证具有提示作用,反映了本病本虚标实、虚实错杂的病因病机及证治特点。总体来看,对糖尿病肾病相关概念、证治方药及发展进程等,其考辨结论是:源于《内经》,拓展于汉唐;成熟于宋金元;完善发展于明清。(二)现代方药证治规律研究1研究方法现代方剂的选择以维普数据库为主要检索途径,结合图书手工检索的方式,对重要期刊杂志、期刊杂志中有关专家及重要书籍近20余年来所报道的中医药治疗DN的临床文献进行筛选。以“糖尿病肾病”、“消渴(病)肾病”、“肾消”、“消肾”为入选标准进行选取方药,然后规范数据,建立方药数据库,运用统计学方法,进行证型、用药频数、聚类等分析,总结其方药证治规律。2研究结果有关DN352首方药统计分析结果,其中涉及主要证型有:气阴两虚,82例,脾肾亏虚,70例,分别占23.30%、19.89%。用药以黄芪、茯苓、丹参等药物使用频数较高;以补虚药(35.82%)、活血化瘀药(13.78%)、清热药(12.53%)、利水渗湿药(12.39%)所占比例较大,累积频率达74.52%。药性以温平为主,药味以甘为主;药物归经主入肝(19.35%)、肾(18.76%)、脾(17.56%);聚类分析药物组合中,以治疗DN气阴两虚、肝肾阴虚、瘀血阻滞、痰饮内停等证为主。3结论由DN方药分析可见,以补气药、活血化瘀药、清热药、利水渗湿药的使用比例和频率最高,药性以温平为主,药味以甘为主,主归肝肾脾经;方药聚类组合体中,主要有补益、清热、活血、利湿、行气等几类药,具有补肝肾脾、益气养阴、活血化瘀、利水消肿、化湿泻浊等功效,反映了DN本虚标实、虚实错杂的病因病机特点和补益为主、兼祛实邪的证治规律。而古今证治方药的发展变化,以活血化瘀药使用频率的大大增加最为显著。此外本研究还引入导师的经验进行分析。导师常引古鉴今,总结经验,在长期的临床实践中,用中医药治疗DN取得满意疗效,可较好地改善临床症状,延缓病情发展、恶化,部分病人肾功能明显好转,显示了中医药在DN治疗中的优势和潜力。这也同时提示引古鉴今,古为今用的重要性。更多还原

【Abstract】 Diabetic Dephropathy(DN) is clinical common and intractable one of the microvascular complications about patients with Diabetes Mellitus(DM). With the change in people’s way of life, life extension, the modern disease spectrum fundamental changes have taken place, Diabetes’ incidence rate in the whole world is rising rapidly,the incidence rate of DN is also rising, DN has become the main reason that lead to death of end-stage renal patients.because of the high incidence and mortality rate of DN, there is no ideal drugs and method treating and delaying and retarding the development of DN at home and abroad at present,so now it has becomes the common concern hot spot of the medical profession about how to improving the patient’s quality of life,reducing the mortality rate,preventing and treating DN effectively. However Traditional Chinese Medicine(TCM) not only has its unique advantages on combating DN, the protection of the kidney, disease control, etc,but also has made a good clinical effect. TCM is a great treasure house. Ancient and modern literature of TCM about DN include the valuable diagnosis and treatment experience which is worth to Mining.The paper from ancient and modern literature collation and analysis of prescriptions with theoretical study starts, concluded Ancient and Modem literature research Overview,syndromes and treatment regular of prescriptions of DN, with a view to provide a clinical useful reference.1 Relevant literature researched and differentiated of Traditional Medicine Chinese of Diabetic NephropathyIt is the key point with ancient things as modern reference, exploring flow and finding source. Although there is no the name of DN in the ancient Chinese Medicine books,its symptoms is consistency with diseases of TCM such as"shen-xiao"、"niao-zhuo"、"shui-zhong"、"shen-lao"、"guan-ge". DN also involve a lot of ancient disease names, but some paradoxical, some more controversial.For example"fei-xiao not relevant with DM"、"shi-yi、shi-ye,that is zhong-xiao""ge-xiao means wasting-thirst disease secondary to nephropathy? "identifing the precise meaning of these ancient disease names is very important for DN research. Through the collection、collation of the ancient medical source about DN.and researching and differentiating and analysis seriously,and we have a more objective recognise of this.It is found that the following disease names are more closely linked with DN:①Xiao-dan,could be a complication of DM (including DN), may also be hyperthyroidism and other diseases.②3-xiao, DN belongs to this area.3-xiao continues, there will be urine muddy,edema, superficial infection and other complications that have great relevance with modern DN.③Xia-xiao、xiao-shen, DN are under the scope of xia-xiao. xiao-shen belong to the more serious cases, the disease-site of its mainly in the kidneys, could also be secondary to edema, urine muddy, dilatate and full, Georgia, and others. xia-xiao、xiao-shen and DN have a close relationship.④Nei-xiao,ji-xiao,are more a title for some ancient doctors Experts under similar xia-xiao、xiao-shen.⑤Ke-li,shi-yi and DM with DN have a certain correlation.Therefore,there are close relevance among DN and xiao-dan, shen-xiao (xiao-shen),xia-xiao 3-xiao,which shen-xiao (xiao-shen) is most closely connected with.In addition, by researching and differentiating and analysis seriously,above controversial"fei-xiao" not only can not be completely ruled out its relevance with DM,but also could include the related diseases of wasting-thirst disease secondary to nephropathy;shi-yi、shiye、zhong-xiao, with near-term differences; "ge-xiao" means "ge-xiao",it is little relevance with wasting-thirst disease secondary to nephropathy. Defining the exact meaning of these ancient disease names for reseach of DN can play an important role of amendmenting nature and understanding origin.2 Study on the laws of syndrome differentiation and treatment of prescriptionsThrough analysis of statistical methods for the ancient and modern prescriptions, sum up the using condition and characteristics of