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mTOR and CNI

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https://www.readbyqxmd.com/read/29757021/advagraf%C3%A2-with-or-without-an-induction-therapy-for-de-novo-kidney-transplant-recipients
#1
Johan Noble, Thomas Jouve, Lionel Rostaing, Paolo Malvezzi
Cornerstone immunosuppressive therapy currently relies on immediate-release tacrolimus, a calcineurin inhibitor (CNI) that is potentially nephrotoxic and is more diabetogenic than cyclosporine A. Two new formulations of tacrolimus have been launched: an extended-release formulation (Advagraf®/Astagraf XL®, Astellas company) and a long-lasting formulation (Envarsus®, Veloxis company). Area covered: Herein, we assess the efficacy of an extended-release formulation of tacrolimus (Advagraf®/Astagraf XL®) used in conjunction with or without an induction therapy (i...
May 14, 2018: Expert Review of Clinical Immunology
https://www.readbyqxmd.com/read/29659588/effects-of-mtor-is-on-malignancy-and-survival-following-renal-transplantation-a-systematic-review-and-meta-analysis-of-randomized-trials-with-a-minimum-follow-up-of-24-months
#2
Sebastian Wolf, Verena S Hoffmann, Antje Habicht, Teresa Kauke, Julian Bucher, Markus Schoenberg, Jens Werner, Markus Guba, Joachim Andrassy
BACKGROUND: mTOR-Is positively influence the occurrence and course of certain tumors after solid organ transplantation. The effect of mTOR-Is on the overall incidence of tumors irrespective of their origin is not entirely clear. Furthermore, conflicting data have been shown on mortality under mTOR-Is. METHODS: The current literature was searched for prospective randomized controlled renal transplantation trials. There were 1415 trials screened of which 13 could be included (pts...
2018: PloS One
https://www.readbyqxmd.com/read/29605470/outcomes-associated-with-mammalian-target-of-rapamycin-mtor-inhibitors-in-heart-transplant-recipients-a-meta-analysis
#3
Douglas L Jennings, Nicholas Lange, Michael Shullo, Farhana Latif, Susan Restaino, Veli K Topkara, Koji Takeda, Hiroo Takayama, Yoshifumi Naka, Maryjane Farr, Paolo Colombo, William L Baker
BACKGROUND: Data evaluating mTOR inhibitor use heart transplant (HT) patients comes from relatively small studies and controversy exists regarding their specific role. We performed a meta-analysis of randomized trials to evaluate the efficacy and safety of mTOR inhibitors in HT patients. METHODS: We performed a systematic literature search of Medline and Embase through July 2017 identifying studies evaluating mTOR inhibitors in HT patients reporting effects on coronary allograft vasculopathy (CAV), renal function, acute cellular rejection (ACR), cytomegalovirus (CMV) infection, and discontinuation due to adverse drug events (ADE)...
March 24, 2018: International Journal of Cardiology
https://www.readbyqxmd.com/read/29226570/campath-calcineurin-inhibitor-reduction-and-chronic-allograft-nephropathy-the-3c-study-results-of-a-randomized-controlled-clinical-trial
#4
(no author information available yet)
Calcineurin inhibitors (CNIs, eg, tacrolimus) reduce short-term kidney transplant failure, but chronic nephrotoxicity may contribute to late transplant loss. Elective conversion to inhibitors of the mammalian target of rapamycin (mTOR, eg, sirolimus) pathway might avoid long-term CNI renal damage and improve outcomes. The 3C Study was a pragmatic randomized controlled trial of sequential randomizations between alemtuzumab and basiliximab induction therapy (at the time of surgery) and between tacrolimus and sirolimus maintenance therapy at 6 months posttransplantation...
December 11, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/29130236/-occurrence-diagnosis-and-treatment-of-de-novo-gastrointestinal-malignancies-after-organ-transplantation
#5
Linhua Ji, Gang Zhao
With the continuous use of immunosuppressive agents routinely, the long-term survival rate of organ transplant recipients has been incessantly improved. However, the risk of de novo malignancies is also increasing, which has become the second cause of death after organ transplantation. De novo gastrointestinal malignancies are common after liver or kidney transplantation, mostly with advanced stage when diagnosed and poor prognosis. There is a significant trend in the development of de novo malignancies in transplant recipients, which is probably related to factors, including direct or indirect effects of immunosuppressive agents, precancerosis and survival time of transplanted grafts and recipients...
October 25, 2017: Zhonghua Wei Chang Wai Ke za Zhi, Chinese Journal of Gastrointestinal Surgery
https://www.readbyqxmd.com/read/29111569/the-influence-of-immunosuppressants-on-direct-acting-antiviral-therapy-is-dependent-on-the-hepatitis-c-virus-genotype
#6
Alexandra Frey, Katja Piras-Straub, Andreas Walker, Jörg Timm, Guido Gerken, Kerstin Herzer
BACKGROUND: Direct-acting antivirals (DAAs) have substantially increased sustained virological response rates after liver transplantation, with improved tolerance compared to interferon-based therapy. The influence of immunosuppressive agents on the efficacy of DAAs has not been clarified. METHODS: Subgenomic hepatitis C virus (HCV) replicons for genotype (GT) 1b, 2b, 3a, and 4a were treated with the mammalian target of rapamycin (mTOR) inhibitors everolimus and sirolimus or with the calcineurin inhibitors (CNIs) cyclosporine or tacrolimus, either alone or in combination with selected DAAs...
February 2018: Transplant Infectious Disease: An Official Journal of the Transplantation Society
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
COMPARATIVE STUDY
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
#14
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
#15
RANDOMIZED CONTROLLED TRIAL
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
#16
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
#17
Bruno Vergès
The mammalian targets of rapamycin (mTOR) inhibitors are potent immunosuppressors used for prevention of acute rejection after transplantation and have been more recently used as anticancer drugs. mTOR inhibitors have a significant impact on glucose metabolism and frequently induce diabetes. mTOR inhibitors, when used as immunosuppressive agents (sirolimus, everolimus), can induce diabetes with an incidence which is low when used without calcineurin inhibitors but high when used in combination with calcineurin inhibitors (from 11...
February 2018: Transplantation
https://www.readbyqxmd.com/read/28230639/mtor-inhibition-and-clinical-transplantation-liver
#18
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 calcineurin inhibitor (CNI) therapy after introduction of an mTOR inhibitor consistently demonstrated a substantial improvement in renal function versus standard CNI therapy...
February 2018: 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
#19
REVIEW
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
#20
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
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