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Rainer Ganschow,1 Jörg-Matthias Pollok,2 Martin Jankofsky,3 Guido Junge4 1Department of Pediatrics, 2Department of General, Visceral, Thoracic, and Vascular Surgery, 3Department of Pediatrics, University of Bonn, Bonn, Germany; 4Integrated Hospital Care, Novartis Pharma AG, Basel, SwitzerlandAbstract: During the last 5 decades, liver transplantation has witnessed rapid development in terms of both technical and pharmacologic advances. Since their discovery, calcineurin inhibitors (CNIs) have remained the standard of care for immunosuppression therapy in liver transplantation, improving both patient and graft survival. However, adverse events, particularly posttransplant nephrotoxicity, associated with long-term CNI use have necessitated the development of alternate treatment approaches. These include combination therapy with a CNI and the inosine monophosphate dehydrogenase inhibitor mycophenolic acid and use of mammalian target of rapamycin (mTOR) inhibitors. Everolimus, a 40-O-(2-hydroxyethyl) derivative of mTOR inhibitor sirolimus, has a distinct pharmacokinetic profile. Several studies have assessed the role of everolimus in liver transplant recipients in combination with CNI reduction or as a CNI withdrawal strategy. The efficacy of everolimus-based immunosuppressive therapy has been demonstrated in both de novo and maintenance liver transplant recipients. A pivotal study in 719 de novo liver transplant recipients formed the basis of the recent approval of everolimus in combination with steroids and reduced-dose tacrolimus in liver transplantation. In this study, everolimus introduced at 30 days posttransplantation in combination with reduced-dose tacrolimus (exposure reduced by 39%) showed comparable efficacy (composite efficacy failure rate of treated biopsy-proven acute rejection, graft loss, or death) and achieved superior renal function as early as month 1 and maintained it over 2 years versus standard exposure tacrolimus. This review provides an overview of the efficacy and safety of everolimus-based regimens in liver transplantation in the de novo and maintenance settings, as well as in special populations such as patients with hepatocellular carcinoma recurrence, hepatitis C virus-positive patients, and pediatric transplant recipients. We also provide an overview of ongoing studies and discuss potential expansion of the role for everolimus in these settings.Keywords: mTOR inhibitors, everolimus, liver transplantation, efficacy, safety

Markus van der Giet,1 Josep M Cruzado,2 Johan W de Fijter,3 Hallvard Holdaas,4 Zailong Wang,5 Antonio Speziale,6 Guido Junge61Department of Nephrology, Campus Benjamin Franklin, Charite'-Universitätsmedizin, Berlin, Germany; 2Department of Nephrology, University Hospital of Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain; 3Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands; 4Section of Nephrology, Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; 5Biometrics and Statistical Science, Novartis Pharmaceuticals, East Hanover, NJ, USA; 6Research and Development, Novartis Pharma AG, Basel, SwitzerlandAbstract: Progressive decline in allograft function and cardiovascular mortality after kidney transplantation remain major clinical challenges that can potentially be addressed by the mammalian target of rapamycin (mTOR) inhibitors, everolimus and sirolimus. mTOR inhibitors maintain immunosuppressive efficacy after minimization of calcineurin inhibitor (CNI) therapy and can achieve significant long-term improvements in renal function. Recently, data have accumulated that suggest mTOR inhibitors may offer cardioprotective effects. In animal models, inhibition of mTOR leads to regression of cardiac hypertrophy, and the limited data consistently point to a remodeling benefit following heart transplantation. Experimentally, mTOR inhibitors restrict atherogenesis, confirmed clinically by intravascular ultrasound data demonstrating lower rates of transplant vasculopathy in heart transplant recipients on everolimus. Lastly, mTOR inhibitors appear to ameliorate arterial stiffness, a known risk factor for post-transplant cardiovascular events, but data remain sparse. The ELEVATE study will examine the renal effect of early conversion from CNI therapy to everolimus after kidney transplantation. Key secondary endpoints include the change in left ventricular mass index, the first time this endpoint has been included in a prospective study of an mTOR inhibitor. The occurrence of cardiovascular events will be rigorously documented and pulse wave velocity is being measured in a subpopulation of patients. Results from this innovative trial are awaited with interest.Keywords: cardiovascular, calcineurin inhibitors, ELEVATE, everolimus, kidney transplantation, mammalian target of rapamycin