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mTOR and CNI

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https://www.readbyqxmd.com/read/28828166/is-early-conversion-to-mtor-inhibitors-represent-a-suitable-choice-in-renal-transplant-recipients-a-systemic-review-of-medium-term-outcomes
#1
REVIEW
J Kumar, I Reccia, T Kusano
BACKGROUND: Immunosuppressive therapies are important parts of renal transplantation. OBJECTIVE: To assess the present literature on the effectiveness of early introduction of mTOR inhibitors with or without calcineurin inhibitors (CNI) in renal transplant recipients in terms of renal functioning and graft survival. METHODS: The current literature was reviewed following PROSPERO approval, assessing the role of immunosuppressive agent, mTOR inhibitors as an alternative to CNI within 6 months of renal transplantation by searching PubMed, EMBASE, Cochrane, Crossref, and Scopus...
2017: International Journal of Organ Transplantation Medicine
https://www.readbyqxmd.com/read/28730648/calcineurin-inhibitor-withdrawal-or-tapering-for-kidney-transplant-recipients
#2
REVIEW
Krishna M Karpe, Girish S Talaulikar, Giles D Walters
BACKGROUND: Calcineurin inhibitors (CNI) can reduce acute transplant rejection and immediate graft loss but are associated with significant adverse effects such as hypertension and nephrotoxicity which may contribute to chronic rejection. CNI toxicity has led to numerous studies investigating CNI withdrawal and tapering strategies. Despite this, uncertainty remains about minimisation or withdrawal of CNI. OBJECTIVES: This review aimed to look at the benefits and harms of CNI tapering or withdrawal in terms of graft function and loss, incidence of acute rejection episodes, treatment-related side effects (hypertension, hyperlipidaemia) and death...
July 21, 2017: Cochrane Database of Systematic Reviews
https://www.readbyqxmd.com/read/28652705/renal-function-in-heart-transplant-patients-after-switch-to-combined-mammalian-target-of-rapamycin-inhibitor-and-calcineurin-inhibitor-therapy
#3
Matthias Helmschrott, Rasmus Rivinius, Thomas Bruckner, Hugo A Katus, Andreas O Doesch
BACKGROUND: A calcineurin inhibitor (CNI)-based immunosuppression combined with mammalian target of rapamycin inhibitors (mTORs) seems to be attractive in patients after heart transplantation (HTX) in special clinical situations, for example, in patients with adverse drug effects of prior immunosuppression. Previous studies in patients after HTX detected advantageous effects regarding renal function of a tacrolimus (TAC)-based vs cyclosporine-A (CSA)-based immunosuppression (in combination with mycophenolate mofetil)...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28576905/cmv-and-bkpyv-infections-in-renal-transplant-recipients-receiving-an-mtor-inhibitor-based-regimen-versus-a-cni-based-regimen-a-systematic-review-and-meta-analysis-of-randomized-controlled-trials
#4
Samir G Mallat, Bassem Y Tanios, Houssam S Itani, Tamara Lotfi, Ciaran McMullan, Steven Gabardi, Elie A Akl, Jamil R Azzi
BACKGROUND AND OBJECTIVES: The objective of this meta-analysis is to compare the incidences of cytomegalovirus and BK polyoma virus infections in renal transplant recipients receiving a mammalian target of rapamycin inhibitor (mTOR)-based regimen compared with a calcineurin inhibitor-based regimen. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a comprehensive search for randomized, controlled trials up to January of 2016 addressing our objective. Other outcomes included acute rejection, graft loss, serious adverse events, proteinuria, wound-healing complications, and eGFR...
August 7, 2017: Clinical Journal of the American Society of Nephrology: CJASN
https://www.readbyqxmd.com/read/28507917/systemic-meta-analysis-assessing-the-short-term-applicability-of-early-conversion-to-mammalian-target-of-rapamycin-inhibitors-in-kidney-transplant
#5
Jayant Kumar, Isabella Reccia, Tomokazu Kusano, Bridson M Julie, Ajay Sharma, Ahmed Halawa
AIM: To consolidate the present evidence of effectiveness in renal functioning and graft survival following early introduction of mammalian target of rapamycin (mTOR) inhibitors with or without calcineurin inhibitors (CNIs) in renal transplant recipients. METHODS: We analysed the current literature following PROSPERO approval describing the role of immunosuppressive agent, mTOR inhibitors as an alternative to CNI within six months of renal transplant by searching the PubMed, EMBASE, Cochrane, Crossref, and Scopus using MeSH terms...
