慢性马兜铃酸肾病病程进展的初步分析
摘要
背景与目的
马兜铃酸肾病(AAN)是马兜铃类中药引起的肾小管间质疾病,临床以慢性AAN最为多见,其病理以寡细胞性慢性肾间质纤维化为特征。迄今为止,对慢性AAN尚无成熟的治疗方案。近年国内外已有少量关于糖皮质激素治疗慢性AAN的报告,提示该治疗对延缓AAN进展有一定疗效。
本文对轻中度肾衰及重度肾衰的慢性AAN患者应用小剂量糖皮质激素治疗,以观察该治疗对慢性AAN的病程有何有益作用。
方法
自2000年10月至2008年6月在北京协和医院肾内科诊治的慢性AAN患者共58例入组,根据治疗前血清肌酐分为轻中度肾衰组(Scr＜530umol/l,44例)与重度肾衰组(Scr＞530umol/l,14例)。
轻中度肾哀组AAN患者分为激素治疗组(n=23)与对照组(n=21),两组患者的性别(女16/男7 vs女18/男3,P=0.287)、平均年龄(55.96±11.3岁vs56.19±13.2岁,P=0.950)、治疗前血清肌酐(334±98umol/l vs 292±95umol/l,P=0.153)均无显著差异。对1年的观察时间内两组患者的血清肌酐进行自身对照分析及两组间比较分析,以评价激素治疗对轻中度肾衰的慢性AAN的病程进展有无影响。
重度肾衰组14例均接受激素治疗,女11例,男3例,平均年龄54.43±10.4岁,治疗前血清肌酐640±66umol/l。对1年的观察时间内该组患者血清肌酐进行自身对照分析,以评价激素治疗对重度肾衰的慢性AAN的病程进展有无影响。
应用激素治疗的全部AAN患者为37例(女27例,男10例),平均年龄55.38±10.8岁,入组前血清肌酐为450±173umol/l。对糖皮质激素治疗的全部AAN患者的血清肌酐水平的变化进行自身对照分析,以评价激素治疗对慢性AAN病程进展的影响;同时对轻中度。肾衰组与重度肾衰组的血清肌酐变化情况进行比较分析,以评价不同程度肾衰的AAN患者从激素治疗中的获益有无差别。
结果
轻中度肾衰AAN患者中,激素治疗组在3个月、6个月、9个月、1年时的血清肌酐与治疗前比较无显著差异(P＞0.05),在最初3个月内血肌酐有所下降(300±78umol/l vs 334±98umol/l,P=0.196),3个月时Scr较治疗前下降33.6±4lumol/l(下降幅度8.2±11.4%),3个月后至1年内Scr维持稳定(1年后Scr为305±75umol/l)。对照组在6个月、9个月、1年时的血清肌酐与治疗前比较有显著升高(P均＜0.05),在1年的观察时间内,血肌酐呈持续性显著升高(411±167umol/l vs 292±95umol/l,P=0.031)。
轻中度肾衰AAN患者中激素治疗组与对照组两组间比较,在6个月、9个月、1年时,激素治疗组的血清肌酐均显著低于对照组(各观察点P均＜0.05)。在1年内观察时间内,激素治疗组延缓加逆转的总有效率19例/20例(95%),对照组肾功能延缓加逆转的总有效率5/13例(38.5%),激素治疗组总有效率明显高于对照组(P＜0.001)。
重度肾衰AAN患者在治疗后3个月、6个月、9个月、1年时,其血清肌酐水平与治疗前比较,均有显著下降(P均＜0.05)。在最初3个月内血肌酐下降明显(539±86umol/l vs 640±66umol/l,P=0.002),3个月时Scr较治疗前下降101±67umol/l(下降幅度15.7±10.6%),3个月后至1年内Scr维持稳定(1年后Scr为555±111umol/l)。
应用激素治疗的全部慢性AAN患者在治疗后3个月、6个月、9个月、1年时的血清肌酐与治疗前比较无显著差异(P＞0.05),在最初3个月内血肌酐有所下降(393±143umol/l vs 450±173umol/l,P=0.130),3个月时Scr较治疗前下降60±61umol/l(下降幅度11.1±11.5%),3个月后至1年内Scr维持稳定(1年后Scr为399±151umol/l)。
轻中度肾衰AAN患者与重度肾衰AAN患者接受激素治疗后,在治疗后3个月内重度肾衰组比轻中度肾衰组获益更明显(Scr下降数值101±67umol/l vs 33.6±41umol/l,P=0.003);3个月至1年内两组获益无显著差异;治疗前至治疗后1年内两组获益无明显差异(Scr下降数值87±126umol/l vs 28±70umol/1,P=0.158)。在1年的观察时间内,重度肾衰组延缓加逆转的总有效率为11例/12例(91.7%),轻中度肾衰组延缓加逆转的总有效率为19例/20例(95.5%),两组间有效率比较无显著差异(P=0.706)。
治疗过程中的不良反应:轻中度肾衰AAN患者中激素治疗组有9例出现不良反应,4例类固醇性糖尿病、4例疱疹病毒感染、1股骨头坏死;重度肾衰AAN患者1例出现血糖升高。股骨头坏死发生在治疗后1年时,此后改例退出本研究。其余发生不良反应患者经对症治疗好转,仍坚持应用原治疗方案。
结论对轻中度肾衰的慢性AAN患者应用小剂量糖皮质激素治疗,能逆转或延缓肾功能不全的进展,有明显保护肾功能的作用;重度肾衰AAN患者接受小剂量激素治疗亦能改善其肾功能。上述的激素保护作用在3个月内即出现,维持至少1年。重度肾衰组比轻中度肾衰组从激素治疗中获益在3个月内显著,1年内无明显差异。对AAN患者长期应用小剂量糖皮质激素治疗的安全性较好,大多数患者可以耐受。
Background and Objective
Aristolochic acid(AA)- induced kidney disease, aristolochic acid nephropathy(AAN), is characterized pathologically by chronic interstitial fibrosis with few cell infiltration. It is believed that chronic AAN is difficult to be cured with the routine treatment for chronic renal failure. In recent years, a few of reports suggested that glucocorticoid steroid could retard the progression of renal impairment in patients with ANN. In this study, we used low-dosage steroid therapy in ANN patients with mild-to-moderate and severe chronic renal failure to observe the effects of the steroid on the progression of renal failure in chronic AAN.
