Safety of Mycophenolate Mofetil versus Azathioprin in Renal Transplantation: A Systematic Review_Chinese Journal of Evidence-Based Medicine

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1.Department of Urology; West China Hospital; Sichuan University; Chengdu 610041; China2.Department of Neurology; the Third People s Hospital of Chengdu; Chengdu 6100313.Chinese Evidence-Based Medicine Center4.Key Lab of Transplant Engineering and Immunlogy of MOH;

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Keywords：

Mycophenolate acid; Azathioprine; Renal transplantation; Adverse drug reaction; Systematic review

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Objective 　To evaluate the safety of mycophenolate mofetil (MMF) versus azathioprine (AZA) for rejection after renal transplantation.
Methods 　We searched MEDLINE (1966 to Jun. 2004), EMBASE (1984 to Jun. 2004), The Cochrane Library (Issue 2, 2004) and Chinese Biomedical Database (CBM, 1979 to Jun. 2004). Randomized controlled trials (RCTs) comparing MMF with AZA for rejection after renal transplantation were included. The quality of included studies such as randomization, blinding, allocation concealment was evaluated and meta-analysis was performed using RevMan 4.1.1 software.
Results 　Twenty-Four RCTs comparing MMF (2 g/day or 3 g/day) with AZA for rejection after renal transplantation were identified. The digest system morbidity of MMF group was higher than that of AZA group. The incidence of vomiting, bellyache and diarrhea of MMF 3 g/day group was statistical by higher than that of AZA group (P＜0.05). The cytom egalovirus (CMV) infection morbidity of MMF 3 g/day group during 6 months, 1 year and 2 years follow-up was higher than AZA group with statistical difference, but for MMF 2 g/day group, this difference was only seen during 1 year follow-up. Leukopenia incidence of MMF 3g/day group was higher than AZA group with statistical difference, but this difference was not seen in MMF 2 g/day group. Thrombocytopenia incidence of MMF 3 g/day group was lower than AZA group with statistical difference. For skin carcinoma morbidity, no statistical difference was found among MMF 3 g/day, MMF 2 g/day and AZA groups.
Conclusions 　Compared with AZA, MMF represents higher digest system side-effects incidence, higher morbidity of leucopenia and CMV infection and lower incidence of thrombocytopenia. The dose-response relationship of adverse drug reaction is found.

Citation： WANG Kunjie,ZHANG Haitao,LI Youping,LU Yiping,WEI Qiang,LI Hong,YANG Yuru. Safety of Mycophenolate Mofetil versus Azathioprin in Renal Transplantation: A Systematic Review. Chinese Journal of Evidence-Based Medicine, 2005, 05(5): 365-374. doi: Copy

