雷公藤多苷片治疗CAN的临床及实验研究
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摘要
慢性移植肾肾病(Chronic allogrdft nephropathy, CAN)的发生与各种免疫、非免疫因素相关。本文详细阐述了慢性移植肾肾病的实验和临床防治策略及相关病理分子对CAN的影响、雷公藤多苷片(Glucosida tripterygii total, GTT)药理作用及对CAN发生相关因素的防治作用,并进一步通过临床和实验研究观察GTT治疗CAN的疗效并探讨其机理,评价其临床疗效。
目的：通过临床和实验研究观察雷公藤多苷片治疗CAN的疗效,进一步探讨防治CAN更有效的方法。
方法：1.临床研究：收集2009年9月至2011年3月至江苏省中医院就诊,确诊为CAN并符合纳入标准的患者共20例,按照随机分组原则,分为治疗组(GTT组)和对照组(各10例),所有患者均常规根据血药浓度调整免疫抑制剂用量,调整血脂、血压及血糖。在此基础上治疗组加服雷公藤多苷片40mg／次,每日3次,1个月后改为20mg,每日三次,长期服用。根据血常规和肝功能调整该药物剂量,对照组不加用任何药,治疗疗程为6个月,治疗前及治疗6个月后分别记录血常规、肝肾功能、尿蛋白。2.实验研究：用F344大鼠为供鼠,LWISE大鼠为受鼠,建立CAN模型大鼠共14只,按照随机分组原则,分为对照组(8只)和实验组(6只)。实验组用雷公藤多苷片以生理盐水配制灌胃30mg/kg/d,对照组用生理盐水灌胃,两组肾移植大鼠饲养观察4个月,期间留取24小时尿标本、血标本,4个月后宰杀大鼠取移植肾,行肾组织病理光镜检查,并用RT—PCR检测肾组织中胶原Ⅰ、Ⅲ及纤维连接蛋白(Fibronectin, FN) mRNA含量。所有数据采用SPSS17.0进行统计学处理及分析。
结果：临床观察发现：治疗组与对照组血常规及肝功能相关指标治疗前后组内比较及组间比较(P>0.05)无统计学意义,雷公藤多苷片组有少部分患者出现肝功能及血常规轻度异常,停药后给予相应处理好转,并未出现严重并发症。治疗组24小时尿蛋白由治疗前2021.22±942.91 mg/L降为治疗后220.00+120.00 mg/L,治疗后尿蛋白显著下降(P<0.01),对照组无显著差异；治疗组Cr由治疗前182.58±15.07umol/L降为治疗后136.94±17.92umol/L, BUN由治疗前10.89±1.36mmol/L变为治疗后8.12±1.07mmol/L,治疗后肌酐和尿素氮均有下降(P<0.01,)；而对照组治疗后的肌酐、尿素氮并没有降低。实验研究发现：肾移植术后4个月时实验组大鼠肾功能各项指标较比对照组好,尤其是24小时尿蛋白排泄明显低于对照组；实验组大鼠移植肾病理损害程度轻,且肾组织细胞外基质胶原Ⅰ、Ⅲ、FN mRNA的表达量明显低于对照组。
结论：1.雷公藤多苷片可以保护肾功能,延缓CAN的进展,其作用机制可能与降低肾组织细胞外基质胶原Ⅰ、Ⅲ、FN mRNA表达而抗肾纤维化相关。2.雷公藤多苷片可辅助免疫抑制剂防治CAN,期间未发现严重不良反应。
The occurrence of chronic allograft nephropathy (CAN) is related with immune and nonimmune factors. The CAN's experimental and clinical preventive and therapeutic strategies will be expounded in this paper, and the influence of related pathology molecule to CAN, the pharmacologic actions of Tripterygium Glycosides and its preventive and therapeutic effect to the CAN's occurrence factors will be represented. And also further through the clinical and experimental research to observe the Tripterygium Glycosides' influence to the CAN, discuss the mechanism of the Tripterygium Glycosides, and evaluate its therapeutic effect.
Objective:Through the clinical and experimental research to observe the Tripterygium Glycosides' curative effect to CAN, and further explore a better way to prevent and treat the CAN.
