Treatment of Refractory Glomerular Diseases in Patients with Multitarget Therapy_West China Medical Journal

Authors：

LIU Xuelan ,  TAO Ye , WU Dan , JIANG Dan , YU Xiao , WEI Mian , JIN Qiaoling

Department of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

TAO Ye, Email: 279819327@qq.com

Keywords：

肾小球疾病; 霉酚酸酯; 他克莫司; 治疗

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【摘要】　目的　观察激素加霉酚酸酯（mycophenolate mofetil，MMF）和他克莫司（tacrolimus，FK506）的多靶点方案治疗难治性肾小球疾病的疗效及安全性。　方法　 2008年5月-2010年3月收治的15例狼疮性肾炎（lupus nephritis，LN）、3例膜增生性肾小球肾炎（membranoproliferative glomerulonephritis，MPGN）及3例膜性肾病（membranous nephropathy，MN）患者，因多种免疫抑制剂治疗无效或复发而改用多靶点疗法。泼尼松以30~40 mg/d起始，逐渐减量。MMF 和FK506起始剂量分别为0.5 g/d或1 mg/d，目标血药浓度分别为20~40 mg/（h·L）或5~8 ng/mL。定期随访观察肝肾功能、尿蛋白定量、不良反应等指标。　结果　治疗6个月时15例LN中7例（46.7%）完全缓解（complete remission，CR），5例（33.3%）部分缓解（partial remission，PR），3例（20%）无效（no response，NR）。3例MPGN均表现为NR。3例MN中2例（66.7%）PR，1例（33.3%）NR。治疗过程中呼吸道感染及脱发各1例，胃肠不适2例，肌酐逐步升高3例，无死亡或退出者。　结论　多靶点疗法对难治性LN安全、有效，可作为其他免疫抑制剂治疗无效或复发时的选择方案，但对MPGN和MN疗效欠佳，需进一步研究。
【Abstract】　Objective　 To investigate the efficacy and safety of multitarget therapy with steroid, mycophenolate mofetil (MMF) and tacrolimus (FK506) in the treatment of refractory glomerular diseases. 　Methods　 Fifteen patients with lupus nephritis (LN), 3 patients with membranoproliferative glomerulonephritis (MPGN) and 3 patients with membranous nephropathy (MN) who failed the previous immunosuppressive therapy from May 2008 to March 2010 in our hospital were treated with multitarget therapy. The initial dose of prednisone was 30-40 mg/d and then tapered gradually. MMF and FK506 were started at 0.5 g/d or 1 mg/d, and the target blood concentration of the two drugs was 20-40 mg/(h·L) and 5-8 ng/mL respectively. Clinical parameters such as liver and renal function, urine protein, and side effects were recorded and analyzed in the regular follow-up.　Results　 After 6 months of treatment, 7 (46.7%) of the 15 LN patients achieved complete remission (CR), 5 (33.3%) achieved partial remission (PR), while 3 (20%) failed this treatment and had no response (NR). All of the three MPGN patents had NR to this combined therapy. Two (66.7%) of the 3 MN patents achieved PR while 1 (33.3%) had NR. No patient withdrew or died because of side effects. One patient developed upper respiratory infection, one experienced alopecia, two developed gastrointestinal syndrome and three experienced gradual increasing in the serum creatinine.　Conclusion　 Multitarget therapy with FK506, MMF and steroid is an effective and safe therapy for refractory lupus nephritis and it can be used in patients who are resistant to the conventional immunosuppressive therapy. However, this combined therapy does not meet a satisfactory result in patients with MN and MPGN, which entails further study.

Citation： LIU Xuelan,TAO Ye,WU Dan,JIANG Dan,YU Xiao,WEI Mian,JIN Qiaoling. Treatment of Refractory Glomerular Diseases in Patients with Multitarget Therapy. West China Medical Journal, 2011, 26(4): 496-499. doi: Copy

