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mTOR and CNI

Elena Crespo, Loreto Fernandez, Marc Lúcia, Edoardo Melilli, Ricardo Lauzurica, Rosa Maria Penin, Ariadna Quer, Sergio Luque, Maria Quero, Anna Manonelles, Joan Torras, Josep Maria Cruzado, Laura Cañas, Josep Maria Grinyó, Oriol Bestard
BACKGROUND: Chronic immunosuppression promotes Nonmelanocytic Squamous Cell Carcinoma (SCC) after kidney transplantation. Adaptive and innate immunity play a key role controlling tumor growth and are influenced by different immunosuppressive agents. We hypothesized that functional impairment of tumor-specific T cell responses due to CNI could contribute to SCC development, whereas conversion to mTOR-i could recover this protective immune response. METHODS: Peripheral tumor-specific T cell responses against main SCC-derived antigens using the IFN-γ ELISPOT assay and intratumor and circulating immune phenotypes (CD4+T, CD8+T, CD20+B, CD56+NK, FOXP3+Tregs) were explored in a cross-sectional analysis in 59 kidney transplant patients with SCC on CNI (KT-CNI-SCC) or mTOR-i (KT-mTORi-SCC), 25 nontransplants developing SCC (NoKT-SCC) and 6 healthy controls...
April 11, 2017: Transplantation
Luis Gustavo Modelli de Andrade, Helio Tedesco-Silva
Registry studies and systematic reviews have shown higher risk for mortality and graft loss in patients in use of mTOR inhibitors (mTORi) compared to calcineurin-based (CNI) immunosuppressive regimens. The majority of these studies pooled data from early trials using different strategies such as "de novo" combination of the high dose mTOR inhibitors with standard dose of CNI or high dose mTORi combined with mycophenolate. The large heterogeneity of these initial exploratory studies, many of them no longer in use, turns difficult any comparison with a well-defined standard of care regimen...
March 2017: Jornal Brasileiro de Nefrologia: ʹorgão Oficial de Sociedades Brasileira e Latino-Americana de Nefrologia
Hallvard Holdaas, Johan W de Fijter, Josep M Cruzado, Pablo Massari, Björn Nashan, John Kanellis, Oliver Witzke, Alex Gutierrez-Dalmau, Aydin Turkmen, Zailong Wang, Patricia Lopez, Peter Bernhardt, Jossy Kochuparampil, Markus van der Giet, Klaus Murbraech
BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitors may confer cardioprotective advantages but clinical data are limited. METHODS: In the open-label ELEVATE trial, kidney transplant patients were randomized at 10-14 weeks posttransplant to convert from calcineurin inhibitor (CNI) to everolimus or remain on standard CNI therapy. Prespecified endpoints included left ventricular mass index (LVMi) and, in a subpopulation of patients, arterial stiffness as measured by pulse wave velocity (PWV)...
March 22, 2017: Transplantation
Teun van Gelder, Lutz Fischer, Fuad Shihab, Maria Shipkova
The mammalian target of rapamycin (mTOR) inhibitor everolimus is a narrow therapeutic index drug for which optimal exposure levels are essential. The consistent pharmacokinetic profile of everolimus allows trough concentration (C0) measurement to be an appropriate and reliable index for therapeutic drug monitoring (TDM). Exposure-response analyses of data from early fixed-dose trials demonstrated that rates of biopsy-proven acute rejection (BPAR) are significantly higher if everolimus C0 declines below 3 ng/mL, an observation confirmed in subsequent concentration-controlled trials...
February 27, 2017: Transplantation Reviews
Bruno Vergès
The mammalian targets of rapamycin (mTOR) inhibitors are potent immunosuppressors used for prevention of acute rejection following transplantation and have been more recently used as anticancer drugs. mTOR inhibitors have a significant impact on glucose metabolism and induce frequently diabetes. mTOR inhibitors, when used as immunosuppressive agents (sirolimus, everolimus), can induce diabetes with an incidence which is low when used without calcineurin inhibitors (CNI) but high when used in combination with CNI (from 11...
March 4, 2017: Transplantation
Björn Nashan
The evidence base concerning use of mammalian target of rapamycin (mTOR) inhibitor therapy after liver transplantation is evolving rapidly, clarifying their benefits and disadvantages in different clinical scenarios. The H2304 trial showed that starting everolimus at 1 month posttransplant, with reduced tacrolimus, achieves a sustained improvement in renal function versus standard tacrolimus-based therapy, with at least equivalent immunosuppressive efficacy. Randomized studies evaluating early discontinuation of CNI therapy after introduction of an mTOR inhibitor consistently demonstrated a substantial improvement in renal function versus standard CNI therapy...
February 23, 2017: Transplantation
Michael Lin, Sahil Mittal, Farhad Sahebjam, Abbas Rana, Gagan K Sood
Calcineurin inhibitors (CNI) are the mainstay of immunosuppression after liver transplantation (LT), but CNIs are associated with significant nephrotoxicity. Recently, mTOR inhibitors such as sirolimus and everolimus (EVR) have been used with or without CNIs in LT recipients for their renal-sparing effect. We conducted a systematic review and meta-analysis of randomized controlled trials (RCT) that examined the effect of EVR with CNI minimization or withdrawal on renal function in LT recipients. RCT of primary adult LT recipients with baseline GFR >30 mL/min who received EVR with CNI minimization or withdrawal were included...