Methods
58 chronic AAN patients in Peking Union Medical College Hospital from October 2000 to July 2008 were included in this study. According to the levels of serum creatinine before treatment, the patients were divided into mild-to-moderate group(n=44, Scr < 530umol/l) and severe group(n=14, Scr> 530umol/l).
The mild-to-moderate group was devided into steroid group(SG, n=23, prednisolone 0.5mg/kg for 1-3 month ,tapered off 0.04mg/kg every month) and control group(CG, n=21). The gender ratio, average age and serum creatinine levels before treatment were similar in the two groups. In the observation period of 1 year, the serum creatinine levels were compared between the SG and CG groups to examine the effects of steroid on renal failure progression of AAN.
The patients of severe group(n=14) all accepted steroid therapy. The serum levels of crteatinine before and after 1 year treatment were compared to test the effects of steroid on the progression of renal failure of AAN.
The serum creatinine levels of all patients who were given steroid therapy were compared before and after treatment to evaluate the impact of steroid on the progression of chronic AAN. At the same time, the creatinine levels of mild-to-moderate group was compared to that of severe group to determine whether there was any difference of the benefits which was obtained from steroid therapy between different degrees of renal failure.
Results
In the mild-to-moderate group, the creatinine levels of the patients accepted steroid therapy at the month 3, 6, 9 and 12 after therapy were not significantly different compared with that before therapy, respectively. During the first 3 months, the serum creatinine levels were decreased, then kept steadily. While the renal function of the CG patients kept deteriorating and the creatinine levels were obviously higher than that of the SG patients. The results got from the severe group and all steroid-received patients resembled that of the the mild-to-moderate group .
Our data also showed that during the first 3 months steroid therapy the decrease of creatinine levels in severe group were more significant than that in mild-to-moderate group, but there was no such difference for the whole 1 year.
During the steroid therapy, 4 cases of DM, 4 cases of herpes infection, 1 case of femoral head necrosis occurred in the mild-to-moderate group, and 1 case of serum glucose increasing occurred in the severe group.
Conclusions
Low-dosage seroids therapy could reverse or delay the progression of renal failure in AAN both for mild-to-moderate CRF and sever CRF. The protective effect mainly occured in the first 3 months, and kept at least for 1 year. The side effects of low-dosage seroid therapy were not severe and could be toleranced to the AAN patients.