Methods:1. Clinical research:collect from September 2009 to March 2011 to Jiangsu provincial Hospital for treatment, diagnosis of CAN and patients met the inclusion criteria were 20 cases. In accordance with the principles of randomized, the 20 patients were divided into two group on average, the therapy group and the control group. All patients were routinely adjusted the immunodepressant dosage, blood fat, blood pressure, blood glucose according to the blood drug level. On this basis, the treatment group took Tripterygium Glycosides 20mg every time, and 3 times a day, and the time of therapy is 6 months. They were adjusted the doses according to the blood common practice and the hepatic function. But the control group without using any additional drugs. We respectively recorded their blood common practice, urine common practice, hepatic and renal function, renal pathology.2. Empirical study:F344 rats were used as donor mice, LWISE rats as recipient mice. And we chose 14 rats as CAN rats. In accordance with the principles of randomized, the 14 rats were divided into two groups, the experimental (6 rats) group and the control group (8 rats). The experimental group rats were laved by Tripterygium Glycosides,3mg/kg/d, and the control group rats were laved by physiological saline. We reared the two groups of kidney transplantation rats for 4 months and collected urine and blood as specimens from 24-hour. After this 4 months, we killed them for pathological kidney transplantation, detected transplant renal graft biopsy tissues epimatrix collagenⅠ、Ⅲ、FN (mRNA detection) by RT-PCR before the treatment and after 6 months' treatment, All data were statistically processed and analyzed by SPSS17.0.
Findings:The Clinical observations:The comparison in the related indicators (P>0.05) of blood common practice and hepatic function between therapy group and control group or in the same group has no statistics significance no matter before or after the therapy. Few patients in the Tripterygium Glycosides group have been slightly abnormal in the blood common practice and hepatic function. However when those patients stopped using the medicine their symptoms has been lightented and they have no other severe complications. The indicators of Urine protein in 24 hours in the therapy group have obviously reduced from 2021.22±942.91 mg/L to 220.00±120.00 mg/L after treatment while the control group has no difference. Meanwhile the indicators of Cr in the therapy group have reduced from 182.58±15.07umol/L to 136.94±17.92umol/L, BUN from 10.89±1.36mmol/L to 8.12±1.07mmol/L after treatment, and the indicators of the creatinine and urea nitrogen have also reduced (P<0.01). However the indicators of the creatinine and urea nitrogen in the control group have not reduced at all. The experimental research findings:The indicators of renal function of Rats in test group have been better than those in model group. In particular the urine protein excretion within 24 hours in the test group has obviously less than that in the control group. The allogrdft nephropathy of Rats in the test group has injured less than that in the model group, especially the indicators in terms of renal tissue cells extracellular matrix collagenⅠ、Ⅲ、FN mRNA has lower than those of model group.
Conclusion:1. Tripterygium Glycosides can protect renal function, and delay the progress of CAN. The mechanism may be related to reduce renal extracellular matrix collagenⅠ,Ⅲ, FN mRNA expression of anti-renal fibrosis.2. Tripterygium Glycosides immunosuppressive agents can assist prevent and treat CAN, found no adverse reactions during the experimental period.
目的：通过临床和实验研究观察雷公藤多苷片治疗CAN的疗效,进一步探讨防治CAN更有效的方法。
方法：1.临床研究：收集2009年9月至2011年3月至江苏省中医院就诊,确诊为CAN并符合纳入标准的患者共20例,按照随机分组原则,分为治疗组(GTT组)和对照组(各10例),所有患者均常规根据血药浓度调整免疫抑制剂用量,调整血脂、血压及血糖。在此基础上治疗组加服雷公藤多苷片40mg／次,每日3次,1个月后改为20mg,每日三次,长期服用。根据血常规和肝功能调整该药物剂量,对照组不加用任何药,治疗疗程为6个月,治疗前及治疗6个月后分别记录血常规、肝肾功能、尿蛋白。2.实验研究：用F344大鼠为供鼠,LWISE大鼠为受鼠,建立CAN模型大鼠共14只,按照随机分组原则,分为对照组(8只)和实验组(6只)。实验组用雷公藤多苷片以生理盐水配制灌胃30mg/kg/d,对照组用生理盐水灌胃,两组肾移植大鼠饲养观察4个月,期间留取24小时尿标本、血标本,4个月后宰杀大鼠取移植肾,行肾组织病理光镜检查,并用RT—PCR检测肾组织中胶原Ⅰ、Ⅲ及纤维连接蛋白(Fibronectin, FN) mRNA含量。所有数据采用SPSS17.0进行统计学处理及分析。
结果：临床观察发现：治疗组与对照组血常规及肝功能相关指标治疗前后组内比较及组间比较(P>0.05)无统计学意义,雷公藤多苷片组有少部分患者出现肝功能及血常规轻度异常,停药后给予相应处理好转,并未出现严重并发症。治疗组24小时尿蛋白由治疗前2021.22±942.91 mg/L降为治疗后220.00+120.00 mg/L,治疗后尿蛋白显著下降(P<0.01),对照组无显著差异；治疗组Cr由治疗前182.58±15.07umol/L降为治疗后136.94±17.92umol/L, BUN由治疗前10.89±1.36mmol/L变为治疗后8.12±1.07mmol/L,治疗后肌酐和尿素氮均有下降(P<0.01,)；而对照组治疗后的肌酐、尿素氮并没有降低。实验研究发现：肾移植术后4个月时实验组大鼠肾功能各项指标较比对照组好,尤其是24小时尿蛋白排泄明显低于对照组；实验组大鼠移植肾病理损害程度轻,且肾组织细胞外基质胶原Ⅰ、Ⅲ、FN mRNA的表达量明显低于对照组。
结论：1.雷公藤多苷片可以保护肾功能,延缓CAN的进展,其作用机制可能与降低肾组织细胞外基质胶原Ⅰ、Ⅲ、FN mRNA表达而抗肾纤维化相关。2.雷公藤多苷片可辅助免疫抑制剂防治CAN,期间未发现严重不良反应。
The occurrence of chronic allograft nephropathy (CAN) is related with immune and nonimmune factors. The CAN's experimental and clinical preventive and therapeutic strategies will be expounded in this paper, and the influence of related pathology molecule to CAN, the pharmacologic actions of Tripterygium Glycosides and its preventive and therapeutic effect to the CAN's occurrence factors will be represented. And also further through the clinical and experimental research to observe the Tripterygium Glycosides' influence to the CAN, discuss the mechanism of the Tripterygium Glycosides, and evaluate its therapeutic effect.
