Three-year outcomes from the CRADLE study in de novo pediatric kidney transplant recipients receiving everolimus with reduced tacrolimus and early steroid withdrawal

Burkhard Tönshoff, Helio Tedesco-Silva, Robert Ettenger, Martin Christian, Anna Bjerre, Luca Dello Strologo, Stephen D Marks, Lars Pape, Udaykiran Veldandi, Patricia Lopez, Marc Cousin, Priti Pandey, Matthias Meier, Burkhard Tönshoff, Helio Tedesco-Silva, Robert Ettenger, Martin Christian, Anna Bjerre, Luca Dello Strologo, Stephen D Marks, Lars Pape, Udaykiran Veldandi, Patricia Lopez, Marc Cousin, Priti Pandey, Matthias Meier

Abstract

CRADLE was a 36-month multicenter study in pediatric (≥1 to <18 years) kidney transplant recipients randomized at 4 to 6 weeks posttransplant to receive everolimus + reduced-exposure tacrolimus (EVR + rTAC; n = 52) with corticosteroid withdrawal at 6-month posttransplant or continue mycophenolate mofetil + standard-exposure TAC (MMF + sTAC; n = 54) with corticosteroids. The incidence of composite efficacy failure (biopsy-proven acute rejection [BPAR], graft loss, or death) at month 36 was 9.8% vs 9.6% (difference: 0.2%; 80% confidence interval: -7.3 to 7.7) for EVR + rTAC and MMF + sTAC, respectively, which was driven by BPARs. Graft loss was low (2.1% vs 3.8%) with no deaths. Mean estimated glomerular filtration rate at month 36 was comparable between groups (68.1 vs 67.3 mL/min/1.73 m2 ). Mean changes (z-score) in height (0.72 vs 0.39; P = .158) and weight (0.61 vs 0.82; P = .453) from randomization to month 36 were comparable, whereas growth in prepubertal patients on EVR + rTAC was better (P = .050) vs MMF + sTAC. The overall incidence of adverse events (AEs) and serious AEs was comparable between groups. Rejection was the leading AE for study drug discontinuation in the EVR + rTAC group. In conclusion, though AE-related study drug discontinuation was higher, an EVR + rTAC regimen represents an alternative treatment option that enables withdrawal of steroids as well as reduction of CNIs for pediatric kidney transplant recipients. ClinicalTrials.gov: NCT01544491.

Keywords: clinical research/practice; glomerular filtration rate (GFR); graft survival; immunosuppressant-mechanistic target of rapamycin: everolimus; immunosuppressive regimens-minimization/withdrawal; kidney transplantation/nephrology; patient safety.

© 2020 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.