马兜铃酸肾病(AAN)是马兜铃类中药引起的肾小管间质疾病,临床以慢性AAN最为多见,其病理以寡细胞性慢性肾间质纤维化为特征。迄今为止,对慢性AAN尚无成熟的治疗方案。近年国内外已有少量关于糖皮质激素治疗慢性AAN的报告,提示该治疗对延缓AAN进展有一定疗效。
本文对轻中度肾衰及重度肾衰的慢性AAN患者应用小剂量糖皮质激素治疗,以观察该治疗对慢性AAN的病程有何有益作用。
方法
自2000年10月至2008年6月在北京协和医院肾内科诊治的慢性AAN患者共58例入组,根据治疗前血清肌酐分为轻中度肾衰组(Scr＜530umol/l,44例)与重度肾衰组(Scr＞530umol/l,14例)。
轻中度肾哀组AAN患者分为激素治疗组(n=23)与对照组(n=21),两组患者的性别(女16/男7 vs女18/男3,P=0.287)、平均年龄(55.96±11.3岁vs56.19±13.2岁,P=0.950)、治疗前血清肌酐(334±98umol/l vs 292±95umol/l,P=0.153)均无显著差异。对1年的观察时间内两组患者的血清肌酐进行自身对照分析及两组间比较分析,以评价激素治疗对轻中度肾衰的慢性AAN的病程进展有无影响。
重度肾衰组14例均接受激素治疗,女11例,男3例,平均年龄54.43±10.4岁,治疗前血清肌酐640±66umol/l。对1年的观察时间内该组患者血清肌酐进行自身对照分析,以评价激素治疗对重度肾衰的慢性AAN的病程进展有无影响。
应用激素治疗的全部AAN患者为37例(女27例,男10例),平均年龄55.38±10.8岁,入组前血清肌酐为450±173umol/l。对糖皮质激素治疗的全部AAN患者的血清肌酐水平的变化进行自身对照分析,以评价激素治疗对慢性AAN病程进展的影响;同时对轻中度。肾衰组与重度肾衰组的血清肌酐变化情况进行比较分析,以评价不同程度肾衰的AAN患者从激素治疗中的获益有无差别。
结果
轻中度肾衰AAN患者中,激素治疗组在3个月、6个月、9个月、1年时的血清肌酐与治疗前比较无显著差异(P＞0.05),在最初3个月内血肌酐有所下降(300±78umol/l vs 334±98umol/l,P=0.196),3个月时Scr较治疗前下降33.6±4lumol/l(下降幅度8.2±11.4%),3个月后至1年内Scr维持稳定(1年后Scr为305±75umol/l)。对照组在6个月、9个月、1年时的血清肌酐与治疗前比较有显著升高(P均＜0.05),在1年的观察时间内,血肌酐呈持续性显著升高(411±167umol/l vs 292±95umol/l,P=0.031)。
轻中度肾衰AAN患者中激素治疗组与对照组两组间比较,在6个月、9个月、1年时,激素治疗组的血清肌酐均显著低于对照组(各观察点P均＜0.05)。在1年内观察时间内,激素治疗组延缓加逆转的总有效率19例/20例(95%),对照组肾功能延缓加逆转的总有效率5/13例(38.5%),激素治疗组总有效率明显高于对照组(P＜0.001)。
重度肾衰AAN患者在治疗后3个月、6个月、9个月、1年时,其血清肌酐水平与治疗前比较,均有显著下降(P均＜0.05)。在最初3个月内血肌酐下降明显(539±86umol/l vs 640±66umol/l,P=0.002),3个月时Scr较治疗前下降101±67umol/l(下降幅度15.7±10.6%),3个月后至1年内Scr维持稳定(1年后Scr为555±111umol/l)。
应用激素治疗的全部慢性AAN患者在治疗后3个月、6个月、9个月、1年时的血清肌酐与治疗前比较无显著差异(P＞0.05),在最初3个月内血肌酐有所下降(393±143umol/l vs 450±173umol/l,P=0.130),3个月时Scr较治疗前下降60±61umol/l(下降幅度11.1±11.5%),3个月后至1年内Scr维持稳定(1年后Scr为399±151umol/l)。
轻中度肾衰AAN患者与重度肾衰AAN患者接受激素治疗后,在治疗后3个月内重度肾衰组比轻中度肾衰组获益更明显(Scr下降数值101±67umol/l vs 33.6±41umol/l,P=0.003);3个月至1年内两组获益无显著差异;治疗前至治疗后1年内两组获益无明显差异(Scr下降数值87±126umol/l vs 28±70umol/1,P=0.158)。在1年的观察时间内,重度肾衰组延缓加逆转的总有效率为11例/12例(91.7%),轻中度肾衰组延缓加逆转的总有效率为19例/20例(95.5%),两组间有效率比较无显著差异(P=0.706)。
治疗过程中的不良反应:轻中度肾衰AAN患者中激素治疗组有9例出现不良反应,4例类固醇性糖尿病、4例疱疹病毒感染、1股骨头坏死;重度肾衰AAN患者1例出现血糖升高。股骨头坏死发生在治疗后1年时,此后改例退出本研究。其余发生不良反应患者经对症治疗好转,仍坚持应用原治疗方案。
结论对轻中度肾衰的慢性AAN患者应用小剂量糖皮质激素治疗,能逆转或延缓肾功能不全的进展,有明显保护肾功能的作用;重度肾衰AAN患者接受小剂量激素治疗亦能改善其肾功能。上述的激素保护作用在3个月内即出现,维持至少1年。重度肾衰组比轻中度肾衰组从激素治疗中获益在3个月内显著,1年内无明显差异。对AAN患者长期应用小剂量糖皮质激素治疗的安全性较好,大多数患者可以耐受。
Background and Objective
Aristolochic acid(AA)- induced kidney disease, aristolochic acid nephropathy(AAN), is characterized pathologically by chronic interstitial fibrosis with few cell infiltration. It is believed that chronic AAN is difficult to be cured with the routine treatment for chronic renal failure. In recent years, a few of reports suggested that glucocorticoid steroid could retard the progression of renal impairment in patients with ANN. In this study, we used low-dosage steroid therapy in ANN patients with mild-to-moderate and severe chronic renal failure to observe the effects of the steroid on the progression of renal failure in chronic AAN.
