从气血水论治特发性膜性肾病及乙酰肝素酶与IMN尿蛋白相关性的研究
摘要
特发性膜性肾病(IMN)是原发性肾小球疾病的重要病理类型,随着肾脏病理活检技术的推广应用,该疾病的确诊率逐年提高,其治疗方法也广受关注。西医对于该病的治疗虽有一定经验,但是使用免疫抑制剂后的安全性及有效性仍值得商榷。导师在深入研究祖国传统医学理论基础上,结合临床实践经验,认为IMN的发生主要在于气血水三者的失调,其核心病机在于气虚血瘀水停,故而创立了以益气活血利水法为主的治疗特发性膜性肾病的方法。本临床研究主要探讨从气血水论治IMN的治疗特色和优势。
乙酰肝素酶作为一种新近得到广泛关注的葡糖核苷内切酶,其在体内具有多项生物学功能；一些研究表明其表达可能与肾脏疾病有关。本课题的实验研究主要探讨乙酰肝素酶与特发性膜性肾病的尿蛋白之间的相关性,为今后进一步探讨中药减轻特发膜性肾病尿蛋白的作用机制奠定基础。
研究一：益气活血利水法治疗特发性膜性肾病的临床研究
目的：以中医气血水理论为指导,观察益气活血利水法治疗特发性膜性肾病的临床疗效。
方法：本研究采用随机、开放、对照的临床试验方法,将符合病例纳入标准的60例患者按就诊时间顺序随机分组为试验组(基础治疗+益气活血利水方药)和对照组[基础治疗+血管紧张素转化酶抑制剂(ACEI)],比较两组患者治疗前后以及两组间的中医证候疗效、疾病综合疗效、尿蛋白及其它相关理化指标的变化,初步评价益气活血利水法治疗特发膜性肾病的临床疗效。以SPSS17.0建立数据库并进行统计学分析,认为P值≤0.05表示有统计学意义。
结果：
1.整体疗效的分析：在对60例入组病例进行分析后得出①中医证候疗效评价：试验组总有效率88.6%,对照组总有效率88%；②西医综合疗效评价：试验组总有效率85.7%,对照组总有效率80%；③主要理化指标比较：在治疗前后的组内比较上,试验组和对照组患者治疗前后的Scr、BUN、ALB、24小时尿蛋白定量以及eGFR的指标变化均具有显著的统计学差异(P<0.05)；两组各项指标在治疗前以及治疗后的组间比较上,差异均不具有统计学意义(P>0.05)。
2.24小时尿蛋白定量的分层分析
24小时尿蛋白定量小于3.5g患者组：①中医证候疗效评价：试验组总有效率88.5%,对照组总有效率91.7%；②西医综合疗效评价：试验组总有效率80.7%,对照组总有效率83.3%；③主要理化指标比较：在治疗前后的组内比较上,试验组和对照组患者治疗前后的Scr、BUN、ALB及eGFR的指标变化均具有显著的统计学差异(P<0.05)；两组各项指标在治疗前以及治疗后的组间比较上,差异均不具有统计学意义(P>0.05)。
24小时尿蛋白定量大于3.5g患者组：①中医证候疗效评价：试验组总有效率88.9%,对照组总有效率84.6%；②西医综合疗效评价：试验组总有效率100%,对照组总有效率76.9%。③主要理化指标比较：在治疗前后的组内比较上,试验组和对照组患者治疗前后的Scr、ALB、eGFR及24小时尿蛋白定量的指标变化均具有显著的统计学差异(P<0.05)；两组各项指标在治疗前以及治疗后的组间比较上,差异均不具有统计学意义(P>0.05)。
3.影响疗效的相关因素的分析：疗前的肾功能指标(Scr、BUN),24小时尿蛋白定量,ALB, APTT以及eGFR与疗效间存在显著的相关性(P<0.05)；疗程对疗效的影响差异具有显著的统计学意义(P<0.05),治疗4个月及更长疗程时,患者疗效较明显；而性别、年龄及病理分期等对疗效的影响差异无统计学意义(P>0.05)。
结论：
1.从中医病机理论分析,特发性膜性肾病的中医病机责之于气血水三者的失调,气虚、血瘀、水停可能是特发性膜性肾病的核心病机。
2.益气活血利水法具有较好的缓解特发性膜性肾病的中医症状、减轻尿蛋白的作用,其疗效与血管紧张素转换酶抑制剂相当。
3.理化指标与疗效的相关性分析结果提示：疗前的肾功能指标(Scr、BUN),24小时尿蛋白定量,ALB, APTT以及eGFR等指标对治疗效果均可产生一定的影响；疗程与疗效显著相关,长疗程时患者疗效较明显；而性别、年龄及病理分期等对疗效无明显影响。
研究二：乙酰肝素酶与特发性膜性肾病患者尿蛋白相关性的实验研究
目的：通过对特发性膜性肾病患者及健康人群的外周血中乙酰肝素酶含量的检测,并将其与24小时尿蛋白定量进行比较分析,初步探索乙酰肝素酶与尿蛋白之间的相互关系,为今后进一步探讨中药减轻特发膜性肾病尿蛋白的作用机制奠定基础。
方法：本研究中共采集血样48例,其中特发性膜性肾病患者33例,根据患者的24小时尿蛋白定量的含量将其分为缓解组(24小时尿蛋白定量小于1.5g/24h)17例和未缓解组(24小时尿蛋白定量≥1.5g/24h)16例,并采集健康人群(24小时尿蛋白定量均小于200mg/24h)15例血样,用人乙酰肝素酶(HPA)酶联免疫分析(ELISA)试剂盒测定样本的乙酰肝素酶含量,并与入组病例的24小时尿蛋白定量进行比较,以SPSS17.0建立数据库并进行统计学分析,认为P值≤0.05表示有统计学意义。
结果：对研究病例的分析表明：①缓解组、未缓解组和健康人群在24小时尿蛋白定量和乙酰肝素酶含量的组间比较上差异有统计学意义(P<0.05)；且乙酰肝素酶的含量随24小时尿蛋白定量的不同而表现出显著差异,24小时尿蛋白定量较高的未缓解组,乙酰肝素酶的含量也较高。②经对入组数据的Pearson相关性分析得出,乙酰肝素酶含量与24小时尿蛋白定量之间存在着显著的线性相关。③经SPSS17.0统计软件对数据进行分析后,模拟出乙酰肝素酶含量与24小时尿蛋白定量直线回归的方程式：Y=88.561+6.357X。
结论：本研究结果显示,在特发性膜性肾病患者与健康人群对比的外周血乙酰肝素酶含量和24小时尿蛋白定量的相关性分析中,发现外周血乙酰肝素酶含量与24小时尿蛋白定量存在显著的线性相关。
Idiopathic membranous nephropathy (IMN) is an important pathological ty pe of glomerular disease, along with the popularization and application of the technology, the disease diagnosis rates were increased year by year. There is also a widespread concern about the IMN's treatment. Western medicine treatment for the disease has certain experience, but safety and effectiveness of the use of immunosuppressive agents are still debatable. Mentors in the in-depth study of traditional Chinese medical theory, combi ned with clinical experience, argued that this disease mainly lies in the dis orders of Qi Xue and Shui, due to Qi deficiency, blood stasis and water s tagnation, he founded the Yiqi Huoxue Lishui method to treat the disease of idiopathic membranous nephropathy. The clinical study mainly discusse d the characteristics and advantages of Yiqi Huoxue Lishui methods in tre ating IMN.
Heparanase is a new glucose nucleosides enzyme which received extensi ve attention in these years, it has many biological functions; some studies show that its expression may be associated with renal disease. In this ex perimental study, we paid attention to the correlation of the heparanase and the urinary protein in the idiopathic membranous nephropathy patient s, to lay the foundation for the further study of the herbal curative effect f or relief the urinary protein in the idiopathic membranous nephropathy pati ents.
Part1:The effect of Yiqi Huoxue Lishui therapy for treating the dise ase of idiopathic membranous nephropathy
Objective:As the guide of QiXueShui theories of TCM, we observed the effects of Yiqi Huoxue Lishui therapy for treating IMN.
Methods:This study used a randomized, open, controlled clinical trials,60patients that conformed to the case inclusion criteria were randomly divi ded into experimental group (basic therapy+Yiqi Huoxue Lishui herbs) a nd control group (basic therapy+ACEI) according to the time sequence. We compared with two groups patients before and after treatment as wel l as among two groups of TCM efficacy, disease comprehensive curative effect, urinary protein and other related physical and biochemical index ch ange.Preliminary evaluation the effects of Yiqi Huoxue Lishui therapy for tr eating IMN. We used SPSS17.0to establish database and analyzed statis tically, that P value<0.05indicated the statistical significance.
Results:
1. Total efficacy analysis:The results of the60cases indicated:①TCM ef ficacy evaluation:the total effective rate of the experimental group was88.6%, the total effective rate of the control group was88%;②The western medicine comprehensive effectiveness evaluation:the total effective rate of the experimental group was85.7%, the total effective rate of the control group was80%;③The main physicochemical index:In the comparison wit hin groups, two groups of patients before and after the treatment, Scr, BU N, ALB,24hUpro and eGFR index changes had statistical significance(P <0.05); In the comparison between groups, two groups of patients befor e and after the treatment, all of the index changes had no statistical signif icance(P>0.05).