these prescriptions treating DN, to explore the regularity of syndrome differentiation and treatment and removal of the drug group about DN, for clinical drug reference,and be benefit to the literature research and theoretical improvement on this disease.I The laws of syndrome differentiation and treatment study of ancient prescriptions(I) MethodsAncient prescriptions’ choice as A dictionary of Chinese Medicine Prescriptions for the main Search goal, screened up to the Eastern Han Dynasty, down to the end of the Qing dynasty and republic prescription literature data about the treatment of DN.As the prescriptions in each history and dynasty about xiao-ke complications from kidney treatment for major research areas, to take means of differentiation、from symptoms、from herbs、testing syndromes to prescriptions, collected prescriptions in each history and dynasty about diseases and syndromes of "xia-xiao" "xiao-shen" "shen-xiao""xiao-ke complicating urine muddy". And standardize data, establish prescription database, and make analysis of 3-xiao typings frequency of use、cluster through the use of statistical methods, the Third Consumers type,to summing up its syndrome and treatment regularity of prescription.(II) ResultsIn the statistical analysis of prescription of results before the Song dynasty,xia-xiao as main symptoms among 3-xiao typing accounted for 80%; Medication to Poria,Radix Ginseng, Radix Paeoniae Alba; there is the larger proportion to replenishing drugs (37.22%),heat-clearing drugs(15.74%),drugs for arresting discharge(12.56%),diuretics for eliminating dampness(10.08%), cumulative frequency up to 75.60%. medication Partial to warm and bland; mainly to sweet taste; the drugs mainly into the kidney meridian (22.80%)、the liver meridian(16.07%)、the heart meridian(15.57%); in drug combinations by cluster analysis,to mainly treat 3-xiao(such as asthenia of Qi,imbalance between heart-yang and kidney-yin), xiao-ke with kidney deficiency, kidney deficiency following thirst, xiao-shen, xia-xiao,and find white muddy and sliding multi-urine,the virtual lack, polydipsia,and other symptoms.In the statistical analysis of prescription of results during the Jinyuan dynasty,xia-xiao as main symptoms among 3-xiao typing accounted for 77.36%; Medication to Poria,Radix Glycyrrhizae,Radix Ginseng; there is the larger proportion to replenishing drugs (29.55%),heat-clearing drugs(20.90%), diuretics for eliminating dampness (11.59%)drugs for arresting discharge (7.27%),drugs for relieving exterior syndrome (6.14%),cumulative frequency up to 75.45%.medication Partial to cold and cool,mainly to warm and cold; mainly to sweet taste; the drugs mainly into the lung meridian(18.59%)、the spleen meridian(15.28%)、the gastrin meridian(15.20%); in drug combinations by cluster analysis,to mainly treat xia-xiao,3-xiao(such as deficiency of both Qi and Yin,fire-heat filling internus,consumption of yin-fluid),kidney deficiency following thirst, xiao-shen, xia-xiao,and find drenching and muddy urine,thirst to drink, dryness-heat,and other symptoms.In the statistical analysis of prescription of results during the Ming dynasty,xia-xiao as main symptoms among 3-xiao typing accounted for 96.67%; Medication to Poria,Radix Paeoniae,Fructus Corni; there is the larger proportion to replenishing drugs(43.07%), diuretics for eliminating dampness (13.63%),drugs for arresting discharge(12.90%), heat-clearing drugs (10.46%), cumulative frequency up to 80.05%.medication Partial to warm,mainly to sweet taste; the drugs mainly into the kidney meridian(26.25%)、the liver meridian (16.89%)、the spleen meridian(16.17%); in drug combinations by cluster analysis, to mainly treat 3-xiao(such as yang asthenia, kidney deficiency),xiao-shen, kidney deficiency following thirstand find white muddy and frequent multi-urine, polydipsia,dryness-heat,and other symptoms.In the statistical analysis of prescription of results during the Qing dynasty,xia-xiao as main symptoms among 3-xiao typing accounted for 95.50%; Medication to Poria,Radix Paeoniae Alba,Rhizoma Dioscoreae; there is the larger proportion to replenishing drugs(42.29%),heat-clearing drugs (18.89%), diuretics for eliminating dampness (11.70%),drugs for arresting discharge (11.12%),cumulative frequency up to 84.01%. medication Partial to warm and bland; mainly to sweet and bitter taste; the drugs mainly into the kidney meridian(27.29%)、the liver meridian(15.85%)、the heart meridian (15.23%); in drug combinations by cluster analysis,to mainly treat xia-xiao and 3-xiao,and find thirst to drink,frequently and multi-urine,mastic and fat of urine.and other symptoms.