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Masuda S, Lemaitre F, Barten MJ, Bergan S, Shipkova M, van Gelder T, Vinks S, Wieland E, Bornemann-Kolatzki K, Brunet M, de Winter B, Dieterlen MT, Elens L, Ito T, Johnson-Davis K, Kunicki PK, Lawson R, Lloberas N, Marquet P, Millan O, Mizuno T, Moes DJAR, Noceti O, Oellerich M, Pattanaik S, Pawinski T, Seger C, van Schaik R, Venkataramanan R, Walson P, Woillard JB, Langman LJ. Everolimus Personalized Therapy: Second Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. Ther Drug Monit 2025; 47:4-31. [PMID: 39331837 DOI: 10.1097/ftd.0000000000001250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 06/09/2024] [Indexed: 09/29/2024]
Abstract
ABSTRACT The Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology established the second consensus report to guide therapeutic drug monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice 7 years after the first version was published in 2016. This version provides information focused on new developments that have arisen in the last 7 years. For the general aspects of the pharmacology and TDM of EVR that have retained their relevance, readers can refer to the 2016 document. This edition includes new evidence from the literature, focusing on the topics updated during the last 7 years, including indirect pharmacological effects of EVR on the mammalian target of rapamycin complex 2 with the major mechanism of direct inhibition of the mammalian target of rapamycin complex 1. In addition, various concepts and technical options to monitor EVR concentrations, improve analytical performance, and increase the number of options available for immunochemical analytical methods have been included. Only limited new pharmacogenetic information regarding EVR has emerged; however, pharmacometrics and model-informed precision dosing have been constructed using physiological parameters as covariates, including pharmacogenetic information. In clinical settings, EVR is combined with a decreased dose of calcineurin inhibitors, such as tacrolimus and cyclosporine, instead of mycophenolic acid. The literature and recommendations for specific organ transplantations, such as that of the kidneys, liver, heart, and lungs, as well as for oncology and pediatrics have been updated. EVR TDM for pancreatic and islet transplantation has been added to this edition. The pharmacodynamic monitoring of EVR in organ transplantation has also been updated. These updates and additions, along with the previous version of this consensus document, will be helpful to clinicians and researchers treating patients receiving EVR.
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Affiliation(s)
- Satohiro Masuda
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Japan
| | - Florian Lemaitre
- Université de Rennes, CHU Rennes, Inserm, EHESP, IRSET-UMR S 1085, Rennes, France
- INSERM, Centre d'Investigation Clinique 1414, Rennes, France
- FHU SUPPORT, Rennes, France
| | - Markus J Barten
- Department of Cardiac and Vascular Surgery, University Heart and Vascular Center Hamburg, Hamburg, Germany
| | - Stein Bergan
- Department of Pharmacology, Oslo University Hospital and Department of Pharmacy, University of Oslo, Norway
| | | | - Teun van Gelder
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, the Netherlands
| | - Sander Vinks
- Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
- NDA Partners, A Propharma Group Company, Washington District of Columbia
| | | | | | - Mercè Brunet
- Pharmacology and Toxicology Laboratory, Biochemistry and Molecular Genetics Department, Biomedical Diagnostic Center, Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBERehd, Spain
| | - Brenda de Winter
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Maja-Theresa Dieterlen
- Laboratory Management Research Laboratory, Cardiac Surgery Clinic, Heart Center Leipzig GmbH, University Hospital, Leipzig, Germany
| | - Laure Elens
- Integrated Pharmacometrics, Pharmacogenetic and Pharmacokinetics Research Group (PMGK) Louvain Drug for Research Institute (LDRI), Catholic University of Louvain, (UCLouvain), Brussels, Belgium
| | - Taihei Ito
- Department of Organ Transplant Surgery; Fujita Health University School of Medicine, Toyoake Aichi, Japan
| | - Kamisha Johnson-Davis
- University of Utah Health Sciences Center and ARUP Laboratories, Salt Lake City, Utah
| | - Pawel K Kunicki
- Department of Drug Chemistry, Pharmaceutical and Biomedical Analysis, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland
| | - Roland Lawson
- University of Limoges, Inserm U1248, Pharmacology & Transplantation, Limoges, France
| | - Nuria Lloberas
- Nephrology Department, Hospital Universitari de Bellvitge-Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
| | - Pierre Marquet
- University of Limoges, Inserm U1248, Pharmacology & Transplantation, Limoges, France
- Department of Pharmacology, Toxicology and Pharmacovigilance, CHU de Limoges, France
| | - Olga Millan
- Pharmacology and Toxicology Laboratory, Biochemistry and Molecular Genetics Department, Biomedical Diagnostic Center, Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBERehd, Spain
| | - Tomoyuki Mizuno
- Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Dirk Jan A R Moes
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, the Netherlands
| | - Ofelia Noceti
- National Center for Liver Transplantation and Liver Diseases, Army Forces Hospital, Montevideo, Uruguay
| | - Michael Oellerich
- Department of Clinical Pharmacology, University Medical Center Göttingen, Georg-August-University Göttingen, Göttingen, Germany
| | - Smita Pattanaik
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Tomasz Pawinski
- Department of Drug Chemistry, Pharmaceutical and Biomedical Analysis, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland
| | | | - Ron van Schaik
- Department of Clinical Chemistry, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Raman Venkataramanan
- Department of Pharmaceutical Sciences, School of Pharmacy and Department of Pathology, Starzl Transplantation Institute, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Phil Walson
- University Medical School, Göttingen, Germany
| | - Jean-Baptiste Woillard
- Department of Pharmacology, Toxicology and Pharmacovigilance, CHU de Limoges, Limoges, France; and
| | - Loralie J Langman
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
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Berg T, Aehling NF, Bruns T, Welker MW, Weismüller T, Trebicka J, Tacke F, Strnad P, Sterneck M, Settmacher U, Seehofer D, Schott E, Schnitzbauer AA, Schmidt HH, Schlitt HJ, Pratschke J, Pascher A, Neumann U, Manekeller S, Lammert F, Klein I, Kirchner G, Guba M, Glanemann M, Engelmann C, Canbay AE, Braun F, Berg CP, Bechstein WO, Becker T, Trautwein C. [Not Available]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:1397-1573. [PMID: 39250961 DOI: 10.1055/a-2255-7246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
Affiliation(s)
- Thomas Berg
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Niklas F Aehling
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Tony Bruns
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martin-Walter Welker
- Medizinische Klinik I Gastroent., Hepat., Pneum., Endokrin. Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Tobias Weismüller
- Klinik für Innere Medizin - Gastroenterologie und Hepatologie, Vivantes Humboldt-Klinikum, Berlin, Deutschland
| | - Jonel Trebicka
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Deutschland
| | - Frank Tacke
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Pavel Strnad
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martina Sterneck
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Hamburg, Hamburg, Deutschland
| | - Utz Settmacher
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Jena, Deutschland
| | - Daniel Seehofer
- Klinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Eckart Schott
- Klinik für Innere Medizin II - Gastroenterologie, Hepatologie und Diabetolgie, Helios Klinikum Emil von Behring, Berlin, Deutschland
| | | | - Hartmut H Schmidt
- Klinik für Gastroenterologie und Hepatologie, Universitätsklinikum Essen, Essen, Deutschland
| | - Hans J Schlitt
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg, Regensburg, Deutschland
| | - Johann Pratschke
- Chirurgische Klinik, Charité Campus Virchow-Klinikum - Universitätsmedizin Berlin, Berlin, Deutschland
| | - Andreas Pascher
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Münster, Münster, Deutschland
| | - Ulf Neumann
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Essen, Essen, Deutschland
| | - Steffen Manekeller
- Klinik und Poliklinik für Allgemein-, Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Bonn, Bonn, Deutschland
| | - Frank Lammert
- Medizinische Hochschule Hannover (MHH), Hannover, Deutschland
| | - Ingo Klein
- Chirurgische Klinik I, Universitätsklinikum Würzburg, Würzburg, Deutschland
| | - Gabriele Kirchner
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg und Innere Medizin I, Caritaskrankenhaus St. Josef Regensburg, Regensburg, Deutschland
| | - Markus Guba
- Klinik für Allgemeine, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie, Universitätsklinikum München, München, Deutschland
| | - Matthias Glanemann
- Klinik für Allgemeine, Viszeral-, Gefäß- und Kinderchirurgie, Universitätsklinikum des Saarlandes, Homburg, Deutschland
| | - Cornelius Engelmann
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Ali E Canbay
- Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum, Bochum, Deutschland
| | - Felix Braun
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
| | - Christoph P Berg
- Innere Medizin I Gastroenterologie, Hepatologie, Infektiologie, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - Wolf O Bechstein
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Thomas Becker
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
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Ntobe-Bunkete B, Lemaitre F. Therapeutic drug monitoring in kidney and liver transplantation: current advances and future directions. Expert Rev Clin Pharmacol 2024; 17:505-514. [PMID: 38725273 DOI: 10.1080/17512433.2024.2354276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Accepted: 05/08/2024] [Indexed: 05/24/2024]
Abstract
INTRODUCTION Immunosuppressive drugs (ISD) present a narrow therapeutic window and extremely high inter- and intra-individual pharmacokinetic variability, which complicates their use in solid organ transplant recipients. In order to find a narrow appropriate equilibrium for each patient with the aim of maintaining clinical efficacy and reducing the risk of adverse drug reactions, a complex both clinical and biological monitoring is required, in particular through the use of therapeutic drug monitoring (TDM). AREA COVERED This review provides an overview of the available information on the relationship between exposure to immunosuppressive drugs and their efficacy and/or toxicity in kidney and liver transplantation. The aim of the review is to describe the pharmacodynamic/pharmacokinetic relationship that exists for immunosuppressive drugs, to summarize the studies that assess the value of TDM for these drugs in clinical practice, and to present the target and monitoring strategies aimed at optimizing patient immunosuppression, which could help to take a step forward in the field of solid organ transplant patient care. EXPERT OPINION To improve the care of transplant patients, several TDM innovations can be pursued by investigators. Among these, the development of microsampling methods for TDM or the combination of pharmacodynamic biomarkers with ISD exposure measurements appear to be relevant strategies.
