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Randomized Controlled Trial
. 2024 Jan 1;108(1):261-275.
doi: 10.1097/TP.0000000000004749. Epub 2023 Aug 1.

A Head-to-head Comparison of De Novo Sirolimus or Everolimus Plus Reduced-dose Tacrolimus in Kidney Transplant Recipients: A Prospective and Randomized Trial

Juliana Toniato de Rezende Freschi  1   2 , Marina Pontello Cristelli  1 , Laila Almeida Viana  1 , Klaus Nunes Ficher  1 , Monica Rika Nakamura  1 , Henrique Proença  1 , Yasmim Cardoso Dreige  1 , Renato de Marco  3 , Maria Gerbase de Lima  3 , Renato Demarchi Foresto  1 , Wilson Ferreira Aguiar  1   4 , Jose Medina-Pestana  1   2 , Helio Tedesco-Silva  1   2
Affiliations
Randomized Controlled Trial

A Head-to-head Comparison of De Novo Sirolimus or Everolimus Plus Reduced-dose Tacrolimus in Kidney Transplant Recipients: A Prospective and Randomized Trial

Juliana Toniato de Rezende Freschi et al. Transplantation. .

Abstract

Background: Mammalian target of rapamycin inhibitors (mTORi), sirolimus (SRL) and everolimus (EVR), have distinct pharmacokinetic/pharmacodynamics properties. There are no studies comparing the efficacy and safety of de novo use of SRL versus EVR in combination with reduced-dose calcineurin inhibitor.

Methods: This single-center prospective, randomized study included first kidney transplant recipients receiving a single 3 mg/kg antithymocyte globulin dose, tacrolimus, and prednisone, without cytomegalovirus (CMV) pharmacological prophylaxis. Patients were randomized into 3 groups: SRL, EVR, or mycophenolate sodium (MPS). Doses of SRL and EVR were adjusted to maintain whole blood concentrations between 4 and 8 ng/mL. The primary endpoint was the 12-mo incidence of the first CMV infection/disease.

Results: There were 266 patients (SRL, n = 86; EVR, n = 90; MPS, n = 90). The incidence of the first CMV event was lower in the mTORi versus MPS groups (10.5% versus 7.8% versus 43.3%, P < 0.0001). There were no differences in the incidence of BK polyomavirus viremia (8.2% versus 10.1% versus 15.1%, P = 0.360). There were no differences in survival-free from treatment failure (87.8% versus 88.8% versus 93.3%, P = 0.421) and incidence of donor-specific antibodies. At 12 mo, there were no differences in kidney function (75 ± 23 versus 78 ± 24 versus 77 ± 24 mL/min/1.73 m 2 , P = 0.736), proteinuria, and histology in protocol biopsies. Treatment discontinuation was higher among patients receiving SRL or EVR (18.6% versus 15.6% versus 6.7%, P = 0.054).

Conclusions: De novo use of SRL or EVR, targeting similar therapeutic blood concentrations, shows comparable efficacy and safety. The reduced incidence of CMV infection/disease and distinct safety profile of mTORi versus mycophenolate were confirmed in this study.

Trial registration: ClinicalTrials.gov NCT03468478.

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Conflict of interest statement

The authors declare no funding or conflicts of interest.

References

    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;15:2655–2664.
    1. Pascual J, Berger SP, Witzke O, et al.; TRANSFORM Investigators. Everolimus with reduced calcineurin inhibitor exposure in renal transplantation. J Am Soc Nephrol. 2018;29:1979–1991.
    1. Kaplan B, Qazi Y, Wellen JR. Strategies for the management of adverse events associated with mTOR inhibitors. Transplant Rev (Orlando). 2014;28:126–133.
    1. Tedesco-Silva H, Pascual J, Viklicky O, et al.; TRANSFORM Investigators. Safety of everolimus with reduced calcineurin inhibitor exposure in de novo kidney transplants: an analysis from the randomized TRANSFORM study. Transplantation. 2019;103:1953–1963.
    1. Miranda TA, Felipe CR, Santos RHN, et al. Immunosuppressive drug-associated adverse event profiles in de novo kidney transplant recipients receiving everolimus and reduced tacrolimus doses. Ther Drug Monit. 2020;42:811–820.

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