2. The further analysis for the different groups according to the24hUpro. The group of the patients that24hUpro was less than3.5g:①TCM efficac y evaluation:the total effective rate of the experimental group was88.5%, the total effective rate of the control group was91.7%;②The western m edicine comprehensive effectiveness evaluation:the total effective rate of t he experimental group was80.7%, the total effective rate of the control gr oup was83.3%;③The main physicochemical index:In the comparison wit hin groups, two groups of patients before and after the treatment, Scr, BU N, ALB and eGFR index changes had statistical significance (P<0.05); I n the comparison between groups, two groups of patients before and after the treatment, all of the index changes had no statistical significance(P>0.05).
The group of the patients that24hUpro was more than3.5g:①TCM effica cy evaluation:the total effective rate of the experimental group was88.9%, the total effective rate of the control group was84.6%;②The western me dicine comprehensive effectiveness evaluation:the total effective rate of th e experimental group was100%, the total effective rate of the control gro up was76.9%;③The main physicochemical index:In the comparison with in groups, two groups of patients before and after the treatment, Scr, ALB, 24hUpro and eGFR index changes had statistical significance (P<0.05); In the comparison between groups, two groups of patients before and a fter the treatment, all of the index changes had no statistical significance(P>0.05).
3. Analysis for the related factors that influenced the curative effect:the in fluences differences of the renal function indexes (Scr, BUN),24hUpro,a lbumin, APTT and eGFR index for the effects had statistical significance (P<0.05); the influences differences of the course of treatment with the cl inical effects had statistical significance(P<0.05), as the treatment for4months and longer course, the curative effcts were more obvious; the inf luences differences of gender, age and pathologic stage for curative effect s did not have statistical significance (P>0.05).
Conclusion:
1. From the TCM theory analysis, TCM pathogenesis of idiopathic membr anous nephropathy is the disorders of Qi, blood and water, Qi deficiency with blood stasis and water stagnation may be the main type of the patho genesis.
2. The Yiqi Huoxue Lishui therapy can relief the TCM symptoms, reduceth e urinary protein effectively for the patients of IMN, the clinical effects of Yiqi Huoxue Lishui therapy are almost as same as the functions of ACE I.
3. The related factors, such as the renal function indexes (Scr, BUN),24hUpro, albumin, APTT and eGFR can produce certain influence on the clinical effect. The treatment course has certain influence on the curative effect, as the course is longer, the effect is more obvious. However, gen der, age and pathologic stage do not have certain influence on the clinical effect.
Part2:The experimental research for the relationship between the h eparanase and the urinary protein of the idiopathic membranous nep hropathy patients
Objective:Detect and analyze the quantity of HPA in the blood of IMN p atience and healthy persons, found the relationships between the urinary protein and the heparanase, to lay the foundation for the further study of t he mechanism of herbal function for relieving the urinary protein of the pa tients of IMN.
Methods:The study collected48patients, including33patients of idiopat hic membranous nephropathy,17patients were divided into clinical remissi on group (24hUpro was less than1.5g/24h) according to the24hUpro, also,16cases were divided into not mission group (24hUpro was more th an or equal to1.5g/24h). We also detected the HPA of15healthy per sons (24hUpro was less than200mg/24h).We used the human hepara nase (HPA) enzyme immunoassay (ELISA) kit for the determination of sample of heparanase level, and compared with the24hUpro of the cases. We used SPSS17.0to set up database for statistical analysis, The P val ue<0.05indicated a statistical significance.
Results:The case study analysis showed that:①In the comparison betw een groups, the difference of the HPA quantity and the24hUpro in the re mission group, not remission group and healthy persons had statistical sig nificance (P<0.05). The difference through the HPA quantity with the24h Upro showed significant differences, in the not remission group, as the hig her level of24hUpro, the expression of heparanase level was higher than the remission one.②The group of data by Pearson correlation analysis s howed that, heparanase quantity and24hUpro had significant linear correl ation.③The SPSS17.0statistical software for data analysis simulated sim ulation chart of the linear regression equation of the heparanase quantity and24hUpro:Y=88.561+6.357X.
Conclusion:This study indicates:In the analysis of the relationship betwe en the HPA quantity in the peripheral blood and the24hUpro in idiopathic membranous nephropathy patients, we find that the HPA quantity and the24hUpro have a significant linear correlation.
乙酰肝素酶作为一种新近得到广泛关注的葡糖核苷内切酶,其在体内具有多项生物学功能；一些研究表明其表达可能与肾脏疾病有关。本课题的实验研究主要探讨乙酰肝素酶与特发性膜性肾病的尿蛋白之间的相关性,为今后进一步探讨中药减轻特发膜性肾病尿蛋白的作用机制奠定基础。
研究一：益气活血利水法治疗特发性膜性肾病的临床研究
目的：以中医气血水理论为指导,观察益气活血利水法治疗特发性膜性肾病的临床疗效。
方法：本研究采用随机、开放、对照的临床试验方法,将符合病例纳入标准的60例患者按就诊时间顺序随机分组为试验组(基础治疗+益气活血利水方药)和对照组[基础治疗+血管紧张素转化酶抑制剂(ACEI)],比较两组患者治疗前后以及两组间的中医证候疗效、疾病综合疗效、尿蛋白及其它相关理化指标的变化,初步评价益气活血利水法治疗特发膜性肾病的临床疗效。以SPSS17.0建立数据库并进行统计学分析,认为P值≤0.05表示有统计学意义。
结果：
1.整体疗效的分析：在对60例入组病例进行分析后得出①中医证候疗效评价：试验组总有效率88.6%,对照组总有效率88%；②西医综合疗效评价：试验组总有效率85.7%,对照组总有效率80%；③主要理化指标比较：在治疗前后的组内比较上,试验组和对照组患者治疗前后的Scr、BUN、ALB、24小时尿蛋白定量以及eGFR的指标变化均具有显著的统计学差异(P<0.05)；两组各项指标在治疗前以及治疗后的组间比较上,差异均不具有统计学意义(P>0.05)。
2.24小时尿蛋白定量的分层分析
24小时尿蛋白定量小于3.5g患者组：①中医证候疗效评价：试验组总有效率88.5%,对照组总有效率91.7%；②西医综合疗效评价：试验组总有效率80.7%,对照组总有效率83.3%；③主要理化指标比较：在治疗前后的组内比较上,试验组和对照组患者治疗前后的Scr、BUN、ALB及eGFR的指标变化均具有显著的统计学差异(P<0.05)；两组各项指标在治疗前以及治疗后的组间比较上,差异均不具有统计学意义(P>0.05)。
24小时尿蛋白定量大于3.5g患者组：①中医证候疗效评价：试验组总有效率88.9%,对照组总有效率84.6%；②西医综合疗效评价：试验组总有效率100%,对照组总有效率76.9%。③主要理化指标比较：在治疗前后的组内比较上,试验组和对照组患者治疗前后的Scr、ALB、eGFR及24小时尿蛋白定量的指标变化均具有显著的统计学差异(P<0.05)；两组各项指标在治疗前以及治疗后的组间比较上,差异均不具有统计学意义(P>0.05)。
3.影响疗效的相关因素的分析：疗前的肾功能指标(Scr、BUN),24小时尿蛋白定量,ALB, APTT以及eGFR与疗效间存在显著的相关性(P<0.05)；疗程对疗效的影响差异具有显著的统计学意义(P<0.05),治疗4个月及更长疗程时,患者疗效较明显；而性别、年龄及病理分期等对疗效的影响差异无统计学意义(P>0.05)。
结论：
1.从中医病机理论分析,特发性膜性肾病的中医病机责之于气血水三者的失调,气虚、血瘀、水停可能是特发性膜性肾病的核心病机。
2.益气活血利水法具有较好的缓解特发性膜性肾病的中医症状、减轻尿蛋白的作用,其疗效与血管紧张素转换酶抑制剂相当。
3.理化指标与疗效的相关性分析结果提示：疗前的肾功能指标(Scr、BUN),24小时尿蛋白定量,ALB, APTT以及eGFR等指标对治疗效果均可产生一定的影响；疗程与疗效显著相关,长疗程时患者疗效较明显；而性别、年龄及病理分期等对疗效无明显影响。
研究二：乙酰肝素酶与特发性膜性肾病患者尿蛋白相关性的实验研究
目的：通过对特发性膜性肾病患者及健康人群的外周血中乙酰肝素酶含量的检测,并将其与24小时尿蛋白定量进行比较分析,初步探索乙酰肝素酶与尿蛋白之间的相互关系,为今后进一步探讨中药减轻特发膜性肾病尿蛋白的作用机制奠定基础。
方法：本研究中共采集血样48例,其中特发性膜性肾病患者33例,根据患者的24小时尿蛋白定量的含量将其分为缓解组(24小时尿蛋白定量小于1.5g/24h)17例和未缓解组(24小时尿蛋白定量≥1.5g/24h)16例,并采集健康人群(24小时尿蛋白定量均小于200mg/24h)15例血样,用人乙酰肝素酶(HPA)酶联免疫分析(ELISA)试剂盒测定样本的乙酰肝素酶含量,并与入组病例的24小时尿蛋白定量进行比较,以SPSS17.0建立数据库并进行统计学分析,认为P值≤0.05表示有统计学意义。
结果：对研究病例的分析表明：①缓解组、未缓解组和健康人群在24小时尿蛋白定量和乙酰肝素酶含量的组间比较上差异有统计学意义(P<0.05)；且乙酰肝素酶的含量随24小时尿蛋白定量的不同而表现出显著差异,24小时尿蛋白定量较高的未缓解组,乙酰肝素酶的含量也较高。②经对入组数据的Pearson相关性分析得出,乙酰肝素酶含量与24小时尿蛋白定量之间存在着显著的线性相关。③经SPSS17.0统计软件对数据进行分析后,模拟出乙酰肝素酶含量与24小时尿蛋白定量直线回归的方程式：Y=88.561+6.357X。
结论：本研究结果显示,在特发性膜性肾病患者与健康人群对比的外周血乙酰肝素酶含量和24小时尿蛋白定量的相关性分析中,发现外周血乙酰肝素酶含量与24小时尿蛋白定量存在显著的线性相关。
Idiopathic membranous nephropathy (IMN) is an important pathological ty pe of glomerular disease, along with the popularization and application of the technology, the disease diagnosis rates were increased year by year. There is also a widespread concern about the IMN's treatment. Western medicine treatment for the disease has certain experience, but safety and effectiveness of the use of immunosuppressive agents are still debatable. Mentors in the in-depth study of traditional Chinese medical theory, combi ned with clinical experience, argued that this disease mainly lies in the dis orders of Qi Xue and Shui, due to Qi deficiency, blood stasis and water s tagnation, he founded the Yiqi Huoxue Lishui method to treat the disease of idiopathic membranous nephropathy. The clinical study mainly discusse d the characteristics and advantages of Yiqi Huoxue Lishui methods in tre ating IMN.
