Effectiveness and Safety of Rapamycin-based Immunosuppression Regimen With Or Without CsA in Renal Transplantation：A Systematic Review_Chinese Journal of Evidence-Based Medicine

Authors：

ZHANg Yanyany ¹ , TENG Donghai ¹ , WANG Li ² , XIONG Wei ¹ , BAI Ansheng ¹ , WU Taixiang ² , LU Yiping ¹

1. Department of Urology, West China Hospital, Sichuan Urtiversity, Chengdu 610041, China2. Chinese Evidence-Based Medicine Center, West China Hospital, Sichuan University, Chertgdu, 610041, China;

Corresponding author：

Keywords：

Kidney transplantation; Rapamycin; CsA; Systematic review; Randomized controlled trials

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Objective 　To evaluate the short and long term effectiveness and safety of rapamycin-based immunosuppression regimes with CsA preserving versus CsA withdrawal. Methods 　We searched MEDLINE, EMBASE, The Cochrane Library and CNKI from Jan. 1995 to Dec. 2005. We identified randomized controlled trials of rapamycin-hased immunosuppression regimes with CsA preserving versus CsA withdrawal for renal transplantation patients. The quality of included trials was evaluated by two reviewers. Meta-analysis was conducted on homogeneous studies.
Results 　Ten studies （1 121 patients） undergoing renal transplantation were included. All included studies were graded in term of randomization, allocation concealment and bhnding. Six studies were graded A and the other 4 were graded B. Meta-analysis results showed CsA withdrawal in sirolimus-based therapy in renal transplantation patients survival rate OR.（95% CI ） values were 0,77（0.17, 3.52）, 1.24（0.48, 3.16）, 1.32（0.57, 3.08）, 1.21（0.60, 2.41） at the end of 6, 12, 24, 36 months respectively; renal allografts survival rate OR. （95% CI） values were 1.79 （0.63, 5.06）, 1.15 （ 0.56, 2.36） , 1.39 （0.68, 2.85）, 1.80（0.99, 3.29）, 2. 13（1.16, 3.89）, 2.01（1.15, 3.51） at the end of 6, 12, 24, 36, 48, 54 months respectively; and acute rejection OP,（95% CI） values were 0.92（0.48, 1.78）, 1.90（1.25, 2.89）, 2. 01 （0.94,4.27）, 1.93（0.93, 4.00）, 1.52（0.77, 3.02） at the end of6, 12, 24, 36, 48 months respectively.
Conclusions 　Available evidence shows that compared with CsA preserving, CsA withdrawal in rapamycin-based immunosuppression regimes can lead to higher incidence rates of acute rejection at the end of one year while there is no statistical difference to survival rate of patients/renal allograft in cases with stabilized renal function post-transplantation. And CsA withdrawal is of benefit to allografts for long term survival rate and is helpful to recovery of renal function. Owing to high possibility of selection bias and measurement bias in included studies, there must be a negative impact on evidence intensity of our results. We expect best evidence from with high quality double blind randomized control trials.

Citation： ZHANg Yanyany,TENG Donghai,WANG Li,XIONG Wei,BAI Ansheng,WU Taixiang,LU Yiping. Effectiveness and Safety of Rapamycin-based Immunosuppression Regimen With Or Without CsA in Renal Transplantation：A Systematic Review. Chinese Journal of Evidence-Based Medicine, 2006, 06(2): 94-106. doi: Copy

