他克莫司治疗膜性肾病30例临床观察
|
摘要
背景与目的
膜性肾病(membranous nephropathy, MN)是成人肾病综合征(nephrotic syndrome, NS)的常见病理类型。目前发病机制未明,最近研究认为膜性肾病发病机制与抗磷脂酶A2受体抗体(PLA2R)相关PLA2R抗体有关。其临床表现不一,有自发缓解和肾功能逐渐恶化两种倾向。膜性肾病属于难治性肾病综合征,尚无公认的治疗方案,目前治疗主要是免疫抑制治疗。激素联合免疫抑制剂治疗存在缺陷,不少患者难以耐受不良反应从而中断治疗。他克莫司作为新型免疫抑制剂,目前有文献报道用于治疗特发性膜性肾病。本研究观察他克莫司(Tacrolimus, FK506)联合激素治疗特发性膜性肾病的疗效及安全性,为临床治疗特发性膜性肾病提供实验依据。
方法
选择2004年3月至2012年12月在郑大二附院经肾活检诊断为膜性肾病患者30例,随机分为2组,治疗组给予他克莫司(0.05mg/kg/d)联合激素(0.5mg/kg/d),对照组给予来氟米特(20mg/d)联合激素(0.5mg/kg/d)。观察治疗前及治疗2、4、8、12、24周后血清白蛋白、血糖、24小时尿蛋白的定量、血清胆固醇、血清甘油三酯及血肌酐的变化。
结果
治疗组治疗24周后总有效率明显高于对照组(80%v53.3%),治疗组治疗12、24周时24小时尿蛋白定量、甘油三酯明显低于对照组,差异有统计学意义(P<0.05)。治疗组治疗12、24周时白蛋白明显高于对照组,差异有统计学意义(P<0.05)。两组患者治疗2、4、8、12、24周后血肌酐、血糖变化无统计学意义(P>0.05)。
结论
与来氟米特(Leflunomide, LEF)联合激素治疗膜性肾病比较,他克莫司联合激素治疗效果更好,安全性更高,有一定延缓肾功能恶化风险。
Background and Objectives
Membranous nephropathy is a common cause of nephrotic syndrome (NS) in adults. The etiology and pathogenesis of the transformation are poorly understood, and most of the observations are hypothetical. Recently, M-type phospholipase A2receptor (PLA2-R) has been discovered as the main podocyte antigen in the pathogenesis of idiopathic MN. It has a very variable clinical course with all possible outcomes, ranging from spontaneous remission to progressive deterioration and development of end-stage renal disease (ESRD). Membranous nephropathy is refractory nephrotic syndrome, no recognized treatment plan, the treatment is immunosuppressive therapy. The hormone combined with immunosuppressant treatment options exist many deficiencies, many patients can not tolerate the adverse reactions had to give up treatment. Tacrolimus as a new immunosuppressive agents was reported in the literature for the treatment of idiopathic membranous nephropathy. This study evaluated the efficacy and safety of tacrolimus plus prednisone in membranous nephropathy manifested with nephrotic syndrome, which provide a experimental basis for the clinical treatment of idiopathic membranous nephropathy.
Methods
Thirty patients diagnosed with membranous nephropathy by renal biopsy between March2004and December2012in the Second Affiliated Hospital of Zhengzhou University were randomly divided into two groups, with15cases in each group. The treatment group was received tacrolimus(0.05mg/kg/d) plus prednisolone(0.5mg/kg/d), the control group was given leflunomide(20mg/d) combined with prednisolone(0.5mg/kg/d). Albumin, blood glucose,24-hour urine protein quantification, cholesterol, triglycerides, serum creatinine were determined before and after treatment for2,4,8,12,24weeks.
Result
After treatment for24weeks, compared with control group, tacrolimus combined with prednisolone increased the total effective rate(80.0%V53.3%), decreased24-hour urinary protein excretion and triglyceride (P<0.05), and raised serum Alb level (P<0.05). No obvious changes in levels of serum creatinine and blood sugar were observed after treatment for2,4,8,12,24weeks in both groups(P>0.05).
Conclusions
Compared with combined treatment with Leflunomide and prednisolone, tacrolimus combined prednisolone can alleviate disease condition, enhance safety and reduce the risk of deterioration of renal function in membranous nephropathy.