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Affiliation(s)
- Béni Ntobe-Bunkete
- Univ Rennes, CHU Rennes, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail) - UMR S 1085, Rennes, France
- INSERM, Centre d'Investigation Clinique 1414, Rennes, France
| | - Florian Lemaitre
- Univ Rennes, CHU Rennes, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail) - UMR S 1085, Rennes, France
- INSERM, Centre d'Investigation Clinique 1414, Rennes, France
- FHU SUPORT, Rennes, France
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Mehtani R, Saigal S. Long Term Complications of Immunosuppression Post Liver Transplant. J Clin Exp Hepatol 2023; 13:1103-1115. [PMID: 37975039 PMCID: PMC10643541 DOI: 10.1016/j.jceh.2023.06.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 06/18/2023] [Indexed: 11/19/2023] Open
Abstract
Improvement in immunosuppression has led to a remarkable improvement in short-term and long-term outcomes post-liver transplant (LT). However, with improvements in long-term survival, complications related to immunosuppressive drugs, either directly or indirectly, have also increased. The adverse events could be drug-specific, class-specific, or generic. Calcineurin inhibitors (cyclosporine and tacrolimus) are the backbone of the immunosuppression after LT and the main culprit associated with most of the complications, including renal failure, post-transplant diabetes mellitus (PTDM), and metabolic syndrome. Steroids are also implicated in the development of diabetes, osteoporosis, and metabolic syndrome post-LT. The development of infections and de novo malignancies (DNMs) is a generic effect linked to the overall cumulative immunosuppression. The development of these complications significantly hampers the quality of life and leads to increased morbidity and mortality post-LT. Thus, it is important to minimize the cumulative immunosuppression dose while simultaneously preventing allograft rejection. This review provides up-to-date, comprehensive knowledge of the complications of long-term immunosuppression post-LT along with associated risk factors and strategies to minimize the risk of complications.
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Affiliation(s)
- Rohit Mehtani
- Department of Hepatology, Amrita Institute of Medical Sciences and Research, Faridabad, Haryana – 121001, India
| | - Sanjiv Saigal
- Transplant Hepatology, Centre for Liver and Biliary Sciences, Max Superspecialty Hospital, Saket, New Delhi, India
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Henkel L, Jehn U, Thölking G, Reuter S. Tacrolimus-why pharmacokinetics matter in the clinic. FRONTIERS IN TRANSPLANTATION 2023; 2:1160752. [PMID: 38993881 PMCID: PMC11235362 DOI: 10.3389/frtra.2023.1160752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 08/07/2023] [Indexed: 07/13/2024]
Abstract
The calcineurin inhibitor (CNI) Tacrolimus (Tac) is the most prescribed immunosuppressant drug after solid organ transplantation. After renal transplantation (RTx) approximately 95% of recipients are discharged with a Tac-based immunosuppressive regime. Despite the high immunosuppressive efficacy, its adverse effects, narrow therapeutic window and high intra- and interpatient variability (IPV) in pharmacokinetics require therapeutic drug monitoring (TDM), which makes treatment with Tac a major challenge for physicians. The C/D ratio (full blood trough level normalized by daily dose) is able to classify patients receiving Tac into two major metabolism groups, which were significantly associated with the clinical outcomes of patients after renal or liver transplantation. Therefore, the C/D ratio is a simple but effective tool to identify patients at risk of an unfavorable outcome. This review highlights the challenges of Tac-based immunosuppressive therapy faced by transplant physicians in their daily routine, the underlying causes and pharmacokinetics (including genetics, interactions, and differences between available Tac formulations), and the latest data on potential solutions to optimize treatment of high-risk patients.
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Affiliation(s)
- Lino Henkel
- Department of Medicine D, University of Münster, Münster, Germany
| | - Ulrich Jehn
- Department of Medicine D, University of Münster, Münster, Germany
| | - Gerold Thölking
- Department of Medicine D, University of Münster, Münster, Germany
- Department of Internal Medicine and Nephrology, University Hospital of Münster Marienhospital Steinfurt, Steinfurt, Germany
| | - Stefan Reuter
- Department of Medicine D, University of Münster, Münster, Germany
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Cabeza Rivera FH, Concepcion BP, Levea SLL. Chronic Kidney Disease After Liver Transplantation. ADVANCES IN KIDNEY DISEASE AND HEALTH 2023; 30:368-377. [PMID: 37657883 DOI: 10.1053/j.akdh.2023.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/03/2023]
Abstract
Chronic kidney disease among liver transplant recipients is common and associated with an increased mortality risk. Several risk factors and causes for the development of chronic kidney disease have been identified. They can be divided into perioperative factors, such as unresolved acute kidney injury; donor-related factors, such as the use of extended criteria liver allografts; and recipient-related factors, such as the use of calcineurin inhibitors and the presence of metabolic syndrome, diabetes, and obesity. There is a bimodal progression, more prominent during the initial post-transplant months, followed by a gradual but progressive decline over the subsequent years. Management strategies to prevent and treat chronic kidney disease in the general population can be reasonably applied to the liver transplant population and include addressing comorbidities such as hypertension and diabetes. Strategies to minimize or withdraw calcineurin inhibitors from the immunosuppressive regimen can slow progression of kidney dysfunction. Patients with advanced chronic kidney disease should be considered for kidney transplantation due to its survival advantage. Allocation policy in the United States confers safety-net allocation priority for liver transplant recipients who develop advanced chronic kidney disease within the first year of liver transplantation.