Objective:Through the clinical and experimental research to observe the Tripterygium Glycosides' curative effect to CAN, and further explore a better way to prevent and treat the CAN.
Methods:1. Clinical research:collect from September 2009 to March 2011 to Jiangsu provincial Hospital for treatment, diagnosis of CAN and patients met the inclusion criteria were 20 cases. In accordance with the principles of randomized, the 20 patients were divided into two group on average, the therapy group and the control group. All patients were routinely adjusted the immunodepressant dosage, blood fat, blood pressure, blood glucose according to the blood drug level. On this basis, the treatment group took Tripterygium Glycosides 20mg every time, and 3 times a day, and the time of therapy is 6 months. They were adjusted the doses according to the blood common practice and the hepatic function. But the control group without using any additional drugs. We respectively recorded their blood common practice, urine common practice, hepatic and renal function, renal pathology.2. Empirical study:F344 rats were used as donor mice, LWISE rats as recipient mice. And we chose 14 rats as CAN rats. In accordance with the principles of randomized, the 14 rats were divided into two groups, the experimental (6 rats) group and the control group (8 rats). The experimental group rats were laved by Tripterygium Glycosides,3mg/kg/d, and the control group rats were laved by physiological saline. We reared the two groups of kidney transplantation rats for 4 months and collected urine and blood as specimens from 24-hour. After this 4 months, we killed them for pathological kidney transplantation, detected transplant renal graft biopsy tissues epimatrix collagenⅠ、Ⅲ、FN (mRNA detection) by RT-PCR before the treatment and after 6 months' treatment, All data were statistically processed and analyzed by SPSS17.0.
Findings:The Clinical observations:The comparison in the related indicators (P>0.05) of blood common practice and hepatic function between therapy group and control group or in the same group has no statistics significance no matter before or after the therapy. Few patients in the Tripterygium Glycosides group have been slightly abnormal in the blood common practice and hepatic function. However when those patients stopped using the medicine their symptoms has been lightented and they have no other severe complications. The indicators of Urine protein in 24 hours in the therapy group have obviously reduced from 2021.22±942.91 mg/L to 220.00±120.00 mg/L after treatment while the control group has no difference. Meanwhile the indicators of Cr in the therapy group have reduced from 182.58±15.07umol/L to 136.94±17.92umol/L, BUN from 10.89±1.36mmol/L to 8.12±1.07mmol/L after treatment, and the indicators of the creatinine and urea nitrogen have also reduced (P<0.01). However the indicators of the creatinine and urea nitrogen in the control group have not reduced at all. The experimental research findings:The indicators of renal function of Rats in test group have been better than those in model group. In particular the urine protein excretion within 24 hours in the test group has obviously less than that in the control group. The allogrdft nephropathy of Rats in the test group has injured less than that in the model group, especially the indicators in terms of renal tissue cells extracellular matrix collagenⅠ、Ⅲ、FN mRNA has lower than those of model group.
Conclusion:1. Tripterygium Glycosides can protect renal function, and delay the progress of CAN. The mechanism may be related to reduce renal extracellular matrix collagenⅠ,Ⅲ, FN mRNA expression of anti-renal fibrosis.2. Tripterygium Glycosides immunosuppressive agents can assist prevent and treat CAN, found no adverse reactions during the experimental period.
引文
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