(III) ConclusionAnalysis from syndrome differentiaton and treatment prescriptions’ distribution of 3-xiao typing indicates that Song-Jin-Yuan dynasty (including the Song Dynasty ago) is at the early stages of 3-xiao typing.the Ming and Qing dynasties is in the development period of 3-xiao typing.From ancient prescription frequency analysis it is found that there is higher using proportion and frequency for heat-clearing drugs,diuretics for eliminating dampness,drugs for arresting discharge,mainly to replenishing drugs, medication Partial to warm and bland; mainly to sweet taste,the drugs mainly into the kidney meridian; in drug combinations by cluster analysis,often involves four drug category such as replenishing drugs,heat-clearing drugs, diuretics for eliminating dampness,drugs for arresting discharge,with invigorating and consolidating the kidney,heat-clearing and nourishing yin, promoting the production of body fluid to quench thirst,convergence to unsmooth, inducing diuresis for treating strangurtia,to hint that it can treat these syndromes such as 3-xiao,xia-xiao, shen-xiao, etc,reflects the feature of asthenia in origin and sthenia in superficiality and deficiency syndrome mingling with excess syndrome about cause and pathogenesis of disease and syndrome differentiation and treatment.Overall,about the concept of DN、prescription of syndrome differentiation and treatment and the development process,the conclusion is: from ((Emperor Classic)) ; expanding in the Han and Tang dynasties; maturing in the Song- yuan-jin dynasties; and improving and developing in the Ming and Qing Dynasties.II The laws of syndrome differentiation and treatment study of mordern prescriptions(I) Methods Modern prescriptions’ choice as VIP database for the main search way, with manual retrieval of books,screened important magazines, journals with the relevant experts and important books in recent years by more than 20 reported in clinical literature of Chinese Medicine treatment of DN.To select prescriptions as "Diabetic Nephropathy"、"wasting-thirst disease secondary to nephropathy"、"shen-xiao"、"xiao-shen"for choosing standards, and standardize data,establish prescription database,and make analysis of syndromes typing、frequency of use、cluster through the use of statistical methods,to summing up its syndrome and treatment regularity of prescription.(II) ResultsIn the statistical analysis results of 352 prescriptions of DN,it involves the following major syndromes as deficiency of both qi and yin,82 cases,asthenia of the spleen and kidney,70 cases,accouts of 23.30%, 19.89% Respectively.Medication to Radix Astragall,Poria,Radix Salviae Miltiorrhizae; there is the larger proportion to replenishing drugs (35.82%),drugs activating blood circulation to dissipate blood stasis (13.78%), heat-clearing drugs(12.53%),diuretics for eliminating dampness (12.39%),cumulative frequency up to 74.52%.medication Partial to warm and bland,mainly to sweet taste; the drugs mainly into the liver meridian(19.35%)、the kidney meridian(18.76%)、the spleen meridian (17.56%); in drug combinations by cluster analysis,to mainly treat these syndromes of asthenia of both qi and yin、hepatic and renal yin deficiency、stagnation of blood stasis、phlegm and body fluid stayed internal about DN,and other symptoms.(III) ConclusionAnalysis from prescriptions about DN indicates that there is higher using proportion and frequency for drugs invigorating vital energy,drugs activating blood circulation to dissipate blood stasis,heat-clearing drugs,diuretics for eliminating dampness,medication partial to warm and bland; mainly to sweet taste,the drugs mainly into the liver、the kidney、the spleen meridian; in drug combinations by cluster analysis, mainly involves drug category such as replenishing drugs,heat-clearing drugs,activating blood circulation drugs,diuretics for eliminating dampness, qi-unobstructed drugs,with tonifing the liver and kidney and spleen,benefiting vital energy and nourishing yin, activating blood circulation to dissipate blood stasis,diureting for eliminating dampness, reflecting the feature of asthenia in origin and sthenia in superficiality,deficiency syndrome mingling with excess syndrome about cause and pathogenesis of DN,the laws of syndrome differentiation and treatment of replenishing healthy energy mainly and eliminating sthenia pathogenic factors. However,about the development and changes of ancient and modern prescriptions of the laws of syndrome differentiation and treatment,it is most significant that the using frequency of drugs activating blood circulation to dissipate blood stasis greatly increased.Additionally,the experience of instructors is also introduced about this study. Instructors often cited this ancient knowledges as modern reference, sum up experience, in the long-term clinical practice,the treatment of DN by using TCM achieves satisfactory effect,which may be better to improve the clinical symptoms and delay disease progression, deterioration,and some patients significantly improved of kidney function, it shows the strengths and potential of TCM in the treatment of DN.It also suggests its importance of with ancient things as modern reference, making the past serving the present.更多还原