Immunosuppression management in renal transplant recipients with normal-immunological risk: 10-year results from the Swiss Transplant Cohort Study
AIMS OF THE STUDY
Primary maintenance immunosuppressive therapies for renal transplant recipients underwent significant changes in recent years. We aimed to assess time trends and the impact of immunosuppressive regimens in first renal transplant recipients without immunological risk (blood group incompatibility, pre-existing donor-specific antibodies, positive B/T cell cross-match) in a prospective national multicentre cohort.
The Swiss Transplant Cohort Study (STCS) prospectively enrols all patients receiving solid organ transplants in Switzerland since 2008 and systematically collects high quality clinical and laboratory data using standardised definitions. The current STCS nested study enrolled all adult transplant-naïve normal-immunological risk renal transplant recipients up to the end of 2017 and investigated different immunosuppressive strategies across a variety of transplantation relevant outcomes.
Of 1191 recipients enrolled at six transplant centres, 115 (10%) died with a functioning allograft and 92 (8%) lost their allograft during a median follow-up time of 5.8 years. The predominant immunosuppressive therapy comprised tacrolimus, mycophenolate mofetil and prednisone (73.7%), whereas 24.3% were treated with ciclosporin instead of tacrolimus. Primary immunosuppression with an mTOR inhibitor (1.1%) or other immunosuppressive combinations (0.8%) was rare. In the years following 2011, ciclosporin-based immunosuppression decreased significantly. The incidence of graft loss was significantly higher in patients with ciclosporin-based than with tacrolimus-based immunosuppression (adjusted hazard ratio [HR] 1.66, 95% confidence interval [CI] 1.29–2.14; p <0.01), but the occurrence of acute transplant rejections did not differ significantly (adjusted HR 1.48, 95% CI 0.82–2.65; p = 0.19). The longitudinal course of the renal allograft function was significantly better (p = 0.013) in recipients of tacrolimus-based immunosuppressive therapy. Graft failure-free survival was higher (HR 1.25, 95% CI 0.97– 1.6; p = 0.08) with tacrolimus-based than with ciclosporin-based immunosuppression. Cytomegalovirus infections occurred more frequently with ciclosporin-based immunosuppression (9.7% vs 6.4% after 1 year), whereas the incidence of BK virus infections was similar in both groups. The median time to prednisone discontinuation was 1.9 years and did not differ between the two groups. Eleven cases of post-transplantation lymphoproliferative disorder were observed during the follow-up period (1 with ciclosporin-based and 10 with tacrolimus-based immunosuppression).
The available data show that primary maintenance immunosuppression with tacrolimus has displaced ciclosporin-based therapies. The tacrolimus-based immunosuppression therapy showed consistently better results across almost all assessed clinically relevant outcomes. (ClinicalTrials.gov Number: NCT01204944)
- Webster AC, Woodroffe RC, Taylor RS, Chapman JR, Craig JC. Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data. BMJ. 2005;331(7520):810. doi:.https://doi.org/10.1136/bmj.38569.471007.AE
- Ekberg H, Tedesco-Silva H, Demirbas A, Vítko S, Nashan B, Gürkan A, et al.; ELITE-Symphony Study. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007;357(25):2562–75. doi:.https://doi.org/10.1056/NEJMoa067411
- Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. Transplantation. 1997;63(7):977–83. doi:.https://doi.org/10.1097/00007890-199704150-00013
- Mayer AD, Dmitrewski J, Squifflet JP, Besse T, Grabensee B, Klein B, et al. Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection: a report of the European Tacrolimus Multicenter Renal Study Group. Transplantation. 1997;64(3):436–43. doi:.https://doi.org/10.1097/00007890-199708150-00012
- Krämer BK, Montagnino G, Del Castillo D, Margreiter R, Sperschneider H, Olbricht CJ, et al.; European Tacrolimus vs Cyclosporin Microemulsion Renal Transplantation Study Group. Efficacy and safety of tacrolimus compared with cyclosporin A microemulsion in renal transplantation: 2 year follow-up results. Nephrol Dial Transplant. 2005;20(5):968–73. doi:.https://doi.org/10.1093/ndt/gfh739
- Bosmans JL, Verpooten GA. Malignancy after kidney transplantation: still a challenge. Kidney Int. 2007;71(12):1197–9. doi:.https://doi.org/10.1038/sj.ki.5002306
- Penn I. Occurrence of cancers in immunosuppressed organ transplant recipients. Clin Transpl. 1998;63(7):147–58.
- Wimmer CD, Rentsch M, Crispin A, Illner WD, Arbogast H, Graeb C, et al. The janus face of immunosuppression - de novo malignancy after renal transplantation: the experience of the Transplantation Center Munich. Kidney Int. 2007;71(12):1271–8. doi:.https://doi.org/10.1038/sj.ki.5002154
- Koller MT, van Delden C, Müller NJ, Baumann P, Lovis C, Marti HP, et al. Design and methodology of the Swiss Transplant Cohort Study (STCS): a comprehensive prospective nationwide long-term follow-up cohort. Eur J Epidemiol. 2013;28(4):347–55. doi:.https://doi.org/10.1007/s10654-012-9754-y
- Swiss Transplant Cohort Study. Study description. 2020; Available from: https://www.stcs.ch/about/study-description.