膜性肾病(membranous nephropathy, MN)是成人肾病综合征(nephrotic syndrome, NS)的常见病理类型。目前发病机制未明,最近研究认为膜性肾病发病机制与抗磷脂酶A2受体抗体(PLA2R)相关PLA2R抗体有关。其临床表现不一,有自发缓解和肾功能逐渐恶化两种倾向。膜性肾病属于难治性肾病综合征,尚无公认的治疗方案,目前治疗主要是免疫抑制治疗。激素联合免疫抑制剂治疗存在缺陷,不少患者难以耐受不良反应从而中断治疗。他克莫司作为新型免疫抑制剂,目前有文献报道用于治疗特发性膜性肾病。本研究观察他克莫司(Tacrolimus, FK506)联合激素治疗特发性膜性肾病的疗效及安全性,为临床治疗特发性膜性肾病提供实验依据。
方法
选择2004年3月至2012年12月在郑大二附院经肾活检诊断为膜性肾病患者30例,随机分为2组,治疗组给予他克莫司(0.05mg/kg/d)联合激素(0.5mg/kg/d),对照组给予来氟米特(20mg/d)联合激素(0.5mg/kg/d)。观察治疗前及治疗2、4、8、12、24周后血清白蛋白、血糖、24小时尿蛋白的定量、血清胆固醇、血清甘油三酯及血肌酐的变化。
结果
治疗组治疗24周后总有效率明显高于对照组(80%v53.3%),治疗组治疗12、24周时24小时尿蛋白定量、甘油三酯明显低于对照组,差异有统计学意义(P<0.05)。治疗组治疗12、24周时白蛋白明显高于对照组,差异有统计学意义(P<0.05)。两组患者治疗2、4、8、12、24周后血肌酐、血糖变化无统计学意义(P>0.05)。
结论
与来氟米特(Leflunomide, LEF)联合激素治疗膜性肾病比较,他克莫司联合激素治疗效果更好,安全性更高,有一定延缓肾功能恶化风险。
Background and Objectives
Membranous nephropathy is a common cause of nephrotic syndrome (NS) in adults. The etiology and pathogenesis of the transformation are poorly understood, and most of the observations are hypothetical. Recently, M-type phospholipase A2receptor (PLA2-R) has been discovered as the main podocyte antigen in the pathogenesis of idiopathic MN. It has a very variable clinical course with all possible outcomes, ranging from spontaneous remission to progressive deterioration and development of end-stage renal disease (ESRD). Membranous nephropathy is refractory nephrotic syndrome, no recognized treatment plan, the treatment is immunosuppressive therapy. The hormone combined with immunosuppressant treatment options exist many deficiencies, many patients can not tolerate the adverse reactions had to give up treatment. Tacrolimus as a new immunosuppressive agents was reported in the literature for the treatment of idiopathic membranous nephropathy. This study evaluated the efficacy and safety of tacrolimus plus prednisone in membranous nephropathy manifested with nephrotic syndrome, which provide a experimental basis for the clinical treatment of idiopathic membranous nephropathy.
Methods
Thirty patients diagnosed with membranous nephropathy by renal biopsy between March2004and December2012in the Second Affiliated Hospital of Zhengzhou University were randomly divided into two groups, with15cases in each group. The treatment group was received tacrolimus(0.05mg/kg/d) plus prednisolone(0.5mg/kg/d), the control group was given leflunomide(20mg/d) combined with prednisolone(0.5mg/kg/d). Albumin, blood glucose,24-hour urine protein quantification, cholesterol, triglycerides, serum creatinine were determined before and after treatment for2,4,8,12,24weeks.
Result
After treatment for24weeks, compared with control group, tacrolimus combined with prednisolone increased the total effective rate(80.0%V53.3%), decreased24-hour urinary protein excretion and triglyceride (P<0.05), and raised serum Alb level (P<0.05). No obvious changes in levels of serum creatinine and blood sugar were observed after treatment for2,4,8,12,24weeks in both groups(P>0.05).
Conclusions
Compared with combined treatment with Leflunomide and prednisolone, tacrolimus combined prednisolone can alleviate disease condition, enhance safety and reduce the risk of deterioration of renal function in membranous nephropathy.
引文
[1]Honkanen E, von Willebrand E, Teppo A M, et al. Adhesion molecules and urinary tumor necrosis factor-&agr; in idiopathic membranous glomerulonephritis [J]. Kidney international, 1998,53(4):909-917.
[2]陈楠.膜性肾病的治疗[J].肾脏病与透析肾移植杂志,2002,11(3)：251-251.
[3]Quaglia M, Stratta P. Idiopat hic membranous nephropathy [J]. Drugs,2009,69(10): 1303-1317.
[4]Cattran D. Management of membranous nephropathy:when and what for treatment [J]. Journal of the American Society of Nephrology,2005,16(5):1188-1194.
[5]5、ZHENG Y B, XU H, ZHOU L J, et al. Time to reflect our renal biopsy indications:a thirty-one-year review of renal biopsy histopathology [J]. Chinese Journal of Evidence-Based Pediatrics,2011,3:011.
[6]孙广东,许钟镐,罗萍,等.他克莫司治疗特发性膜性肾病的临床疗效观察[J].中国老年学杂志,2008,28(5)：469-471.
[7]Beck Jr L H, Bonegio R G B, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy [J]. New England Journal of Medicine,2009, 361(1):11-21.
[8]刘志红.膜性肾病的治疗[J].肾脏病与透析肾移植杂志,2009(004)：353-355.
[9]Beck Jr L H, Bonegio R G B, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy [J]. New England Journal of Medicine,2009, 361(1):11-21.
[10]Pascual J, Orte J, Marcen R, et al. Use of leflunomide in human renal transplantation [J]. Transplantation,2001,72(10):1709.
[11]Thomson A W, Starzl T E. New immunosuppressive drugs:mechanistic insights and potential therapeutic advances [J]. Immunological reviews,1993,136(1):71-97.
[12]Ahuja M, Goumenos D, Shortland J R, et al. Does immunosuppression with prednisolone and azathioprine alter the progression of idiopathic membranous nephropathy? [J]. American journal of kidney diseases,1999,34(3):521-529.
[13]Shaw K T, Ho A M, Raghavan A, et al. Immunosuppressive drugs prevent a rapid dephosphorylation of transcription factor NFAT1 in stimulated immune cells [J]. Proceedings of the National Academy of Sciences,1995,92(24):11205-11209.
