Effectiveness and Safety of Calcineurin Inhibitor Withdrawal from Target-of-Rapamycin-Inhibitor-Based Immunosuppression in Kidney Transplantation: A MetaAnalysis_Chinese Journal of Evidence-Based Medicine

Authors：

WU Bin ^1,2 , WU Fengbo ¹ , YU Lei ¹ , LI Tianping ¹ ,  TANG Yao ¹

1. Department of Pharmacy, West China Hospital, Sichuan University, Chengdu 610041, China;2. West China school of Pharmacy, Sichuan University, Chengdu 610041, China;

Corresponding author：

TANG Yao, Email: yaotangwch@yahoo.cn

Keywords：

Cyclosporine; Tacrolimus; Sirolimus; Everolimus; Kidney transplantation; Meta-analysis

DOI：

10.7507/1672-2531.20100088

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Objective 　To evaluate the effectiveness and safety of calcineurin inhibitor (CNI) withdrawal from target-of-rapamycin-inhibitor(TOR-I)-based immunosuppression in kidney transplant recipients.
Methods 　We searched MEDLINE, EMbase, SCI, CBM and The Cochrane Library to screen randomized controlled trials (RCT) of calcineurin inhibitor (CNI) withdrawal from target-of-rapamycin-inhibitor-(TOR-I)-based immunosuppression in kidney transplant recipients. The search was updated in Semptember 2009. The quality of the included trials was assessed. RevMan 5.0 software was used for meta-analyses.
Results 　A total of 14 reports from 10 RCTs were identified. Five RCTs were graded A and five graded B. The meta-analyses indicated: RR (95%CI) values of the 1, 2, 4-year acute rejection rates were 1.64 (1.19, 2.27), 1.53 (1.06, 2.22) and 1.21 (0.73, 1.98), respectively; RD (95%CI) values of 1, 2, 4-year patient survival rates were – 0.01 (– 0.02, 0.01), – 0.00 (– 0.03, 0.02) and 0.03 (– 0.01, 0.08), respectively; RD (95%CI) values of 1, 2, 4-year graft survival rates were 0.00 (– 0.02, 0.02), 0.00 (– 0.03, 0.04) and 0.07 (0.01, 0.12), respectively; and glomerular filtration rate WMD was 9.50 and 95%CI 2.96 to 16.03.
Conclusion 　Based on the current evidence, compared to CNI, CNI withdrawal from sirolimus-based immunosuppression in kidney transplantation could be advantageous for renal function. One-year acute rejection rate and 4-year graft survival rate increase. One-year patient/graft survival and fouryear acute rejection rate remain virtually unvariable. The long-term results need further confirmation.

Citation： WU Bin,WU Fengbo,YU Lei,LI Tianping,TANG Yao. Effectiveness and Safety of Calcineurin Inhibitor Withdrawal from Target-of-Rapamycin-Inhibitor-Based Immunosuppression in Kidney Transplantation: A MetaAnalysis. Chinese Journal of Evidence-Based Medicine, 2010, 10(1): 33-39. doi: 10.7507/1672-2531.20100088 Copy