1.	纪玉莲, 杨彦强, 杨光宝, 余学清,姜宗培,沈清端,吴培根,朱兰英. 霉酚酸酯预防肾移植术后急性排斥反应临床观察[J]. 中山医科大学学报,2001; 22(3): 215-217.
2.	黄丽萍, 杨诗玉, 武小桐, 陈再彬, 王振兴, 卫熹. 肾移植患者术后早期应用霉酚酸酯的临床观察[J]. 中华器官移植杂志, 2000; 21(5): 294-295.
3.	郭宏波, 张玉海. 霉酚酸酯(MMF)在肾移植中的应用[J]. 中国新药杂志, 1998; 7(6): 444-446.
4.	凌建煜, 祝宇, 孙福康. 骁悉与小剂量环孢素A在尸体肾移植中的联合应用[J]. 中华器官移植杂志, 1998; 19(3): 175-176.
5.	王庆文, 季曙明, 陈劲松, 殷立平, 徐斌, 陈惠萍, 黎磊石. 霉酚酸酯预防尸体肾移植急性排斥反应[J]. 肾脏病与透析肾移植杂志,1998; 7(1): 34-37.
6.	张海涛, 王坤杰, 李幼平, 高励, 刘瑾, 蔡羽嘉. 肾移植术后骁悉与硫唑嘌呤抗排斥反应随机对照试验的系统评价 [J]. 中国循证医学杂志, 2004; 4(2): 79-91.
7.	US Renal Transplant Mycophenolate Mofetil Study Group. Mycophenolate mofetil in cadaveric renal transplantation[J]. Am J Kidney Disease, 1999; 34(2): 296-303.
8.	Miller J, Mendez R, Pirsch JD, Jensik SC. Safety and efficacy of tacrolimus in combination with mycophenolate mofetil in cadaveric renal transplant recipients[J]. Transplantation, 2000; 69(5): 875-880.
9.	The Mycophenolate Mofetil Acute Renal Rejection Study Group. Mycophenolate mofetil for the treatment of a first acute renal allograft rejection: three-year follow-up[J]. Transplantation, 2001; 71(8): 1091-1097.
10.	Johnson C, Ahsan N, Gonwa T, Hallorax P, Stegall M, Hardy M, Metzger R, Shield C, Rocher L, Scandling J. Random trial of tacrolimus in combination with AZAthioprine or mycophenolate mofetil versus cyclosporine with mycophenolate mofetil after cadaveric kidney transplantation[J]. Transplantation, 2000; 69(5): 834-841.
11.	Jirasiritham S, Sumethkul V, Mavichak V, Chalermsanyakorn P. The treatment of chronic rejection with mycophenolate mofetil versus AZAthioprine in kidney transplantation[J]. Transplant Proc, 2000; 32(7): 2040-2042.
12.	Suhail SM, Vathsala A, Lou HX, Woo KT. Safety and efficacy of mycophenolate mofetil for prophylaxis in Asian renal transplant recipients[J]. Transplant Proc, 2000; 32(7):1757-1758.
13.	Mathew TH. A blinded, long-time, randomized multicenter study of mycophenolate mofetil in cadaveric renal transplantation: result at three years[J]. Transplantation, 1998; 65(11): 1450-1454.
14.	Mendez R. FK506 and mycophenolate mofetil in renal transplant recipients: six-month result of a multicenter, randomized dose ranging trial[J]. Transplantation Proc, 1998; 30(4):1287-1289.
15.	The Mycophenolate mofetil Acute Renal Rejection Study Group. Mycophenolate mofetil for the treatment of a first acute renal allograft rejection[J]. Transplantation, 1998; 65(2): 235-241.
16.	Neylan JE. Immunosupppressive therapy in high-risk transplant patients: dose-dependent efficacy of mycophenolate mofetil in African-American renal allograft recipients[J]. Transplantation, 1997; 64(9): 1277-1282.
17.	The U.S. Mycophenolate Mofetil Study Group. Mycophenolate mofetil for the prevention of acute rejection of primary cadaveric kidney transplants: status of the MYC 1866 study at 1 year[J]. Transplant Proc, 1997; 29(1-2): 348-349.
18.	The Tricontinental Mycophnolate Mofetil Rneal Transplantation Study Group. A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation[J]. Transplantation, 1996; 61(7): 1029-1037.
19.	European Mycophenolate Mofetil Cooperative Study Group. Mycophenolate in renal transplantation: 3-year results from the placebo-controlled trial[J]. Transplantation, 1999; 68(3): 391-396.
20.	Solinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients[J]. Transplantation, 1995; 60(3): 225-232.