Heparanase is a new glucose nucleosides enzyme which received extensi ve attention in these years, it has many biological functions; some studies show that its expression may be associated with renal disease. In this ex perimental study, we paid attention to the correlation of the heparanase and the urinary protein in the idiopathic membranous nephropathy patient s, to lay the foundation for the further study of the herbal curative effect f or relief the urinary protein in the idiopathic membranous nephropathy pati ents.
Part1:The effect of Yiqi Huoxue Lishui therapy for treating the dise ase of idiopathic membranous nephropathy
Objective:As the guide of QiXueShui theories of TCM, we observed the effects of Yiqi Huoxue Lishui therapy for treating IMN.
Methods:This study used a randomized, open, controlled clinical trials,60patients that conformed to the case inclusion criteria were randomly divi ded into experimental group (basic therapy+Yiqi Huoxue Lishui herbs) a nd control group (basic therapy+ACEI) according to the time sequence. We compared with two groups patients before and after treatment as wel l as among two groups of TCM efficacy, disease comprehensive curative effect, urinary protein and other related physical and biochemical index ch ange.Preliminary evaluation the effects of Yiqi Huoxue Lishui therapy for tr eating IMN. We used SPSS17.0to establish database and analyzed statis tically, that P value<0.05indicated the statistical significance.
Results:
1. Total efficacy analysis:The results of the60cases indicated:①TCM ef ficacy evaluation:the total effective rate of the experimental group was88.6%, the total effective rate of the control group was88%;②The western medicine comprehensive effectiveness evaluation:the total effective rate of the experimental group was85.7%, the total effective rate of the control group was80%;③The main physicochemical index:In the comparison wit hin groups, two groups of patients before and after the treatment, Scr, BU N, ALB,24hUpro and eGFR index changes had statistical significance(P <0.05); In the comparison between groups, two groups of patients befor e and after the treatment, all of the index changes had no statistical signif icance(P>0.05).
2. The further analysis for the different groups according to the24hUpro. The group of the patients that24hUpro was less than3.5g:①TCM efficac y evaluation:the total effective rate of the experimental group was88.5%, the total effective rate of the control group was91.7%;②The western m edicine comprehensive effectiveness evaluation:the total effective rate of t he experimental group was80.7%, the total effective rate of the control gr oup was83.3%;③The main physicochemical index:In the comparison wit hin groups, two groups of patients before and after the treatment, Scr, BU N, ALB and eGFR index changes had statistical significance (P<0.05); I n the comparison between groups, two groups of patients before and after the treatment, all of the index changes had no statistical significance(P>0.05).
The group of the patients that24hUpro was more than3.5g:①TCM effica cy evaluation:the total effective rate of the experimental group was88.9%, the total effective rate of the control group was84.6%;②The western me dicine comprehensive effectiveness evaluation:the total effective rate of th e experimental group was100%, the total effective rate of the control gro up was76.9%;③The main physicochemical index:In the comparison with in groups, two groups of patients before and after the treatment, Scr, ALB, 24hUpro and eGFR index changes had statistical significance (P<0.05); In the comparison between groups, two groups of patients before and a fter the treatment, all of the index changes had no statistical significance(P>0.05).
3. Analysis for the related factors that influenced the curative effect:the in fluences differences of the renal function indexes (Scr, BUN),24hUpro,a lbumin, APTT and eGFR index for the effects had statistical significance (P<0.05); the influences differences of the course of treatment with the cl inical effects had statistical significance(P<0.05), as the treatment for4months and longer course, the curative effcts were more obvious; the inf luences differences of gender, age and pathologic stage for curative effect s did not have statistical significance (P>0.05).
Conclusion:
1. From the TCM theory analysis, TCM pathogenesis of idiopathic membr anous nephropathy is the disorders of Qi, blood and water, Qi deficiency with blood stasis and water stagnation may be the main type of the patho genesis.
2. The Yiqi Huoxue Lishui therapy can relief the TCM symptoms, reduceth e urinary protein effectively for the patients of IMN, the clinical effects of Yiqi Huoxue Lishui therapy are almost as same as the functions of ACE I.
3. The related factors, such as the renal function indexes (Scr, BUN),24hUpro, albumin, APTT and eGFR can produce certain influence on the clinical effect. The treatment course has certain influence on the curative effect, as the course is longer, the effect is more obvious. However, gen der, age and pathologic stage do not have certain influence on the clinical effect.
Part2:The experimental research for the relationship between the h eparanase and the urinary protein of the idiopathic membranous nep hropathy patients
Objective:Detect and analyze the quantity of HPA in the blood of IMN p atience and healthy persons, found the relationships between the urinary protein and the heparanase, to lay the foundation for the further study of t he mechanism of herbal function for relieving the urinary protein of the pa tients of IMN.
Methods:The study collected48patients, including33patients of idiopat hic membranous nephropathy,17patients were divided into clinical remissi on group (24hUpro was less than1.5g/24h) according to the24hUpro, also,16cases were divided into not mission group (24hUpro was more th an or equal to1.5g/24h). We also detected the HPA of15healthy per sons (24hUpro was less than200mg/24h).We used the human hepara nase (HPA) enzyme immunoassay (ELISA) kit for the determination of sample of heparanase level, and compared with the24hUpro of the cases. We used SPSS17.0to set up database for statistical analysis, The P val ue<0.05indicated a statistical significance.
Results:The case study analysis showed that:①In the comparison betw een groups, the difference of the HPA quantity and the24hUpro in the re mission group, not remission group and healthy persons had statistical sig nificance (P<0.05). The difference through the HPA quantity with the24h Upro showed significant differences, in the not remission group, as the hig her level of24hUpro, the expression of heparanase level was higher than the remission one.②The group of data by Pearson correlation analysis s howed that, heparanase quantity and24hUpro had significant linear correl ation.③The SPSS17.0statistical software for data analysis simulated sim ulation chart of the linear regression equation of the heparanase quantity and24hUpro:Y=88.561+6.357X.
Conclusion:This study indicates:In the analysis of the relationship betwe en the HPA quantity in the peripheral blood and the24hUpro in idiopathic membranous nephropathy patients, we find that the HPA quantity and the24hUpro have a significant linear correlation.
引文
[1]Li LS, Liu ZH. Epidemiologic data of renal disease from a single u nit in China analysis based on 13519 renal biopsy[J]. Kidney Int,200 4,66(3):920-923.
[2]余学清,杨琼琼.特发性膜性肾病的治疗[J].中国实用内科杂志,2003,23(5)：261-263.
[3]Nachman PH, Jennette JC, Falk RJ. Primary glomerular disease [J]. I m BrennerBM, ed The Kidney.2008,987-1066.
[4]崔应珉,禄保平,海霞.气血理论临证指南[M].郑州：郑州大学出版社,2002.11：177-287.
[5]王丽华,严玉澄等.蛋白尿发生机制的研究进展[J].上海：上海医学,2010.33(5)：491.
[6]郑美玲,樊均明.肾性蛋白尿发生发展机制进展[J].中国误诊学杂志,2009.9(20)：4803.
[7]万毅刚,顾刘宝等.蛋白尿的分子机制[J].国外医学泌尿系统分册,2004.24(3)：422.
[8]李平.时振声教授治疗蛋白尿经验[J].中国中西医结合肾病杂志,2005.6(8)：438.
[9]陈明.刘渡舟辨治慢性肾小球肾炎主要症状的经验[J].北京中医杂志,2003.22(2)：11.
[10]杨彦,魏明刚等.叶传蕙教授诊治肾性蛋白尿经验[J].四川中医,2001.19(5)：4.
[11]卞华,吕芹.李学铭教授治疗肾性蛋白尿的经验[J].国医论坛,2003.18(6)：11-12.
[12]王海燕.肾脏病学(第3版)[M].北京：人民卫生出版社,2008：1829.
[13]尉冬英,张光芬,张川波.小剂量激素对原发性慢性肾小球肾炎中等量蛋白尿治疗的观察[J].四川医学,1999.2 0(3)：245-246.
