Longitudinal growth on an everolimus- versus an MMF-based steroid-free immunosuppressive regimen in paediatric renal transplant recipients

Billing, Heiko; Burmeister, Greta; Plotnicki, L.; Ahlenstiel, Thurid; Fichtner, Alexander; Sander, Anja; Höcker, Britta; Tönshoff, Burkhard; Pape, Lars

doi:10.1111/tri.12148

Cited by 26 publications

(14 citation statements)

References 18 publications

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“…Longitudinal growth, based on the change in height z‐scores, and sexual maturation were unaffected by the introduction of everolimus. It is possible that over longer‐term follow‐up steroid withdrawal in the EVR/rTAC cohort might lead to an improved longitudinal growth but this was not observed in the short 6‐month window between initiation of steroid discontinuation and the end of the current observation period.…”

Section: Discussionmentioning

confidence: 94%

Early conversion of pediatric kidney transplant patients to everolimus with reduced tacrolimus and steroid elimination: Results of a randomized trial

Tönshoff

Ettenger

Strologo

et al. 2019

American Journal of Transplantation

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In a 12-month, multicenter, open-label study, 106 children were randomized at 4 to 6 weeks after kidney transplantation to switch to everolimus with reduced TAC (EVR/rTAC) and steroid elimination from month 5 posttransplant or to continue standard tacrolimus with mycophenolate mofetil (sTAC/MMF) and steroids. The cumulative incidence of a co-primary efficacy end point (biopsy-proven acute rejection [BPAR], graft loss, or death from randomization to month 12) was 10.3% with EVR/rTAC and 5.8% with sTAC/MMF (difference 4.4%; P = .417). BPAR occurred in 9.6% and 5.6% of patients, respectively. Patient and renal allograft survival were 100%. The co-primary end point of mean estimated glomerular filtration rate at month 12 was 76.2 mL/min/1.73 m with EVR/rTAC and 72.5 mL/min/1.73 m for sTAC/MMF (difference 3.8 mL/min/1.73m ; P = .49). One EVR/rTAC patient developed posttransplant lymphoproliferative disease. Longitudinal growth and sexual maturation were equivalent between groups. The randomized drug regimen was discontinued in 34.6% and 13% of patients in the EVR/rTAC and sTAC/MMF groups, respectively (P = .024), and discontinued due to adverse events/infections in 25.0% and 11.1% of patients (P = .062). In conclusion, early conversion of pediatric kidney transplant patients from TAC, MMF, and steroids to EVR/rTAC and steroid withdrawal maintains immunosuppressive efficacy and preserves renal function.

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Section: Discussionmentioning

confidence: 94%

Early conversion of pediatric kidney transplant patients to everolimus with reduced tacrolimus and steroid elimination: Results of a randomized trial

Tönshoff

Ettenger

Strologo

et al. 2019

American Journal of Transplantation

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“…Also longitudinal growth was comparable between the groups; but these data are difficult to interpret, because the percentage of steroid-free and growth-hormone treated patients was different between the two groups. We previously reported that longitudinal growth over 2 years in steroid-free pediatric patients on low-dose EVR and CsA is not different to that of a matched steroid-free control group on an immunosuppressive regimen with standard-dose CNI and MMF [ 23 ]. Hence, low-dose EVR does not appear to negatively impact longitudinal growth in pediatric renal transplant recipients.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of an Everolimus- vs. a Mycophenolate Mofetil-Based Regimen in Pediatric Renal Transplant Recipients

et al. 2015

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IntroductionData on the efficacy and safety of everolimus in pediatric renal transplantation compared to other immunosuppressive regimens are scarce.Patients/MethodsWe therefore performed a multicenter, observational, matched cohort study over 4 years post-transplant in 35 patients on everolimus plus low-dose cyclosporine, who were matched (1:2) with a control group of 70 children receiving a standard-dose calcineurin-inhibitor- and mycophenolate mofetil-based regimen.ResultsCorticosteroids were withdrawn in 83% in the everolimus vs. 39% in the control group (p<0.001). Patient and graft survival were comparable. The rate of biopsy-proven acute rejection episodes Banff score ≥ IA during the first year post-transplant was 6% in the everolimus vs. 13% in the control group (p = 0.23). The rate of de novo donor-specific HLA antibodies (11% in everolimus, 18% in controls) was comparable (p = 0.55). At 4 years post-transplant, mean eGFR in the everolimus group was 56±33 ml/min per 1.73 m² vs. 63±22 ml/min per 1.73 m² in the control group (p = 0.14). Everolimus therapy was associated with less BK polyomavirus replication (3% vs. 17% in controls; p = 0.04), but with a higher percentage of arterial hypertension and more hyperlipidemia (p<0.001).ConclusionIn pediatric renal transplantation, an everolimus-based regimen with low-dose cyclosporine yields comparable four year results as a standard regimen, but with a different side effect profile.

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“…No change in sex hormone levels occurred in more recent trials of everolimus in children which used lower immunosuppressant doses [94]. There is some evidence that everolimus in combination with low-dose CNIs does not have a negative effect on growth in pediatric transplant patients [95,96]. In terms of sirolimus, albeit in combination with standard-exposure CNIs, case and case-control studies have reported mixed results of either negative or no effects [94].…”

Section: Comparison Of Sirolimus and Everolimus In Clinical Trialsmentioning

confidence: 99%

Everolimus and sirolimus in transplantation-related but different

Klawitter

Nashan

Christians

2015

Expert Opinion on Drug Safety

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109

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Introduction The inhibitors of the mammalian target of rapamycin (mTOR) sirolimus and everolimus are used as immunosuppressants after organ transplantation in combination with calcineurin inhibitors, but also as proliferation signal inhibitors coated on drug eluting stents and in cancer therapy. Notwithstanding their related chemical structures both have distinct pharmacokinetic, pharmacodynamic and toxicodynamic properties. Areas covered The additional hydroxyethyl group at the C(40) of the everolimus molecule results in different tissue and subcellular distribution, different affinities to active drug transporters and drug metabolizing enzymes as well as differences in drug-target protein interactions including a much higher potency in terms of interacting with the mTOR complex 2 (mTORC2) than sirolimus. Said mechanistic differences as well as differences found in clinical trials in transplant patients are reviewed. Expert opinion In comparison to sirolimus, everolimus has higher bioavailability, a shorter terminal half-life, different blood metabolite patterns, the potential to antagonize the negative effects of calcineurin inhibitors on neuronal and kidney cell metabolism (which sirolimus enhances), the ability to stimulate mitochondrial oxidation (which sirolimus inhibits), and to reduce vascular inflammation to a greater extent. A head-to-head, randomized trial comparing the safety and tolerability of these two mTOR inhibitors in solid organ transplant recipients is merited.

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Longitudinal growth on an everolimus- versus an MMF-based steroid-free immunosuppressive regimen in paediatric renal transplant recipients

Cited by 26 publications

References 18 publications

Early conversion of pediatric kidney transplant patients to everolimus with reduced tacrolimus and steroid elimination: Results of a randomized trial

Early conversion of pediatric kidney transplant patients to everolimus with reduced tacrolimus and steroid elimination: Results of a randomized trial

Efficacy and Safety of an Everolimus- vs. a Mycophenolate Mofetil-Based Regimen in Pediatric Renal Transplant Recipients

Everolimus and sirolimus in transplantation-related but different

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