[14]Denys A, Allain F, Masy E, et al. Enhancing the Effect of Secreted Cyclophilin B on Immunosuppressive Activity of Cyclosporine 1 [J]. Transplantation,1998,65(8):1076.
[15]Undre N A, Stevenson P, Schafer A. Pharmacokinetics of tacrolimus:clinically relevant aspects [C]. Transplantation proceedings.1999,31(7A):21S.
[16]Praga M, Barrio V, Juarez G F, et al. Tacrolimus monotherapy in membranous nephropathy:a randomized controlled trial [J]. Kidney international,2007,71(9):924-930.
[17]章海涛,胡伟新,谢红浪,等.普乐可复与环磷酰胺诱导治疗V型狼疮性肾炎的疗效比较[J].肾脏病与透析肾移植杂志,2006,15(6)：501.
[18]苗里宁,孙晶,远航,等.小剂量普乐可复治疗系膜增生性肾小球肾炎的临床研究[J].Am J Kidney Dis,2002,39(31):580-586.
[19]Wetzels J F M. Tacrolimus in membranous nephropathy [J]. Kidney international,2008, 73(2):238.
[20]孙广东,许钟镐,罗萍,等.他克莫司治疗特发性膜性肾病的临床疗效观察[J].中国老年学杂志,2008,28(5)：469-471.
[21]童宗武,高秀芳,孙阳,等.普乐可复治疗膜性肾病一例[J].中华肾脏病杂志,2002,18(3)：184-184.
[22]Li X, Lv R, He Q, et al. Early initiation of tacrolimus or cyclophosphamide therapy for idiopathic membranous nephropathy with severe proteinuria [J]. Journal of nephrology,2008, 21(4):584.
[23]Szeto C C, Leung C B, Lai F M, et al. Tacrolimus in resistant primary membranous nephropathy--a report of 3 cases [J]. Clinical nephrology,2003,59(4):293.
[1]陈惠萍,曾彩虹,胡伟新,等.10594例肾活检病理资料分析[J].肾脏病与透析肾移植杂志,2000,9(6)：501-509.
[2]陈以平,邓跃毅.特发性膜性肾病[J].中国中西医结合肾病杂志,2007,8(8)：435-437
[3][Wakai S, Magil A B. Focal glomerulosclerosis in idiopathic membranous glomerulonephritis [J]. Kidney Int,1992,41(2):428-434.
[4]陆再英,钟南山.内科学[M].北京：人民卫生出版社,2004：514-516.
[5]Glassock R J. Hematuria and pigmenturia [J]. Textbook of nephrology.4th ed. Philadelphia: Lippincott Williams & Wilkins,2001:503-12.
[6]刘春凤,徐元钊,丁小强,等.特发性膜性肾病预后影响因素[J].复旦学报：医学版,2005,32(2)：192-196.
[7]Li L S, Liu Z H. Epidemiologic data of renal diseases from a single unit in China:analysis based on 13,519 renal biopsies [J]. Kidney international,2004,66(3):920-923.
[8]Dumoulin A, Hill G S, Montseny J J, et al. Clinical and morphological prognostic factors in membranous nephropathy:significance of focal segmental glomerulosclerosis [J]. American journal of kidney diseases,2003,41(1):38-48.
[9]Wasserstein A G. Membranous glomerulonephritis [J].Journal of the American Society of Nephrology,1997,8(4):664-674.
[10]ZHENG Y B, XU H, ZHOU L J, et al. Time to reflect our renal biopsy indications:a thirty-one-year review of renal biopsy histopathology [J]. Chinese Journal of Evidence-Based Pediatrics,2011,3:011.
[11]Ehrenreich T, Churg J. Pathology of membranous nephropathy [J]. Pathol Annu,1968,3: 145-186.
[12]Bijl M, Dijstelbloem H M, Oost W W, et al. IgG subclass distribution of autoantibodies differs between renal and extra-renal relapses in patients with systemic lupus erythematosus [J]. Rheumatology,2002,41(1):62-67.
[13]Lombel R M, Hodson E M, Gipson D S. Treatment of steroid-resistant nephrotic syndrome in children:new guidelines from KDIGO [J]. Pediatric Nephrology,2013,28(3):409-414.
[14]Hirayama K, Ebihara I, Yamamoto S, et al. Predominance of type-2 immune response in idiopathic membranous nephropathy [J]. Nephron,2002,91(2):255-261.
[15]Bellomo R, Atkins R C. Membranous nephropathy and thromboembolism:is prophylactic anticoagulation warranted? [J]. Nephron,2008,63(3):249-254.
[16]刘志红.膜性肾病的治疗[J].肾脏病与透析肾移植杂志,2009(004)：353-355.
[17]Beck Jr L H, Bonegio R G B, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy [J]. New England Journal of Medicine,2009, 361(1):11-21.
[18]Troyanov S, Wall C A, Miller J A, et al. Idiopathic membranous nephropathy:definition and relevance of a partial remission [J]. Kidney international,2004,66(3):1199-1205.
[19]Waldman M, Austin lii H A. Controversies in the treatment of idiopathic membranous nephropathy [J]. Nature Reviews Nephrology,2009,5(8):469-479.
[20]Glassock R J. Diagnosis and natural course of membranous nephropathy [C]//Seminars in nephrology. WB Saunders,2003,23(4):324-332.
[21]陈惠萍,朱茂艳.膜性肾病[J].肾脏病与透析肾移植杂志,1998,7(4)：389-393.