1.	de Mattos AM, Olyaei AJ, Bennett WM. Nephrotoxicity of immunosuppressive drugs: long-term consequences and challenges for the future. Am J Kidney Dis, 2000, 35(2): 333-346.
2.	Webster AC, Lee VW, Chapman JR, et al. Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients. Cochrane Database Syst Rev, 2006, 19(2): CD004290.
3.	Mulay AV, Hus sain N, Fergus son D, e t al . Calcineur i n Inhibitor Withdrawal from Sirolimus-Based Therapy in Kidney Transplantation: A Systematic Review of Randomized Trials. Am J Transplant, 2005, 5(7): 1748-1756.
4.	Johnson RW, Kreis H, Oberbauer R, et al. Sirolimus allows early cyclosporine withdrawal in renal transplantation resulting in improved renal function and lower blood pressure. Transplantation, 2001, 72(5): 777-786.
5.	Oberbauer R, Kreis H, Johnson RW, et al. Long-term improvement in renal function with sirolimus after early cyclosporine withdrawal in renal transplant recipients: 2-year results of the Rapamune Maintenance Regimen Study. Transplantation, 2003, 76(2): 364-370.
6.	Kreis H, Oberbauer R, Campistol JM, et al. Long-term benefits with sirolimus-based therapy after early cyclosporine withdrawal. J Am Soc Nephrol, 2004, 15(3): 809-817.
7.	Oberbauer R, Segoloni G, Campistol JM, et al. Early cyclosporine withdrawal from a sirolimus-based regimen results in better renal allograft survival and renal function at 48 months after transplantation. Transpl Int, 2005, 18(1): 22-28.
8.	Gonwa TA, Hricik DE, Brinker K, et al. Improved renal function in sirolimus-treated renal transplant patients after early cyclosporine elimination. Transplantation, 2002, 74(11): 1560-1567.
9.	Baboolal K. A phase III prospective, randomized study to evaluate concentration-controlled sirolimus (rapamune) with cyclosporine dose minimization or elimination at six months in de novo renal allograft recipients. Transplantation, 2003, 75(8): 1404-1408.
10.	Stallone G, Di Paolo S, Schena A, et al. Early withdrawal of cyclosporine A improves 1-year kidney graft structure and function in sirolimus-treated patients. Transplantation, 2003, 75(7): 998-1003.
11.	Grinyo JM, Campistol JM, Paul J, et al. Pilot randomized study of early tacrolimus withdrawal from a regimen with sirolimus plus tacrolimus in kidney transplantation. Am J Transplant, 2004, 4(8): 1308-1314.
12.	Morales JM, Grinyó JM, Campistol JM, et al. Improved renal function, with similar proteinuria, after two years of early tacrolimus withdrawal from a regimen of sirolimus plus tacrolimus. Transplantation, 2008, 86(4): 620-622.
13.	Watson CJ, Firth J, Williams PF, et al. A randomized controlled trial of late conversion from CNI-based to sirolimus-based immunosuppression following renal transplantation. Am J Transplant, 2005, 5(10): 2496-2503.
14.	Barsoum RS, Morsey AA, Iskander IR, et al. The Cairo kidney center protocol for rapamycin-based sequential immunosuppression in kidney transplant recipients: 2-year outcomes. Exp Clin Transplant, 2007, 5(2): 649-657.
15.	Smith MP, Newstead CG, Ahmad N, et al. Poor tolerance of sirolimus in a steroid avoidance regimen for renal transplantation. Transplantation, 2008, 85(4): 636-639.
16.	Lebranchu Y, Thierry A, Toupance O, et al. Efficacy on renal function of early conversion from cyclosporine to sirolimus 3 months after renal transplantation: concept study. Am J Transplant, 2009, 9(5): 1115-1123.
17.	Schena FP, Pascoe MD, Alberu J, et al. Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial. Transplantation, 2009, 87(2): 233-242.
18.	Oberbauer R. Protocol conversion from a calcineurin inhibitor based therapy to sirolimus. Transplantation, 2009, 87(8 Suppl): S7-10.
19.	Haller M, Oberbauer R. Calcineurin inhibitor minimization, withdrawal and avoidance protocols after kidney transplantation. Transpl Int, 2009, 22(1): 69-77.
20.	Webster A, Woodroffe RC, Taylor RS, et al. Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev, 2005, (4): CD003961.