[14]韩述岭,于立新.肾移植术后蛋白尿的临床治疗[J].广东医学,2006,27(10)：1515-1516.
[15]王海燕.肾脏病临床概览[M].北京：北京大学医学出版社2010：614.
[16]黎磊石,关天俊,刘志红等.4298例成年人肾小球疾病病理类型及流行病学特点[J].肾脏病与透析肾移植杂志,1997,6(2)：103.
[17]姚小丹.原发性膜性肾病治疗中的争议[J].肾脏病与透析肾移植杂志,1997, 6(2)：194.
[18]Salant DJ, Belok S, Madaio MP, et al. A new role for complement i n experimental membranous nephropathy in rats[J]. J Clin Invest,1980, 66:1339-1350.
[19]Brenchley PE, Coupes B, Short CD, et al. Urinary C3dg and C5b-9 i ndicate active immune disease in human membranous nephropathy[J]. Kid ney Int,1993,41:933-937.
[20]Coupes BM, Kon SP, Brenchley PE, et al. The temporal relationship between urinary C5b-9 and C3dg and clinical parameters in human memb ranous nephropathy [J]. Nephrol Dial Transplant,1993,8:397-401.
[21]Schulze M, Baker PJ, Perkinson DT, et al. Increased urinary excre tion of C5b-9 distinguishes passive Heymann nephritis in the rat[J]. Kidney Int,1989,35:60-68.
[22]Couser WG, Steinmuller DR, Stilmant NM, et al. Experimental glome rulonephritis in the isolated perfused rat kidney[J]. J Clin Invest, 1978,62:1275-1287.
[23]VanDamme BJC, Fleuren GJ, Bakker WW, et al. Experimental glomerul onephritis in the rat induced by antibodies directed against tubular antigens V. Fixed glomerular antigens in the pathogenesis of heterol ogous immune complex glomerulonephritis[J]. Lab Invest.1978,38:502-510.
[24]Couser WG, Salant DJ. In situ immune complex formation and glomer ular injury[J]. Kidney Int,1980,17:1-13.
[25]Debiec H, Guigonis V, Ronco PM, et al. Antenatal membranous glome rulonephritis due to anti-neutral endopeptidase antibodies [J]. N Engl JMed,2002,346:2053-2060.
[26]Debiec H, Nauta J, Ronco P, et al. Role of truncatingmutations in MME gene in fetomaternal alloimmunisation and antenatal glomeru-lopa thies[J]. Lancet,2004,364(9441):1252-1259.
[27]McMillan JI, Riordan JW, Couser WG, et al. Characterization of a glomerular epithelial cell metalloproteinase as matrix metalloprotein ase-9 with enhanced expression in amodel ofmembranous nephropathy[J]. J Clin Invest,1996,97:1094-1101.
[28]ChevrierD, Giral M, Braud V, et al. Membranous Nephropathy and a TAP1 Gene Polymorphism[J]. N Engl JMed,1994,331(2):133-134.
[29]Oliveira DB. The immunopathogenesis of membranous nephropathy[J]. Minerva Med,2002,93(5):323-328.
[30]解放军肾脏病研究所.特发性膜性肾病的诊断及治疗规范[J].肾脏病与透析肾移植杂志,2004,13(6)：558-559.
[31]Ehrenreich T and Churg J. Pathology of membranous nephropathy[J]. Pathology annual,1968,3:145-154.
[32]Schieppati A, Perna A, Zamora J, et al. Immunosuppressive treatme nt for idiopathic membranous nephropathy in adults with nephrotic syn drome [J].Cochrane Database Syst Rev,2004,18 (4):CD004293.
[33]刘刚,王海燕.特发性膜性肾病的特异性治疗[J].中华肾脏病杂志,2002,18(6),450-451.
[34]Cattran DC. Management of membranous nephropathy:when and what f or treatment[J]. J Am Soc Nephrol,2005,16 (5):1188-1194.
[35]Goumenos DS, Katopodis KP, Passadakis P, et al.Corticosteroids an d ciclosporin A in idiopathic membranous nephropathy:higher remissio n rates of nephrotic syndrome and less adverse reactions than after t raditional treatment with cytotoxic drugs [J]. Am J Nephrol,2007,27 (3):226-231.
[36]Fritsche L, Budde K, Farber L, et al. Treatment of membranous glom erulopathy with cyclosporine A:How much patience is required? [J]. N ephrol Dial Transplant,1999,14,1036-1037.
[37]Cattran DC, Alexopoulos E, Heering P, et al.Cyclosporin in idiopa thic glomerular disease associated with the nephrotic syndrome:Works hop recommendations[J]. Kidney Int,2007,72 (12):1429-1447.
[38]Michael J, Choi, Joseph A, et al. Mycophenolate mofetil treatment foprimary glomerular diseases[J]. Kidney Int,2002,61,1098-1114.
[39]Branten AJ, du Buf-Vereijken PW, Vervloet M, et al. Mycophenolate Mofetil in idiopathic membranous nephropathy:A clinical trial with c omparison to a historic control group treated with cyclophosphamide [J]. Am J Kidney Dis,2007,50(2):248-256.
[40]Miller G, Zimmerman R, Radhakrishnan J, et al. Use of mycophenola temofetil in resistant membranous nephropathy[J]. Am J Kidney Dis,20 00,36,250-256.
[41]杜娟.吗替麦考酚酯联合泼尼松治疗特发性膜性肾病的临床观察.防治慢性肾脏病的危险因素[J].中华医学会肾脏病学分会2007年学术年会论文集,2007.361.
[42]陈强,刘志红,胡伟新等.他克莫司联合激素治疗V型狼疮性肾炎的疗效[J].肾脏病与透析肾移植杂志,2004；13(2)：1.
[43]Praga M, BarrioV, Juarez GF, et al.Tacroli musmono therapy in mem branous nephropathy:A randomized controlled trial [J]. Kidney Int,20 07; 71(9):924-930.
[44]Roberto Pisoni, Piero Ruggenenti, Fabio Sangalli, et al. Effect o f high dose ramipril with or without indomethacin on glomerular selec tivity[J]. Kidney Int,2002,62(3),1523-1755.
[45]黎磊石,姚小丹.特发性膜性肾病的治疗[J].肾脏病与透析肾移植杂志,2002,11,250-251.
[46]Carla Zoja, Daniela, Corna Daniela Rottoli, et al. Effect of comb ining ACE inhibitor and statin in severe experimental nephropathy. Kid ney Int,2002,61 (5),1523-1755.
[47]刘玉宁.中西医结合治疗特发性膜性肾病[J].浙江中西医结合杂志,2006,(16)：1.
[48]刘宏伟,时振声.30例原发性膜性肾病与辨证分型的关系[J].浙江中医杂志,1991,(10)：437.
[49]刘宏伟.膜性肾病的中医证治探讨[J].辽宁中医杂志,1992,(4)：5.
[50]唐利群,陈以平.膜性肾炎的治疗进展[J].山西中医,1993,9(3)：49.
[51]唐利群.益气活血系列方治疗膜性肾炎的临床观察和实验研究[J].上海中医药杂志,1998,(10)：4.
[52]聂跃华,叶任高.中西医结合治疗原发性膜性肾炎肾病综合征的临床观察[J].中国中西医结合肾脏病杂志,2002,3(1)：18.
[53]刘宏伟.中医辨证治疗膜性肾病的临床研究[J].辽宁中医,1998,25(7)：306-307.
[54]高志卿,邓跃毅,王琳.陈以平教授分期论治膜性肾病[J].上海中医药杂志,2004,38(2)：35-36.
[55]Dong J, Kukula AK, Toyoshima M, et al.Genomic organization and chr omosome localization of the newly identified human heparanase gene[J]. Gene,2000,253:171-178.
[56]Vlodavsky I, Friedmann Y, Elkin M, et al. Mammalian heparanase:g ene cloning, expression and function in tumor progression and metasta sis [J]. Nat Med,1999,5:793-802.
[57]FairbanksMB, MildnerAM, Leone JW, et al. Processing of the human heparanase precursor and evidence that the active enzyme is a heterod imer[J]. J Biol Chem,1999,274:29587-29590.
[58]Sajnani-Perez G,Chiltion JK, A ricescu AR, et al. Lsof orm-specifi c binding of the tyrosine phosophataseptp to a ligand in developing m uscle[J]. Molcell NEURO SCI,2003,22(1):37-48.
[59]Levidiotis V, Kanellis J, Ierino FL, et al. Increased expression of heparanase in puromycina minonucleoside nephrosis[J]. Kidney Int,2 001,60(4):1287-1296.
[60]Ilan N, Elkin M, Vlodavsky I. Regulation, function and clinical s ignificance of heparanase in cancer metastasis and angiogenesis[J].In t J Bio-chem Cell Biol,2006,38(6):2018-2039.
[61]Jiang P, Kumar A, Parrillo JE, et al.Cloning and characterization of the human heparanase-1(HPR1)gene promoter:role of GA-binding pro tein and Spl in regulating HPR1 basal promoter activity [J].J Biol Che m,2002,277 (11):8989-8998.
[62]Lu WC, Liu YN, Kang BB, et al. Trans-activation of heparanase prom oter by ETS t ranscription factors[J]. Oncogene,2003,22(6):919-923.
[63]Gilat D, Hershkoviz R, Golakorn I, et al. Moleuclar behavior adap ts to context:heparanase functions as an ext racelular matrix-degrad ing enzyme or as a T cell adhesion molecule, depending on the local p H[J]. J Exp Med,1995,181 (5):1929-1934.