21.	European Mycophenolate Mofetil Cooperative Study Group. Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroid for prevention of acute rejection[J]. Lancet, 1995; 345(8 961): 1321-1325.
22.	Ji YL, Yang YQ, Yang GB, Yu XQ, Jiang PZ, Shen QD, Wu PG, Zhu LY. The clinical investigation of mycophenolate mofetil for the prevention of acute rejection[J]. Acad J SUMS, 2001; 22(3): 215-217.
23.	Huang LP, Yang SY, Wu XT, Chen ZB, Wang ZX, Wei X. Clinical observation on the early application of cellcept following cadaveric renal tansplantation[J]. Chin J Organ Transplant, 2000; 21(5): 294-295.
24.	Guo HB, Zhang YH. The use of mycophenolate mofetil in renal tansplantation[J]. China J New Drug, 1998; 7(6): 444-446.
25.	Ling JY, Zhu Y, Sun FK. Combined use of MMF with low dosage of cyclosporine A in renal tansplantation[J]. Chin J Organ Transplant, 1998; 19(3): 175-176.
26.	Wang QW, Ji SM, Chen JS, Yin LP, Xu B, Chen HP, Li LS. Prevention acute rejection of MMF in renal transplantation[J]. J Nephrol Dialy Transplant, 1998; 7(1): 34-37.
27.	Giuseppe R, Mariadomenica L, Eliana G, Maria G, Borislav DD, Bogdan EI, Giulia G, Donato D, Maurizio S, Silvio S, Umberto V, Giuseppe S, Georges M, Stefano F, Paolo R, Vito S, Jean-Louis B, Norberto P, Piero R. Mycophenolate mofetil versus AZAthioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial[J]. Lancet, 2004; 364(7): 503-512.
28.	Sami S, Jos′e M, Manuel A, Jacques S, Jean-paul S, Bruno V, Short-term combination of mcophenolate mofetil with cyclosporine as a therapeutic option for renal transplant recipients[J]. Transplantation, 2002; 74(4): 511-517.
29.	Miladipour AH, Ghods AJ, Nejadgashti H. Effect of mcophenolate mofetil on the prevention of acute renal allograft rejection[J]. Transplantation Proceedings, 2002; 34: 2089-2090.
30.	Metcalfe MS, Jain S, Waller JR, Saunders RN, Bicknell GR, Nicholson ML. A randomized trial of mycophenolate mofetil versus AZAthioprine as calcineurin inhibitor sparing agents in the treatment of chronic allograft nephropathy[J]. Transplantation Proceedings, 2002; 34:1812-1814.
31.	Zhang HT, Wang KJ, Li YP, Gao L, Liu J, Cai YJ. Systematic review of clinical research literatures about comparison mycophenolate acid and AZAthioprine after renal transplantation[J]. Chin J of EBM, 2004; 4(2): 79-91.
32.	Halloran P, Mathew T, Tomlanovich S, Groth C, Hooftman L, Barker C. Mycophenolate mofetil in renal allograft recipients: a pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection[J]. Transplantation, 1997; 63(1): 39-47.
33.	Warrens AN. The evolving role of mycophenolate mofetil in renal transplantation[J]. Q J Med, 2000; 93(3): 15-20.
34.	Smak Gregoor PJ, Hesse CJ, van Gelder T. Relation of mycophenolic acid trough levels and adverse events in kidney allograft recipients[J]. Transplant Proc, 1998; 30(423): 1192-1193.
35.	Van Gelder T, Hilbrands LB, Vanrenterghem Y. A randomized double-blind, multicenter plasma concentration controlled study of the safety and efficacy of oral mycophenolate mofetil for the prevention of acute rejection after kidney transplantation[J]. Transplantation, 1999; 68(563): 261-266.
36.	Shaw LM, Sollinger HW, Halloran P. Mycophenolate mofetil: a report of the consensus panel[J]. Ther Drug Monit, 1995; 17(43): 690-699.
37.	Pillans PI, Rigby RJ, Kubler P. A retrospective analysis of mycophenolic acid and cyclosporin concentrations with acute rejection in renal transplant recipients[J]. Clin Biochem, 2001; 34(43):77-81.