Methods
58 chronic AAN patients in Peking Union Medical College Hospital from October 2000 to July 2008 were included in this study. According to the levels of serum creatinine before treatment, the patients were divided into mild-to-moderate group(n=44, Scr < 530umol/l) and severe group(n=14, Scr> 530umol/l).
The mild-to-moderate group was devided into steroid group(SG, n=23, prednisolone 0.5mg/kg for 1-3 month ,tapered off 0.04mg/kg every month) and control group(CG, n=21). The gender ratio, average age and serum creatinine levels before treatment were similar in the two groups. In the observation period of 1 year, the serum creatinine levels were compared between the SG and CG groups to examine the effects of steroid on renal failure progression of AAN.
The patients of severe group(n=14) all accepted steroid therapy. The serum levels of crteatinine before and after 1 year treatment were compared to test the effects of steroid on the progression of renal failure of AAN.
The serum creatinine levels of all patients who were given steroid therapy were compared before and after treatment to evaluate the impact of steroid on the progression of chronic AAN. At the same time, the creatinine levels of mild-to-moderate group was compared to that of severe group to determine whether there was any difference of the benefits which was obtained from steroid therapy between different degrees of renal failure.
Results
In the mild-to-moderate group, the creatinine levels of the patients accepted steroid therapy at the month 3, 6, 9 and 12 after therapy were not significantly different compared with that before therapy, respectively. During the first 3 months, the serum creatinine levels were decreased, then kept steadily. While the renal function of the CG patients kept deteriorating and the creatinine levels were obviously higher than that of the SG patients. The results got from the severe group and all steroid-received patients resembled that of the the mild-to-moderate group .
Our data also showed that during the first 3 months steroid therapy the decrease of creatinine levels in severe group were more significant than that in mild-to-moderate group, but there was no such difference for the whole 1 year.
During the steroid therapy, 4 cases of DM, 4 cases of herpes infection, 1 case of femoral head necrosis occurred in the mild-to-moderate group, and 1 case of serum glucose increasing occurred in the severe group.
Conclusions
Low-dosage seroids therapy could reverse or delay the progression of renal failure in AAN both for mild-to-moderate CRF and sever CRF. The protective effect mainly occured in the first 3 months, and kept at least for 1 year. The side effects of low-dosage seroid therapy were not severe and could be toleranced to the AAN patients.
引文
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15、张聪,谌贻璞,董鸿瑞.波生坦及缬沙坦对马兜铃酸肾病大鼠肾间质纤维化的影响.中华医学杂志,2005,85(37):2601-2606.
16、李艳秋,范秋灵,姚丽,等.前列腺素E1和羟苯磺酸钙联合应用对马兜铃酸肾病临床疗效分析.中国实用内科杂,2006,26(12):934-935.
17、王巍巍,张金元.促红细胞生成素对马兜铃酸致肾小管上皮细胞损伤保护作用的初步观察.中国中西医结合。肾病杂志,2007,8(3):135-137.
18、Marie-Carmen Muniz Martinez,Jolle Nortier,Pierre Vereerstraeten and Jean-Louis Vanherweghem.Steroid therapy in chronic interstitial renal fibrosis:the case of Chinese-herb nephropathy.Nephrol Dial Transplant,2002,17:2033-2034.
1、王智民.含有马兜铃酸的中成药情况分析.中国中药杂志,2002,27(10):800-801.
2、鲁静.马兜铃酸相关中药材的探讨.中国药品标准,2002,3(2):49-50.
3、Wen YJ,Su T,Tang JW,et al.Cytotoxicity of phenanthrenes extracted from aristolochia contorta in human proximal tubular epithelial cell line.Nephron Exp Nephrol,2006,103(3):95-102.
4、苏涛,屈磊,张春丽,等.马兜铃酸Ⅰ在大鼠体内的代谢特征研究.中国中药杂志,2004,29(7):676.
5、相正心,何兴全,周桂芬,等.马兜铃酸含量的紫外分光光度测定法及药代动力学研究.药学学报,1984,19(3):224-7.