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Affiliation(s)
- Franco H Cabeza Rivera
- Katz Family Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, Miami, FL
| | | | - Swee-Ling L Levea
- Division of Nephrology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX
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Panackel C, Mathew JF, Fawas N M, Jacob M. Immunosuppressive Drugs in Liver Transplant: An Insight. J Clin Exp Hepatol 2022; 12:1557-1571. [PMID: 36340316 PMCID: PMC9630030 DOI: 10.1016/j.jceh.2022.06.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 06/16/2022] [Indexed: 12/12/2022] Open
Abstract
Liver transplantation (LT) is the standard of care for end-stage liver failure and hepatocellular carcinoma. Over the years, immunosuppression regimens have improved, resulting in enhanced graft and patient survival. At present, the side effects of immunosuppressive agents are a significant threat to post-LT quality of life and long-term outcome. The role of personalized immunosuppression is to reach a delicate balance between optimal immunosuppression and minimal side effects. Today, immunosuppression in LT is more of an art than a science. There are no validated markers for overimmunosuppression and underimmunosuppression, only a few drugs have therapeutic drug monitoring and immunosuppression regimens vary from center to center. The immunosuppressive agents are broadly classified into biological agents and pharmacological agents. Most regimens use multiple agents with different modes of action to reduce the dosage and minimize the toxicities. The calcineurin inhibitor (CNI)-related toxicities are reduced by antibody induction or using mTOR inhibitor/antimetabolites as CNI sparing or CNI minimization strategies. Post-liver transplant immunosuppression has an intensive phase in the first three months when alloreactivity is high, followed by a maintenance phase when immunosuppression minimization protocols are implemented. Over time some patients achieve "tolerance," defined as the successful stopping of immunosuppression with good graft function and no indication of rejection. Cell-based therapy using immune cells with tolerogenic potential is the future and may permit complete withdrawal of immunosuppressive agents.
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Key Words
- AMR, Antibody-mediated rejection
- APCs, Antigen-presenting cells
- ATG, Anti-thymocyte globulin
- CNI, Calcineurin inhibitors
- CsA, Cyclosporine A
- EVR, Everolimus
- IL-2R, Interleukin 2 Receptor
- LT, Liver transplantation
- MMF, Mycophenolate mofetil
- MPA, Mycophenolic acid
- SRL, Sirolimus
- TAC, Tacrolimus
- TCMR, T-cell-mediated rejection
- antimetabolites
- basiliximab
- calcineurin inhibitors
- cyclosporine
- everolimus
- immunosuppression
- liver transplantation
- mTORi, mammalian targets of rapamycin inhibitor
- mycophenolate mofetil
- tacrolimus
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Affiliation(s)
- Charles Panackel
- Aster Integrated Liver Care, Aster Medcity, Kochi, Kerala, 682027, India
| | - Joe F Mathew
- Aster Integrated Liver Care, Aster Medcity, Kochi, Kerala, 682027, India
| | - Mohamed Fawas N
- Aster Integrated Liver Care, Aster Medcity, Kochi, Kerala, 682027, India
| | - Mathew Jacob
- Aster Integrated Liver Care, Aster Medcity, Kochi, Kerala, 682027, India
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Saliba F, Duvoux C, Dharancy S, Dumortier J, Calmus Y, Gugenheim J, Kamar N, Salamé E, Neau‐Cransac M, Vanlemmens C, Durand F, Pageaux G, Hardwigsen J, Benkhatar Y, Derquenne F, Conti F. Five-year outcomes in liver transplant patients receiving everolimus with or without a calcineurin inhibitor: Results from the CERTITUDE study. Liver Int 2022; 42:2513-2523. [PMID: 35962772 PMCID: PMC9826472 DOI: 10.1111/liv.15396] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 07/01/2022] [Accepted: 08/11/2022] [Indexed: 01/18/2023]
Abstract
BACKGROUND AND AIMS To report 5-year outcomes of the CERTITUDE study. METHODS An observational study in patients with liver transplantation (LTx) compared the long-term impact of immunosuppression (with/without a calcineurin inhibitor) on renal function, cancers, major cardiovascular events (MACEs) and other safety parameters. All patients completing the 6-month SIMCER study were recruited and analysed according to treatment received at randomization and actual treatment received during the follow-up. RESULTS Of the 143 enrolled patients, 119 completed the 5-year follow-up (everolimus [EVR], n = 55; tacrolimus [TAC], n = 64). The mean absolute change in estimated glomerular filtration rate was not statistically different between both groups (TAC, -15.53 ml/min/1.73 m2 and EVR, -14.56 ml/min/1.73 m2 ). In the treatment subgroups based on actual treatment received, renal function was preserved better in the EVR subgroup compared with other subgroups (p = .051). Treated biopsy-proven acute rejection was higher in the EVR group (15.4% vs. 6.4%); however, the majority of events were mild in severity. MACE occurred in 9.2% vs. 14.1% of patients in the EVR and TAC groups respectively (p = .370). De novo cancer was reported in 14 and 5 patients in EVR and TAC groups respectively. Hepatocellular carcinoma (HCC) recurrence was observed in the TAC group alone (n = 4). Adverse events and treatment discontinuation owing to an adverse event were higher in the EVR group. CONCLUSIONS The CERTITUDE study demonstrated that EVR- and TAC-based regimens have comparable efficacy, safety and tolerability up to 5 years post-LTx.
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Affiliation(s)
- Faouzi Saliba
- AP‐HP, Hôpital Paul Brousse, Centre Hépato‐Biliaire, INSERM Unit 1193Université Paris SaclayVillejuifFrance
| | | | - Sébastien Dharancy
- Service Hépatologie‐Transplantation, Hôpital Huriez, CHRU LilleLilleFrance
| | - Jérôme Dumortier
- Hospices civils de Lyon, Hôpital Edouard Herriot, Université Claude Bernard Lyon 1LyonFrance
| | - Yvon Calmus
- APHP, Unité Médicale de Transplantation Hépatique, service d'hépato‐gastroentérologie, Hôpital Pitié Salpêtrière, Sorbonne Université, INSERM UMR S 938, Centre de recherche Saint‐Antoine (CRSA), Institute of Cardiometabolisme and Nutrition (ICAN)ParisFrance
| | - Jean Gugenheim
- Department of Digestive Surgery and Liver TransplantationArchet Hospital, Université Côte d'Azur, 151Route de Saint‐Antoine de Ginestière, NiceFrance
| | - Nassim Kamar
- Department of Nephrology and Organ TransplantationToulouse University Hospital, Université Paul SabatierToulouseFrance
| | - Ephrem Salamé
- Service de Chirurgie Hépato‐Biliare et de Transplantation Hépatique,Hôpital Trousseau, Chambray les Tours,ToursFrance
| | - Martine Neau‐Cransac
- Service de Chirurgie Hépatobiliaire et Transplantation Hépatique, Bâtiment Magellan, Hôpital Haut LévèquePessacFrance
| | - Claire Vanlemmens
- Service Hépatologie et Soins Intensifs Digestifs, CHU Jean MinjozBesançon CedexFrance
| | | | | | | | | | | | - Filomena Conti
- Department of Digestive Surgery and Liver TransplantationArchet Hospital, Université Côte d'Azur, 151Route de Saint‐Antoine de Ginestière, NiceFrance
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Galeev SR, Gautier SV. Risks and ways of preventing kidney dysfunction in drug-induced immunosuppression in solid organ recipients. RUSSIAN JOURNAL OF TRANSPLANTOLOGY AND ARTIFICIAL ORGANS 2022. [DOI: 10.15825/1995-1191-2022-4-24-38] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Immunosuppressive therapy (IMT) is the cornerstone of treatment after transplantation. The goal of immunosuppression is to prevent acute and chronic rejection while maximizing patient survival and long-term graft function. However, the expected effects of IMT must be balanced against the major adverse effects of these drugs and their toxicity. The purpose of this review is to summarize world experience on current immunosuppressive strategies and to assess their effects on renal function.
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Affiliation(s)
- Sh. R. Galeev
- Shumakov National Medical Research Center of Transplantology and Artificial Organs
| | - S. V. Gautier
- Shumakov National Medical Research Center of Transplantology and Artificial Organs; Sechenov University
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Kniepeiss D, Rosenkranz AR, Fickert P, Schemmer P. [Update: Immunosuppression in organ transplantation]. Dtsch Med Wochenschr 2022; 147:1199-1212. [PMID: 36070738 DOI: 10.1055/a-1716-8031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Abstract
Immunosuppression is an essential prerequisite for successful transplantation. In order to reduce the sometimes-considerable side effects, combination therapies with different agents are used. This article aims to provide an up-to-date overview of immunosuppression after liver and kidney transplantation.
