• 四川大學(xué)華西醫(yī)院腎臟內(nèi)科（成都，610041）;

【摘要】　目的　 觀察激素加霉酚酸酯（mycophenolate mofetil，MMF）和他克莫司（tacrolimus，F(xiàn)K506）的多靶點(diǎn)方案治療難治性腎小球疾病的療效及安全性。　方法　 2008年5月-2010年3月收治的15例狼瘡性腎炎（lupus nephritis，LN）、3例膜增生性腎小球腎炎（membranoproliferative glomerulonephritis，MPGN）及3例膜性腎病（membranous nephropathy，MN）患者，因多種免疫抑制劑治療無效或復(fù)發(fā)而改用多靶點(diǎn)療法。潑尼松以30~40 mg/d起始，逐漸減量。MMF 和FK506起始劑量分別為0.5 g/d或1 mg/d，目標(biāo)血藥濃度分別為20~40 mg/（h·L）或5~8 ng/mL。定期隨訪觀察肝腎功能、尿蛋白定量、不良反應(yīng)等指標(biāo)。　結(jié)果　 治療6個(gè)月時(shí)15例LN中7例（46.7%）完全緩解（complete remission，CR），5例（33.3%）部分緩解（partial remission，PR），3例（20%）無效（no response，NR）。3例MPGN均表現(xiàn)為NR。3例MN中2例（66.7%）PR，1例（33.3%）NR。治療過程中呼吸道感染及脫發(fā)各1例，胃腸不適2例，肌酐逐步升高3例，無死亡或退出者。　結(jié)論　 多靶點(diǎn)療法對難治性LN安全、有效，可作為其他免疫抑制劑治療無效或復(fù)發(fā)時(shí)的選擇方案，但對MPGN和MN療效欠佳，需進(jìn)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.

引用本文： 劉學(xué)蘭,陶冶,吳丹,姜丹,于笑,魏冕,金巧玲. 多靶點(diǎn)治療難治性腎小球疾病臨床觀察. 華西醫(yī)學(xué), 2011, 26(4): 496-499. doi: 復(fù)制

1. 　黎磊石, 劉志紅. 腎小球疾病免疫抑制劑治療的新方向--多靶點(diǎn)免疫抑制治療[J]. 腎臟病與透析腎移植雜志, 2007, 16(1): 3-4.
2. 　鮑浩, 章海濤, 張馨, 等. 難治性狼瘡性腎炎多靶點(diǎn)治療前瞻性臨床研究[J]. 腎臟病與透析腎移植雜志, 2007, 16(1): 5-13.
3. 　鮑浩, 劉志紅, 胡偉新, 等. 多靶點(diǎn)誘導(dǎo)治療增殖性和膜性狼瘡性腎炎前瞻對照性臨床研究[J]. 腎臟病與透析腎移植雜志, 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. 　劉春蓓, 胡偉新, 謝紅浪, 等. 霉酚酸酯與環(huán)磷酰胺治療Ⅳ型伴V型狼瘡性腎炎的療效比較[J]. 腎臟病與透析腎移植雜志, 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. 　章海濤, 胡偉新, 謝紅浪, 等. 前瞻性比較普樂可復(fù)與環(huán)磷酰胺誘導(dǎo)治療Ⅴ型伴Ⅳ型狼瘡性腎炎的療效[J]. 腎臟病與透析腎移植雜志, 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, 李曉玫, 趙明輝, 等.腎臟病學(xué)[M]. 3版. 北京: 人民衛(wèi)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. 　李紅梅, 施向東. 他克莫司治療激素抵抗性腎病綜合征[J]. 實(shí)用醫(yī)學(xué)雜志, 2009, 25(22): 3871-3872.
  1. 1. 　黎磊石, 劉志紅. 腎小球疾病免疫抑制劑治療的新方向--多靶點(diǎn)免疫抑制治療[J]. 腎臟病與透析腎移植雜志, 2007, 16(1): 3-4.
  2. 2. 　鮑浩, 章海濤, 張馨, 等. 難治性狼瘡性腎炎多靶點(diǎn)治療前瞻性臨床研究[J]. 腎臟病與透析腎移植雜志, 2007, 16(1): 5-13.
  3. 3. 　鮑浩, 劉志紅, 胡偉新, 等. 多靶點(diǎn)誘導(dǎo)治療增殖性和膜性狼瘡性腎炎前瞻對照性臨床研究[J]. 腎臟病與透析腎移植雜志, 2009, 18(3): 201-206.
  4. 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. 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. 6. 　劉春蓓, 胡偉新, 謝紅浪, 等. 霉酚酸酯與環(huán)磷酰胺治療Ⅳ型伴V型狼瘡性腎炎的療效比較[J]. 腎臟病與透析腎移植雜志, 2006, 15(1): 1-6.
  7. 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. 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. 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. 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. 11. 　章海濤, 胡偉新, 謝紅浪, 等. 前瞻性比較普樂可復(fù)與環(huán)磷酰胺誘導(dǎo)治療Ⅴ型伴Ⅳ型狼瘡性腎炎的療效[J]. 腎臟病與透析腎移植雜志, 2006, 15(6): 508-514.
  12. 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. 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. 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. 15. 　Alchi B, Jayne D. Membranoproliferative glomerulonephritis[J]. Pediatr Nephrol, 2010, 25(8): 1409-1418.
  16. 16. 　王海燕, 李曉玫, 趙明輝, 等.腎臟病學(xué)[M]. 3版. 北京: 人民衛(wèi)生出版社, 2008: 1053-1058.
  17. 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. 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. 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. 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. 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. 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. 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. 24. 　李紅梅, 施向東. 他克莫司治療激素抵抗性腎病綜合征[J]. 實(shí)用醫(yī)學(xué)雜志, 2009, 25(22): 3871-3872.