6、Pfau W,Schmeiser HH,Wiessler M.Aristolochic acid binds covalently to the exocyclic amino group of purine nucleotides in DNA[J]Carcinogenesis,1990,11:313-319.
7、Debelle FD,Nortier JL,De Prez EG,et al.Aristolochic acid induce chronic renal failure with interstitial fibrosis in salt-depleted rats.J Am Soc Nephrol,2002,13:431-436.
8、李彪,李晓玫,张翠英,等.马兜铃酸Ⅰ及马兜铃内酰胺Ⅰ导致。肾小管上皮细胞损伤的差异[J].北京大学学报(医学版),2004,36(1):36-40.
9、高瑞通,郑法雷,刘彦信,等.马兜铃酸Ⅰ诱导的LLC-PK1细胞凋亡及其意义.中华肾脏病杂志,1999:15(3):162-165.
10、李彪,李晓玫,张翠英,等.马兜铃内酰胺Ⅰ对肾小管上皮细胞的损伤作用.中国中药杂志,2004,29:78-83.
11、李恒,刘志红,陈惠萍,等.马兜铃酸Ⅰ对肾小管上皮细胞超微结构的影响.肾脏病与透析肾移植杂志,2001,10(3):243-245.
12、戚新明,肖瑛,蔡燕,等.马兜铃酸(从)Ⅰ毒性作用机制的初步探讨.毒理学杂志,2005,19(3):266.
13、马红梅,张伯礼,徐崇佩,等.关木通。肾毒性机制的实验研究[J].中药新药与临床药理,2001,12(6):404.
14、杨莉,李晓玫,王海燕.关木通与抗生素致急性肾小管坏死细胞生物学特征的比较研究.中国中西医结合杂志,2003,23(5):329-334.
15、王海燕主编.肾脏病学[M].第2版.北京:人民卫生出版社,1996:787
16、文晓彦,郑法雷,高瑞通,等.马兜铃酸Ⅰ诱导人肾小管上皮细胞转分化的作用及机制.肾脏病、透析和肾移植杂志,2000,9(3):206-209.
17、郑法雷,文晓彦,李雪梅,等.单个核细胞趋化蛋白-1和马兜铃酸Ⅰ在诱导人类肾小管上皮细胞转分化中的协同作用.中华内科杂志,2000,39(12):831-834.
18、张聪,董鸿瑞,谌贻璞.慢性马兜铃酸。肾病大鼠肾小管上皮细胞转分化与肾间质纤维化的关系.中国中西医结合肾病杂志,2007,8(2):69-72.
19、Yang J,Liu Y.Dissection of key events in tubular epithelial to myofibro-blast transition and its implications in renal interstitial fibrosis.Am J Pathol,2001,159(4):1465-1475.
20、杨莉,李晓玫,王海燕.结缔组织生长因子在关木通相关肾小管间质肾病肾间质纤维化中的作用.中华肾病杂志,2003,19(4):213-218.
21、叶志斌,许静,李珍,等.前列腺素系统异常在关木通所致慢性肾脏损害发生中的作用.中草药,2003,34(2):149-152.
22、杨莉,李晓玫,王素霞,等.关木通致急性肾小管坏死患者肾间质微血管病变的研究.中华内科杂志,2005,525(7):525-529.
23、Schmeiser HH,Bieler CA.Detection of DNA adducts formed by aristolochic acid in renal tissue from patients with Chinese herbs nephropathy.Cancer Res,1996,56(9):2025-2028.
24、Lebeau C,Arlt VM,Schmeiser HH,et al.Aristolochic acid impedes endocytosis and induces DNA adducts in proximal tubule cells[J].Kidney Int,2001,60(4):1332-1334.
25、Schmeiser HH,Janssen JWG,Lyons J,et al.Aristolochic acid activates ras genes in rat tumors at deoxyadenosine residues.Cancer Research,1990,50:5464-5469.
26、Arlt VM,Schmeiser HH,Pfeifer GP,etal.Sequence specific detection of aristolochic acid-DNA adducts in the human p53 gene by terminal transferase-dependent PCR.Carcinogenesis,2001,22(1):133-140.
27、王迎春,仲来福.中草药致肾损害机理的研究进展.时珍国医国药,2006,17(5):834-835.
28、谌贻璞,陈文.马兜铃酸肾病的临床病理表现及治疗.中药新药与临床药理,2001,12(6):391-393.
29、F.Reginster,M.Jadoul and C.van Ypersele de Strihou.Chinese herbs nephropathy presentation,natural history and fate after transplantation.Nephrol Dial Transplant,1997,12:81-86.
30、周咏红,杨莉,秦卫,等.慢性马兜铃酸。肾病患者的肾脏B超特征及其临床意义.中华肾病杂志,2006,22(7):393-397.