November 16, 2016: Clinical Transplantation
Gabriel Fernandes-Silva, Mayara Ivani de Paula, Érika B Rangel
Patient and pancreas allograft survival improved following reductions in surgical complications, tighter donor selection and optimization in immunosuppressive protocols. However, long-term survival of pancreas allografts is adversely affected by rejection and immunosuppressive regimen toxicity. Areas covered: This article reviews the existing literature and knowledge of mammalian target of rapamycin inhibitors (mTORi). Some clinically relevant drug-drug interactions are highlighted. We summarize the nephrotoxic and diabetogenic mechanisms of mTORi after pancreas transplant, the alternatives to minimize these effects, and report on other adverse events...
April 2017: Expert Opinion on Drug Metabolism & Toxicology
Carlos Cervera, Frederic Cofan, Cristina Hernandez, Dolors Soy, Maria Angeles Marcos, Gemma Sanclemente, Marta Bodro, Asunción Moreno, Fritz Diekmann, Josep Maria Campistol, Frederic Oppenheimer
Mammalian target of rapamycin inhibitors (mTORi) prevents cytomegalovirus (CMV) infection in kidney transplant (KT) patients. From May 2010 to December 2013, all KT recipients were retrospectively analysed. Maintenance immunosuppression regimen was divided into mTORi or calcineurin inhibitors (CNI)-based regimen. Since June 2011, CMV-seropositive recipients (R+) treated with high-intensity immunosuppression and mTORi did not receive anti-CMV prophylaxis. We analysed 350 consecutive patients, of which 95 (27%) received mTORi and 255 (73%) CNI-based immunosuppression...
November 2016: Transplant International: Official Journal of the European Society for Organ Transplantation
Susanne Brakemeier, Dennis Kannenkeril, Michael Dürr, Tobias Braun, Friederike Bachmann, Danilo Schmidt, Michael Wiesener, Klemens Budde
In kidney transplant recipients with chronic graft dysfunction, long-term immunosuppression with calcineurin inhibitors (CNIs) or mTOR inhibitors (mTORi) can be challenging due to adverse effects, such as nephrotoxicity and proteinuria. Seventy-nine kidney transplant recipients treated with CNI-based or mTORi-based maintenance immunosuppression who had CNI-induced nephrotoxicity or severe adverse events were switched to belatacept. Mean time from transplantation to belatacept conversion was 69.0 months. Mean estimated glomerular filtration rate (eGFR) ± standard deviation at baseline was 26...
November 2016: Transplant International: Official Journal of the European Society for Organ Transplantation
Paolo De Simone, Stefano Fagiuoli, Matteo Cescon, Luciano De Carlis, Giuseppe Tisone, Riccardo Volpes, Umberto Cillo
Immunosuppression after liver transplantation (LT) is presently based on use of calcineurin inhibitors (CNI), although they are associated with an increased incidence of renal dysfunction, cardiovascular complications, and de novo and recurrent malignancies. Over the past decade, mammalian target of rapamycin inhibitors have received considerable attention as immunosuppressants because they are associated with a more favorable renal profile versus CNI, as well as antiproliferative activity in clinical studies...
2017: Transplantation
Christina L Avila, Jason M Zimmerer, Steven M Elzein, Thomas A Pham, Mahmoud Abdel-Rasoul, Ginny L Bumgardner
BACKGROUND: De novo alloantibodies (donor-specific antibody) contribute to antibody-mediated rejection and poor long-term graft survival. Because the development of donor-specific antibody is associated with early graft loss of cell transplants and reduced long-term survival of solid organ transplants, we hypothesized that conventional immunosuppressives, calcineurin inhibitors (CNi), and mammalian target of rapamycin inhibitors (mTORi), may not be as effective for suppression of humoral alloimmunity as for cell-mediated immunity...
September 2016: Transplantation
Fritz Diekmann, Josep M Campistol
Immunosuppressive therapy after kidney transplantation is based on calcineurin inhibitors (CNI). In most cases CNI therapy is combined with mycophenolate and steroids. In spite of good short-term results this therapy is associated with long-term toxicities, graft loss and patient death. Therefore, alternative immunosuppressive strategies are needed that combine excellent efficacy with low incidences of long-term adverse outcomes. This review focuses on the strategies based on mTOR- inhibitors in combination with minimized exposure to CNI...
2015: Transplantation Research
A Baisi, F Nava, B Baisi, E Rubbiani, G Guaraldi, F Di Benedetto, M Giovannoni, A Solazzo, D Bonucchi, G Cappelli
BACKGROUND: In Human immunodeficiency virus (HIV)-positive patients undergoing kidney transplantation, outcomes and immunosuppression (IS) protocol are not yet established due to infectious and neoplastic risks as well as to pharmacokinetic interactions with antiretroviral therapy (TARV). METHODS: We report a retrospective, 1-center study on 18 HIV+ patients undergoing, between October 2007 and September 2015, kidney transplantation (13 cases) or combined kidney-liver transplant (5 cases)...