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11
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De Simone P, Bronzoni J, Martinelli C. Everolimus versus mycophenolate mofetil in liver transplantation: every improvement in renal function matters. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2022; 114:312-313. [PMID: 35545915 DOI: 10.17235/reed.2022.8902/2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2025]
Abstract
The current edition of the journal features a Spanish, nationwide, multi-institutional study by Gomez Bravo MA et al. exploring the advantages of everolimus (EVR)-facilitated tacrolimus (TAC) minimization versus TAC in combination with mycophenolate mofetil (MMF) after liver transplantation (LT).
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Affiliation(s)
- Paolo De Simone
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Italia
| | - Jessica Bronzoni
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Italia
| | - Caterina Martinelli
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Italia
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12
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Nashan B, Schemmer P, Braun F, Schlitt HJ, Pascher A, Klein CG, Neumann UP, Kroeger I, Wimmer P. Early Everolimus-Facilitated Reduced Tacrolimus in Liver Transplantation: Results From the Randomized HEPHAISTOS Trial. Liver Transpl 2022; 28:998-1010. [PMID: 34525259 PMCID: PMC9291476 DOI: 10.1002/lt.26298] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 08/05/2021] [Accepted: 09/08/2021] [Indexed: 12/13/2022]
Abstract
Everolimus-facilitated reduced-exposure tacrolimus (EVR + rTAC) at 30 days after liver transplantation (LT) has shown advantages in renal preservation. This study evaluated the effects of early initiation of EVR + rTAC in de novo LT recipients (LTRs). In HEPHAISTOS (NCT01551212, EudraCT 2011-003118-17), a 12-month, multicenter, controlled study, LTRs were randomly assigned at 7 to 21 days after LT to receive EVR + rTAC or standard-exposure tacrolimus (sTAC) with steroids. The primary objective was to demonstrate superior renal function (assessed by estimated glomerular filtration rate [eGFR]) with EVR + rTAC versus sTAC at month 12 in the full analysis set (FAS). Other assessments at month 12 included the evaluation of renal function in compliance set and on-treatment (OT) patients, efficacy (composite endpoint of graft loss, death, or treated biopsy-proven acute rejection [tBPAR] and individual components) in FAS, and safety. In total, 333 patients (EVR + rTAC, 169; sTAC, 164) were included in the FAS. A high proportion of patients was nonadherent in maintaining tacrolimus trough levels (EVR + rTAC, 36.1%; sTAC, 34.7%). At month 12, the adjusted least square mean eGFR was numerically higher with EVR + rTAC versus sTAC (76.2 versus 72.1 mL/minute/1.73 m2 , difference: 4.1 mL/minute/1.73 m2 ; P = 0.097). A significant difference of 8.3 mL/minute/1.73 m2 (P = 0.03) favoring EVR + rTAC was noted in the compliance set. Incidence of composite efficacy endpoint (7.7% versus 7.9%) and tBPAR (7.1% versus 5.5%) at month 12 as well as incidence of treatment-emergent adverse events (AEs) and serious AEs were comparable between groups. A lower proportion of patients discontinued EVR + rTAC than sTAC treatment (27.2% versus 34.1%). Early use of everolimus in combination with rTAC showed comparable efficacy, safety, and well-preserved renal function versus sTAC therapy at month 12. Of note, renal function was significantly enhanced in the compliance set.
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Affiliation(s)
- Björn Nashan
- Department of Hepatobiliary Surgery and Visceral TransplantationUniversity Medical Center Hamburg‐EppendorfHamburgGermany
- Present address:
Organ Transplantation CenterThe First Affiliated Hospital of University of Science and Technology of ChinaAnhui Provincial HospitalHefeiChina
| | - Peter Schemmer
- Department of General, Visceral and Transplant SurgeryUniversity Hospital HeidelbergHeidelbergGermany
- Present address:
General, Visceral and Transplant SurgeryDepartment of SurgeryMedical University of GrazGrazAustria
| | - Felix Braun
- Department of General, Visceral, Thoracic, Transplant and Pediatric SurgeryUniversity Medical Center Schleswig‐HolsteinKielGermany
| | - Hans J. Schlitt
- Department of SurgeryUniversity Hospital RegensburgRegensburgGermany
| | - Andreas Pascher
- Department of General, Visceral and Transplant SurgeryCharité–Universitätsmedizin BerlinBerlinGermany
- Present address:
Department of General, Visceral and Transplantation SurgeryUniversity Hospital MünsterMünsterGermany
| | - Christian G. Klein
- Department of General, Visceral and Transplantation SurgeryUniversity Hospital EssenEssenGermany
| | - Ulf P. Neumann
- Department of General, Visceral and Transplant SurgeryUniversity Hospital AachenAachenGermany
- Present address:
Department of GeneralVisceral and Transplant SurgeryUniversity Hospital AachenAachenGermany
- Present address:
Department of General SurgeryMaastricht University Medical Centre (MUMC)Maastrichtthe Netherlands
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13
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Pacheco MP, Carneiro-D'Albuquerque LA, Mazo DF. Current aspects of renal dysfunction after liver transplantation. World J Hepatol 2022; 14:45-61. [PMID: 35126839 PMCID: PMC8790396 DOI: 10.4254/wjh.v14.i1.45] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 10/24/2021] [Accepted: 01/06/2022] [Indexed: 02/06/2023] Open
Abstract
The development of chronic kidney disease (CKD) after liver transplantation (LT) exerts a severe effect on the survival of patients. The widespread adoption of the model for end-stage liver disease score strongly impacted CKD incidence after the procedure, as several patients are transplanted with previously deteriorated renal function. Due to its multifactorial nature, encompassing pre-transplantation conditions, perioperative events, and nephrotoxic immunosuppressor therapies, the accurate identification of patients under risk of renal disease, and the implementation of preventive approaches, are extremely important. Methods for the evaluation of renal function in this setting range from formulas that estimate the glomerular filtration rate, to non-invasive markers, although no option has yet proved efficient in early detection of kidney injury. Considering the nephrotoxicity of calcineurin inhibitors (CNI) as a factor of utmost importance after LT, early nephroprotective strategies are highly recommended. They are based mainly on delaying the application of CNI during the immediate postoperative-period, reducing their dosage, and associating them with other less nephrotoxic drugs, such as mycophenolate mofetil and everolimus. This review provides a critical assessment of the causes of renal dysfunction after LT, the methods of its evaluation, and the interventions aimed at preserving renal function early and belatedly after LT.