31、陈文.慢性马兜铃酸肾病与泌尿系统肿瘤.肾脏病与透析肾移植杂志,2005,14(6):543-544.
32、李卫华,杨莉,苏涛,等.服用含马兜铃酸成分药物对尿毒症透析患者伴发尿路移行细胞癌的影响.中华医学杂志,2005,85(35):2487-2491.
33、刘志红,李瑛,黎磊石,等.马兜铃酸Ⅰ致大鼠急性。肾损伤的远期效应及其致肿瘤作用.肾脏病与透析。肾移植杂志,2003,12(4):318-323.
34、Yu FY,Lin YH,Su CC.A sensitive enzyme-linked immunosorbent assay for detecting carcinogenic aristolochic acid in herbal remedies.J Agric Food Chem,2006,54(7):2496-2500.
35、Vanherweghem JL,Abramowicz D,Tielemans C,Depierreux M.Effects of steroids on the progression of renal failure in chronic interstitial renal fibrosis:a pilot study in Chinese herbs nephropathy.Am J Kidney Dis,1996,27(2):209-215.
36、Marie-Carmen Muniz Martinez,Jolle Nortier,Pierre Vereerstraeten and Jean-Louis Vanherweghem.Steroid therapy in chronic interstitial renal fibrosis:the case of Chinese-herb nephropathy.Nephrol Dial Transplant,2002,17:2033-2034.
37、Marie-Carmen Muniz Martinez,Jolle Nortier,Pierre Vereerstraeten and Jean-Louis Vanherweghem.Progression rate of Chinese herb nephropathy:impact of Aristolochia fangchi ingested dose.Nephrol Dial Transplant,2002,17:408-412.
38、王会玲,张金元,黄建.甘草酸和泼尼松对慢性马兜铃酸肾病大鼠肾组织病理及超微病理改变的影响.中国中西医结合杂志,2007,27(1):45-49.
39、张聪,谌贻璞,董鸿瑞.波生坦及缬沙坦对马兜铃酸肾病大鼠。肾间质纤维化的影响.中华医学杂志,2005,85(37):2601-2606.
40、Debelle FD,Nortier Jh,Husson CP,et al.The reninangiotensin system blockade does not prevent renal interstitial fibrosis induced by aristolochic acids.Kidney Int,2004,66:1815-1825.
41、李艳秋,范秋灵,姚丽,等.前列腺素E1和羟苯磺酸钙联合应用对马兜铃酸肾病临床疗效分析.中国实用内科杂,2006,26(12):934-935.
42、王巍巍,张金元.促红细胞生成素对马兜铃酸致肾小管上皮细胞损伤保护作用的初步观察.中国中西医结合。肾病杂志,2007,8(3):135-137.
43、李航,熊瑕,周全荣.中药防治肾间质纤维化的研究新进展.中国中西医结合肾病杂志,2006,7(11):680-682.
2、Vanherweghem JL,Depierreux M,Tielemans C et al.Rapidly progressive insterstitial renal fibrosis in young women:association with slimming regimen including Chinese herbs.Lancet,1993;341:387-391.
3、郑法雷.马兜铃酸肾病的特点及其防治中的有关问题.肾脏病与透析肾移植杂志,2005,14(6):540-541.
4、尹广,黎磊石.马兜铃酸肾病的临床诊断体会.肾脏病与透析肾移植杂志,2005,14(6):541-543.
5、周咏红,杨莉,秦卫,等.慢性马兜铃酸肾病患者的肾脏B超特征及其临床意义.中华肾病杂志,2006,22(7):393-397.
6、Vanherweghem JL,Abramowicz D,Tielemans C,Depierreux M.Effects of steroids on the progression of renal failure in chronic interstitial renal fibrosis:a pilot study in Chinese herbs nephropathy.Am J Kidney Dis,1996,27(2):209-15.
7、Marie-Carmen Muniz Martinez,Jolle Nortier,Pierre Vereerstraeten and Jean-Louis Vanherweghem.Progression rate of Chinese herb nephropathy:impact of Aristolochia fangchi ingested dose.Nephrol Dial Transplant,2002,17:408-412.
8、王会玲,张金元,黄建.甘草酸和泼尼松对慢性马兜铃酸肾病大鼠肾组织病理及超微病理改变的影响.中国中西医结合杂志,2007,27(1):45-49.
9、吴松寒.木通所致急性肾功能衰竭2例报告.江苏中医,1964;10:12.
10、Pfau W,Schmeiser HH,Wiessler M.Aristolochic acid binds covalently to the exocyclic amino group of purine nucleotides in DNA[J].Carcinogenesis,1990,11:313-319.
11、Debelle FD,Nortier JL,De Prez EG,et al.Aristolochic acid induce chronic renal failure with interstitial fibrosis in salt-depleted rats.J Am Soc Nephrol,2002,13:431-436.
