Budde, Klemens

Halleck, Fabian

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INVITED COMMENTARYRisks and benefits of everolimusKlemens Budde & Fabian HalleckDepartment of Nephrology, ChariteUniversit€atsmedizin Berlin, Berlin,GermanyCorrespondenceKlemens Budde, Department ofNephrology, ChariteUniversit€atsmedizin Berlin, 10117Berlin, Germany.Tel.: +49 3 0450 514002;fax: +49 3 0450 514902;e-mail: klemens.budde@charite.deTransplant International 2019; 32: 1124–1126Received: 31 July 2019; Accepted: 4 August 2019In the current version of this journal, Ferreira et al. [1]report the outcome of a 12-month, prospective, ran-domized, controlled trial from Sao Paolo, Brazil com-paring mycophenolate (MPA) and everolimus in low/standard risk, de-novo kidney transplant recipients fromextended criteria deceased donors (donor age >60 years,mean kidney donor profile index 89). All patientsreceived standard steroids, up to 4 days of 1.5 mg/kgATG induction and delayed introduction of low-dose(0.05 mg/kg BID) tacrolimus aiming at trough levelsbetween 3 and 5 ng/ml (median level in everolimus armwas 5 ng/ml vs. 5–6 ng/ml in MPA arm). The authorsrandomized 171 patients to either everolimus (n = 88,1.5 mg BID, aiming at trough levels of 4–8 ng/ml) orMPA (n = 83, 720 mg BID). The study highlights therisks and benefits of everolimus and is an example forthe general dilemma in transplantation between under-immunosuppresion (= rejection) and overimmunosup-pression (=infection).According to last international CMV consensusguidelines [2], universal prophylaxis and preemptivetherapy are both recommended in patients with inter-mediate CMV risk. Because of reimbursement issues inBrazil for the expensive valganciclovir prophylaxis,drug-related side effects, and only 6% CMV high-riskpatients, the Sao Paolo group explored the option of apreemptive CMV treatment strategy with tight CMVmonitoring together with the use of mTOR inhibitors[1,3]. The observation of lower CMV infection ratesunder mTOR inhibitors compared with MPA dates backfrom early clinical trials [4] and was confirmed inrecent trials [3,5,6] and meta-analyzes [7–10].The incidence of delayed graft function (DGF;defined as one or more dialysis in the first week post-transplant) was high (on average 69%) despite delayedintroduction of tacrolimus, questioning the benefit ofdelaying tacrolimus. As expected, patients receivingeverolimus had an 89% risk reduction of CMV (13.6%vs. 71.6%) at 12 months compared with MPA. How-ever, all other outcome parameters such as rejection(16% vs. 5%), treatment discontinuation (40% vs.28%), kidney function (32 vs. 43 ml/min), duration ofDGF (6 vs. 4 days), graft loss (11% vs. 1%), and death-(10% vs. 1%) favored MPA, and the study was termi-nated prematurely due to poor outcomes and safetyconcerns in the everolimus arm.What are the lessons from this trial?Obviously, the combination of MPA and tacrolimusremains the standard of care for patients receivingkidneys from extended criteria donors, despite higherincidence of CMV infections. The current trial demon-strates, that CMV infections, although frequent inMPA-treated patients, can be managed successfully,while the use of everolimus is far more challenging,ª 2019 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use anddistribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.doi:10.1111/tri.134891124Transplant Internationaleven in an extremely experienced and large center, suchas Sao Paolo. In this study, the problems with the useof everolimus started right after transplantation withlonger DGF duration, wound-healing issues requiringsurgical interventions, and more rejections due to diffi-culties in reaching adequate early everolimus exposure.This trial adds further evidence to previous observations[11], which are summarized in the recommendationfrom a recent consensus conference [12], that everoli-mus levels >3 ng/ml are crucial for sufficient rejectionprophylaxis.Besides underimmunosuppression, typical drug-re-lated side effects (hyperlipidemia, stomatitis, edema,proteinuria, wound-healing, and lymphoceles), remain amajor concern in everolimus-treated patients, leading tofrequent discontinuations. All clinical trials [1,3–6,13]and recent meta-analyzes [7–10] clearly demonstrateinferior tolerability of everolimus compared with MPA,as evidenced by higher discontinuation rates due toadverse events. Contrary to everolimus, MPA has a widetherapeutic range. By far most MPA-associated sideeffects such as leucopenia, gastrointestinal problems,and viral infections are managed sucessfully by dosereductions and/or concomittant treatment. In contrast,everolimus-associated side effects are more diverse andobviously more difficult to treat. Inexperience of theinvestigator and center differences may account forsome of the observed differences, but 15 years afterapproval in Europe, even experienced investigatorsrather discontinue everolimus and switch to standard ofcare, than to manage the adverse event and continueeverolimus, as evidenced by high discontinuation ratesin recent large trials [1,3,5,6,13].Finally, frequent rejections followed by intense rejec-tion treatment, severe infections, and aggravatednephrotoxicity caused renal problems, graft loss, anddeath in this trial. Again, this trial, like many other clin-ical trials [1,3–6] and meta-analyzes [8–10] demon-strates, that renal dysfunction is more frequent inpatients treated with combination of mTOR inhibitorsand CNIs, especially if CNI levels are not adequatelylowered [10–12,14]. A thorough