[22]Coggins C H. for the Collaborative Study of the Adult Idiopathic Nephrotic Syndrome A controlled study of short-term prednisone treatment in adults with membranous nephropathy [J]. N Engl J Med,1979,301(24):1301-1306.
[23]Shiiki H, Saito T, Nishitani Y, et al. Prognosis and risk factors for idiopathic membranous nephropathy with nephrotic syndrome in Japan [J]. Kidney international,2004,65(4): 1400-1407.
[24]Cattran D C, Delmore T, Roscoe J, et al. A randomized controlled trial of prednisone in patients with idiopathic membranous nephropathy [J]. The New England journal of medicine, 1989,320(4):210.
[25]CAMERON J S, Healy M J R, Adu D. The Medical Research Council trial of short-term high-dose alternate day prednisolone in idiopathic membranous nephropathy with nephrotic syndrome in adults [J]. QJM,1990,74(2):133-156.
[26]Ponticelli C, Zucchelli P, Passerini P, et al. A randomized trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy [J]. The New England journal of medicine,1989,320(1):8.
[27]Eriguchi M, Oka H, Mizobuchi T, et al. Long-term outcomes of idiopathic membranous nephropathy in Japanese patients treated with low-dose cyclophosphamide and prednisolone [J]. Nephrology Dialysis Transplantation,2009,24(10):3082-3088.
[28]Ponticelli C, Altieri P, Scolari F, et al. A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy [J]. Journal of the American Society of Nephrology,1998,9(3): 444-450.
[29]Cattran D C, Delmore T, Roscoe J, et al. A randomized controlled trial of prednisone in patients with idiopathic membranous nephropathy [J]. The New England journal of medicine, 1989,320(4):210.
[30]Ponticelli C, Altieri P, Scolari F, et al. A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy [J]. Journal of the American Society of Nephrology,1998,9(3): 444-450.
[31]YUAN J, FANG W E I, ZHANG W, et al. Treatment of nephrotic idiopathic membranous nephropathy with monthly iv pulse cyclophosphamide and oral steroids:A single centre's retrospective study [J]. Nephrology,2011,16(4):440-445.
[32]Chen M, Li H, Li X Y, et al. Tacrolimus combined with corticosteroids in treatment of nephrotic idiopathic membranous nephropathy:a multicenter randomized controlled trial [J]. The American journal of the medical sciences,2010,339(3):233-238.
[33]du Buf-Vereijken P W G, Feith G W, Hollander D, et al. Restrictive use of immunosuppressive treatment in patients with idiopathic membranous nephropathy:high renal survival in a large patient cohort [J]. Qjm,2004,97(6):353-360.
[34]Perna A, Schieppati A, Zamora J, et al. Immunosuppressive treatment for idiopathic membranous nephropathy:a systematic review [J]. American journal of kidney diseases, 2004,44(3):385-401.
[35]Ponticelli C, Zucchelli P, Imbasciati E, et al. Controlled trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy [J]. The New England journal of medicine,1984,310(15):946.
[36]Ponticelli C, Zucchelli P, Passerini P, et al. A randomized trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy [J]. The New England journal of medicine,1989,320(1):8.
[37]Ponticelli C, Zucchelli P, Passerini P, et al. Methylprednisolone plus chlorambucil as compared with methylprednisolone alone for the treatment of idiopathic membranous nephropathy [J]. New England Journal of Medicine,1992,327(9):599-603.
[38]BIzzARRI D, BANFI G. A 10-year follow-up of a randomized study with methyiprednisolone and chlorambucil in membranous nephropathy [J]. Kidney international, 1995,48:1600-1604.
[39]Chen B J. Triptolide, a novel immunosuppressive and anti-inflammatory agent purified from a Chinese herb Tripterygium wilfordii Hook F [J]. Leukemia & lymphoma,2001,42(3): 253-265.
[40]王洪武,陈菊花.雷公藤多苷联合小剂虽泼尼松治疗肾病综合征临床观察[J].中国中西医结合肾病杂志,2008,9(2)：165.166.
[41]刘志红.足细胞损伤及其防治.[J]肾小球疾病金陵论坛,2006,15-24.
[42]Branten A J, du Buf-Vereijken P W, Vervloet M, et al. Mycophenolate mofetil in idiopathic membranous nephropathy:a clinical trial with comparison to a historic control group treated with cyclophosphamide [J]. American journal of kidney diseases:the official journal of the National Kidney Foundation,2007,50(2):248.
[43]Cattn mDC, Appel GB, Heberte, et al. Cydmporine in patients with steroid-resistant men branous nephropathy. A random trial [J]. Kindey,2001,59(4):1484-1490.
[44]Cannm DC, Alexopoulos E, Heering, et al. Cyciosporin in idiopathie glomerular dim associated with the nephrotie syndrome Workshop reeom mendatione [J]. Kindey Int,2007, 72(12):1429-1447.
[45]Gotmaenos D S, Katopodis K P, Passadakis P, et al. Cortiecmteroids and ciclosporin A in idiopathic membranous nephropathy:higher 1-elnission rates of nephrotie syndrome and less adverse reaetious than after traditional treatment with cytotoxic drugs [J]. AmJ Nephrol, 2007,27(3):226-231.