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Affiliation(s)
- Mariana P Pacheco
- Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo School of Medicine, Sao Paulo 05403-900, Sao Paulo, Brazil
| | - Luiz Augusto Carneiro-D'Albuquerque
- Division of Digestive Organs Transplant, Department of Gastroenterology, University of São Paulo School of Medicine, Sao Paulo 05403-900, Sao Paulo, Brazil
| | - Daniel F Mazo
- Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo School of Medicine, Sao Paulo 05403-900, Sao Paulo, Brazil
- Division of Gastroenterology, Department of Internal Medicine, School of Medical Sciences of University of Campinas, Campinas 13083-878, Sao Paulo, Brazil
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14
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Gómez-Bravo M, Prieto Castillo M, Navasa M, Sánchez-Antolín G, Lladó L, Otero A, Serrano T, Jiménez Romero C, García González M, Valdivieso A, González-Diéguez ML, de la Mata M, Pons JA, Salcedo M, Rodrigo JM, Cuervas-Mons V, González Rodríguez A, Caralt M, Pardo F, Varo Pérez E, Crespo G, Rubin Á, Guilera M, Aldea A, Santoyo J. Everolimus plus minimized tacrolimus on kidney function in liver transplantation: REDUCE, a prospective, randomized controlled study. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2022; 114:335-342. [DOI: 10.17235/reed.2022.8549/2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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15
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Tedesco-Silva H, Saliba F, Barten MJ, De Simone P, Potena L, Gottlieb J, Gawai A, Bernhardt P, Pascual J. An overview of the efficacy and safety of everolimus in adult solid organ transplant recipients. Transplant Rev (Orlando) 2021; 36:100655. [PMID: 34696930 DOI: 10.1016/j.trre.2021.100655] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 09/17/2021] [Accepted: 09/17/2021] [Indexed: 12/15/2022]
Abstract
As the risk of graft loss due to acute rejection has declined, the goal of post-transplant management has switched to long-term preservation of organ function. Minimizing calcineurin inhibitor (CNI)-related nephrotoxicity is a key component of this objective. Everolimus is a mammalian target of rapamycin inhibitor/proliferation-signal inhibitor with potent immunosuppressive and anti-proliferative effects. It has been widely investigated in large randomized clinical studies that have shown it to have similar anti-rejection efficacy compared with standard-of-care regimens across organ transplant indications. With demonstrated potential to facilitate the reduction of CNI therapy and preserve renal function, everolimus is an alternative to the current standard-of-care CNI-based regimens used in de novo and maintenance solid organ transplantation recipients. Here, we provide an overview of the evidence from the everolimus clinical study program across kidney, liver, heart, and lung transplants, as well as other key data associated with its use in CNI reduction strategies in adult transplant recipients.
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Affiliation(s)
| | - Faouzi Saliba
- AP-HP_Hôpital Paul Brousse, Hepato-Biliary Centre, Villejuif, France; Université Paris-Saclay, INSERM Unit 1193, France
| | - Markus J Barten
- Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany
| | | | - Luciano Potena
- Heart Failure and Transplant Program, Cardiology Unit, IRCCS Policlinico di Sant'Orsola, Bologna, Italy
| | - Jens Gottlieb
- Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
| | | | | | - Julio Pascual
- Department of Nephrology, Hospital del Mar, Barcelona, Spain.
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16
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Renal Protective Effect of Everolimus in Liver Transplantation: A Prospective Randomized Open-Label Trial. Transplant Direct 2021; 7:e709. [PMID: 34124345 PMCID: PMC8191692 DOI: 10.1097/txd.0000000000001159] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 03/18/2021] [Accepted: 03/20/2021] [Indexed: 11/26/2022] Open
Abstract
Supplemental Digital Content is available in the text. Renal dysfunction is associated with poor long-term outcomes after liver transplantation. We examined the renal sparing effect of everolimus (EVR) compared to standard calcineurin inhibitor (CNI) immunosuppression with direct measurements of renal function over 24 months.
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17
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Saliba F, Dharancy S, Salamé E, Conti F, Eyraud D, Radenne S, Antonini T, Guillaud O, Guguenheim J, Neau-Cransac M, Demartin E, Lasailly G, Duvoux C, Sobesky R, Coilly A, Tresson S, Cailliez V, Boillot O, Pageaux GP, Samuel D, Calmus Y, Dumortier J. Time to Conversion to an Everolimus-Based Regimen: Renal Outcomes in Liver Transplant Recipients From the EVEROLIVER Registry. Liver Transpl 2020; 26:1465-1476. [PMID: 32869469 DOI: 10.1002/lt.25879] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 06/12/2020] [Accepted: 06/28/2020] [Indexed: 12/14/2022]
Abstract
Longterm use of a calcineurin inhibitor (CNI)-based regimen is one of the major reasons for chronic renal failure in liver transplantation recipients (LTRs). The Everolimus Liver registry (EVEROLIVER) evaluated renal function in LTRs who were converted to everolimus (EVR). This observational registry included all LTRs receiving EVR across 9 centers from France. Data are being collected in an electronic database over 10 years (12 visits/patient) to evaluate efficacy, renal function (estimated glomerular filtration rate [eGFR]), and safety of EVR use in clinical practice, and the current analysis is reporting up to 60 months of findings. Until September 2017, 1045 patients received EVR after a mean time of 3.6 ± 5.1 years. CNI withdrawal was feasible in 57.7% of patients as of month 60. Mean eGFR improved in patients with baseline eGFR <60 mL/minute/1.73 m2 and was maintained in those with baseline eGFR ≥60 mL/minute/1.73 m2 . Among patients with chronic kidney disease (CKD; baseline eGFR <60 mL/minute/1.73 m2 ), 55% converted to EVR within 3 months (early conversion) and 39.4% converted between 4 and 12 months after transplantation (mid-conversion) experienced improvement in eGFR (≥60 mL/minute/1.73 m2 ) at month 36. Only 20.9% and 17.4% among those converted beyond 12 months (late conversion) experienced improvement respectively at month 36 and 60. A logistic regression analysis in patients with CKD stage ≥3 demonstrated that late conversion, age, and female sex were associated with nonimprovement of eGFR (≥60 mL/minute/1.73 m2 ). Data from this real-life use of EVR indicate that renal function was maintained from the preconversion period until month 36 even in patients with advanced CKD. However, early rather than late conversion appears to be a safe approach to preserve longterm renal function in LTRs.
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Affiliation(s)
- Faouzi Saliba
- Centre Hépato-Biliaire, AP-HP Hôpital Paul Brousse, INSERM, Unité 1193, Université Paris Saclay, Villejuif, France
| | - Sébastien Dharancy
- Service d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Ephrem Salamé
- Service de Chirurgie Hépato-Biliaire et Digestive, Hôpital Trousseau, Centre Hospitalier Universitaire Tours, Tours, France
| | - Filoména Conti
- Service de Chirurgie Digestive et Hépato-Biliaire, AP-HP Hôpital Pitié Salpêtrière, Transplantation Hépatique, Paris, France
| | - Daniel Eyraud
- Département d'Anesthésie-Réanimation, Service de Chirurgie Digestive et Hépato-Biliaire et de Transplantation Hépatique, Groupe Hospitalier Pitié Salpêtrière, Paris, France
| | - Sylvie Radenne
- Service de Chirurgie Digestive et Transplantation Hépatique, Hôpital la Croix Rousse, Lyon, France
| | - Térésa Antonini
- Centre Hépato-Biliaire, AP-HP Hôpital Paul Brousse, INSERM, Unité 1193, Université Paris Saclay, Villejuif, France
| | - Olivier Guillaud
- Unité de Transplantation Hépatique, Hôpital Edouard Herriot, Lyon, France
| | - Jean Guguenheim
- Département de Chirurgie Digestive et Transplantation Hépatique, Hôpital Archet, University of Nice Sophia Antipolis, Nice, France
| | - Martine Neau-Cransac
- Unité de Chirurgie Hépato-Biliaire et de Transplantation Hépatique, Hôpital Magellan, Centre Hospitalier Universitaire Bordeaux, Pessac, France
| | - Eléonora Demartin
- Centre Hépato-Biliaire, AP-HP Hôpital Paul Brousse, INSERM, Unité 1193, Université Paris Saclay, Villejuif, France
| | - Guillaume Lasailly
- Service d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Christophe Duvoux
- Service d'Hépato-Gastro-Entérologie, AP-HP Hôpital Henri Mondor, Créteil, France
| | - Rodolphe Sobesky
- Centre Hépato-Biliaire, AP-HP Hôpital Paul Brousse, INSERM, Unité 1193, Université Paris Saclay, Villejuif, France
| | - Audrey Coilly
- Centre Hépato-Biliaire, AP-HP Hôpital Paul Brousse, INSERM, Unité 1193, Université Paris Saclay, Villejuif, France
| | - Sylvie Tresson
- Centre Hépato-Biliaire, AP-HP Hôpital Paul Brousse, INSERM, Unité 1193, Université Paris Saclay, Villejuif, France
| | - Valérie Cailliez
- Centre Hépato-Biliaire, AP-HP Hôpital Paul Brousse, INSERM, Unité 1193, Université Paris Saclay, Villejuif, France
| | - Olivier Boillot
- Unité de Transplantation Hépatique, Hôpital Edouard Herriot, Lyon, France
| | - Georges Philippe Pageaux
- Service d'Hépato-Gastro-Entérologie, Centre Hospitalier Universitaire Montpellier, Montpellier, France
| | - Didier Samuel
- Centre Hépato-Biliaire, AP-HP Hôpital Paul Brousse, INSERM, Unité 1193, Université Paris Saclay, Villejuif, France
| | - Yvon Calmus
- Service de Chirurgie Digestive et Hépato-Biliaire, AP-HP Hôpital Pitié Salpêtrière, Transplantation Hépatique, Paris, France
| | - Jérôme Dumortier
- Unité de Transplantation Hépatique, Hôpital Edouard Herriot, Lyon, France
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18
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Kniepeiss D, Rosenkranz AR, Fickert P, Schemmer P. Update: Immunsuppression bei Organtransplantationen. TRANSFUSIONSMEDIZIN 2020. [DOI: 10.1055/a-1238-3285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
ZusammenfassungDie Immunsuppression ist eine wesentliche Grundvoraussetzung für eine erfolgreiche Transplantation. Zur Reduktion der teils beträchtlichen Nebenwirkungen werden Kombinationstherapien mit unterschiedlichen Wirkstoffen durchgeführt. Dieser Beitrag soll einen aktuellen Überblick zur Immunsuppression nach Leber- und Nierentransplantation geben.