March 2016: Transplantation Proceedings
Jérôme Dumortier, Sebastien Dharancy, Yvon Calmus, Christophe Duvoux, François Durand, Ephrem Salamé, Faouzi Saliba
The mammalian target of rapamycin (mTOR) inhibitor everolimus is approved for rejection prophylaxis after liver transplantation. The current article pools the experience of French liver transplant surgeons and physicians in use of everolimus and, particularly, practical guidance on dosing, appropriate concomitant immunosuppression and management of adverse events. In terms of indication, introduction of everolimus from week 4 after liver transplantation, with or without concomitant calcineurin inhibitor (CNI) therapy, offers a significant renal benefit without loss of immunosuppressive efficacy...
July 2016: Transplantation Reviews
Mitra Rashidi, Sorosh Esmaily, Arnt E Fiane, Einar Gude, Kim A Tønseth, Thor Ueland, Finn Gustafsson, Hans Eiskjær, Göran Rådegran, Göran Dellgren
OBJECTIVES: The use of mammalian target of rapamycin (mTOR) inhibitors have been limited by adverse events (AE), including delayed wound healing. We retrospectively reviewed all AE and serious AE (SAE) in The Scandinavian heart transplant (HTx) everolimus (EVE) de novo trial with early calcineurin (CNI) avoidance (SCHEDULE). The aim of the study was to compare wound complications between EVE and CNI based regimen. MATERIALS AND METHODS: A total of 115 patients (mean age 51 ± 13 years, 73% men) were randomized within five days post-HTx to low dose EVE and reduced dose Cyclosporine (CyA) followed by early CyA withdrawal (EVE group; n=56) or standard CyA regimen (CyA group; n=59)...
May 1, 2016: International Journal of Cardiology
James N Fleming, David J Taber, Nicole A Pilch, John W McGillicuddy, Titte R Srinivas, Prabhakar K Baliga, Kenneth D Chavin, Charles F Bratton
BACKGROUND: There is a lack of conclusive evidence to suggest if calcineurin inhibitor (CNI) withdrawal or minimization with sirolimus is the best strategy for African Americans. METHODS: This was a randomized, prospective, open-label, pilot study comparing the two mammalian target of rapamycin (mTOR) transition strategies in adult African Americans between six and 24 wk post-transplant. The primary outcome was a comparison of the eGFR at one yr after conversion...
May 2016: Clinical Transplantation
Kerstin Herzer, Christian P Strassburg, Felix Braun, Cornelius Engelmann, Markus Guba, Frank Lehner, Silvio Nadalin, Andreas Pascher, Marcus N Scherer, Andreas A Schnitzbauer, Tim Zimmermann, Björn Nashan, Martina Sterneck
In recent years, immunosuppression (IS) after liver transplantation (LT) has become increasingly diversified as the choice of agents has expanded and clinicians seek to optimize the balance of immunosuppressive potency with the risk of adverse events in individual patients. Calcineurin inhibitors (CNIs) are the primary agents used for patients undergoing liver transplantation. Other therapeutic agents like interleukin-2 receptor antagonists are not universally administered, but can be considered for the delay or reduction in CNI exposure...
May 2016: Clinical Transplantation
Irene Latorre, Ana Esteve-Sole, Dolores Redondo, Sandra Giest, Jordi Argilaguet, Sara Alvarez, Cristina Peligero, Isabelle Forstmann, Marta Crespo, Julio Pascual, Andreas Meyerhans
BACKGROUND: Regulatory B (Breg) and T (Treg) cells represent a biomarker for tolerance in transplant patients. Despite the importance of Treg and Breg in transplantation and the suggested crosstalk between both suppressive cell populations, little is known on how they are influenced by long-term immunosuppressive treatment. The aim of the present study was to investigate the effect of different immunosuppressive drugs used in routine clinical practice on Treg and Breg cell numbers. METHODS: Thirty-six kidney transplant recipients with stable graft function were recruited and classified according to their concomitant therapy: 22 patients received calcineurin inhibitors (CNI) and 14 patients received mammalian target of rapamycin (mTOR) inhibitors...
March 2016: Transplant Immunology
Ying-Yu Huang, Chia-Chen Hsu, Chia-Lin Chou, Che-Chuan Loong, Min-Shan Wu, Yueh-Ching Chou
PURPOSE: During the past two decades, many novel immunosuppressive drugs have been approved for transplant recipients. Trends in the use of maintenance immunosuppressants after liver transplantation in Asia are unclear. Thus, we aimed to analyze the prescription trends in maintenance immunosuppressive drugs among liver transplant recipients in Taiwan and compare the results with the trends reported from western countries. METHODS: We conducted a retrospective nationwide population-based study utilizing the National Health Insurance Research Database (NHIRD) to analyze the prescribing patterns of immunosuppressants used in Taiwanese liver transplant recipients from 2000 to 2009...
June 2016: Pharmacoepidemiology and Drug Safety
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