[64]Van den Hoven MJ, Rops AL, Vlodavsky I, et al. Heparanase in glom erular diseases[J]. Kidney Int,2007,72(5):543-548.
[65]Pikas DS, Li JP, Vlodavsky I,et al. Substrate specificity of hepa ranases from human hepatoma and platelets[J]. JB iolChem,1998, (273):18 770-18777.
[66]Dempsey LA, Plummer TB, Coombes SL, et al. Platelet heparanase in vascular responses to xeno transplantation[J]. Transplant Proc,2000,3 2(5):972.
[67]Irony-Tur-Sinai M, Vlodavsky I, Ben Sasson SA, et al. A synthetic heparin-mimicking polyanionic compound inhibits central nervous syst em inflammation[J]. J Neurol Sci,2003,206 (1):49-57.
[68]Vlodavsky I, Friedmann Y, Elkin M, et al. Mammalian heparanase:g enecloning, expression and function in tumor progression and metastas is [J]. Nat Med,1999,5:793-802.
[69]Vlodavsky I, Miao HQ, Medalion B, et al. Involvement of heparan s ulfate and related molecules in sequestration and growth promoting ac tivity of fibroblast growth factor [J]. Cancer Metastasis Rev,1996, (15):177-186.
[70]Gingis-Velitski S, Zet ser A, Flugelman MY, et al. Heparanase ind uces endothelial cell migration Via protein kinase B/Akt Activation [J].J Biol Chem,2004,279 (22):23536-23541.
[71]Goldshmidt 0, Zcharia E, Cohen M, et al. Heparanase mediates cell adhesion independent of its enzymatic activity [J]. FA SEB J,2003,17 (9):1015-1025.
[72]Kuniyasu H, Chihara Y, Kubozoe T, et al. Coexpression of CD44v3 a nd heparanase is correlated with metastasis of human colon cancer [J]. Int J Mol Med,2002,10(3):333-337.
[73]Nobuhisa T, Naomoto Y, Okawa T, et al. Trans location of heparanas e into nucleus result s in cell differentiation[J]. Cancer Sci,2007,9 8(4):535-540.
[74]Koliopanos A, Friess H, Kleeff J, et al. Heparanase expression in pr imary and metastatic pancreatic cancer[J]. Cancer Res,2001,61 (12):4655-4659.
[75]Staquicini FI, Moreira CR, Nascimento FD, et al. Enzymeand integr in expression by high and low metastatic melanoma cell lines[J].Melan oma Res,2003,13(1):11-18.
[76]Zcharia E, Metzger S, Chajek-Shaul T, et al. Molecular properties and involvement of heparanase in cancer progression and mammary gland morphogenesis [J].J Mammary Gland Biol Neoplasia,2001,6 (3):311-322.
[77]Friedmann Y, Vlodavsky I, Aingom H, et al. Expression of heparana se in normal, dysplastic and neoplastic human colon mucosa and stro ma[J].Am J Pathol,2000,157:1167-1175.
[78]Vlodavsky I, Friedmann Y. Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis[J]. J Clin Invest, 2001,108(3):341-347.
[79]Dempsey LA, Plummer TB, Coombes SL, et al. Heparanase expression in invasive trophyblasts and acute vascular damage [J].Glycobiology,20 00,10 (5):467-475.
[80]Rohde LH, Janatpore MJ, Me Master MT, et al. Complementary express ion of HIP,a cell-surface heparan sulfate binding protein, and perlec an at the human fetal-maternal interface [J]. Biol Reprod,1998,58(4):1 075-83.
[81]Goshen R, Hochberg AA, Korner G, et al. Purification and character ization of placental heparanase and its expression by cultured cytotr ophoblasts[J]. Mol Hum Reprod,1996,2 (9):679-84.
[82]BiOrnson A, Moses J, Ingemansson A, et al. Primary human glomerul ar endothelial cells produce proteoglycans, and puromyein affects the ir posttranslational modification [J]. Am J PhysiolRenal Physiol,2005, 288:F748-F756.
[83]Morita H, Yoshimurs A, Inui K, et al. Heparan sulfate of perlecan is involved in glomerular filtration[J]. J Am Soc Nephrol,2005,16:1 703-1710.
[84]Singh A, Satchell Sc, Neal CR, et al. Glomerular endo the lial gl ycocalyx constitute sabarrier to protein permeability[J]. J AmSoc Ne phrol,2007,18:2885-2893.
[85]KramerA, VanDen Hoven M, Rops A, et al. J Am Soc Nephml,2006,17: 2513-2520.
[86]Holt RC, webb NJ, Ralph S, et al. Kidney Int,2005,67(1):122-12 9.
[87]Levidiotis V, Freeman C, Tikellis C, et al. J Am Soc Nephrol,200 4,15(1):68-78.
[88]Levidiotis V, Freeman C, Punler M, et al. J Am Soc Nephml,2004,1 5(11):2882-2892.
[89]van den Hoven MJ, Rops AL, Bakker MA, et al. Increased expression of heparanase in oven diabetic nephropathy[J]. Kidney Int,2006,70:2 100-2108.
[90]Maxhimer JB, Somenek M, Rao G, et al. Heparanase-1 gene expressio n and regulation by high glucose in renal epithelial cells:a potenti al role in the pathogenesis of proteinuris in diabetic patients[J]. D iabetes,2005,54:2172-2178.
[91]Katz A, Van-Dijk DJ, Aingom H, et al. Isr Med Assoc J,2002,4:9 96-1002.
[92]Ferro V, Dredge K, Liu L, et al. PI-88 and novel heparan sulfatem imetics inhibit angiogenesis[J]. Semin Thromb Hemost,2007,33(5):557-568.
[93]Rossing P, Parving HH, de Zeeuw D. Renoprotection by blocking the RAAS in diabetic nephropathy-fact or fiction[J]. Nephrol Dial Trans plant,2006,21(9):2354-2357.
[94]孙广仁.中医基础理论[M].北京：中国中医药出版社,2002.8：128-153.
[95]聂莉芳.蛋白尿诊断与中医治疗[M].北京：人民军医出版社,2011.6：51,55.
[96]刘汉丹,瞿佐发.黄芪的药理作用研究进展[J].现代中西医结合杂志,2002,11(18)：1862.
[97]耿长山.黄芪多糖对去T细胞小鼠促进抗体产生机理探讨[J].中国药理通讯,1985,2(2)：4.
[98]索贞,任敏,周好田.黄芪的化学成分及现代药理[J].现代医院,2005,5(9)：85.
[99]李勤,刘宏.黄芪的药理作用及临床应用[J].医学综述,2004,10(10)：634.
[100]李明,田永云,祝捷.黄芪的临床药理研究简介[J].中国乡村医药杂志,2004,3(11)：51.
[101]郭宪清,张丽香等.黄芪皂苷类组分的现代药理研究进展[J].河南中医,2001,2(15)：66.
[102]李丽英,王海燕,朱世乐等.黄芪当归对肾病综合征鼠肝白蛋白的表达作用[J].中华医学杂志,1995,75(5)：276-279.
[103]陈少刚,李长潮,庄学煊等.当归注射液对家兔心肌缺血再灌注损伤的保护作用[J].中国中西医结合杂志,1995,15(8)：486-488.
[104]王亚平,黄晓芹,祝彼得等.当归多糖诱导L—细胞产生造血生长因子的实验研究[J].解剖学报,1996,27(1)：69-74.
[105]宋之娟,梁念慈.当归对猪血小板膜磷脂酰肌醇磷酸化的抑制作用[J].中草药,1992,23(3)：138-140.
[106]Deng Jian Yun,Guo Xue Cong.Study on the Protection of Astragulus, SCEs and Micronelei Induced by Cyclophosphamide in Mice [J]. Bejing Shi fan Daxue Xudbao, Ziran Kexueban,1992,28(2):221-226.
[107]郑凌,段福牛,张珍祥.当归对肺血管扩张作用的实验和临床研究[J].同济医科大学学报,1991,20(6)：398-403.
[108]Chen Q, Huang JD, Yin HJ, et al. The applications of affinity bi osensors:IAsys biosensor and quartz crystal microbalance to the stud y on interaction between Paeoniae radix 801 and endothelin-1[J]. Sens ActuatorsB,2006,116-122.
[109]Zheng YQ, Wei W,Zhu L,et al. Effects and mechanismsof Paeonilorin, a bioactive glucoside from paeony root, on adjuvant arthritis in rats [J]. Inf lamm Res,2007,56:182-188.
[110]Zhu L, Wei W, Zheng YQ, et al.Effects and mechanisms of total gl ucosides of paeony on joint damage in rat collagen-induced arthritis [J]. Inf lamm Res,2005,54:211-220.
[111]Lee B, Shin YW, Bae EA, et al.Antiallergic effect of the root of Paeonia lactiflora and its constituents paeoniflorin and paeonol[J]. Arch Pharm Res,2008,31(4):445-450.
[112]Dong X P, Xu TL. Radix paeoniae rubra suppression of sodium curren t in acutely dissociated rat hippocampal CA1 neurons[J]. Brain Res,200 2,940 (1-2):1-9.
[113]梁雯若等.白芍的抗炎免疫药理作用研究[J].新中医,1989；21(3)：51.
[114]王志坚等.白芍总甙治疗类风湿关节炎的临床药理研究[J].中国药理学通报,1994；10(2)：38.
[115]李金才.白芍食疗的回顾与展望[J].中药通报,1987；12(8)：54.