pharmacodynamicanalysis from a large registration trial [11] showed thatalready tacrolimus levels of 4 ng/ml increased the riskof low and/or decreasing renal function as early as12 months post-transplant. In the ATHENA study [6],GFR of tacrolimus/everolimus combination was 7 ml/min lower compared with tacrolimus/MPA, most likelydue to inadequate high tacrolimus concentrations ofaround 6 ng/ml. In the large TRANSFORM trial, GFRwas 2.3 ml/min lower in CNI/everolimus combinationtherapy (tacrolimus levels around 4 ng/ml) comparedto CNI/MPA with tacrolimus concentrations of 6–7 ng/ml. These data together with the current study [1], fur-ther support the results from the pharmacodynamicanalysis [11], suggesting aggravated nephrotoxicity evenat “low” tacrolimus levels. The observation of inferiorrenal function after only 1–2 years of everolimus/tacro-limus combination therapy is worrisome, as nephrotoxi-city usually presents many years post-transplant, and nolong-term data on the evolution of renal function areavailable for everolimus/tacrolimus combination ther-apy.Thus, in summary, this trial together with the resultsof other recent data [1,3–11,13] provides further evi-dence, that MPA/tacrolimus remains current standardof care in de-novo renal allograft recipients, despite allthe well known-limitations of this combination therapy.Everolimus is a well-proven second-line treatmentoption in case of MPA intolerability, such as severe viralinfections, which are difficult to treat. Future researchshould aim to improve tacrolimus/MPA combinationtherapy with a focus on a reduction of side effects, andshould aim to optimize the protocol for important sub-groups such as patients receiving kidney from extendedcriteria donors, living donor transplants, elderlypatients, and immunized recipients.FundingThe authors have declared no funding.Conflicts of interestDr Budde reports research grants, travel support and/orhonoraria from Abbvie, Alexion, Astellas, Bristol-Myers-Squibb, Chiesi, CSL Behring, Fresenius, Hexal, Novartis,Otsuka Pfizer, Roche, Sandoz, SAP, Shire, Veloxis.REFERENCES1. Ferreira AN, Rosso Felipe C, MarinaCristelli M, et al. Prospectiverandomized study comparingeverolimus and mycophenolatesodium in de novo kidney transplantrecipients from expanded criteriadeceased donor. Transpl Int 2019; 32:1127.Transplant International 2019; 32: 1124–1126 1125ª 2019 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.Invited Commentary2. Kotton CN, Kumar D, Caliendo AM,et al. The third international consensusguidelines on the management ofcytomegalovirus in solid-organtransplantation. Transplantation 2018;102: 900.3. Tedesco-Silva H, Felipe C, Ferreira A,et al. Reduced incidence ofcytomegalovirus infection in kidneytransplant recipients receivingeverolimus and reduced tacrolimusdoses. Am J Transplant 2015; 15: 2655.4. Vıtko S, Margreiter R, Weimar W,et al. Three-year efficacy and safetyresults from a study of everolimusversus mycophenolate mofetil in denovo renal transplant patients. Am JTransplant 2005; 5: 2521.5. Berger SP, Sommerer C, Witzke O,et al. Two-year outcomes in de novorenal transplant recipients receivingeverolimus-facilitated calcineurininhibitor reduction regimen fromTRANSFORM study. Am J Transplant2019. [Epub ahead of print] https://doi.org/10.1111/ajt.154806. Sommerer C, Suwelack B, Dragun D,et al. An open-label, randomized trialindicates that everolimus withtacrolimus or cyclosporine is comparableto standard immunosuppression in denovo kidney transplant patients. KidneyInt 2019; 96: 231.7. Andrassy J, Hoffmann VS, Rentsch M,et al. Is cytomegalovirus prophylaxisdispensable in patients receiving an mTORinhibitor-based immunosuppression? Asystematic review and meta-analysis.Transplantation 2012; 94: 1208.8. He L, Deng J, Yang B, Jiang W.Efficacy and safety of everolimus pluslow-dose calcineurin inhibitor vs.mycophenolate mofetil plus standard-dose calcineurin inhibitor in renaltransplant recipients: a systematicreview and meta-analysis. Clin Nephrol2018; 89: 336.9. Xie X, Jiang Y, Lai X, Xiang S, Shou Z,Chen J. mTOR inhibitor versusmycophenolic acid as the primaryimmunosuppression regime combinedwith calcineurin inhibitor for kidneytransplant recipients: a meta-analysis.BMC Nephrol 2015; 16: 91.10. Montero N, Quero M, Melilli E, et al.Mammalian target of rapamycininhibitors combined with calcineurininhibitors as initial immunosuppressionin renal transplantation: a meta-analysis. Transplantation 2019. [Epubahead of print] https://doi.org/10.1097/TP.000000000000276911. Shihab F, Qazi Y, Mulgaonkar S, et al.Association of clinical events witheverolimus exposure in kidneytransplant patients receiving low dosesof tacrolimus. Am J Transplant 2017;17: 2363.12. Shipkova M, Hesselink DA, Holt DW,et al. Therapeutic drug monitoring ofeverolimus: a consensus report. TherDrug Monit 2016; 38: 143.13. Qazi Y, Shaffer D, Kaplan B, et al.Efficacy and safety of everolimus pluslow-dose tacrolimus versusmycophenolate mofetil plus standard-dose tacrolimus in de novo renaltransplant recipients: 12-month data.Am J Transplant 2017; 17: 1358.14. Brunet M, van Gelder T, Asberg A,et al. Therapeutic drug monitoring oftacrolimus-personalized therapy:second consensus report. Ther DrugMonit 2019; 41: 261.1126 Transplant International 2019; 32: 1124–1126ª 2019 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.

Risks and benefits of everolimus

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Risks and benefits of everolimus

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