12、Wen YJ,Su T,Tang JW,et al.Cytotoxicity of phenanthrenes extracted from aristolochia contorta in human proximal tubular epithelial cell line.Nephron Exp Nephrol,2006,103(3):95-102.
13、苏涛,屈磊,张春丽,等.马兜铃酸Ⅰ在大鼠体内的代谢特征研究.中国中药杂志,2004,29(7):676.
14、相正心,何兴全,周桂芬,等.马兜铃酸含量的紫外分光光度测定法及药代动力学研究.药学学报,1984,19(3):224-7。
15、张聪,谌贻璞,董鸿瑞.波生坦及缬沙坦对马兜铃酸肾病大鼠肾间质纤维化的影响.中华医学杂志,2005,85(37):2601-2606.
16、李艳秋,范秋灵,姚丽,等.前列腺素E1和羟苯磺酸钙联合应用对马兜铃酸肾病临床疗效分析.中国实用内科杂,2006,26(12):934-935.
17、王巍巍,张金元.促红细胞生成素对马兜铃酸致肾小管上皮细胞损伤保护作用的初步观察.中国中西医结合。肾病杂志,2007,8(3):135-137.
18、Marie-Carmen Muniz Martinez,Jolle Nortier,Pierre Vereerstraeten and Jean-Louis Vanherweghem.Steroid therapy in chronic interstitial renal fibrosis:the case of Chinese-herb nephropathy.Nephrol Dial Transplant,2002,17:2033-2034.
1、王智民.含有马兜铃酸的中成药情况分析.中国中药杂志,2002,27(10):800-801.
2、鲁静.马兜铃酸相关中药材的探讨.中国药品标准,2002,3(2):49-50.
3、Wen YJ,Su T,Tang JW,et al.Cytotoxicity of phenanthrenes extracted from aristolochia contorta in human proximal tubular epithelial cell line.Nephron Exp Nephrol,2006,103(3):95-102.
4、苏涛,屈磊,张春丽,等.马兜铃酸Ⅰ在大鼠体内的代谢特征研究.中国中药杂志,2004,29(7):676.
5、相正心,何兴全,周桂芬,等.马兜铃酸含量的紫外分光光度测定法及药代动力学研究.药学学报,1984,19(3):224-7.
6、Pfau W,Schmeiser HH,Wiessler M.Aristolochic acid binds covalently to the exocyclic amino group of purine nucleotides in DNA[J]Carcinogenesis,1990,11:313-319.
7、Debelle FD,Nortier JL,De Prez EG,et al.Aristolochic acid induce chronic renal failure with interstitial fibrosis in salt-depleted rats.J Am Soc Nephrol,2002,13:431-436.
8、李彪,李晓玫,张翠英,等.马兜铃酸Ⅰ及马兜铃内酰胺Ⅰ导致。肾小管上皮细胞损伤的差异[J].北京大学学报(医学版),2004,36(1):36-40.
9、高瑞通,郑法雷,刘彦信,等.马兜铃酸Ⅰ诱导的LLC-PK1细胞凋亡及其意义.中华肾脏病杂志,1999:15(3):162-165.
10、李彪,李晓玫,张翠英,等.马兜铃内酰胺Ⅰ对肾小管上皮细胞的损伤作用.中国中药杂志,2004,29:78-83.
11、李恒,刘志红,陈惠萍,等.马兜铃酸Ⅰ对肾小管上皮细胞超微结构的影响.肾脏病与透析肾移植杂志,2001,10(3):243-245.
12、戚新明,肖瑛,蔡燕,等.马兜铃酸(从)Ⅰ毒性作用机制的初步探讨.毒理学杂志,2005,19(3):266.
13、马红梅,张伯礼,徐崇佩,等.关木通。肾毒性机制的实验研究[J].中药新药与临床药理,2001,12(6):404.
14、杨莉,李晓玫,王海燕.关木通与抗生素致急性肾小管坏死细胞生物学特征的比较研究.中国中西医结合杂志,2003,23(5):329-334.
15、王海燕主编.肾脏病学[M].第2版.北京:人民卫生出版社,1996:787
16、文晓彦,郑法雷,高瑞通,等.马兜铃酸Ⅰ诱导人肾小管上皮细胞转分化的作用及机制.肾脏病、透析和肾移植杂志,2000,9(3):206-209.
17、郑法雷,文晓彦,李雪梅,等.单个核细胞趋化蛋白-1和马兜铃酸Ⅰ在诱导人类肾小管上皮细胞转分化中的协同作用.中华内科杂志,2000,39(12):831-834.
18、张聪,董鸿瑞,谌贻璞.慢性马兜铃酸。肾病大鼠肾小管上皮细胞转分化与肾间质纤维化的关系.中国中西医结合肾病杂志,2007,8(2):69-72.