1. 纪玉莲, 杨彦强, 杨光宝, 余学清,姜宗培,沈清端,吴培根,朱兰英. 霉酚酸酯预防肾移植术后急性排斥反应临床观察[J]. 中山医科大学学报,2001; 22(3): 215-217.
2. 黄丽萍, 杨诗玉, 武小桐, 陈再彬, 王振兴, 卫熹. 肾移植患者术后早期应用霉酚酸酯的临床观察[J]. 中华器官移植杂志, 2000; 21(5): 294-295.
3. 郭宏波, 张玉海. 霉酚酸酯(MMF)在肾移植中的应用[J]. 中国新药杂志, 1998; 7(6): 444-446.
4. 凌建煜, 祝宇, 孙福康. 骁悉与小剂量环孢素A在尸体肾移植中的联合应用[J]. 中华器官移植杂志, 1998; 19(3): 175-176.
5. 王庆文, 季曙明, 陈劲松, 殷立平, 徐斌, 陈惠萍, 黎磊石. 霉酚酸酯预防尸体肾移植急性排斥反应[J]. 肾脏病与透析肾移植杂志,1998; 7(1): 34-37.
6. 张海涛, 王坤杰, 李幼平, 高励, 刘瑾, 蔡羽嘉. 肾移植术后骁悉与硫唑嘌呤抗排斥反应随机对照试验的系统评价 [J]. 中国循证医学杂志, 2004; 4(2): 79-91.
7. US Renal Transplant Mycophenolate Mofetil Study Group. Mycophenolate mofetil in cadaveric renal transplantation[J]. Am J Kidney Disease, 1999; 34(2): 296-303.
8. Miller J, Mendez R, Pirsch JD, Jensik SC. Safety and efficacy of tacrolimus in combination with mycophenolate mofetil in cadaveric renal transplant recipients[J]. Transplantation, 2000; 69(5): 875-880.
9. The Mycophenolate Mofetil Acute Renal Rejection Study Group. Mycophenolate mofetil for the treatment of a first acute renal allograft rejection: three-year follow-up[J]. Transplantation, 2001; 71(8): 1091-1097.
10. Johnson C, Ahsan N, Gonwa T, Hallorax P, Stegall M, Hardy M, Metzger R, Shield C, Rocher L, Scandling J. Random trial of tacrolimus in combination with AZAthioprine or mycophenolate mofetil versus cyclosporine with mycophenolate mofetil after cadaveric kidney transplantation[J]. Transplantation, 2000; 69(5): 834-841.
11. Jirasiritham S, Sumethkul V, Mavichak V, Chalermsanyakorn P. The treatment of chronic rejection with mycophenolate mofetil versus AZAthioprine in kidney transplantation[J]. Transplant Proc, 2000; 32(7): 2040-2042.
12. Suhail SM, Vathsala A, Lou HX, Woo KT. Safety and efficacy of mycophenolate mofetil for prophylaxis in Asian renal transplant recipients[J]. Transplant Proc, 2000; 32(7):1757-1758.
13. Mathew TH. A blinded, long-time, randomized multicenter study of mycophenolate mofetil in cadaveric renal transplantation: result at three years[J]. Transplantation, 1998; 65(11): 1450-1454.
14. Mendez R. FK506 and mycophenolate mofetil in renal transplant recipients: six-month result of a multicenter, randomized dose ranging trial[J]. Transplantation Proc, 1998; 30(4):1287-1289.
15. The Mycophenolate mofetil Acute Renal Rejection Study Group. Mycophenolate mofetil for the treatment of a first acute renal allograft rejection[J]. Transplantation, 1998; 65(2): 235-241.
16. Neylan JE. Immunosupppressive therapy in high-risk transplant patients: dose-dependent efficacy of mycophenolate mofetil in African-American renal allograft recipients[J]. Transplantation, 1997; 64(9): 1277-1282.
17. The U.S. Mycophenolate Mofetil Study Group. Mycophenolate mofetil for the prevention of acute rejection of primary cadaveric kidney transplants: status of the MYC 1866 study at 1 year[J]. Transplant Proc, 1997; 29(1-2): 348-349.
18. The Tricontinental Mycophnolate Mofetil Rneal Transplantation Study Group. A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation[J]. Transplantation, 1996; 61(7): 1029-1037.
19. European Mycophenolate Mofetil Cooperative Study Group. Mycophenolate in renal transplantation: 3-year results from the placebo-controlled trial[J]. Transplantation, 1999; 68(3): 391-396.
20. Solinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients[J]. Transplantation, 1995; 60(3): 225-232.
21. European Mycophenolate Mofetil Cooperative Study Group. Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroid for prevention of acute rejection[J]. Lancet, 1995; 345(8 961): 1321-1325.