April 24, 2017: World Journal of Transplantation
https://www.readbyqxmd.com/read/28445619/mtor-inhibitors-and-risk-of-chronic-antibody-mediated-rejection-after-kidney-transplantation-where-are-we-now
#6
REVIEW
Philippe Grimbert, Olivier Thaunat
Antibody-mediated rejection (AMR) usually starts with generation of donor-specific anti-HLA antibodies (DSAs), arising from a B-cell response to antigen recognition. In vitro and preclinical data demonstrate that mammalian target of rapamycin (mTOR) inhibition attenuates the mTOR-mediated intracellular signaling pathway involved in AMR-related kidney damage. The limited available data from immunological studies in kidney transplant patients, however, have not shown such effects in vivo. In terms of clinical immunosuppression, the overriding influence on rates of de novo DSA (dnDSA) or AMR-regardless of the type of regimen-is patient adherence...
July 2017: Transplant International: Official Journal of the European Society for Organ Transplantation
https://www.readbyqxmd.com/read/28403126/effector-antitumor-and-regulatory-t-cell-responses-influence-the-development-of-nonmelanoma-skin-cancer-in-kidney-transplant-patients
#7
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 calcineurin inhibitors (CNI) could contribute to SCC development, whereas conversion to mammalian target of rapamycin inhibitors (mTOR-i) could recover this protective immune response...
September 2017: Transplantation
https://www.readbyqxmd.com/read/28355407/critical-analysis-of-graft-loss-and-death-in-kidney-transplant-recipients-treated-with-mtor-inhibitors
#8
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
https://www.readbyqxmd.com/read/28333860/cardiovascular-parameters-to-2-years-after-kidney-transplantation-following-early-switch-to-everolimus-without-calcineurin-inhibitor-therapy-an-analysis-of-the-randomized-elevate-study
#9
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 inhibitors may confer cardioprotective advantages, but clinical data are limited. METHODS: In the open-label ELEVATE trial, kidney transplant patients were randomized at 10 to 14 weeks after transplant to convert from calcineurin inhibitor (CNI) to everolimus or remain on standard CNI therapy. Prespecified end points included left ventricular mass index and, in a subpopulation of patients, arterial stiffness as measured by pulse wave velocity...
October 2017: Transplantation
https://www.readbyqxmd.com/read/28279567/optimizing-everolimus-exposure-when-combined-with-calcineurin-inhibitors-in-solid-organ-transplantation
#10
REVIEW
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...
July 2017: Transplantation Reviews
https://www.readbyqxmd.com/read/28263222/mtor-and-cardiovascular-diseases-diabetes-mellitus
#11
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
https://www.readbyqxmd.com/read/28230639/mammalian-target-of-rapamycin-inhibition-clinical-transplantation-liver
#12
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
https://www.readbyqxmd.com/read/27862340/everolimus-with-early-withdrawal-or-reduced-dose-calcineurin-inhibitors-improves-renal-function-in-liver-transplant-recipients-a-systematic-review-and-meta-analysis
#13
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...
February 2017: Clinical Transplantation
https://www.readbyqxmd.com/read/27659512/mtor-inhibitors-in-pancreas-transplant-adverse-effects-and-drug-drug-interactions
#14
REVIEW
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
https://www.readbyqxmd.com/read/27564469/effect-of-mammalian-target-of-rapamycin-inhibitors-on-cytomegalovirus-infection-in-kidney-transplant-recipients-receiving-polyclonal-antilymphocyte-globulins-a-propensity-score-matching-analysis
#15
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
https://www.readbyqxmd.com/read/27514317/experience-with-belatacept-rescue-therapy-in-kidney-transplant-recipients
#16
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
https://www.readbyqxmd.com/read/27495768/use-of-everolimus-in-liver-transplantation-recommendations-from-a-working-group
#17
REVIEW
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...
February 2017: Transplantation
https://www.readbyqxmd.com/read/27362313/mtor-inhibition-suppresses-posttransplant-alloantibody-production-through-direct-inhibition-of-alloprimed-b-cells-and-sparing-of-cd8-antibody-suppressing-t-cells
#18
COMPARATIVE STUDY
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
https://www.readbyqxmd.com/read/27293552/practical-considerations-for-the-use-of-mtor-inhibitors
#19
REVIEW
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
https://www.readbyqxmd.com/read/27109949/kidney-transplantation-in-hiv-infected-recipients-therapeutic-strategy-and-outcomes-in-monocentric-experience
#20
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
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