1.	黎磊石, 刘志红. 肾小球疾病免疫抑制剂治疗的新方向--多靶点免疫抑制治疗[J]. 肾脏病与透析肾移植杂志, 2007, 16(1): 3-4.
2.	鲍浩, 章海涛, 张馨, 等. 难治性狼疮性肾炎多靶点治疗前瞻性临床研究[J]. 肾脏病与透析肾移植杂志, 2007, 16(1): 5-13.
3.	鲍浩, 刘志红, 胡伟新, 等. 多靶点诱导治疗增殖性和膜性狼疮性肾炎前瞻对照性临床研究[J]. 肾脏病与透析肾移植杂志, 2009, 18(3): 201-206.
4.	Bao H, Liu ZH, Xie HL, et al. Successful treatment of class Ⅴ+Ⅳ lupus nephritis with multitarget therapy[J]. J Am Soc Nephrol, 2008, 19(10): 2001-2010.
5.	Weening JJ, D’Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited[J]. J Am Soc Nephrol, 2004, 15 (2): 241-250.
6.	刘春蓓, 胡伟新, 谢红浪, 等. 霉酚酸酯与环磷酰胺治疗Ⅳ型伴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(1): 1-6.
7.	Huang Y, Liu Z, Huang H, et al. Effects of mycophenolic acid on endothelial cells[J]. Int Immunopharmacol, 2005, 5(6): 1029-1039.
8.	Koukoulaki M, Goumenos DS. The accumulated experience with the use of mycophenolate mofetil in primary glomerulonephritis[J]. Expert Opin Investig Drug, 2010, 19(5): 673-687.
9.	Mak A, Cheak AA, Tan JY, et al. Mycophenolate mofetil is as efficacious as, but safer than, cyclophosphamide in the treatment of proliferative lupus nephritis: a meta-analysis and meta-regression[J]. Rheumatology, 2009, 48(8): 944-952.
10.	Iatrou C, Zerbala S, Revela I, et al. Mycophenolate mofetil as maintenance therapy in patients with vasculitis and renal involvement[J]. Clin Nephrol, 2009, 72(1): 31-37.
11.	章海涛, 胡伟新, 谢红浪, 等. 前瞻性比较普乐可复与环磷酰胺诱导治疗Ⅴ型伴Ⅳ型狼疮性肾炎的疗效[J]. 肾脏病与透析肾移植杂志, 2006, 15(6): 508-514.
12.	Rousset F, Garcia E, Defrance T, et al. Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes[J].Proc Natl Acad Sci USA, 1992, 89(5): 1890-1893.
13.	Lanata CM, Mahmood T, Fine DM, et al. Combination therapy of mycophenolate mofetil and tacrolimus in lupus nephritis[J]. Lupus, 2010, 19(8): 935-940.
14.	Cortés-Hernández J, Torres-Salido MT, Medrano AS, et al. Long-term outcomes-mycophenolate mofetil treatment for lupus nephritis with addition of tacrolimus for resistant cases[J]. Nephrol Dial Transplant, 2010, 25(12): 3939-3948.
15.	Alchi B, Jayne D. Membranoproliferative glomerulonephritis[J]. Pediatr Nephrol, 2010, 25(8): 1409-1418.
16.	王海燕, 李晓玫, 赵明辉, 等.肾脏病学[M]. 3版. 北京: 人民卫生出版社, 2008: 1053-1058.
17.	Jones G, Juszczak M, Kingdon E, et al. Treatment of idiopathic membranoproliferative glomerulonephritis with mycophenolate mofetil and steroids[J]. Nephrol Dial Transplant, 2004, 19(12): 3160-3164.
18.	Yuan M, Zou J, Zhang X, et al. Combination therapy with mycophenolate mofetil and prednisone in steroid-resistant idiopathic membranoproliferative glomerulonephritis[J]. Clin Nephrol, 2010, 73(5): 354-359.
19.	Baheri N, Nemati E, Rahbar K, et al. Cyclosporine in treatment of membranoproliferative glomerulonephritis[J]. Arch Iran Med, 2008, 11(1): 26-29.
20.	Li XY, Li H, Ye H, et al. Tacrolimus Therapy in Adults With Steroid- and Cyclophosphamide-Resistant Nephrotic Syndrome and Normal or Mildly Reduced GFR[J]. Am J Kidney Dis, 2009, 54(1): 51-58.
21.	Praga M, Barrio V, Juárez GF, et al. Tacrolimus monotherapy in membranous nephropathy: a randomized controlled trial[J]. Kidney Int, 2007, 71(9): 924-930.
22.	Branten AJ, du Buf-Vereijken PW, Vervloet M, et al. Mycophenolate mofetil in idiopathic membranous nephropathy: a clinical trial with comparison to a historic control group treated with cyclophosphamide[J]. Am J Kidney Dis, 2007, 50(2): 248-256.
23.	Ballarin J, Poveda R, Ara J, et al. Treatment of idiopathic membranous nephropathy with the combination of steroids, tacrolimus and mycophenolate mofetil: results of a pilot study[J]. Nephrol Dial Transplant, 2007, 22(11): 3196-3201.
24.	李红梅, 施向东. 他克莫司治疗激素抵抗性肾病综合征[J]. 实用医学杂志, 2009, 25(22): 3871-3872.