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19
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Di Maira T, Little EC, Berenguer M. Immunosuppression in liver transplant. Best Pract Res Clin Gastroenterol 2020; 46-47:101681. [PMID: 33158467 DOI: 10.1016/j.bpg.2020.101681] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 08/31/2020] [Indexed: 02/07/2023]
Abstract
The increasing potency of immunosuppression (IS) agents resulted in significantly decreased rates of steroid resistant rejection and rejection related graft loss in liver transplantation (LT). Currently, more than two thirds of late mortality after LT is unrelated to graft function. However, the increased benefit of more potent IS drugs, coupled with the prolonged survival of transplant recipients led to longer patients exposure to these drugs and their unwanted adverse effects, creating a double-edged sword. In this article the authors describe the mechanism of action and the adverse effects of the most commonly used immunosuppressed drugs, and the most commonly used IS regimens for both induction and maintenance regimens. The balance between the ideal IS regimen to prevent rejection and the need to minimize the dose of IS drugs in order to prevent the adverse effects related to its use requires the knowledge of the science and the experience with the art of medicine. The different protocols aimed at protecting renal function and preventing the development of de novo cancer and metabolic syndrome are discussed here. The main causes of mortality late after liver transplant are associated with prolonged use of IS medications, and clear evidence exists about over-immunosuppression of recipients of liver transplant. The current status of strategies of IS minimization and withdrawal are reviewed in this article, with evaluation of its benefits and pitfalls.
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Affiliation(s)
- Tommaso Di Maira
- Liver Transplantation and Hepatology Unit, Hospital Universitari I Politècnic La Fe, Avda Fernando Abril Martorell, 106 (Torre F5), Valencia, 46026, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, 28029, Spain; ISS La Fe, Valencia, 46026, Spain.
| | - Ester Coelho Little
- University of Arizona, College of Medicine, 3110 East Minnesona Avenue, Phoenix, AZ, 85016, USA.
| | - Marina Berenguer
- Liver Transplantation and Hepatology Unit, Hospital Universitari I Politècnic La Fe, Avda Fernando Abril Martorell, 106 (Torre F5), Valencia, 46026, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, 28029, Spain; ISS La Fe, Valencia, 46026, Spain; Universidad de Valencia, Facultad de Medicina, Valencia, 46010, Spain.
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20
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Åberg F, Berntsson J, Herlenius G, Castedal M, Bennet W. Everolimus and long-term decline in renal function after liver transplantation: real-life experience with measured GFR. Scand J Gastroenterol 2020; 55:718-724. [PMID: 32479116 DOI: 10.1080/00365521.2020.1770328] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Switching from calcineurin-inhibitors (CNI) to everolimus >6-12-months after liver transplantation (LT) seems inefficient in improving renal function, but whether everolimus halts further renal-function decline compared to low-dose CNI remains unclear. In a retrospective single-center study of everolimus after LT (2008-2016) with routine measured glomerular filtration rates (mGFR; 51Cr-EDTA- or iohexol clearance), we compared by propensity-score matching everolimus therapy to low-dose CNI therapy. The study comprised 36 patients with everolimus introduced on average 22 months post-LT (range 2-105 months, median follow-up 3.4 years), and 36 matched controls. Everolimus introduction was associated with a mean improvement in mGFR of 7 mL/min up to 1 year (p = .003), restricted to patients switched <1-year post-transplant and at tacrolimus trough levels >5 ng/mL. The differences between the everolimus group and controls in delta-mGFR from baseline to 1 year (7.3 vs 4.3 mL/min, p = .25) or 1-year to last follow-up (-0.8 vs -0.2 mL/min/year, p = .71) were non-significant. Proportions with mGFR decline >3 mL/min/year were similar between groups (11% and 14%, p = 1.00). Everolimus was stopped in three patients (8%), and acute rejection occurred in 17%. In conclusion, despite an early improvement in renal function after everolimus introduction, we found no evidence that everolimus halts the long-term mGFR decline compared to continued low-dose CNI therapy. Due to retrospective design, small sample size and heterogenous characteristics, definite conclusions require prospective studies.
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Affiliation(s)
- Fredrik Åberg
- The Transplant Institute, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - John Berntsson
- The Transplant Institute, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Gustaf Herlenius
- The Transplant Institute, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Maria Castedal
- The Transplant Institute, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - William Bennet
- The Transplant Institute, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
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21
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Guan TW, Lin YJ, Ou MY, Chen KB. Efficacy and safety of everolimus treatment on liver transplant recipients: A meta-analysis. Eur J Clin Invest 2019; 49:e13179. [PMID: 31610022 DOI: 10.1111/eci.13179] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 10/12/2019] [Indexed: 12/29/2022]
Abstract
BACKGROUND Everolimus is an effective immunosuppressant in organ transplantation without impaired renal function. The present study aimed to evaluate the efficacy and safety of everolimus therapy in liver transplant recipients. MATERIALS AND METHODS A systematic literature search was conducted to identify the eligible studies. The quality of the included studies was assessed. The outcomes of interest were biopsy-proven acute rejection (BPAR), graft loss, death, renal function and adverse events. RESULTS Eight trials involving 1570 participants were included. Compared to the standard exposure to calcineurin inhibitors (CNIs), the incidences of BPAR, graft loss and death were not increased in the everolimus combined with reduced CNIs group. The renal function was significantly improved after everolimus combined with reduced CNI therapy, and the glomerular filtration rate (GFR) was estimated to be elevated by 5.59 (95% CI: 2.17-9.01, P = .001) as compared to the standard exposure to CNIs. The risk of any adverse event was increased by everolimus combined with reduced CNI therapy (RR = 1.22, 95% CI: 1.04-1.42, P = .01) as compared to the standard exposure to CNIs. The likelihood of infection was not associated with the regimen. Any publication bias was not identified. CONCLUSIONS Although everolimus combined with reduced CNI therapy significantly improved the renal function in liver transplant recipients, it did not influence the incidence of BPAR, graft loss and death. This regimen might be associated with an increased risk of adverse events, which needs to be elucidated further.