19、Yang J,Liu Y.Dissection of key events in tubular epithelial to myofibro-blast transition and its implications in renal interstitial fibrosis.Am J Pathol,2001,159(4):1465-1475.
20、杨莉,李晓玫,王海燕.结缔组织生长因子在关木通相关肾小管间质肾病肾间质纤维化中的作用.中华肾病杂志,2003,19(4):213-218.
21、叶志斌,许静,李珍,等.前列腺素系统异常在关木通所致慢性肾脏损害发生中的作用.中草药,2003,34(2):149-152.
22、杨莉,李晓玫,王素霞,等.关木通致急性肾小管坏死患者肾间质微血管病变的研究.中华内科杂志,2005,525(7):525-529.
23、Schmeiser HH,Bieler CA.Detection of DNA adducts formed by aristolochic acid in renal tissue from patients with Chinese herbs nephropathy.Cancer Res,1996,56(9):2025-2028.
24、Lebeau C,Arlt VM,Schmeiser HH,et al.Aristolochic acid impedes endocytosis and induces DNA adducts in proximal tubule cells[J].Kidney Int,2001,60(4):1332-1334.
25、Schmeiser HH,Janssen JWG,Lyons J,et al.Aristolochic acid activates ras genes in rat tumors at deoxyadenosine residues.Cancer Research,1990,50:5464-5469.
26、Arlt VM,Schmeiser HH,Pfeifer GP,etal.Sequence specific detection of aristolochic acid-DNA adducts in the human p53 gene by terminal transferase-dependent PCR.Carcinogenesis,2001,22(1):133-140.
27、王迎春,仲来福.中草药致肾损害机理的研究进展.时珍国医国药,2006,17(5):834-835.
28、谌贻璞,陈文.马兜铃酸肾病的临床病理表现及治疗.中药新药与临床药理,2001,12(6):391-393.
29、F.Reginster,M.Jadoul and C.van Ypersele de Strihou.Chinese herbs nephropathy presentation,natural history and fate after transplantation.Nephrol Dial Transplant,1997,12:81-86.
30、周咏红,杨莉,秦卫,等.慢性马兜铃酸。肾病患者的肾脏B超特征及其临床意义.中华肾病杂志,2006,22(7):393-397.
31、陈文.慢性马兜铃酸肾病与泌尿系统肿瘤.肾脏病与透析肾移植杂志,2005,14(6):543-544.
32、李卫华,杨莉,苏涛,等.服用含马兜铃酸成分药物对尿毒症透析患者伴发尿路移行细胞癌的影响.中华医学杂志,2005,85(35):2487-2491.
33、刘志红,李瑛,黎磊石,等.马兜铃酸Ⅰ致大鼠急性。肾损伤的远期效应及其致肿瘤作用.肾脏病与透析。肾移植杂志,2003,12(4):318-323.
34、Yu FY,Lin YH,Su CC.A sensitive enzyme-linked immunosorbent assay for detecting carcinogenic aristolochic acid in herbal remedies.J Agric Food Chem,2006,54(7):2496-2500.
35、Vanherweghem JL,Abramowicz D,Tielemans C,Depierreux M.Effects of steroids on the progression of renal failure in chronic interstitial renal fibrosis:a pilot study in Chinese herbs nephropathy.Am J Kidney Dis,1996,27(2):209-215.
36、Marie-Carmen Muniz Martinez,Jolle Nortier,Pierre Vereerstraeten and Jean-Louis Vanherweghem.Steroid therapy in chronic interstitial renal fibrosis:the case of Chinese-herb nephropathy.Nephrol Dial Transplant,2002,17:2033-2034.
37、Marie-Carmen Muniz Martinez,Jolle Nortier,Pierre Vereerstraeten and Jean-Louis Vanherweghem.Progression rate of Chinese herb nephropathy:impact of Aristolochia fangchi ingested dose.Nephrol Dial Transplant,2002,17:408-412.
38、王会玲,张金元,黄建.甘草酸和泼尼松对慢性马兜铃酸肾病大鼠肾组织病理及超微病理改变的影响.中国中西医结合杂志,2007,27(1):45-49.
39、张聪,谌贻璞,董鸿瑞.波生坦及缬沙坦对马兜铃酸肾病大鼠。肾间质纤维化的影响.中华医学杂志,2005,85(37):2601-2606.
40、Debelle FD,Nortier Jh,Husson CP,et al.The reninangiotensin system blockade does not prevent renal interstitial fibrosis induced by aristolochic acids.Kidney Int,2004,66:1815-1825.
41、李艳秋,范秋灵,姚丽,等.前列腺素E1和羟苯磺酸钙联合应用对马兜铃酸肾病临床疗效分析.中国实用内科杂,2006,26(12):934-935.
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