[116]龙子江等.白芍活血化瘀作用的现代药理实验研究[J].安徽中医学院学报,1984;(2)：42.
[117]丁俊杰.再谈白芍利小便[J].辽宁中医杂志,1990；14(3)：40.
[118]张晓平,陈建明.山桃仁水煎提取物对肝纤维化小鼠血清Ⅰ、Ⅱ型前胶原的降解作用[J].福建中医药,2002,33(4)：36-37.
[119]徐列明,刘平.桃仁提取物抗实验性肝纤维化的作用观察——免疫组化和胶原代谢的研究[J].中药药理与临床,1993,(5)：14-16.
[120]徐列明,薛惠明.实验性肝纤维化时贮脂细胞的变化及桃仁提取物对其影响[J].中西医结合肝病杂志,1993,(2)：16-18.
[121]汪宁,刘青云.桃仁不同提取物抗血栓作用的实验研究[J].中药材,2002,(6)：414-415.
[122]耿涛,谢梅林,彭少平.桃仁提取物抗大鼠心肌缺血作用的研究[J].苏州大 学学报：医学版,2005,25(2)：238-240.
[123]高巍,赵铁华.穿山龙总皂苷对小鼠免疫功能的影响[J].承德中医学院学报,2001,18(1)：9-10.
[124]李永茂,何宝俊,刘振庸等.穿山龙水溶性有效成分的研究[J].中国医科大学学报,1979(1)：141.
[125]沈阳医学院慢性气管炎协作组.穿山龙药理实验及有效成分探讨[J].医学研究,1972,(1)：15.
[126]雷励.穿山龙注射液穴位注射治疗重症支气管哮喘临床观察[J].中国中医急症,2005,14(5)：419.
[127]唐丽香.福建穿山龙抗炎镇痛作用的实验研究[J].海峡学,2000,12(3).
[128]刘江涛,陈信义,王玉芝.穿山龙粗提物抗肿瘤体外验研究[J].中国中医药信息杂志,2004,11(3),1.
[129]钟添,钟富荣,李丛民等.川芎提取物的制备及其加料试验[J].烟草科技,22.4：9.
[130]李岩,孙思予,周卓.白术对小鼠胃排空及小肠推进功能影响的实验研究[J].辽宁医学杂志,1996,10(4)：186.
[131]周德文.术类的药理和药效[J].国外医药.植物药分册,1996,11(3)：120-122.
[132]金惠,赵英博,江维等.茯苓药理作用及临床应用研究进展[J].湖北中医杂志,2008,30(4)：59-60.
[133]高同银,崔同淑,孙国香.浅谈甘草解毒作用[J].河北中医,1994,16(3)：46.
[134]田庆来,官月平,张波等.甘草有效成分的药理作用研究进展[J].天然产物研究与开发,2006(18)：343-347.
[135]邓中甲.方剂学[M].北京：中国中医药出版社,2003.1：96-97.
[136]李庆业.临床常用方药应用鉴别.方剂分册[M].北京：人民卫生出版社,2003.6：235-237.
[137]贺庆华.补阳还五汤治疗肾病综合征52例[J].江苏中医,1999,2 0(10)：24.
[138]吴明,李庆珍,赵纪生.补阳还五汤治疗顽固性肾性蛋白尿[J].亚太传统医药,2008,4(3)：80.
[139]李秋芬.补阳还五汤为主治疗原发性膜性肾病32例[J].浙江中医杂志,2006,41(12)：709.
[140]何灵芝,李学铭.补阳还五汤治疗肾病举隅[J].广西中医药,2005,28(6)： 34.
[141]黄叶宁,詹谨.补阳还五汤联合盐酸贝那普利治疗早期糖尿病肾病30例[J].江西中医药,2011,42(9)：37-38.
[142]刘晓微.益肾补阳还五汤治疗肾病综合征32例[J].辽宁中医杂志,2006,33(3)：328.
[2]余学清,杨琼琼.特发性膜性肾病的治疗[J].中国实用内科杂志,2003,23(5)：261-263.
[3]Nachman PH, Jennette JC, Falk RJ. Primary glomerular disease [J]. I m BrennerBM, ed The Kidney.2008,987-1066.
[4]崔应珉,禄保平,海霞.气血理论临证指南[M].郑州：郑州大学出版社,2002.11：177-287.
[5]王丽华,严玉澄等.蛋白尿发生机制的研究进展[J].上海：上海医学,2010.33(5)：491.
[6]郑美玲,樊均明.肾性蛋白尿发生发展机制进展[J].中国误诊学杂志,2009.9(20)：4803.
[7]万毅刚,顾刘宝等.蛋白尿的分子机制[J].国外医学泌尿系统分册,2004.24(3)：422.
[8]李平.时振声教授治疗蛋白尿经验[J].中国中西医结合肾病杂志,2005.6(8)：438.
[9]陈明.刘渡舟辨治慢性肾小球肾炎主要症状的经验[J].北京中医杂志,2003.22(2)：11.
[10]杨彦,魏明刚等.叶传蕙教授诊治肾性蛋白尿经验[J].四川中医,2001.19(5)：4.
[11]卞华,吕芹.李学铭教授治疗肾性蛋白尿的经验[J].国医论坛,2003.18(6)：11-12.
[12]王海燕.肾脏病学(第3版)[M].北京：人民卫生出版社,2008：1829.
[13]尉冬英,张光芬,张川波.小剂量激素对原发性慢性肾小球肾炎中等量蛋白尿治疗的观察[J].四川医学,1999.2 0(3)：245-246.
[14]韩述岭,于立新.肾移植术后蛋白尿的临床治疗[J].广东医学,2006,27(10)：1515-1516.
[15]王海燕.肾脏病临床概览[M].北京：北京大学医学出版社2010：614.
[16]黎磊石,关天俊,刘志红等.4298例成年人肾小球疾病病理类型及流行病学特点[J].肾脏病与透析肾移植杂志,1997,6(2)：103.
[17]姚小丹.原发性膜性肾病治疗中的争议[J].肾脏病与透析肾移植杂志,1997, 6(2)：194.
[18]Salant DJ, Belok S, Madaio MP, et al. A new role for complement i n experimental membranous nephropathy in rats[J]. J Clin Invest,1980, 66:1339-1350.
[19]Brenchley PE, Coupes B, Short CD, et al. Urinary C3dg and C5b-9 i ndicate active immune disease in human membranous nephropathy[J]. Kid ney Int,1993,41:933-937.
[20]Coupes BM, Kon SP, Brenchley PE, et al. The temporal relationship between urinary C5b-9 and C3dg and clinical parameters in human memb ranous nephropathy [J]. Nephrol Dial Transplant,1993,8:397-401.
[21]Schulze M, Baker PJ, Perkinson DT, et al. Increased urinary excre tion of C5b-9 distinguishes passive Heymann nephritis in the rat[J]. Kidney Int,1989,35:60-68.
[22]Couser WG, Steinmuller DR, Stilmant NM, et al. Experimental glome rulonephritis in the isolated perfused rat kidney[J]. J Clin Invest, 1978,62:1275-1287.
[23]VanDamme BJC, Fleuren GJ, Bakker WW, et al. Experimental glomerul onephritis in the rat induced by antibodies directed against tubular antigens V. Fixed glomerular antigens in the pathogenesis of heterol ogous immune complex glomerulonephritis[J]. Lab Invest.1978,38:502-510.
[24]Couser WG, Salant DJ. In situ immune complex formation and glomer ular injury[J]. Kidney Int,1980,17:1-13.
[25]Debiec H, Guigonis V, Ronco PM, et al. Antenatal membranous glome rulonephritis due to anti-neutral endopeptidase antibodies [J]. N Engl JMed,2002,346:2053-2060.
[26]Debiec H, Nauta J, Ronco P, et al. Role of truncatingmutations in MME gene in fetomaternal alloimmunisation and antenatal glomeru-lopa thies[J]. Lancet,2004,364(9441):1252-1259.
[27]McMillan JI, Riordan JW, Couser WG, et al. Characterization of a glomerular epithelial cell metalloproteinase as matrix metalloprotein ase-9 with enhanced expression in amodel ofmembranous nephropathy[J]. J Clin Invest,1996,97:1094-1101.
[28]ChevrierD, Giral M, Braud V, et al. Membranous Nephropathy and a TAP1 Gene Polymorphism[J]. N Engl JMed,1994,331(2):133-134.
[29]Oliveira DB. The immunopathogenesis of membranous nephropathy[J]. Minerva Med,2002,93(5):323-328.
[30]解放军肾脏病研究所.特发性膜性肾病的诊断及治疗规范[J].肾脏病与透析肾移植杂志,2004,13(6)：558-559.
[31]Ehrenreich T and Churg J. Pathology of membranous nephropathy[J]. Pathology annual,1968,3:145-154.
[32]Schieppati A, Perna A, Zamora J, et al. Immunosuppressive treatme nt for idiopathic membranous nephropathy in adults with nephrotic syn drome [J].Cochrane Database Syst Rev,2004,18 (4):CD004293.
[33]刘刚,王海燕.特发性膜性肾病的特异性治疗[J].中华肾脏病杂志,2002,18(6),450-451.
[34]Cattran DC. Management of membranous nephropathy:when and what f or treatment[J]. J Am Soc Nephrol,2005,16 (5):1188-1194.