1. 　黎磊石, 刘志红. 肾小球疾病免疫抑制剂治疗的新方向--多靶点免疫抑制治疗[J]. 肾脏病与透析肾移植杂志, 2007, 16(1): 3-4.
2. 　鲍浩, 章海涛, 张馨, 等. 难治性狼疮性肾炎多靶点治疗前瞻性临床研究[J]. 肾脏病与透析肾移植杂志, 2007, 16(1): 5-13.
3. 　鲍浩, 刘志红, 胡伟新, 等. 多靶点诱导治疗增殖性和膜性狼疮性肾炎前瞻对照性临床研究[J]. 肾脏病与透析肾移植杂志, 2009, 18(3): 201-206.
4. 　Bao H, Liu ZH, Xie HL, et al. Successful treatment of class Ⅴ+Ⅳ lupus nephritis with multitarget therapy[J]. J Am Soc Nephrol, 2008, 19(10): 2001-2010.
5. 　Weening JJ, D’Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited[J]. J Am Soc Nephrol, 2004, 15 (2): 241-250.
6. 　刘春蓓, 胡伟新, 谢红浪, 等. 霉酚酸酯与环磷酰胺治疗Ⅳ型伴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(1): 1-6.
7. 　Huang Y, Liu Z, Huang H, et al. Effects of mycophenolic acid on endothelial cells[J]. Int Immunopharmacol, 2005, 5(6): 1029-1039.
8. 　Koukoulaki M, Goumenos DS. The accumulated experience with the use of mycophenolate mofetil in primary glomerulonephritis[J]. Expert Opin Investig Drug, 2010, 19(5): 673-687.
9. 　Mak A, Cheak AA, Tan JY, et al. Mycophenolate mofetil is as efficacious as, but safer than, cyclophosphamide in the treatment of proliferative lupus nephritis: a meta-analysis and meta-regression[J]. Rheumatology, 2009, 48(8): 944-952.
10. 　Iatrou C, Zerbala S, Revela I, et al. Mycophenolate mofetil as maintenance therapy in patients with vasculitis and renal involvement[J]. Clin Nephrol, 2009, 72(1): 31-37.
11. 　章海涛, 胡伟新, 谢红浪, 等. 前瞻性比较普乐可复与环磷酰胺诱导治疗Ⅴ型伴Ⅳ型狼疮性肾炎的疗效[J]. 肾脏病与透析肾移植杂志, 2006, 15(6): 508-514.
12. 　Rousset F, Garcia E, Defrance T, et al. Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes[J].Proc Natl Acad Sci USA, 1992, 89(5): 1890-1893.
13. 　Lanata CM, Mahmood T, Fine DM, et al. Combination therapy of mycophenolate mofetil and tacrolimus in lupus nephritis[J]. Lupus, 2010, 19(8): 935-940.
14. 　Cortés-Hernández J, Torres-Salido MT, Medrano AS, et al. Long-term outcomes-mycophenolate mofetil treatment for lupus nephritis with addition of tacrolimus for resistant cases[J]. Nephrol Dial Transplant, 2010, 25(12): 3939-3948.
15. 　Alchi B, Jayne D. Membranoproliferative glomerulonephritis[J]. Pediatr Nephrol, 2010, 25(8): 1409-1418.
16. 　王海燕, 李晓玫, 赵明辉, 等.肾脏病学[M]. 3版. 北京: 人民卫生出版社, 2008: 1053-1058.
17. 　Jones G, Juszczak M, Kingdon E, et al. Treatment of idiopathic membranoproliferative glomerulonephritis with mycophenolate mofetil and steroids[J]. Nephrol Dial Transplant, 2004, 19(12): 3160-3164.
18. 　Yuan M, Zou J, Zhang X, et al. Combination therapy with mycophenolate mofetil and prednisone in steroid-resistant idiopathic membranoproliferative glomerulonephritis[J]. Clin Nephrol, 2010, 73(5): 354-359.
19. 　Baheri N, Nemati E, Rahbar K, et al. Cyclosporine in treatment of membranoproliferative glomerulonephritis[J]. Arch Iran Med, 2008, 11(1): 26-29.
20. 　Li XY, Li H, Ye H, et al. Tacrolimus Therapy in Adults With Steroid- and Cyclophosphamide-Resistant Nephrotic Syndrome and Normal or Mildly Reduced GFR[J]. Am J Kidney Dis, 2009, 54(1): 51-58.
21. 　Praga M, Barrio V, Juárez GF, et al. Tacrolimus monotherapy in membranous nephropathy: a randomized controlled trial[J]. Kidney Int, 2007, 71(9): 924-930.
22. 　Branten AJ, du Buf-Vereijken PW, Vervloet M, et al. Mycophenolate mofetil in idiopathic membranous nephropathy: a clinical trial with comparison to a historic control group treated with cyclophosphamide[J]. Am J Kidney Dis, 2007, 50(2): 248-256.
23. 　Ballarin J, Poveda R, Ara J, et al. Treatment of idiopathic membranous nephropathy with the combination of steroids, tacrolimus and mycophenolate mofetil: results of a pilot study[J]. Nephrol Dial Transplant, 2007, 22(11): 3196-3201.
24. 　李红梅, 施向东. 他克莫司治疗激素抵抗性肾病综合征[J]. 实用医学杂志, 2009, 25(22): 3871-3872.

West China Medical Journal

Treatment of Refractory Glomerular Diseases in Patients with Multitarget Therapy

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