Safety and Efficacy of Steroid Withdrawal in Modern Triple Immunosuppressant: A Systematic Review_Chinese Journal of Evidence-Based Medicine

Authors：

TAN Jiying ¹³ , ZHAO Na ¹ , WU Taixiang ² , YANG Kehu ³ , TIAN Jinhui ³ , LIU Yali ³ , WANG Li ² , SUN xin ² , LU Yiping ⁴ ,  LI Youping ¹²

1. Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu 610041, China 2. Evidence-Based Medicine and Clinical Epidemiology Center, West China Hospital, Sichuan University, Chengdu 610041, China 3. Evidence-Based Medicine Center, Lanzhou University, Lanzhou 730000, China 4. Department of Urology, West China Hospital, Sichuan University, Chengdu 610041,China;

Corresponding author：

LI Youping, Email: yzmylab@hotmail.com

Keywords：

Renal transplantation; Modern triple immunosuppressant; Steroid withdrawal; Safety; Efficacy; Systematic review

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Objective 　To evaluate the safety and efficacy of steroid withdrawal in modern triple immunosuppressant (Cycloproine/Tacrolimus, Mycophenolate Mofetil and Steroid) on renal transplantation recipients.
Methods 　We searched MEDLINE (1966-Sep. 2005), OVID (1966-2004), EMBASE (1984-2004), The Cochrane Library (Issue 4, 2005), CBMdisc (1994-2005), and handsearched 7 Chinese Journals. Randomized controlled trials (RCTs) adopting modern triple immunosuppressant, and comparing steroid withdrawal (SW), group and steroid continuing group (SC) were selected. The quality of included studies was evaluated and graded according to Cochrane Reviewer’s Handbook 4.2.5, and meta-analysis was performed by using RevMan 4.2.7 software.
Results 　Nine RCTs including 1 681 patients (845 in SW and 836 in SC) were identified. The average follow-up time was 6-12 months. No significant difference was found in using CsA or Tac in modern triple immunosuppressant. The results of our meta-analysis showed: ① the risk of acute rejection was two times higher in SW than SC (RR 2.05, 95% CI 1.54 to 2.72, P lt;0.000 01), mainly Banff grade I (mild) (RR 1.92, 95% CI 1.16 to 3.17, P =0.01); but no significant differences were found on Banff grade II and III between the two groups. ② the rate of graft and patient survival and chronic rejection were the same between two groups. ③ Steroid withdrawal decreased the incidence of opportunistic infection (mainly caused by simplex herpes virus and Candida) and urinary tract infection. While the incidence of CMV and sepsis infection has no significant difference between two groups.
Conclusion　 Steroid withdrawal within 3 months in modern immunosuppressive regimen ① increases the risk of Banff Grade I rejection reaction, but the moderate and severe rejection are similar between the two groups; ② doesn’t affect the rate of graft, patient survival, and chronic rejection; ③ decreases the incidence of opportunistic and urinary tract infection, but doesn’t improve the CMV infection and sepsis. To prophylaxis serious infection, steroid withdrawal is worth considering under sufficient immunosuppressive regimen. The key point is to balance the benefit and harm for individual recipients.

Citation： TAN Jiying,ZHAO Na,WU Taixiang,YANG Kehu,TIAN Jinhui,LIU Yali,WANG Li,SUN xin,LU Yiping,LI Youping. Safety and Efficacy of Steroid Withdrawal in Modern Triple Immunosuppressant: A Systematic Review. Chinese Journal of Evidence-Based Medicine, 2006, 06(4): 273-281. doi: Copy