22. Ji YL, Yang YQ, Yang GB, Yu XQ, Jiang PZ, Shen QD, Wu PG, Zhu LY. The clinical investigation of mycophenolate mofetil for the prevention of acute rejection[J]. Acad J SUMS, 2001; 22(3): 215-217.
23. Huang LP, Yang SY, Wu XT, Chen ZB, Wang ZX, Wei X. Clinical observation on the early application of cellcept following cadaveric renal tansplantation[J]. Chin J Organ Transplant, 2000; 21(5): 294-295.
24. Guo HB, Zhang YH. The use of mycophenolate mofetil in renal tansplantation[J]. China J New Drug, 1998; 7(6): 444-446.
25. Ling JY, Zhu Y, Sun FK. Combined use of MMF with low dosage of cyclosporine A in renal tansplantation[J]. Chin J Organ Transplant, 1998; 19(3): 175-176.
26. Wang QW, Ji SM, Chen JS, Yin LP, Xu B, Chen HP, Li LS. Prevention acute rejection of MMF in renal transplantation[J]. J Nephrol Dialy Transplant, 1998; 7(1): 34-37.
27. Giuseppe R, Mariadomenica L, Eliana G, Maria G, Borislav DD, Bogdan EI, Giulia G, Donato D, Maurizio S, Silvio S, Umberto V, Giuseppe S, Georges M, Stefano F, Paolo R, Vito S, Jean-Louis B, Norberto P, Piero R. Mycophenolate mofetil versus AZAthioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial[J]. Lancet, 2004; 364(7): 503-512.
28. Sami S, Jos′e M, Manuel A, Jacques S, Jean-paul S, Bruno V, Short-term combination of mcophenolate mofetil with cyclosporine as a therapeutic option for renal transplant recipients[J]. Transplantation, 2002; 74(4): 511-517.
29. Miladipour AH, Ghods AJ, Nejadgashti H. Effect of mcophenolate mofetil on the prevention of acute renal allograft rejection[J]. Transplantation Proceedings, 2002; 34: 2089-2090.
30. Metcalfe MS, Jain S, Waller JR, Saunders RN, Bicknell GR, Nicholson ML. A randomized trial of mycophenolate mofetil versus AZAthioprine as calcineurin inhibitor sparing agents in the treatment of chronic allograft nephropathy[J]. Transplantation Proceedings, 2002; 34:1812-1814.
31. Zhang HT, Wang KJ, Li YP, Gao L, Liu J, Cai YJ. Systematic review of clinical research literatures about comparison mycophenolate acid and AZAthioprine after renal transplantation[J]. Chin J of EBM, 2004; 4(2): 79-91.
32. Halloran P, Mathew T, Tomlanovich S, Groth C, Hooftman L, Barker C. Mycophenolate mofetil in renal allograft recipients: a pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection[J]. Transplantation, 1997; 63(1): 39-47.
33. Warrens AN. The evolving role of mycophenolate mofetil in renal transplantation[J]. Q J Med, 2000; 93(3): 15-20.
34. Smak Gregoor PJ, Hesse CJ, van Gelder T. Relation of mycophenolic acid trough levels and adverse events in kidney allograft recipients[J]. Transplant Proc, 1998; 30(423): 1192-1193.
35. Van Gelder T, Hilbrands LB, Vanrenterghem Y. A randomized double-blind, multicenter plasma concentration controlled study of the safety and efficacy of oral mycophenolate mofetil for the prevention of acute rejection after kidney transplantation[J]. Transplantation, 1999; 68(563): 261-266.
36. Shaw LM, Sollinger HW, Halloran P. Mycophenolate mofetil: a report of the consensus panel[J]. Ther Drug Monit, 1995; 17(43): 690-699.
37. Pillans PI, Rigby RJ, Kubler P. A retrospective analysis of mycophenolic acid and cyclosporin concentrations with acute rejection in renal transplant recipients[J]. Clin Biochem, 2001; 34(43):77-81.

Chinese Journal of Evidence-Based Medicine

Safety of Mycophenolate Mofetil versus Azathioprin in Renal Transplantation: A Systematic Review

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