Jin DENG, Yi LU, Lihong HE, Jihong OU, Hongping XIE

A comparison of mycophenolate mofetil and calcineurin inhibitor as maintenance immunosuppression for kidney transplant recipients: A meta-analysis of randomized controlled trials

Background/aim:We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the comparison and its timing between mycophenolate mofetil (MMF) and calcineurin inhibitor (CNI) as maintenance immunosuppression for kidney transplant recipients. Materials and methods: The RCTs of MMF versus CNI as maintenance immunosuppression for kidney transplant recipients were searched from PubMed, Embase, Cochrane Central Register of Controlled Trials (CCRCT), and ClinicalTrials.gov. After screening relevant RCTs, two authors independently assessed the quality of included studies and performed a meta-analysis using RevMan5.3. Relative risk (RR) was used to report dichotomous data, while mean difference (MD) with 95% confidence interval (CI) was used to report continuous outcomes. The analysis was conducted using the random-effect model due to the expected heterogeneity among different studies. Four subgroups were allocated to compare MMF with CNI as maintenance immunosuppression: (1) after 3 months of CNI-based therapy, (2) after 6 months of CNI-based therapy, (3) after 12 months of CNI-based therapy, and (4) in recipients with allograft dysfunction. Results: Twelve RCTs with 950 renal transplant recipients were included. This meta-analysis presented the following results upon comparison between MMF and CNI as maintenance immunosuppression for kidney transplant recipients: (1) MMF significantly improved the glomerular filtration rate (GFR) not only in the comparison performed after 3, 6, or 12 months of CNI-based therapy but also in the comparison of recipients with allograft dysfunction, (2) MMF may increase the risk of acute rejection in the comparison performed after 3 months of CNI-based therapy, but no increase was noted in the comparison performed after 6 or 12 months of CNIbased therapy. Conclusion: Our present meta-analysis suggested that MMF followed at least 6 months of CNI-based therapy is an effective maintenance immunosuppressive regimen for kidney transplant recipients to improve renal function but not increase rejection.Key words: Kidney transplantation, mycophenolate mofetil, calcineurin inhibitor, meta-analysis