[46]Cherwinski HM, Byars N,,Ballamn , et el. Leflunomide mtederes with pyrimidine nueleotide biosynthesis [J]. Inflamm Res,1995,44(8):317-322,
[47]Xu X, Shen J, Mall J W, et al. In vitro and in vivo antitumor activity of a novel immunomodulatory drug, leflunomide:mechanisms of action [J]. Biochemical pharmacology, 1999,58(9):1405-1413.
[48]Jankovic V, Samardzic T, Stosic-Grujicic S, et al. Cell-specific inhibition of inducible nitric oxide synthase activation by leflunomide [J]. Cellular immunology,2000,199(2):73.
[49]周伟,张五星,张智敏,等.来氟米特治疗膜性肾病临床对照研[J].四川医学,2009,30：1889-1891.
[50]Ahuja M, Goumenos D, Shortland J R, et al. Does immunosuppression with prednisolone and azathioprine alter the progression of idiopathic membranous nephropathy? [J]. American journal of kidney diseases,1999,34(3):521-529.
[51]Shaw K T, Ho A M, Raghavan A, et al. Immunosuppressive drugs prevent a rapid dephosphorylation of transcription factor NFAT1 in stimulated immune cells [J]. Proceedings of the National Academy of Sciences,1995,92(24):11205-11209.
[52]Undre N A, Stevenson P, Schafer A. Pharmacokinetics of tacrolimus:clinically relevant aspects [C]. Transplantation proceedings.1999,31(7A):21-24.
[53]苗里宁,孙晶,远航,等.小剂量普乐可复治疗系膜增生性肾小球肾炎的临床研究[J].中华肾脏病杂志,2005,21(10)：624-625.
[54]Szeto C C, Leung C B, Lai F M, et al. Tacrolimus in resistant primary membranous nephropathy--a report of 3 cases [J]. Clinical nephrology,2003,59(4):293.
[55]Praga M, Barrio V, Juarez G F, et al. Tacrolimus monotherapy in membranous nephropathy:a randomized controlled trial [J]. Kidney international,2007,71(9):924-930.
[56]Praga M, Barrio V, Juarez G F, et al. Tacrolimus monotherapy in membranous nephropathy:a randomized controlled trial [J]. Kidney international,2007,71(9):924-930.
[57]WetzAs JF. Taerolimus in wannbranom nephropathy. [J]. Kidney Int,2008,73(2):238.
[58]王琳.陈以平教授“微观辨证”学术思想在膜性肾病中的应用[J].上海中医药大学学报,2006,20(3)：2-30.
[59]王琳,陈以平,邓跃毅,等.益气活血化湿方案为主治疗膜性肾病临床分析[J].中国中西医结合肾病杂志,2006,7(8)：393-396.
[60]刘志红.足细胞损伤及其防治[J].Diss.2006.
[61]Ruggenenti P, Chiurchiu C, Abbate M, et al. Rituximab for idwiopathic membranous nephropathy:who can bendit? [J]. Chn J Am Soc Nephrol,2006,1(4):738-748.
[62]Cobo M, Hernandez D, Rodriguez C, et al. Successful therapeutic use of rituximab in refractory membranous glomerulonephritis [J]. Clinical nephrology,2006,66(1):54-57.
[63]Cybulsky A V, Quigg R J, Salant D J. Experimental membranous nephropathy redux [J]. American Journal of Physiology-Renal Physiology,2005,289(4):F660-F671.
[64]Cunningham P N, Quigg R J. Contrasting roles of complement activation and its regulation in membranous nephropathy [J]. Journal of the American Society of Nephrology,2005,16(5): 1214-1222.
[65]Zent R, Nagai R, Cattran D C. Idiopathic membranous nephropathy in the elderly:A comparative study [J]. American journal of kidney diseases,1997,29(2):200-206.
[66]Pei Y, Cattran D, Greenwood C. Predicting chronic renal insufficiency in idiopathic membranous glomerulonephritis [J]. Kidney Int,1992,42(4):960-6.
[67]Donadio Jr J V, Torres V E, Velosa J A, et al. Idiopathic membranous nephropathy:the natural history of untreated patients [J]. Kidney Int,1988,33(3):708-715.
[68]Wakai S, Magil A B. Focal glomerulosclerosis in idiopathic membranous glomerulonephritis [J]. Kidney Int,1992,41(2):428-434.
[69]Yoshimoto K, Yokoyama H, Wada T, et al. Pathologic findings of initial biopsies reflect the outcomes of membranous nephropathy [J]. Kidney international,2004,65(1):148-153.
[2]陈楠.膜性肾病的治疗[J].肾脏病与透析肾移植杂志,2002,11(3)：251-251.
[3]Quaglia M, Stratta P. Idiopat hic membranous nephropathy [J]. Drugs,2009,69(10): 1303-1317.
[4]Cattran D. Management of membranous nephropathy:when and what for treatment [J]. Journal of the American Society of Nephrology,2005,16(5):1188-1194.
[5]5、ZHENG Y B, XU H, ZHOU L J, et al. Time to reflect our renal biopsy indications:a thirty-one-year review of renal biopsy histopathology [J]. Chinese Journal of Evidence-Based Pediatrics,2011,3:011.
[6]孙广东,许钟镐,罗萍,等.他克莫司治疗特发性膜性肾病的临床疗效观察[J].中国老年学杂志,2008,28(5)：469-471.
[7]Beck Jr L H, Bonegio R G B, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy [J]. New England Journal of Medicine,2009, 361(1):11-21.
[8]刘志红.膜性肾病的治疗[J].肾脏病与透析肾移植杂志,2009(004)：353-355.