1.	叶平.主编.血脂的基础与临床.第1版北京:人民军医出版社; 2002.205.
2.	Renal Data System.USRDS 1998 annual data report.Bethesda,Md:National Institute of Diabetes and Digestive Kidney Disease,April 1998:39.(NIH publication no.98-3176).
3.	Merion RM,White DJ,Thiru S,et al.Cyclosporine:five years’ experience in cadaveric renal transplantation.N Engl J Med JT-The New England Journal of Medicine,1984; 310(3):148-154.
4.	Thiel G,Bock A,Spondlin M,et al.Long-term benefits and risks of cyclosporin A (sandimmun)-an analysis at 10 years.Transplantation Proceedings,1994; 26(5):2493-2498.
5.	Sehgal SN,Baker H,Vezina C.Rapamycin (AY-22,989),a new antifungal antibiotic.Ⅱ.Fermentation,isolation and characterization.Journal of Antibiotics,1975; 28(10):727-732.
6.	Kuypers DR.Benefit-risk assessment of sirolimus in renal transplantation.Drug Saf,2005; 28:153-181.
7.	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.
8.	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.
9.	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.
10.	Legendre C,Campistol JM,Squifflet JP,et al.Cardiovascular risk factors of sirolimus compared with cyclosporine:early experience from two randomized trials in renal transplantation.Transplantation Proceedings,2003; 35(3 Suppl):151S-153S.
11.	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.
12.	Mathew T,Kreis H,Friend P.Two-year incidence of malignancy in sirolimus-treated renal transplant recipients:Results from five multicenter studies.Clinical Transplantation,2004; 18(4):446-449.
13.	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.
14.	Campistol TM,Kreis H,Oberbauer R,et al.Sirolimus-based therapy following early cyclosporine withdrawal resulted in superior renal allograft survival at 48 months compared with continuous combined sirolimus and cyclosporine.American Journal of Transplantation,2004; (4):S8:344.
15.	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.
16.	Jardine AG.Phase Ⅲ prospective,randomized study to evaluate the safety and efficacy of concentration controlled rapamune (sirolimus) with ciclosporin dose minimisation or elimination in de novo renal allograft recipients at 12 months.American Journal of Transplantation,2004; 260(Suppl 8):286.
17.	Pascual M,Theruvath T,Kawai T,et al.Strategies to improve long-term outcomes after renal transplantation.N Engl J Med,2002; 346(8):580-590.
18.	Bakker RC,Hollander AA,Mallat MJ,et al.Conversion from cyclosporine to azathioprine at three months reduces the incidence of chronic allograft nephropathy.Kidney Int,2003; 64(3):1027-1034.
19.	Gallagher MP,Hall B,Craig J,et al.A randomized controlled trial of cyclosporine withdrawal in renal-transplant recipients:15-year results.Transplantation,2004; 78(11):1653-1660.
20.	Oliveira JG,Xavier P,Sampaio SM,et al.Compared to mycophenolate mofetil,rapamycin induces significant changes on growth factors and growth factor receptors in the early days post-kidney transplantation.Transplantation,2002; 73(6):915-920.
21.	Ye P.Editor-in-Chief.Basic and Clinical Research of Bood Fat.1st Edition.Beijing:The People’s Medicine Press; 2002.205.
22.	Hong JC,Kahan BD.Sirolimus-induced thrombocytopenia and leukopenia in renal transplant recipients:risk factors,incidence,progression,and management.Transplantation,2000; 69(10):2085-2090.
23.	van der Vliet JA,Barendregt WB,Hoitsma AJ,et al.Increased incidence of renal allograft thrombosis after continuous ambulatory peritoneal dialysis.Clin Transplant,1996; 10(1):51-54.
24.	Singh A,Stablein D,Tejani A.Risk factors for vascular thrombosis in pediatric renal transplantation:a special report of the North American Pediatric Renal Transplant Cooperative Study.Transplantation,1997; 63(9):1263-1267.
25.	Wagenknecht DR,Fastenau DR,Torry RJ,et al.Antiphospholipid antibodies are a risk factor for early renal allograft failure:isolation of antiphospholipid antibodies from a thrombosed renal allograft.Transplant Proc,1999; 31(1-2):285-288.
26.	Guo CM.Spontaneity arterial thrombus in children.Foreign Med Sci,1999; 26:331.