PDF

___

1. Anand S, Bitton A, Gaziano T. The gap between estimated incidence of end-stage renal disease and use of therapy. PloS One 2013; 8 (8): e72860-e72860. doi: 10.1371/journal. pone.0072860
2. Bongiovanni I, Couillerot-Peyrondet AL, Sambuc C, Dantony E, Elsensohn MH et al. [Cost-effectiveness analysis of various strategies of end-stage renal disease patients’ care in France]. Nephrologie & Therapeutique 2016;12 (2):104-115. doi: 10.1016/j.nephro.2015.10.004
3. KDIGO clinical practice guideline for the care of kidney transplant recipients. American Journal of Transplantation 2009; 9 Suppl 3: S1-155. doi: 10.1111/j.1600-6143.2009.02834.x
4. Yildirim A. The importance of patient satisfaction and health-related quality of life after renal transplantation. Transplantation Proceedings 2006; 38 (9): 2831-2834. doi: 10.1016/j.transproceed.2006.08.162
5. Wit GAD, Ramsteijn PG, Charro FTD. Economic evaluation of end stage renal disease treatment. Health Policy 1998; 44 (3): 215-232. doi: 10.1016/s0168-8510(98)00017-7
6. Pascual M, Theruvath T, Kawai T, Tolkoffrubin N, Cosimi AB. Strategies to improve outcomes after renal transplantation. New England Journal of Medicine 2002; 346 (8): 580-590. doi: 10.1056/NEJMra011295
7. Shipkova M, Armstrong VW, Oellerich M, Wieland E. Mycophenolate mofetil in organ transplantation: focus on metabolism, safety and tolerability. Expert Opinion on Drug Metabolism & Toxicology 2005; 1 (3): 505-526. doi: 10.1517/17425255.1.3.505
8. Ciancio G, Miller J, Gonwa TA. Review of major clinical trials with mycophenolate mofetil in renal transplantation. Transplantation 2005; 80 (2 Suppl): S191-200. doi: 10.1097/01. tp.0000187035.22298.ba
9. Moore J, Middleton L, Cockwell P, Adu D, Ball S et al. Calcineurin inhibitor sparing with mycophenolate in kidney transplantation: a systematic review and metaanalysis. Transplantation 2009; 87 (4): 591-605. doi: 10.1097/ TP.0b013e318195a421
10. Anders Å, Apeland T, Reisaeter AV, Foss A, Leivestad T et al. Long-term outcomes after cyclosporine or mycophenolate withdrawal in kidney transplantation - results from an aborted trial. Clinical Transplantation 2013; 27 (2): E151–E156. doi: 10.1111/ctr.12076
11. Mourer JS, Jd H, van Zwet EW, Mallat MJ, Dubbeld J et al. Randomized trial comparing late concentration-controlled calcineurin inhibitor or mycophenolate mofetil withdrawal. Transplantation 2012; 93 (9): 887-894. doi: 10.1097/ TP.0b013e31824ad60a
12. Hazzan M, Labalette M, Copin MC, Glowacki F, Provôt F et al. Predictive factors of acute rejection after early cyclosporine withdrawal in renal transplant recipients who receive mycophenolate mofetil: results from a prospective, randomized trial. Journal of the American Society of Nephrology 2005; 16 (8): 2509-2516. doi: 10.1681/ASN.2005030312
13. Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre. The Cochrane Collaboration 2014.
14. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics in Medicine 2002; 21(11): 1539-1558. doi: 10.1002/sim.1186
15. Hoerning A, Köhler S, Lu J, Fu J, Tebbe B et al. Cyclosporin but not everolimus inhibits chemokine receptor expression on CD4 + T cell subsets circulating in the peripheral blood of renal transplant recipients. Clinical and Experimental Immunology 2012; 168 (2): 251-259. doi: 10.1111/j.1365-2249.2012.04571.x
16. Schnuelle P, Jh VDH, Tegzess A, Verburgh CA, Paul LC et al. Open randomized trial comparing early withdrawal of either cyclosporine or mycophenolate mofetil in stable renal transplant recipients initially treated with a triple drug regimen. Journal of the American Society of Nephrology 2002; 13 (2): 536-543. doi: 10.1089/089277902753483745
17. Stevens RB, Foster KW, Miles CD, Kalil AC, Florescu DF et al. A Randomized 2x2 factorial clinical trial of renal transplantation: steroid-free maintenance immunosuppression with calcineurin inhibitor withdrawal after six months associates with improved renal function and reduced chronic histopathology. Plos One 2015; 10 (10): e0139247. doi: 10.1371/journal.pone.0139247
18. Albano L, Alamartine E, Toupance O, Moulin B, Merville P et al. Conversion from everolimus with low-exposure cyclosporine to everolimus with mycophenolate sodium maintenance therapy in kidney transplant recipients: a randomized, openlabel multicenter study. Annals of Transplantation Quarterly of the Polish Transplantation Society 2012; 17 (17): 58-67. doi: 10.12659/aot.882637
19. Cransberg K, Cornelissen M, Lilien M, Van HK, Davin JC et al. Maintenance immunosuppression with mycophenolate mofetil and corticosteroids in pediatric kidney transplantation: temporary benefit but not without risk. Transplantation 2007; 83 (8): 1041-1047. doi: 10.1097/01.tp.0000260146.57898.9c
20. Dudley C, Pohanka E, Riad H, Dedochova J, Wijngaard P et al. Mycophenolate mofetil substitution for cyclosporine a in renal transplant recipients with chronic progressive allograft dysfunction: the “creeping creatinine” study. Transplantation 2005; 79 (4): 466-475. doi: 10.1097/01.tp.0000151632.21551.00
21. Frimat L, Cassutoviguier E, Charpentier B, Noël C, Provôt F et al. Impact of cyclosporine reduction with MMF: a randomized trial in chronic allograft dysfunction. The ‘reference’ study. American Journal of Transplantation 2006; 6 (11): 2725-2734. doi: 10.1111/j.1600-6143.2006.01535.x
22. Mcgrath JS, Shehata M. Chronic allograft nephropathy: prospective randomised trial of cyclosporin withdrawal and mycophenolate mofetil or tacrolimus substitution. Transplantation Proceedings 2001; 33 (3): 2193-2195. doi: 10.1016/s0041-1345(01)01939-x
23. Stoves J, Newstead CG, Baczkowski AJ, Owens G, Paraoan M et al. A randomized controlled trial of immunosuppression conversion for the treatment of chronic allograft nephropathy. Nephrology Dialysis Transplantation 2004; 19 (8): 2113-2120. doi: 10.1093/ndt/gfh188
24. Solez K, ., Vincenti F, ., Filo RS. Histopathologic findings from 2-year protocol biopsies from a U.S. multicenter kidney transplant trial comparing tarolimus versus cyclosporine: a report of the FK506 Kidney Transplant Study Group. Transplantation 1998; 66 (12): 1736-1740. doi: 10.1097/00007890-199812270-00029
25. Goldfarb DA. The natural history of chronic allograft nephropathy. Journal of Urology 2005; 173 (6): 2106. doi: 10.1016/S0022-5347(05)60253-4
26. Houde I, Isenring P, Boucher D, Noel R, Lachanche JG. Mycophenolate mofetil, an alternative to cyclosporine A for long-term immunosuppression in kidney transplantation? Transplantation 2000; 70 (8): 1251-1253. doi: 10.1097/00007890-200010270-00023
27. Schrama YC, Joles JA, Van TA, Boer P, Koomans HA et al. Conversion to mycophenolate mofetil in conjunction with stepwise withdrawal of cyclosporine in stable renal transplant recipients. Transplantation 2000; 69 (3): 376. doi: 10.1097/00007890-200002150-00012
28. Suwelack B, Gerhardt U, Hohage H. Withdrawal of cyclosporine or tacrolimus after addition of mycophenolate mofetil in patients with chronic allograft nephropathy. American Journal of Transplantation 2004; 4 (4): 655-662. doi: 10.1111/j.1600- 6143.2004.00404.x
29. Gonzalez MM, Seron D, Garcia dMR, Carrera M, Sola E et al. Mycophenolate mofetil reduces deterioration of renal function in patients with chronic allograft nephropathy. A follow-up study by the Spanish Cooperative Study Group of Chronic Allograft Nephropathy. Transplantation 2004; 77 (2): 215-220. doi: 10.1097/01.TP.0000100684.59784.FF
30. Merville P, Bergé F, Deminière C, Morel D, Chong G et al. Lower incidence of chronic allograft nephropathy at 1 year post-transplantation in patients treated with mycophenolate mofetil. American Journal of Transplantation 2004; 4 (11): 1769-1775. doi: 10.1111/j.1600-6143.2004.00533.x