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Affiliation(s)
- Tong-Wei Guan
- Institute of Microbiology, Xihua University, Chengdu, China
| | - Yi-Jin Lin
- Institute of Microbiology, Xihua University, Chengdu, China
| | - Meng-Ying Ou
- Institute of Microbiology, Xihua University, Chengdu, China
| | - Ke-Bao Chen
- Institute of Microbiology, Xihua University, Chengdu, China
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22
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Randomized Sirolimus-based Early Calcineurin Inhibitor Reduction in Liver Transplantation: Impact on Renal Function. Transplantation 2019; 104:1003-1018. [PMID: 31577671 DOI: 10.1097/tp.0000000000002980] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND The long-term use of calcineurin inhibitors (CNIs) after liver transplantation (LT) is associated with nephrotoxicity. METHODS Five-year follow-up data were retrieved from the randomized controlled multicenter SiLVER trial. Standard CNI-based mammalian target of rapamycin-free immunosuppression (group A, n = 264) was compared with a 50% reduction of CNI and introduction of the mammalian target of rapamycin inhibitor Sirolimus (SIR) within 4-6 weeks after LT (group B, n = 261). RESULTS Median MELD at LT was low with 10 (7-15) (group A) and 11 (8-15) (group B) in the intention-to-treat approach. CNI dose and CNI trough were reduced by 20% and 8% (group A) versus 55% and 56% (group B) at 3 months posttransplantation. Renal function was preserved at 3 months after LT in the SIR arm (estimated glomerular filtration rate 74 [57-95] versus 67 [55-85] mL/min/1.73m2 P = 0.004) but was similarly impaired thereafter compared with group A. The per protocol analysis identified LT recipients in group B with concomitant early CNI minimization and SIR treatment ≥ year 1 with significantly superior estimated glomerular filtration rate and lowest rate of chronic kidney disease (≥stage 3) from year 1 onwards until study end. Competing risk factors for renal disease (arterial hypertension, fat metabolism disorder, and hyperglycemia) were not associated with worse kidney function. CONCLUSIONS Prevention of CNI nephrotoxicity by SIR-based early CNI minimization protects renal function only short-term after LT in the intention-to-treat analysis of this low MELD cohort. Yet, selected LT recipients compliant with early CNI minimization and SIR maintenance achieved better long-term renal outcomes compared with real-world practice.
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mTOR Inhibitor Everolimus in Regulatory T Cell Expansion for Clinical Application in Transplantation. Transplantation 2019; 103:705-715. [PMID: 30451741 DOI: 10.1097/tp.0000000000002495] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Experimental and preclinical evidence suggest that adoptive transfer of regulatory T (Treg) cells could be an appropriate therapeutic strategy to induce tolerance and improve graft survival in transplanted patients. The University of Kentucky Transplant Service Line is developing a novel phase I/II clinical trial with ex vivo expanded autologous Treg cells as an adoptive cellular therapy in renal transplant recipients who are using everolimus (EVR)-based immunosuppressive regimen. METHODS The aim of this study was to determine the mechanisms of action and efficacy of EVR for the development of functionally competent Treg cell-based adoptive immunotherapy in transplantation to integrate a common EVR-based regimen in vivo (in the patient) and ex vivo (in the expansion of autologous Treg cells). CD25 Treg cells were selected from leukapheresis product with a GMP-compliant cell separation system and placed in 5-day (short) or 21-day (long) culture with EVR or rapamycin (RAPA). Multi-parametric flow cytometry analyses were used to monitor the expansion rates, phenotype, autophagic flux, and suppressor function of the cells. phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway profiles of treated cells were analyzed by Western blot and cell bioenergetic parameters by extracellular flux analysis. RESULTS EVR-treated cells showed temporary slower growth, lower metabolic rates, and reduced phosphorylation of protein kinase B compared with RAPA-treated cells. In spite of these differences, the expansion rates, phenotype, and suppressor function of long-term Treg cells in culture with EVR were similar to those with RAPA. CONCLUSIONS Our results support the feasibility of EVR to expand functionally competent Treg cells for their clinical use.
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Bedreli S, Straub K, Achterfeld A, Willuweit K, Katsounas A, Saner F, Wedemeyer H, Herzer K. The Effect of Immunosuppression on Coagulation After Liver Transplantation. Liver Transpl 2019; 25:1054-1065. [PMID: 31021493 DOI: 10.1002/lt.25476] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 03/30/2019] [Indexed: 12/24/2022]
Abstract
Everolimus (EVR) is a mammalian target of rapamycin (mTOR) inhibitor commonly used for immunosuppression (IS) after liver transplantation (LT). However, there are concerns about whether mTOR inhibitors may move the hemostatic balance toward a higher likelihood of thrombosis. The present study aimed to investigate potential coagulation disorders after the administration of EVR. We evaluated 54 patients after conversion to an EVR-based IS regimen (n = 26) and compared those patients with patients who were switched to extended-release tacrolimus (TAC) but had never received EVR (n = 28). At baseline and again at 1 month and 6 months after conversion, we measured international normalized ratio, activated partial thromboplastin time, and anticoagulation and fibrinolysis factors, and we performed rotational thromboelastometry (ROTEM). Data were analyzed with a Mann-Whitney U test, a repeated-measure analysis of variance, and a Fisher's exact test. Statistical significance was set at the level of P ≤ 0.05. Plasma levels of von Willebrand factor, fibrinogen, and factor VIII were significantly higher than baseline levels at 1 month and 6 months after conversion of IS to EVR (P < 0.001); plasma levels of protein C, protein S, and plasminogen also increased significantly (P < 0.001). ROTEM confirmed a significant increase in maximum clot firmness in EXTEM, INTEM, and FIBTEM assays (P < 0.001). In all assays, maximum lysis was significantly lower than baseline levels at 1 month and 6 months after conversion to EVR. Patients converted to IS with extended-release TAC exhibited no significant changes in coagulation variables. Retrospective analysis showed a significantly higher incidence of thromboembolic complications among patients treated with EVR-based IS than among those treated with extended-release TAC (P < 0.01). In conclusion, the administration of EVR after LT seems to modify hemostasis to a procoagulant state. Thrombophilia screening before conversion may determine which patients will benefit from conversion to EVR-based IS.
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Affiliation(s)
- Sotiria Bedreli
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Katja Straub
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Anne Achterfeld
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Katharina Willuweit
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Antonios Katsounas
- Department of Gastroenterology, Hepatology and Infectious Diseases, University of Magdeburg, Magdeburg, Germany
| | - Fuat Saner
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Kerstin Herzer
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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Tan PS, Muthiah MD, Koh T, Teoh YL, Chan A, Kow A, Zheng Q, Kwon CHD, Lee GH, Lesmana CRA, de Villa V, Fung J, Lim K. Asian Liver Transplant Network Clinical Guidelines on Immunosuppression in Liver Transplantation. Transplantation 2019; 103:470-480. [PMID: 30422953 DOI: 10.1097/tp.0000000000002532] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Most management guidelines and much of the available clinical trial evidence for immunosuppressants in liver transplantation (LT) pertain to Western practice. While evidence from Western studies may not translate to Asian settings, there is a paucity of Asian randomized controlled trials of immunosuppression in liver recipients. Nonetheless, there are notable differences in the indications and procedures for LT between Western and Asian settings. The Asian Liver Transplant Network held its inaugural meeting in Singapore in November 2016 and aimed to provide an Asian perspective on aspects of immunosuppression following LT. Because of their importance to outcome following LT, the meeting focused on (1) reducing the impact of renal toxicity, (2) hepatocellular carcinoma recurrence, and (3) nonadherence with immunosuppressant therapy.