1. 叶平.主编.血脂的基础与临床.第1版北京:人民军医出版社; 2002.205.
2. Renal Data System.USRDS 1998 annual data report.Bethesda,Md:National Institute of Diabetes and Digestive Kidney Disease,April 1998:39.(NIH publication no.98-3176).
3. Merion RM,White DJ,Thiru S,et al.Cyclosporine:five years’ experience in cadaveric renal transplantation.N Engl J Med JT-The New England Journal of Medicine,1984; 310(3):148-154.
4. Thiel G,Bock A,Spondlin M,et al.Long-term benefits and risks of cyclosporin A (sandimmun)-an analysis at 10 years.Transplantation Proceedings,1994; 26(5):2493-2498.
5. Sehgal SN,Baker H,Vezina C.Rapamycin (AY-22,989),a new antifungal antibiotic.Ⅱ.Fermentation,isolation and characterization.Journal of Antibiotics,1975; 28(10):727-732.
6. Kuypers DR.Benefit-risk assessment of sirolimus in renal transplantation.Drug Saf,2005; 28:153-181.
7. 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.
8. 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.
9. 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.
10. Legendre C,Campistol JM,Squifflet JP,et al.Cardiovascular risk factors of sirolimus compared with cyclosporine:early experience from two randomized trials in renal transplantation.Transplantation Proceedings,2003; 35(3 Suppl):151S-153S.
11. 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.
12. Mathew T,Kreis H,Friend P.Two-year incidence of malignancy in sirolimus-treated renal transplant recipients:Results from five multicenter studies.Clinical Transplantation,2004; 18(4):446-449.
13. 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.
14. Campistol TM,Kreis H,Oberbauer R,et al.Sirolimus-based therapy following early cyclosporine withdrawal resulted in superior renal allograft survival at 48 months compared with continuous combined sirolimus and cyclosporine.American Journal of Transplantation,2004; (4):S8:344.
15. 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.
16. Jardine AG.Phase Ⅲ prospective,randomized study to evaluate the safety and efficacy of concentration controlled rapamune (sirolimus) with ciclosporin dose minimisation or elimination in de novo renal allograft recipients at 12 months.American Journal of Transplantation,2004; 260(Suppl 8):286.
17. Pascual M,Theruvath T,Kawai T,et al.Strategies to improve long-term outcomes after renal transplantation.N Engl J Med,2002; 346(8):580-590.
18. Bakker RC,Hollander AA,Mallat MJ,et al.Conversion from cyclosporine to azathioprine at three months reduces the incidence of chronic allograft nephropathy.Kidney Int,2003; 64(3):1027-1034.
19. Gallagher MP,Hall B,Craig J,et al.A randomized controlled trial of cyclosporine withdrawal in renal-transplant recipients:15-year results.Transplantation,2004; 78(11):1653-1660.
20. Oliveira JG,Xavier P,Sampaio SM,et al.Compared to mycophenolate mofetil,rapamycin induces significant changes on growth factors and growth factor receptors in the early days post-kidney transplantation.Transplantation,2002; 73(6):915-920.
21. Ye P.Editor-in-Chief.Basic and Clinical Research of Bood Fat.1st Edition.Beijing:The People’s Medicine Press; 2002.205.
22. Hong JC,Kahan BD.Sirolimus-induced thrombocytopenia and leukopenia in renal transplant recipients:risk factors,incidence,progression,and management.Transplantation,2000; 69(10):2085-2090.
23. van der Vliet JA,Barendregt WB,Hoitsma AJ,et al.Increased incidence of renal allograft thrombosis after continuous ambulatory peritoneal dialysis.Clin Transplant,1996; 10(1):51-54.
24. Singh A,Stablein D,Tejani A.Risk factors for vascular thrombosis in pediatric renal transplantation:a special report of the North American Pediatric Renal Transplant Cooperative Study.Transplantation,1997; 63(9):1263-1267.
25. Wagenknecht DR,Fastenau DR,Torry RJ,et al.Antiphospholipid antibodies are a risk factor for early renal allograft failure:isolation of antiphospholipid antibodies from a thrombosed renal allograft.Transplant Proc,1999; 31(1-2):285-288.
26. Guo CM.Spontaneity arterial thrombus in children.Foreign Med Sci,1999; 26:331.

Chinese Journal of Evidence-Based Medicine

Effectiveness and Safety of Rapamycin-based Immunosuppression Regimen With Or Without CsA in Renal Transplantation：A Systematic Review

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