[35]Goumenos DS, Katopodis KP, Passadakis P, et al.Corticosteroids an d ciclosporin A in idiopathic membranous nephropathy:higher remissio n rates of nephrotic syndrome and less adverse reactions than after t raditional treatment with cytotoxic drugs [J]. Am J Nephrol,2007,27 (3):226-231.
[36]Fritsche L, Budde K, Farber L, et al. Treatment of membranous glom erulopathy with cyclosporine A:How much patience is required? [J]. N ephrol Dial Transplant,1999,14,1036-1037.
[37]Cattran DC, Alexopoulos E, Heering P, et al.Cyclosporin in idiopa thic glomerular disease associated with the nephrotic syndrome:Works hop recommendations[J]. Kidney Int,2007,72 (12):1429-1447.
[38]Michael J, Choi, Joseph A, et al. Mycophenolate mofetil treatment foprimary glomerular diseases[J]. Kidney Int,2002,61,1098-1114.
[39]Branten AJ, du Buf-Vereijken PW, Vervloet M, et al. Mycophenolate Mofetil in idiopathic membranous nephropathy:A clinical trial with c omparison to a historic control group treated with cyclophosphamide [J]. Am J Kidney Dis,2007,50(2):248-256.
[40]Miller G, Zimmerman R, Radhakrishnan J, et al. Use of mycophenola temofetil in resistant membranous nephropathy[J]. Am J Kidney Dis,20 00,36,250-256.
[41]杜娟.吗替麦考酚酯联合泼尼松治疗特发性膜性肾病的临床观察.防治慢性肾脏病的危险因素[J].中华医学会肾脏病学分会2007年学术年会论文集,2007.361.
[42]陈强,刘志红,胡伟新等.他克莫司联合激素治疗V型狼疮性肾炎的疗效[J].肾脏病与透析肾移植杂志,2004；13(2)：1.
[43]Praga M, BarrioV, Juarez GF, et al.Tacroli musmono therapy in mem branous nephropathy:A randomized controlled trial [J]. Kidney Int,20 07; 71(9):924-930.
[44]Roberto Pisoni, Piero Ruggenenti, Fabio Sangalli, et al. Effect o f high dose ramipril with or without indomethacin on glomerular selec tivity[J]. Kidney Int,2002,62(3),1523-1755.
[45]黎磊石,姚小丹.特发性膜性肾病的治疗[J].肾脏病与透析肾移植杂志,2002,11,250-251.
[46]Carla Zoja, Daniela, Corna Daniela Rottoli, et al. Effect of comb ining ACE inhibitor and statin in severe experimental nephropathy. Kid ney Int,2002,61 (5),1523-1755.
[47]刘玉宁.中西医结合治疗特发性膜性肾病[J].浙江中西医结合杂志,2006,(16)：1.
[48]刘宏伟,时振声.30例原发性膜性肾病与辨证分型的关系[J].浙江中医杂志,1991,(10)：437.
[49]刘宏伟.膜性肾病的中医证治探讨[J].辽宁中医杂志,1992,(4)：5.
[50]唐利群,陈以平.膜性肾炎的治疗进展[J].山西中医,1993,9(3)：49.
[51]唐利群.益气活血系列方治疗膜性肾炎的临床观察和实验研究[J].上海中医药杂志,1998,(10)：4.
[52]聂跃华,叶任高.中西医结合治疗原发性膜性肾炎肾病综合征的临床观察[J].中国中西医结合肾脏病杂志,2002,3(1)：18.
[53]刘宏伟.中医辨证治疗膜性肾病的临床研究[J].辽宁中医,1998,25(7)：306-307.
[54]高志卿,邓跃毅,王琳.陈以平教授分期论治膜性肾病[J].上海中医药杂志,2004,38(2)：35-36.
[55]Dong J, Kukula AK, Toyoshima M, et al.Genomic organization and chr omosome localization of the newly identified human heparanase gene[J]. Gene,2000,253:171-178.
[56]Vlodavsky I, Friedmann Y, Elkin M, et al. Mammalian heparanase:g ene cloning, expression and function in tumor progression and metasta sis [J]. Nat Med,1999,5:793-802.
[57]FairbanksMB, MildnerAM, Leone JW, et al. Processing of the human heparanase precursor and evidence that the active enzyme is a heterod imer[J]. J Biol Chem,1999,274:29587-29590.
[58]Sajnani-Perez G,Chiltion JK, A ricescu AR, et al. Lsof orm-specifi c binding of the tyrosine phosophataseptp to a ligand in developing m uscle[J]. Molcell NEURO SCI,2003,22(1):37-48.
[59]Levidiotis V, Kanellis J, Ierino FL, et al. Increased expression of heparanase in puromycina minonucleoside nephrosis[J]. Kidney Int,2 001,60(4):1287-1296.
[60]Ilan N, Elkin M, Vlodavsky I. Regulation, function and clinical s ignificance of heparanase in cancer metastasis and angiogenesis[J].In t J Bio-chem Cell Biol,2006,38(6):2018-2039.
[61]Jiang P, Kumar A, Parrillo JE, et al.Cloning and characterization of the human heparanase-1(HPR1)gene promoter:role of GA-binding pro tein and Spl in regulating HPR1 basal promoter activity [J].J Biol Che m,2002,277 (11):8989-8998.
[62]Lu WC, Liu YN, Kang BB, et al. Trans-activation of heparanase prom oter by ETS t ranscription factors[J]. Oncogene,2003,22(6):919-923.
[63]Gilat D, Hershkoviz R, Golakorn I, et al. Moleuclar behavior adap ts to context:heparanase functions as an ext racelular matrix-degrad ing enzyme or as a T cell adhesion molecule, depending on the local p H[J]. J Exp Med,1995,181 (5):1929-1934.
[64]Van den Hoven MJ, Rops AL, Vlodavsky I, et al. Heparanase in glom erular diseases[J]. Kidney Int,2007,72(5):543-548.
[65]Pikas DS, Li JP, Vlodavsky I,et al. Substrate specificity of hepa ranases from human hepatoma and platelets[J]. JB iolChem,1998, (273):18 770-18777.
[66]Dempsey LA, Plummer TB, Coombes SL, et al. Platelet heparanase in vascular responses to xeno transplantation[J]. Transplant Proc,2000,3 2(5):972.
[67]Irony-Tur-Sinai M, Vlodavsky I, Ben Sasson SA, et al. A synthetic heparin-mimicking polyanionic compound inhibits central nervous syst em inflammation[J]. J Neurol Sci,2003,206 (1):49-57.
[68]Vlodavsky I, Friedmann Y, Elkin M, et al. Mammalian heparanase:g enecloning, expression and function in tumor progression and metastas is [J]. Nat Med,1999,5:793-802.
[69]Vlodavsky I, Miao HQ, Medalion B, et al. Involvement of heparan s ulfate and related molecules in sequestration and growth promoting ac tivity of fibroblast growth factor [J]. Cancer Metastasis Rev,1996, (15):177-186.
[70]Gingis-Velitski S, Zet ser A, Flugelman MY, et al. Heparanase ind uces endothelial cell migration Via protein kinase B/Akt Activation [J].J Biol Chem,2004,279 (22):23536-23541.
[71]Goldshmidt 0, Zcharia E, Cohen M, et al. Heparanase mediates cell adhesion independent of its enzymatic activity [J]. FA SEB J,2003,17 (9):1015-1025.
[72]Kuniyasu H, Chihara Y, Kubozoe T, et al. Coexpression of CD44v3 a nd heparanase is correlated with metastasis of human colon cancer [J]. Int J Mol Med,2002,10(3):333-337.
[73]Nobuhisa T, Naomoto Y, Okawa T, et al. Trans location of heparanas e into nucleus result s in cell differentiation[J]. Cancer Sci,2007,9 8(4):535-540.
[74]Koliopanos A, Friess H, Kleeff J, et al. Heparanase expression in pr imary and metastatic pancreatic cancer[J]. Cancer Res,2001,61 (12):4655-4659.
[75]Staquicini FI, Moreira CR, Nascimento FD, et al. Enzymeand integr in expression by high and low metastatic melanoma cell lines[J].Melan oma Res,2003,13(1):11-18.
[76]Zcharia E, Metzger S, Chajek-Shaul T, et al. Molecular properties and involvement of heparanase in cancer progression and mammary gland morphogenesis [J].J Mammary Gland Biol Neoplasia,2001,6 (3):311-322.
[77]Friedmann Y, Vlodavsky I, Aingom H, et al. Expression of heparana se in normal, dysplastic and neoplastic human colon mucosa and stro ma[J].Am J Pathol,2000,157:1167-1175.
[78]Vlodavsky I, Friedmann Y. Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis[J]. J Clin Invest, 2001,108(3):341-347.
[79]Dempsey LA, Plummer TB, Coombes SL, et al. Heparanase expression in invasive trophyblasts and acute vascular damage [J].Glycobiology,20 00,10 (5):467-475.
[80]Rohde LH, Janatpore MJ, Me Master MT, et al. Complementary express ion of HIP,a cell-surface heparan sulfate binding protein, and perlec an at the human fetal-maternal interface [J]. Biol Reprod,1998,58(4):1 075-83.
[81]Goshen R, Hochberg AA, Korner G, et al. Purification and character ization of placental heparanase and its expression by cultured cytotr ophoblasts[J]. Mol Hum Reprod,1996,2 (9):679-84.
[82]BiOrnson A, Moses J, Ingemansson A, et al. Primary human glomerul ar endothelial cells produce proteoglycans, and puromyein affects the ir posttranslational modification [J]. Am J PhysiolRenal Physiol,2005, 288:F748-F756.