- Swiss Transplant Cohort Study. Annual Report July 2019; Available from: https://www.stcs.ch/internal/reports/2019july-stcs_annual_report.pdf.
- Haas M, Loupy A, Lefaucheur C, Roufosse C, Glotz D, Seron D, et al. The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant. 2018;18(2):293–307. doi:.https://doi.org/10.1111/ajt.14625
- Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al.; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–12. doi:.https://doi.org/10.7326/0003-4819-150-9-200905050-00006
- van Delden C, Stampf S, Hirsch HH, Manuel O, Meylan P, Cusini A, et al.; Swiss Transplant Cohort Study. Burden and Timeline of Infectious Diseases in the First Year After Solid Organ Transplantation in the Swiss Transplant Cohort Study. Clin Infect Dis. 2020;ciz1113. doi:.https://doi.org/10.1093/cid/ciz1113
- Steiner R, Kridel R, Giostra E, McKee T, Achermann R, Mueller N, et al.; The Swiss Transplant Cohort Study Stcs. Low 5-year cumulative incidence of post-transplant lymphoproliferative disorders after solid organ transplantation in Switzerland. Swiss Med Wkly. 2018;148:w14596.
- Koller MT, Raatz H, Steyerberg EW, Wolbers M. Competing risks and the clinical community: irrelevance or ignorance? Stat Med. 2012;31(11-12):1089–97. doi:.https://doi.org/10.1002/sim.4384
- Aalen O. Nonparametric estimation of partial transition probabilities in multiple decrement models. Ann Stat. 1978;6(3):534–45. doi:.https://doi.org/10.1214/aos/1176344198
- Gray RJ. A Class of K-Sample Tests for Comparing the Cumulative Incidence of a Competing Risk. Ann Stat. 1988;16(3):1141–54. doi:.https://doi.org/10.1214/aos/1176350951
- Kalbfleisch JD, Prentice RL. The statistical analysis of failure time data. Hoboken, NJ: John Wiley & Sons, Inc; 1980.
- Diggle P. Analysis of longitudinal data. Oxford: Oxford University Press; 2013.
- Therneau TM, Grambsch PM. Modeling Survival Data: Extending the Cox Model. Berlin: Springer; 2000.
- Coemans M, Süsal C, Döhler B, Anglicheau D, Giral M, Bestard O, et al. Analyses of the short- and long-term graft survival after kidney transplantation in Europe between 1986 and 2015. Kidney Int. 2018;94(5):964–73. doi:.https://doi.org/10.1016/j.kint.2018.05.018
- Opelz G, Döhler B ; Collaborative Transplant Study. Influence of immunosuppressive regimens on graft survival and secondary outcomes after kidney transplantation. Transplantation. 2009;87(6):795–802. doi:.https://doi.org/10.1097/TP.0b013e318199c1c7
- Kamel M, Kadian M, Srinivas T, Taber D, Posadas Salas MA. Tacrolimus confers lower acute rejection rates and better renal allograft survival compared to cyclosporine. World J Transplant. 2016;6(4):697–702. doi:.https://doi.org/10.5500/wjt.v6.i4.697
- Gonzalez-Molina M, Gentil MA, Burgos D, Cabello M, Cobelo C, Bustamante J, et al. Effect of long-term steroid withdrawal in renal transplant recipients: a retrospective cohort study. NDT Plus. 2010;3(Suppl_2):ii32–6.
- Wehmeier C, Georgalis A, Hirt-Minkowski P, Amico P, Hoenger G, Voegele T, et al. 2222 kidney transplantations at the University Hospital Basel: a story of success and new challenges. Swiss Med Wkly. 2016;146:w14317. doi:.https://doi.org/10.4414/smw.2016.14317
- Bonani M, Achermann R, Seeger H, Scharfe M, Müller T, Schaub S, et al. Dialysis after graft loss: a Swiss experience. Nephrol Dial Transplant. 2020;gfaa037. doi:.https://doi.org/10.1093/ndt/gfaa037
- Dharnidharka VR, Cherikh WS, Abbott KC. An OPTN analysis of national registry data on treatment of BK virus allograft nephropathy in the United States. Transplantation. 2009;87(7):1019–26. doi:.https://doi.org/10.1097/TP.0b013e31819cc383
- Hirsch HH, Brennan DC, Drachenberg CB, Ginevri F, Gordon J, Limaye AP, et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation. 2005;79(10):1277–86. doi:.https://doi.org/10.1097/01.TP.0000156165.83160.09
- Santos CA, Brennan DC, Fraser VJ, Olsen MA. Delayed-onset cytomegalovirus disease coded during hospital readmission after kidney transplantation. Transplantation. 2014;98(2):187–94. doi:.https://doi.org/10.1097/TP.0000000000000030
- Evens AM, Roy R, Sterrenberg D, Moll MZ, Chadburn A, Gordon LI. Post-transplantation lymphoproliferative disorders: diagnosis, prognosis, and current approaches to therapy. Curr Oncol Rep. 2010;12(6):383–94. doi:.https://doi.org/10.1007/s11912-010-0132-1