1. de Mattos AM, Olyaei AJ, Bennett WM. Nephrotoxicity of immunosuppressive drugs: long-term consequences and challenges for the future. Am J Kidney Dis, 2000, 35(2): 333-346.
2. Webster AC, Lee VW, Chapman JR, et al. Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients. Cochrane Database Syst Rev, 2006, 19(2): CD004290.
3. Mulay AV, Hus sain N, Fergus son D, e t al . Calcineur i n Inhibitor Withdrawal from Sirolimus-Based Therapy in Kidney Transplantation: A Systematic Review of Randomized Trials. Am J Transplant, 2005, 5(7): 1748-1756.
4. Johnson RW, Kreis H, Oberbauer R, et al. Sirolimus allows early cyclosporine withdrawal in renal transplantation resulting in improved renal function and lower blood pressure. Transplantation, 2001, 72(5): 777-786.
5. Oberbauer R, Kreis H, Johnson RW, et al. Long-term improvement in renal function with sirolimus after early cyclosporine withdrawal in renal transplant recipients: 2-year results of the Rapamune Maintenance Regimen Study. Transplantation, 2003, 76(2): 364-370.
6. Kreis H, Oberbauer R, Campistol JM, et al. Long-term benefits with sirolimus-based therapy after early cyclosporine withdrawal. J Am Soc Nephrol, 2004, 15(3): 809-817.
7. Oberbauer R, Segoloni G, Campistol JM, et al. Early cyclosporine withdrawal from a sirolimus-based regimen results in better renal allograft survival and renal function at 48 months after transplantation. Transpl Int, 2005, 18(1): 22-28.
8. Gonwa TA, Hricik DE, Brinker K, et al. Improved renal function in sirolimus-treated renal transplant patients after early cyclosporine elimination. Transplantation, 2002, 74(11): 1560-1567.
9. Baboolal K. A phase III prospective, randomized study to evaluate concentration-controlled sirolimus (rapamune) with cyclosporine dose minimization or elimination at six months in de novo renal allograft recipients. Transplantation, 2003, 75(8): 1404-1408.
10. Stallone G, Di Paolo S, Schena A, et al. Early withdrawal of cyclosporine A improves 1-year kidney graft structure and function in sirolimus-treated patients. Transplantation, 2003, 75(7): 998-1003.
11. Grinyo JM, Campistol JM, Paul J, et al. Pilot randomized study of early tacrolimus withdrawal from a regimen with sirolimus plus tacrolimus in kidney transplantation. Am J Transplant, 2004, 4(8): 1308-1314.
12. Morales JM, Grinyó JM, Campistol JM, et al. Improved renal function, with similar proteinuria, after two years of early tacrolimus withdrawal from a regimen of sirolimus plus tacrolimus. Transplantation, 2008, 86(4): 620-622.
13. Watson CJ, Firth J, Williams PF, et al. A randomized controlled trial of late conversion from CNI-based to sirolimus-based immunosuppression following renal transplantation. Am J Transplant, 2005, 5(10): 2496-2503.
14. Barsoum RS, Morsey AA, Iskander IR, et al. The Cairo kidney center protocol for rapamycin-based sequential immunosuppression in kidney transplant recipients: 2-year outcomes. Exp Clin Transplant, 2007, 5(2): 649-657.
15. Smith MP, Newstead CG, Ahmad N, et al. Poor tolerance of sirolimus in a steroid avoidance regimen for renal transplantation. Transplantation, 2008, 85(4): 636-639.
16. Lebranchu Y, Thierry A, Toupance O, et al. Efficacy on renal function of early conversion from cyclosporine to sirolimus 3 months after renal transplantation: concept study. Am J Transplant, 2009, 9(5): 1115-1123.
17. Schena FP, Pascoe MD, Alberu J, et al. Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial. Transplantation, 2009, 87(2): 233-242.
18. Oberbauer R. Protocol conversion from a calcineurin inhibitor based therapy to sirolimus. Transplantation, 2009, 87(8 Suppl): S7-10.
19. Haller M, Oberbauer R. Calcineurin inhibitor minimization, withdrawal and avoidance protocols after kidney transplantation. Transpl Int, 2009, 22(1): 69-77.
20. Webster A, Woodroffe RC, Taylor RS, et al. Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev, 2005, (4): CD003961.

Chinese Journal of Evidence-Based Medicine

Effectiveness and Safety of Calcineurin Inhibitor Withdrawal from Target-of-Rapamycin-Inhibitor-Based Immunosuppression in Kidney Transplantation: A MetaAnalysis

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