[9]Beck Jr L H, Bonegio R G B, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy [J]. New England Journal of Medicine,2009, 361(1):11-21.
[10]Pascual J, Orte J, Marcen R, et al. Use of leflunomide in human renal transplantation [J]. Transplantation,2001,72(10):1709.
[11]Thomson A W, Starzl T E. New immunosuppressive drugs:mechanistic insights and potential therapeutic advances [J]. Immunological reviews,1993,136(1):71-97.
[12]Ahuja M, Goumenos D, Shortland J R, et al. Does immunosuppression with prednisolone and azathioprine alter the progression of idiopathic membranous nephropathy? [J]. American journal of kidney diseases,1999,34(3):521-529.
[13]Shaw K T, Ho A M, Raghavan A, et al. Immunosuppressive drugs prevent a rapid dephosphorylation of transcription factor NFAT1 in stimulated immune cells [J]. Proceedings of the National Academy of Sciences,1995,92(24):11205-11209.
[14]Denys A, Allain F, Masy E, et al. Enhancing the Effect of Secreted Cyclophilin B on Immunosuppressive Activity of Cyclosporine 1 [J]. Transplantation,1998,65(8):1076.
[15]Undre N A, Stevenson P, Schafer A. Pharmacokinetics of tacrolimus:clinically relevant aspects [C]. Transplantation proceedings.1999,31(7A):21S.
[16]Praga M, Barrio V, Juarez G F, et al. Tacrolimus monotherapy in membranous nephropathy:a randomized controlled trial [J]. Kidney international,2007,71(9):924-930.
[17]章海涛,胡伟新,谢红浪,等.普乐可复与环磷酰胺诱导治疗V型狼疮性肾炎的疗效比较[J].肾脏病与透析肾移植杂志,2006,15(6)：501.
[18]苗里宁,孙晶,远航,等.小剂量普乐可复治疗系膜增生性肾小球肾炎的临床研究[J].Am J Kidney Dis,2002,39(31):580-586.
[19]Wetzels J F M. Tacrolimus in membranous nephropathy [J]. Kidney international,2008, 73(2):238.
[20]孙广东,许钟镐,罗萍,等.他克莫司治疗特发性膜性肾病的临床疗效观察[J].中国老年学杂志,2008,28(5)：469-471.
[21]童宗武,高秀芳,孙阳,等.普乐可复治疗膜性肾病一例[J].中华肾脏病杂志,2002,18(3)：184-184.
[22]Li X, Lv R, He Q, et al. Early initiation of tacrolimus or cyclophosphamide therapy for idiopathic membranous nephropathy with severe proteinuria [J]. Journal of nephrology,2008, 21(4):584.
[23]Szeto C C, Leung C B, Lai F M, et al. Tacrolimus in resistant primary membranous nephropathy--a report of 3 cases [J]. Clinical nephrology,2003,59(4):293.
[1]陈惠萍,曾彩虹,胡伟新,等.10594例肾活检病理资料分析[J].肾脏病与透析肾移植杂志,2000,9(6)：501-509.
[2]陈以平,邓跃毅.特发性膜性肾病[J].中国中西医结合肾病杂志,2007,8(8)：435-437
[3][Wakai S, Magil A B. Focal glomerulosclerosis in idiopathic membranous glomerulonephritis [J]. Kidney Int,1992,41(2):428-434.
[4]陆再英,钟南山.内科学[M].北京：人民卫生出版社,2004：514-516.
[5]Glassock R J. Hematuria and pigmenturia [J]. Textbook of nephrology.4th ed. Philadelphia: Lippincott Williams & Wilkins,2001:503-12.
[6]刘春凤,徐元钊,丁小强,等.特发性膜性肾病预后影响因素[J].复旦学报：医学版,2005,32(2)：192-196.
[7]Li L S, Liu Z H. Epidemiologic data of renal diseases from a single unit in China:analysis based on 13,519 renal biopsies [J]. Kidney international,2004,66(3):920-923.
[8]Dumoulin A, Hill G S, Montseny J J, et al. Clinical and morphological prognostic factors in membranous nephropathy:significance of focal segmental glomerulosclerosis [J]. American journal of kidney diseases,2003,41(1):38-48.
[9]Wasserstein A G. Membranous glomerulonephritis [J].Journal of the American Society of Nephrology,1997,8(4):664-674.
[10]ZHENG Y B, XU H, ZHOU L J, et al. Time to reflect our renal biopsy indications:a thirty-one-year review of renal biopsy histopathology [J]. Chinese Journal of Evidence-Based Pediatrics,2011,3:011.
[11]Ehrenreich T, Churg J. Pathology of membranous nephropathy [J]. Pathol Annu,1968,3: 145-186.
[12]Bijl M, Dijstelbloem H M, Oost W W, et al. IgG subclass distribution of autoantibodies differs between renal and extra-renal relapses in patients with systemic lupus erythematosus [J]. Rheumatology,2002,41(1):62-67.
[13]Lombel R M, Hodson E M, Gipson D S. Treatment of steroid-resistant nephrotic syndrome in children:new guidelines from KDIGO [J]. Pediatric Nephrology,2013,28(3):409-414.
[14]Hirayama K, Ebihara I, Yamamoto S, et al. Predominance of type-2 immune response in idiopathic membranous nephropathy [J]. Nephron,2002,91(2):255-261.