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2.	Hricik DE, O’Toole MA, Schulak JA, et al. Steroid-free immunosuppression in cyclosporine-treated renal transplant recipients: a meta-analysis. J Am Soc Nephrol, 1993; 4(6): 1300-1305.
3.	Kasiske BL, Chakkera HA, Louis TA, et al. A meta-analysis of immunosuppression withdrawal trials in renal transplantation. J Am Soc Nephrol, 2000; 11(10): 1910-1917.
4.	Pascual J, Quereda C, Zamora J, et al. Steroid withdrawal in renal transplant patients on triple therapy with a calcineurin inhibitor and mycophenolate mofetil: a meta-analysis of randomized, controlled trials. Transplantation, 2004; 78(10): 1548-1556.
5.	Squifflet JP, Vanrenterghem Y, van Hooff JP, et al. Safe withdrawal of corticosteroids or mycophenolate mofetil: results of a large, prospective, multicenter, randomized study. Transplant Proc, 2002; 34(5): 1584-1586.
6.	Vanrenterghem Y, van Hooff JP, Squifflet JP, et al. Minimization of immunosuppressive therapy after renal transplantation: results of a randomized controlled trial. Am J Transplant, 2005; 5(1): 87-95.
7.	Ahsan N, Hricik D, Matas A, et al. Prednisone withdrawal in kidney transplant recipients on cyclosporine and mycophenolate mofetil--a prospective randomized study. Steroid Withdrawal Study Group. Transplantation, 1999; 68(12): 1865-1874.
8.	Vanrenterghem Y, Lebranchu Y, Hene R, et al. Double-blind comparison of two corticosteroid regimens plus mycophenolate mofetil and cyclosporine for prevention of acute renal allograft rejection. Transplantation, 2000; 70(9): 1352-1359.
9.	Boletis JN, Konstadinidou I, Chelioti H, et al. Successful withdrawal of steroid after renal transplantation. Transplant Proc, 2001; 33(1-2): 1231-1233.
10.	Nowacka-Cieciura E, Durlik M, Cieciura T, et al. Steroid withdrawal after renal transplantation--risks and benefits. Transplant Proc, 2002; 34(2):560-563.
11.	Smak Gregoor PJ, de Sevaux RG, Ligtenberg G, et al. Withdrawal of cyclosporine or prednisone six months after kidney transplantation in patients on triple drug therapy: a randomized, prospective, multicenter study. J Am Soc Nephrol, 2002; 13(5): 1365-1373.
12.	. Sola E, Alferez MJ, Cabello M, et al. Low-dose and rapid steroid withdrawal in renal transplant patients treated with tacrolimus and mycophenolate mofetil. Transplant Proc, 2002 ; 34(5): 1689-1690.
13.	. Laftavi MR, Stephan R, Stefanick B, et al. Randomized prospective trial of early steroid withdrawal compared with low-dose steroids in renal transplant recipients using serial protocol biopsies to assess efficacy and safety. Surgery, 2005; 137(3): 364-371.

1. Puig i Mari JM. Induction treatment with mycophenolate mofetil, cyclosporine, and low-dose steroids with subsequent early withdrawal in renal transplant patients: results of the Spanish Group. Spanish Group of the CellCept Study. Transplant Proc, 1999; 31(6): 2256-2258.
2. Hricik DE, O’Toole MA, Schulak JA, et al. Steroid-free immunosuppression in cyclosporine-treated renal transplant recipients: a meta-analysis. J Am Soc Nephrol, 1993; 4(6): 1300-1305.
3. Kasiske BL, Chakkera HA, Louis TA, et al. A meta-analysis of immunosuppression withdrawal trials in renal transplantation. J Am Soc Nephrol, 2000; 11(10): 1910-1917.
4. Pascual J, Quereda C, Zamora J, et al. Steroid withdrawal in renal transplant patients on triple therapy with a calcineurin inhibitor and mycophenolate mofetil: a meta-analysis of randomized, controlled trials. Transplantation, 2004; 78(10): 1548-1556.
5. Squifflet JP, Vanrenterghem Y, van Hooff JP, et al. Safe withdrawal of corticosteroids or mycophenolate mofetil: results of a large, prospective, multicenter, randomized study. Transplant Proc, 2002; 34(5): 1584-1586.
6. Vanrenterghem Y, van Hooff JP, Squifflet JP, et al. Minimization of immunosuppressive therapy after renal transplantation: results of a randomized controlled trial. Am J Transplant, 2005; 5(1): 87-95.
7. Ahsan N, Hricik D, Matas A, et al. Prednisone withdrawal in kidney transplant recipients on cyclosporine and mycophenolate mofetil--a prospective randomized study. Steroid Withdrawal Study Group. Transplantation, 1999; 68(12): 1865-1874.
8. Vanrenterghem Y, Lebranchu Y, Hene R, et al. Double-blind comparison of two corticosteroid regimens plus mycophenolate mofetil and cyclosporine for prevention of acute renal allograft rejection. Transplantation, 2000; 70(9): 1352-1359.
9. Boletis JN, Konstadinidou I, Chelioti H, et al. Successful withdrawal of steroid after renal transplantation. Transplant Proc, 2001; 33(1-2): 1231-1233.
10. Nowacka-Cieciura E, Durlik M, Cieciura T, et al. Steroid withdrawal after renal transplantation--risks and benefits. Transplant Proc, 2002; 34(2):560-563.
11. Smak Gregoor PJ, de Sevaux RG, Ligtenberg G, et al. Withdrawal of cyclosporine or prednisone six months after kidney transplantation in patients on triple drug therapy: a randomized, prospective, multicenter study. J Am Soc Nephrol, 2002; 13(5): 1365-1373.
12. . Sola E, Alferez MJ, Cabello M, et al. Low-dose and rapid steroid withdrawal in renal transplant patients treated with tacrolimus and mycophenolate mofetil. Transplant Proc, 2002 ; 34(5): 1689-1690.
13. . Laftavi MR, Stephan R, Stefanick B, et al. Randomized prospective trial of early steroid withdrawal compared with low-dose steroids in renal transplant recipients using serial protocol biopsies to assess efficacy and safety. Surgery, 2005; 137(3): 364-371.

Chinese Journal of Evidence-Based Medicine

Safety and Efficacy of Steroid Withdrawal in Modern Triple Immunosuppressant: A Systematic Review

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