References

REFERENCES

    1. McDonald SP, Craig JC; Australian and New Zealand Paediatric Nephrology Association. Long-term survival of children with end-stage renal disease. N Engl J Med. 2004;350(26):2654-2662.
    1. Hart A, Smith JM, Skeans MA, et al. OPTN/SRTR 2016 annual data report: kidney. Am J Transplant. 2018;18(Suppl 1):18-113.
    1. Peruzzi L, Amore A, Coppo R. Challenges in pediatric renal transplantation. World J Transplant. 2014;4(4):222-228.
    1. Grenda R, Webb NJ. Steroid minimization in pediatric renal transplantation: early withdrawal or avoidance? Pediatr Transplant. 2010;14(8):961-967.
    1. Franke D, Thomas L, Steffens R, et al. Patterns of growth after kidney transplantation among children with ESRD. Clin J Am Soc Nephrol. 2015;10(1):127-134.
    1. Zhang H, Zheng Y, Liu L, et al. Steroid avoidance or withdrawal regimens in paediatric kidney transplantation: a meta-analysis of randomised controlled trials. PLoS ONE. 2016;11(3):e0146523.
    1. Tsampalieros A, Knoll GA, Molnar AO, Fergusson N, Fergusson DA. Corticosteroid use and growth after pediatric solid organ transplantation: a systematic review and meta-analysis. Transplantation. 2017;101(4):694-703.
    1. Delucchi A, Valenzuela M, Ferrario M, et al. Early steroid withdrawal in pediatric renal transplant on newer immunosuppressive drugs. Pediatr Transplant. 2007;11(7):743-748.
    1. Delucchi Á, Valenzuela M, Lillo AM, et al. Early steroid withdrawal in pediatric renal transplant: five years of follow-up. Pediatr Nephrol. 2011;26(12):2235-2244.
    1. Grenda R, Watson A, Trompeter R, et al. A randomized trial to assess the impact of early steroid withdrawal on growth in pediatric renal transplantation: the TWIST study. Am J Transplant. 2010;10(4):828-836.
    1. Sarwal MM, Ettenger RB, Dharnidharka V, et al. Complete steroid avoidance is effective and safe in children with renal transplants: a multicenter randomized trial with three-year follow-up. Am J Transplant. 2012;12(10):2719-2729.
    1. Webb NJA, Douglas SE, Rajai A, et al. Corticosteroid-free kidney transplantation improves growth: 2-year follow-up of the TWIST randomized controlled trial. Transplantation. 2015;99(6):1178-1185.
    1. Cibrik D, Silva HT, Vathsala A, et al. Randomized trial of everolimus-facilitated calcineurin inhibitor minimization over 24 months in renal transplantation. Transplantation. 2013;95(7):933-942.
    1. Tedesco Silva H Jr, Cibrik D, Johnston T, et al. Everolimus plus reduced-exposure CsA versus mycophenolic acid plus standard-exposure CsA in renal-transplant recipients. Am J Transplant. 2010;10(6):1401-1413.
    1. Berger SP, Sommerer C, Witzke O, et al. Two-year outcomes in de novo renal transplant recipients receiving everolimus-facilitated calcineurin inhibitor reduction regimen from TRANSFORM study. Am J Transplant. 2019;19(11):3018-3034.
    1. Pascual J, Berger SP, Witzke O, et al. Everolimus with reduced calcineurin inhibitor exposure in renal transplantation. J Am Soc Nephrol. 2018;29(7):1979-1991.
    1. Billing H, Burmeister G, Plotnicki L, et al. Longitudinal growth on an everolimus- versus an MMF-based steroid-free immunosuppressive regimen in paediatric renal transplant recipients. Transpl Int. 2013;26(9):903-909.
    1. Brunkhorst LC, Fichtner A, Höcker B, et al. Efficacy and safety of an everolimus- vs a mycophenolate mofetil-based regimen in pediatric renal transplant recipients. PLoS ONE. 2015;10(9):e0135439.
    1. Pape L, Lehner F, Blume C, Ahlenstiel T. Pediatric kidney transplantation followed by de novo therapy with everolimus, low-dose cyclosporine A, and steroid elimination: 3-year data. Transplantation. 2011;92(6):658-662.
    1. Tönshoff B, Ettenger R, Dello Strologo L, et al. Early conversion of pediatric kidney transplant patients to everolimus with reduced tacrolimus and steroid elimination: results of a randomized trial. Am J Transplant. 2019;19(3):811-822.
    1. Schwartz GJ, Muñoz A, Schneider MF, et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009;20(3):629-637.
    1. NAPRTCS. North American Pediatric Renal Trials and Collaborative Studies NAPRTCS: 2014 annual transplant report. 2014.