[15]Bellomo R, Atkins R C. Membranous nephropathy and thromboembolism:is prophylactic anticoagulation warranted? [J]. Nephron,2008,63(3):249-254.
[16]刘志红.膜性肾病的治疗[J].肾脏病与透析肾移植杂志,2009(004)：353-355.
[17]Beck Jr L H, Bonegio R G B, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy [J]. New England Journal of Medicine,2009, 361(1):11-21.
[18]Troyanov S, Wall C A, Miller J A, et al. Idiopathic membranous nephropathy:definition and relevance of a partial remission [J]. Kidney international,2004,66(3):1199-1205.
[19]Waldman M, Austin lii H A. Controversies in the treatment of idiopathic membranous nephropathy [J]. Nature Reviews Nephrology,2009,5(8):469-479.
[20]Glassock R J. Diagnosis and natural course of membranous nephropathy [C]//Seminars in nephrology. WB Saunders,2003,23(4):324-332.
[21]陈惠萍,朱茂艳.膜性肾病[J].肾脏病与透析肾移植杂志,1998,7(4)：389-393.
[22]Coggins C H. for the Collaborative Study of the Adult Idiopathic Nephrotic Syndrome A controlled study of short-term prednisone treatment in adults with membranous nephropathy [J]. N Engl J Med,1979,301(24):1301-1306.
[23]Shiiki H, Saito T, Nishitani Y, et al. Prognosis and risk factors for idiopathic membranous nephropathy with nephrotic syndrome in Japan [J]. Kidney international,2004,65(4): 1400-1407.
[24]Cattran D C, Delmore T, Roscoe J, et al. A randomized controlled trial of prednisone in patients with idiopathic membranous nephropathy [J]. The New England journal of medicine, 1989,320(4):210.
[25]CAMERON J S, Healy M J R, Adu D. The Medical Research Council trial of short-term high-dose alternate day prednisolone in idiopathic membranous nephropathy with nephrotic syndrome in adults [J]. QJM,1990,74(2):133-156.
[26]Ponticelli C, Zucchelli P, Passerini P, et al. A randomized trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy [J]. The New England journal of medicine,1989,320(1):8.
[27]Eriguchi M, Oka H, Mizobuchi T, et al. Long-term outcomes of idiopathic membranous nephropathy in Japanese patients treated with low-dose cyclophosphamide and prednisolone [J]. Nephrology Dialysis Transplantation,2009,24(10):3082-3088.
[28]Ponticelli C, Altieri P, Scolari F, et al. A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy [J]. Journal of the American Society of Nephrology,1998,9(3): 444-450.
[29]Cattran D C, Delmore T, Roscoe J, et al. A randomized controlled trial of prednisone in patients with idiopathic membranous nephropathy [J]. The New England journal of medicine, 1989,320(4):210.
[30]Ponticelli C, Altieri P, Scolari F, et al. A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy [J]. Journal of the American Society of Nephrology,1998,9(3): 444-450.
[31]YUAN J, FANG W E I, ZHANG W, et al. Treatment of nephrotic idiopathic membranous nephropathy with monthly iv pulse cyclophosphamide and oral steroids:A single centre's retrospective study [J]. Nephrology,2011,16(4):440-445.
[32]Chen M, Li H, Li X Y, et al. Tacrolimus combined with corticosteroids in treatment of nephrotic idiopathic membranous nephropathy:a multicenter randomized controlled trial [J]. The American journal of the medical sciences,2010,339(3):233-238.
[33]du Buf-Vereijken P W G, Feith G W, Hollander D, et al. Restrictive use of immunosuppressive treatment in patients with idiopathic membranous nephropathy:high renal survival in a large patient cohort [J]. Qjm,2004,97(6):353-360.
[34]Perna A, Schieppati A, Zamora J, et al. Immunosuppressive treatment for idiopathic membranous nephropathy:a systematic review [J]. American journal of kidney diseases, 2004,44(3):385-401.
[35]Ponticelli C, Zucchelli P, Imbasciati E, et al. Controlled trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy [J]. The New England journal of medicine,1984,310(15):946.
[36]Ponticelli C, Zucchelli P, Passerini P, et al. A randomized trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy [J]. The New England journal of medicine,1989,320(1):8.
[37]Ponticelli C, Zucchelli P, Passerini P, et al. Methylprednisolone plus chlorambucil as compared with methylprednisolone alone for the treatment of idiopathic membranous nephropathy [J]. New England Journal of Medicine,1992,327(9):599-603.
[38]BIzzARRI D, BANFI G. A 10-year follow-up of a randomized study with methyiprednisolone and chlorambucil in membranous nephropathy [J]. Kidney international, 1995,48:1600-1604.
[39]Chen B J. Triptolide, a novel immunosuppressive and anti-inflammatory agent purified from a Chinese herb Tripterygium wilfordii Hook F [J]. Leukemia & lymphoma,2001,42(3): 253-265.
[40]王洪武,陈菊花.雷公藤多苷联合小剂虽泼尼松治疗肾病综合征临床观察[J].中国中西医结合肾病杂志,2008,9(2)：165.166.
[41]刘志红.足细胞损伤及其防治.[J]肾小球疾病金陵论坛,2006,15-24.
[42]Branten A J, du Buf-Vereijken P W, Vervloet M, et al. Mycophenolate mofetil in idiopathic membranous nephropathy:a clinical trial with comparison to a historic control group treated with cyclophosphamide [J]. American journal of kidney diseases:the official journal of the National Kidney Foundation,2007,50(2):248.