[83]Morita H, Yoshimurs A, Inui K, et al. Heparan sulfate of perlecan is involved in glomerular filtration[J]. J Am Soc Nephrol,2005,16:1 703-1710.
[84]Singh A, Satchell Sc, Neal CR, et al. Glomerular endo the lial gl ycocalyx constitute sabarrier to protein permeability[J]. J AmSoc Ne phrol,2007,18:2885-2893.
[85]KramerA, VanDen Hoven M, Rops A, et al. J Am Soc Nephml,2006,17: 2513-2520.
[86]Holt RC, webb NJ, Ralph S, et al. Kidney Int,2005,67(1):122-12 9.
[87]Levidiotis V, Freeman C, Tikellis C, et al. J Am Soc Nephrol,200 4,15(1):68-78.
[88]Levidiotis V, Freeman C, Punler M, et al. J Am Soc Nephml,2004,1 5(11):2882-2892.
[89]van den Hoven MJ, Rops AL, Bakker MA, et al. Increased expression of heparanase in oven diabetic nephropathy[J]. Kidney Int,2006,70:2 100-2108.
[90]Maxhimer JB, Somenek M, Rao G, et al. Heparanase-1 gene expressio n and regulation by high glucose in renal epithelial cells:a potenti al role in the pathogenesis of proteinuris in diabetic patients[J]. D iabetes,2005,54:2172-2178.
[91]Katz A, Van-Dijk DJ, Aingom H, et al. Isr Med Assoc J,2002,4:9 96-1002.
[92]Ferro V, Dredge K, Liu L, et al. PI-88 and novel heparan sulfatem imetics inhibit angiogenesis[J]. Semin Thromb Hemost,2007,33(5):557-568.
[93]Rossing P, Parving HH, de Zeeuw D. Renoprotection by blocking the RAAS in diabetic nephropathy-fact or fiction[J]. Nephrol Dial Trans plant,2006,21(9):2354-2357.
[94]孙广仁.中医基础理论[M].北京：中国中医药出版社,2002.8：128-153.
[95]聂莉芳.蛋白尿诊断与中医治疗[M].北京：人民军医出版社,2011.6：51,55.
[96]刘汉丹,瞿佐发.黄芪的药理作用研究进展[J].现代中西医结合杂志,2002,11(18)：1862.
[97]耿长山.黄芪多糖对去T细胞小鼠促进抗体产生机理探讨[J].中国药理通讯,1985,2(2)：4.
[98]索贞,任敏,周好田.黄芪的化学成分及现代药理[J].现代医院,2005,5(9)：85.
[99]李勤,刘宏.黄芪的药理作用及临床应用[J].医学综述,2004,10(10)：634.
[100]李明,田永云,祝捷.黄芪的临床药理研究简介[J].中国乡村医药杂志,2004,3(11)：51.
[101]郭宪清,张丽香等.黄芪皂苷类组分的现代药理研究进展[J].河南中医,2001,2(15)：66.
[102]李丽英,王海燕,朱世乐等.黄芪当归对肾病综合征鼠肝白蛋白的表达作用[J].中华医学杂志,1995,75(5)：276-279.
[103]陈少刚,李长潮,庄学煊等.当归注射液对家兔心肌缺血再灌注损伤的保护作用[J].中国中西医结合杂志,1995,15(8)：486-488.
[104]王亚平,黄晓芹,祝彼得等.当归多糖诱导L—细胞产生造血生长因子的实验研究[J].解剖学报,1996,27(1)：69-74.
[105]宋之娟,梁念慈.当归对猪血小板膜磷脂酰肌醇磷酸化的抑制作用[J].中草药,1992,23(3)：138-140.
[106]Deng Jian Yun,Guo Xue Cong.Study on the Protection of Astragulus, SCEs and Micronelei Induced by Cyclophosphamide in Mice [J]. Bejing Shi fan Daxue Xudbao, Ziran Kexueban,1992,28(2):221-226.
[107]郑凌,段福牛,张珍祥.当归对肺血管扩张作用的实验和临床研究[J].同济医科大学学报,1991,20(6)：398-403.
[108]Chen Q, Huang JD, Yin HJ, et al. The applications of affinity bi osensors:IAsys biosensor and quartz crystal microbalance to the stud y on interaction between Paeoniae radix 801 and endothelin-1[J]. Sens ActuatorsB,2006,116-122.
[109]Zheng YQ, Wei W,Zhu L,et al. Effects and mechanismsof Paeonilorin, a bioactive glucoside from paeony root, on adjuvant arthritis in rats [J]. Inf lamm Res,2007,56:182-188.
[110]Zhu L, Wei W, Zheng YQ, et al.Effects and mechanisms of total gl ucosides of paeony on joint damage in rat collagen-induced arthritis [J]. Inf lamm Res,2005,54:211-220.
[111]Lee B, Shin YW, Bae EA, et al.Antiallergic effect of the root of Paeonia lactiflora and its constituents paeoniflorin and paeonol[J]. Arch Pharm Res,2008,31(4):445-450.
[112]Dong X P, Xu TL. Radix paeoniae rubra suppression of sodium curren t in acutely dissociated rat hippocampal CA1 neurons[J]. Brain Res,200 2,940 (1-2):1-9.
[113]梁雯若等.白芍的抗炎免疫药理作用研究[J].新中医,1989；21(3)：51.
[114]王志坚等.白芍总甙治疗类风湿关节炎的临床药理研究[J].中国药理学通报,1994；10(2)：38.
[115]李金才.白芍食疗的回顾与展望[J].中药通报,1987；12(8)：54.
[116]龙子江等.白芍活血化瘀作用的现代药理实验研究[J].安徽中医学院学报,1984;(2)：42.
[117]丁俊杰.再谈白芍利小便[J].辽宁中医杂志,1990；14(3)：40.
[118]张晓平,陈建明.山桃仁水煎提取物对肝纤维化小鼠血清Ⅰ、Ⅱ型前胶原的降解作用[J].福建中医药,2002,33(4)：36-37.
[119]徐列明,刘平.桃仁提取物抗实验性肝纤维化的作用观察——免疫组化和胶原代谢的研究[J].中药药理与临床,1993,(5)：14-16.
[120]徐列明,薛惠明.实验性肝纤维化时贮脂细胞的变化及桃仁提取物对其影响[J].中西医结合肝病杂志,1993,(2)：16-18.
[121]汪宁,刘青云.桃仁不同提取物抗血栓作用的实验研究[J].中药材,2002,(6)：414-415.
[122]耿涛,谢梅林,彭少平.桃仁提取物抗大鼠心肌缺血作用的研究[J].苏州大 学学报：医学版,2005,25(2)：238-240.
[123]高巍,赵铁华.穿山龙总皂苷对小鼠免疫功能的影响[J].承德中医学院学报,2001,18(1)：9-10.
[124]李永茂,何宝俊,刘振庸等.穿山龙水溶性有效成分的研究[J].中国医科大学学报,1979(1)：141.
[125]沈阳医学院慢性气管炎协作组.穿山龙药理实验及有效成分探讨[J].医学研究,1972,(1)：15.
[126]雷励.穿山龙注射液穴位注射治疗重症支气管哮喘临床观察[J].中国中医急症,2005,14(5)：419.
[127]唐丽香.福建穿山龙抗炎镇痛作用的实验研究[J].海峡学,2000,12(3).
[128]刘江涛,陈信义,王玉芝.穿山龙粗提物抗肿瘤体外验研究[J].中国中医药信息杂志,2004,11(3),1.
[129]钟添,钟富荣,李丛民等.川芎提取物的制备及其加料试验[J].烟草科技,22.4：9.
[130]李岩,孙思予,周卓.白术对小鼠胃排空及小肠推进功能影响的实验研究[J].辽宁医学杂志,1996,10(4)：186.
[131]周德文.术类的药理和药效[J].国外医药.植物药分册,1996,11(3)：120-122.
[132]金惠,赵英博,江维等.茯苓药理作用及临床应用研究进展[J].湖北中医杂志,2008,30(4)：59-60.
[133]高同银,崔同淑,孙国香.浅谈甘草解毒作用[J].河北中医,1994,16(3)：46.
[134]田庆来,官月平,张波等.甘草有效成分的药理作用研究进展[J].天然产物研究与开发,2006(18)：343-347.
[135]邓中甲.方剂学[M].北京：中国中医药出版社,2003.1：96-97.
[136]李庆业.临床常用方药应用鉴别.方剂分册[M].北京：人民卫生出版社,2003.6：235-237.
[137]贺庆华.补阳还五汤治疗肾病综合征52例[J].江苏中医,1999,2 0(10)：24.
[138]吴明,李庆珍,赵纪生.补阳还五汤治疗顽固性肾性蛋白尿[J].亚太传统医药,2008,4(3)：80.
[139]李秋芬.补阳还五汤为主治疗原发性膜性肾病32例[J].浙江中医杂志,2006,41(12)：709.
[140]何灵芝,李学铭.补阳还五汤治疗肾病举隅[J].广西中医药,2005,28(6)： 34.
[141]黄叶宁,詹谨.补阳还五汤联合盐酸贝那普利治疗早期糖尿病肾病30例[J].江西中医药,2011,42(9)：37-38.
[142]刘晓微.益肾补阳还五汤治疗肾病综合征32例[J].辽宁中医杂志,2006,33(3)：328.