    1. Pape L, Offner G, Kreuzer M, et al. De novo therapy with everolimus, low-dose ciclosporine A, basiliximab and steroid elimination in pediatric kidney transplantation. Am J Transplant. 2010;10(10):2349-2354.
    1. Benfield MR, Bartosh S, Ikle D, et al. A randomized double-blind, placebo controlled trial of steroid withdrawal after pediatric renal transplantation. Am J Transplant. 2010;10(1):81-88.
    1. Qazi Y, Shaffer D, Kaplan B, et al. Efficacy and safety of everolimus plus low-dose tacrolimus versus mycophenolate mofetil plus standard-dose tacrolimus in de novo renal transplant recipients: 12-month data. Am J Transplant. 2017;17(5):1358-1369.
    1. Shihab F, Qazi Y, Mulgaonkar S, et al. Association of clinical events with everolimus exposure in kidney transplant patients receiving low doses of tacrolimus. Am J Transplant. 2017;17(9):2363-2371.
    1. Shihab FS, Cibrik D, Chan L, et al. Association of clinical events with everolimus exposure in kidney transplant patients receiving reduced cyclosporine. Clin Transplant. 2013;27(2):217-226.
    1. González D, García CD, Azócar M, et al. Growth of kidney-transplanted pediatric patients treated with sirolimus. Pediatr Nephrol. 2011;26(6):961-966.
    1. Höcker B, Weber LT, Feneberg R, et al. Prospective, randomized trial on late steroid withdrawal in pediatric renal transplant recipients under cyclosporine microemulsion and mycophenolate mofetil. Transplantation. 2009;87(6):934-941.
    1. Hocker B, Weber LT, Feneberg R, et al. Improved growth and cardiovascular risk after late steroid withdrawal: 2-year results of a prospective, randomised trial in paediatric renal transplantation. Nephrol Dial Transplant. 2010;25(2):617-624.
    1. Bonthuis M, Groothoff JW, Ariceta G, et al. Growth patterns after kidney transplantation in European children over the past 25 years: an ESPN/ERA-EDTA registry study. Transplantation. 2019;104(1):137-144.
    1. Forster J, Ahlenstiel-Grunow T, Zapf A, Mynarek M, Pape L. Pubertal development in pediatric kidney transplant patients receiving mammalian target of rapamycin inhibitors or conventional immunosuppression. Transplantation. 2016;100(11):2461-2470.
    1. Krämer BK, Neumayer H-H, Stahl R, et al. Graft function, cardiovascular risk factors, and sex hormones in renal transplant recipients on an immunosuppressive regimen of everolimus, reduced dose of cyclosporine, and basiliximab. Transplant Proc. 2005;37(3):1601-1604.
    1. Kranz B, Wingen AM, Vester U, Konig J, Hoyer PF. Long-term side effects of treatment with mTOR inhibitors in children after renal transplantation. Pediatr Nephrol. 2013;28(8):1293-1298.
    1. Höcker B, Zencke S, Pape L, et al. Impact of everolimus and low-dose cyclosporin on cytomegalovirus replication and disease in pediatric renal transplantation. Am J Transplant. 2016;16(3):921-929.
    1. Nashan B, Gaston R, Emery V, et al. Review of cytomegalovirus infection findings with mammalian target of rapamycin inhibitor-based immunosuppressive therapy in de novo renal transplant recipients. Transplantation. 2012;93(11):1075-1085.
    1. Brennan DC, Legendre C, Patel D, et al. Cytomegalovirus incidence between everolimus versus mycophenolate in de novo renal transplants: pooled analysis of three clinical trials. Am J Transplant. 2011;11(11):2453-2462.
    1. Tedesco- Silva H, Felipe C, Ferreira A, et al. Reduced incidence of cytomegalovirus infection in kidney transplant recipients receiving everolimus and reduced tacrolimus doses. Am J Transplant. 2015;15(10):2655-2664.
    1. Ettenger R, Chin H, Kesler K, et al. Relationship among viremia/viral infection, alloimmunity, and nutritional parameters in the first year after pediatric kidney transplantation. Am J Transplant. 2017;17(6):1549-1562.
    1. Ganschow R, Ericzon B-G, Dhawan A, et al. Everolimus and reduced calcineurin inhibitor therapy in pediatric liver transplant recipients: results from a multicenter, prospective study. Pediatr Transplant. 2017;21(7):e13024.

Source: PubMed

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