[43]Cattn mDC, Appel GB, Heberte, et al. Cydmporine in patients with steroid-resistant men branous nephropathy. A random trial [J]. Kindey,2001,59(4):1484-1490.
[44]Cannm DC, Alexopoulos E, Heering, et al. Cyciosporin in idiopathie glomerular dim associated with the nephrotie syndrome Workshop reeom mendatione [J]. Kindey Int,2007, 72(12):1429-1447.
[45]Gotmaenos D S, Katopodis K P, Passadakis P, et al. Cortiecmteroids and ciclosporin A in idiopathic membranous nephropathy:higher 1-elnission rates of nephrotie syndrome and less adverse reaetious than after traditional treatment with cytotoxic drugs [J]. AmJ Nephrol, 2007,27(3):226-231.
[46]Cherwinski HM, Byars N,,Ballamn , et el. Leflunomide mtederes with pyrimidine nueleotide biosynthesis [J]. Inflamm Res,1995,44(8):317-322,
[47]Xu X, Shen J, Mall J W, et al. In vitro and in vivo antitumor activity of a novel immunomodulatory drug, leflunomide:mechanisms of action [J]. Biochemical pharmacology, 1999,58(9):1405-1413.
[48]Jankovic V, Samardzic T, Stosic-Grujicic S, et al. Cell-specific inhibition of inducible nitric oxide synthase activation by leflunomide [J]. Cellular immunology,2000,199(2):73.
[49]周伟,张五星,张智敏,等.来氟米特治疗膜性肾病临床对照研[J].四川医学,2009,30：1889-1891.
[50]Ahuja M, Goumenos D, Shortland J R, et al. Does immunosuppression with prednisolone and azathioprine alter the progression of idiopathic membranous nephropathy? [J]. American journal of kidney diseases,1999,34(3):521-529.
[51]Shaw K T, Ho A M, Raghavan A, et al. Immunosuppressive drugs prevent a rapid dephosphorylation of transcription factor NFAT1 in stimulated immune cells [J]. Proceedings of the National Academy of Sciences,1995,92(24):11205-11209.
[52]Undre N A, Stevenson P, Schafer A. Pharmacokinetics of tacrolimus:clinically relevant aspects [C]. Transplantation proceedings.1999,31(7A):21-24.
[53]苗里宁,孙晶,远航,等.小剂量普乐可复治疗系膜增生性肾小球肾炎的临床研究[J].中华肾脏病杂志,2005,21(10)：624-625.
[54]Szeto C C, Leung C B, Lai F M, et al. Tacrolimus in resistant primary membranous nephropathy--a report of 3 cases [J]. Clinical nephrology,2003,59(4):293.
[55]Praga M, Barrio V, Juarez G F, et al. Tacrolimus monotherapy in membranous nephropathy:a randomized controlled trial [J]. Kidney international,2007,71(9):924-930.
[56]Praga M, Barrio V, Juarez G F, et al. Tacrolimus monotherapy in membranous nephropathy:a randomized controlled trial [J]. Kidney international,2007,71(9):924-930.
[57]WetzAs JF. Taerolimus in wannbranom nephropathy. [J]. Kidney Int,2008,73(2):238.
[58]王琳.陈以平教授“微观辨证”学术思想在膜性肾病中的应用[J].上海中医药大学学报,2006,20(3)：2-30.
[59]王琳,陈以平,邓跃毅,等.益气活血化湿方案为主治疗膜性肾病临床分析[J].中国中西医结合肾病杂志,2006,7(8)：393-396.
[60]刘志红.足细胞损伤及其防治[J].Diss.2006.
[61]Ruggenenti P, Chiurchiu C, Abbate M, et al. Rituximab for idwiopathic membranous nephropathy:who can bendit? [J]. Chn J Am Soc Nephrol,2006,1(4):738-748.
[62]Cobo M, Hernandez D, Rodriguez C, et al. Successful therapeutic use of rituximab in refractory membranous glomerulonephritis [J]. Clinical nephrology,2006,66(1):54-57.
[63]Cybulsky A V, Quigg R J, Salant D J. Experimental membranous nephropathy redux [J]. American Journal of Physiology-Renal Physiology,2005,289(4):F660-F671.
[64]Cunningham P N, Quigg R J. Contrasting roles of complement activation and its regulation in membranous nephropathy [J]. Journal of the American Society of Nephrology,2005,16(5): 1214-1222.
[65]Zent R, Nagai R, Cattran D C. Idiopathic membranous nephropathy in the elderly:A comparative study [J]. American journal of kidney diseases,1997,29(2):200-206.
[66]Pei Y, Cattran D, Greenwood C. Predicting chronic renal insufficiency in idiopathic membranous glomerulonephritis [J]. Kidney Int,1992,42(4):960-6.
[67]Donadio Jr J V, Torres V E, Velosa J A, et al. Idiopathic membranous nephropathy:the natural history of untreated patients [J]. Kidney Int,1988,33(3):708-715.
[68]Wakai S, Magil A B. Focal glomerulosclerosis in idiopathic membranous glomerulonephritis [J]. Kidney Int,1992,41(2):428-434.
[69]Yoshimoto K, Yokoyama H, Wada T, et al. Pathologic findings of initial biopsies reflect the outcomes of membranous nephropathy [J]. Kidney international,2004,65(1):148-153.