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Affiliation(s)
- Poh Seng Tan
- Division of Gastroenterology and Hepatology, National University Hospital, National University Health System, Singapore
- National University Centre for Organ Transplantation, National University Hospital, National University Health System, Singapore
| | - Mark D Muthiah
- Division of Gastroenterology and Hepatology, National University Hospital, National University Health System, Singapore
- National University Centre for Organ Transplantation, National University Hospital, National University Health System, Singapore
| | - Tsingyi Koh
- Department of Pharmacy, National University Hospital, National University Health System, Singapore
| | | | - Albert Chan
- Division of Hepatobiliary and Pancreatic Surgery, and Liver Transplantation, Department of Surgery, Queen Mary Hospital, Hong Kong
| | - Alfred Kow
- National University Centre for Organ Transplantation, National University Hospital, National University Health System, Singapore
- Division of Hepatopancreatobiliary Surgery and Division of Liver Transplantation, Department of Surgery, University Surgical Cluster, National University Health System, National University of Singapore, Singapore
| | - Qishi Zheng
- Singapore Clinical Research Institute, Singapore
| | - Choon Hyuck David Kwon
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Guan Huei Lee
- Division of Gastroenterology and Hepatology, National University Hospital, National University Health System, Singapore
- National University Centre for Organ Transplantation, National University Hospital, National University Health System, Singapore
| | - Cosmas Rinaldi A Lesmana
- Hepatobiliary Division, Department of Internal Medicine, Cipto Mangunkusumo Hospital, Universitas Indonesia, Jakarta, Indonesia
- Digestive Disease & GI Oncology Center, Medistra Hospital, Jakarta, Indonesia
| | - Vanessa de Villa
- Department of Surgery and Center for Liver Disease Management and Transplantation, The Medical City, Pasig City, Philippines
| | - James Fung
- Department of Medicine, Queen Mary Hospital, Hong Kong
| | - Kieron Lim
- Division of Gastroenterology and Hepatology, National University Hospital, National University Health System, Singapore
- National University Centre for Organ Transplantation, National University Hospital, National University Health System, Singapore
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Abstract
The standard therapy for decompensated end-stage chronic liver disease of any etiology and acute fulminant hepatic failure is liver transplantation (LT). Advances in immunosuppressive therapy decreased the rates of acute and chronic rejections. Thus, graft and patient survivals have significantly improved. However, long-term adverse effects of prolonged use of immunosuppressive agents such as malignancies, opportunistic infections, metabolic disorders, and other organ toxicities have now become a major concern. Consequently, alternative approaches are needed to deescalate the customary drugs and their side effects. Therapy must be individualized and additional preventive measures should be taken by patients with particular risk factors or predisposed to certain adverse effects. Current opinion favors a combination of agents with different mechanism of actions and toxicity profiles. Corticosteroids are employed in immediate and early postoperative period. Although they have a pronounced side effect profile, calcineurin inhibitors (CNIs) are still the backbone of early and late phase immunosuppressive regimens because of their proved efficacy. Antimetabolites are frequent choices for steroid and/or CNI-sparing strategies. Studies also have established a role for mammalian target of rapamycin (mTOR) inhibitors in specific groups of recipients. Biologic agents are a hot topic of interest and made their way into current strategies for induction. Agents extrapolated from other transplantation or immunologic experience are being evaluated.
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Affiliation(s)
- Burcak E Tasdogan
- Department of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Michelle Ma
- Department of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Cem Simsek
- Department of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Behnam Saberi
- Department of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Ahmet Gurakar
- Department of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Saliba F, Fischer L, de Simone P, Bernhardt P, Bader G, Fung J. Association Between Renal Dysfunction and Major Adverse Cardiac Events After Liver Transplantation: Evidence from an International Randomized Trial of Everolimus-Based Immunosuppression. Ann Transplant 2018; 23:751-757. [PMID: 30361470 PMCID: PMC6248043 DOI: 10.12659/aot.911030] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Background Prospective evidence is lacking regarding the association between renal dysfunction and cardiovascular events after liver transplantation. Material/Methods Data were analyzed post hoc regarding renal function and major adverse cardiac events in a two-year prospective trial of de novo liver transplant recipients randomized at 30 days post-transplant to (i) everolimus [EVR]/reduced tacrolimus [EVR/rTAC] (ii) EVR with tacrolimus discontinued [TAC Elimination] or (iii) standard tacrolimus [TAC Control]. Results By month 24 post-transplant, 32/716 patients had experienced a first major cardiac event (4.5%): 4.1% (10/245), 2.2% (5/229) and 7.0% (17/242) of patients in the EVR/rTAC, TAC Elimination and TAC Control groups, respectively (p=0.043). The cumulative eGFR area under the curve (AUC) from randomization to month 24 was 119 706, 123 082, and 105 946 mL in the EVR/rTAC, TAC Elimination, and TAC Control groups, respectively, corresponding to a mean eGFR AUC of 82.4, 83.0, and 71.9 mL/min/1.73 m2. Cox regression modeling showed that mean eGFR AUC was inversely associated with time to first major cardiac event: the hazard ratio per mL/min/1.73 m2 was −0.0000015 [95% CI −0.00000078; −0.0000024] (p<0.001). Conclusions These findings confirm retrospective evidence that the risk of major cardiac events increases with deteriorating renal function after liver transplantation and demonstrate the need for careful cardiovascular risk management in patients with renal impairment. Immunosuppression based on everolimus with tacrolimus withdrawal, or to a lesser extent tacrolimus reduction, improves both renal function and the risk of major cardiac events compared to standard tacrolimus therapy in liver transplant recipients.
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Affiliation(s)
- Faouzi Saliba
- Hepato-Biliary Center, AP-HP Hôpital Paul Brousse, Université Paris-Sud, Villejuif, France
| | - Lutz Fischer
- Department of Hepatobiliary Surgery and Transplantation, University Medical Center Eppendorf, Hamburg, Germany
| | - Paolo de Simone
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa, Pisa, Italy
| | | | | | - John Fung
- Transplantation Center, Cleveland Clinic, Cleveland, OH, USA
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28
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De Simone P, Carrai P, Coletti L, Ghinolfi D, Petruccelli S, Precisi A, Campani D, Marchetti P, Filipponi F. Everolimus vs Mycophenolate Mofetil in Combination With Tacrolimus: A Propensity Score-matched Analysis in Liver Transplantation. Transplant Proc 2018; 50:3615-3620. [PMID: 30577246 DOI: 10.1016/j.transproceed.2018.07.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Accepted: 07/04/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND No trial has investigated the long-term outcome of everolimus (EVR)-incorporating immunosuppression vs tacrolimus (TAC) and mycophenolate mofetil (MMF) after liver transplantation. MATERIALS AND METHODS With a propensity score methodology, 178 recipients on TAC and MMF were compared to 178 patients on TAC and EVR. RESULTS At a median (interquartile range) follow-up of 45 (46.3) months, the probability of treated biopsy-proven acute rejection, graft loss, and death was 36.6% for MMF and 28.1% for EVR (P = .0891). Treated biopsy-proven acute rejection was numerically lower for EVR (3.3% vs 7.3%, P = .09), while adverse events (70.2% vs 58.9%, P = .02) and drug discontinuations (21.3% vs 11.8%, P = .01) were significantly higher with regard to hypercholesterolemia (P = .001), thrombocytopenia (P = .0062), and edema (P = .0107). Patients on MMF showed more hypertension (P = .0315), tremor (P = .0006), cytomegalovirus infection (P = .0165), and malignancies (P = .0175). EVR was associated with lesser deterioration in mean (SD) renal function at the latest follow-up (-2.2 (1.8) vs -5.1 (3.2) mL/min/1.73 m2, t = 3.6, P = .005). CONCLUSIONS The efficacy of the combination of TAC and EVR is comparable to that of TAC and MMF. Drug discontinuations and adverse events were higher for patients on EVR, but these latter showed less hypertension, cytomegalovirus infection, and renal dysfunction. The observed reduction in posttransplant malignancies for EVR requires longer follow-up to be confirmed.
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Affiliation(s)
- P De Simone
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy.
| | - P Carrai
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - L Coletti
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - D Ghinolfi
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - S Petruccelli
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - A Precisi
- Laboratory, University of Pisa Medical School Hospital, Pisa, Italy
| | - D Campani
- Department of Pathology, University of Pisa Medical School Hospital, Pisa, Italy
| | - P Marchetti
- Department of Clinical and Experimental Medicine, University of Pisa Medical School Hospital, Pisa, Italy
| | - F Filipponi
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
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29
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Yee ML, Tan HH. Use of everolimus in liver transplantation. World J Hepatol 2017; 9:990-1000. [PMID: 28878864 PMCID: PMC5569278 DOI: 10.4254/wjh.v9.i23.990] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 05/20/2017] [Accepted: 06/12/2017] [Indexed: 02/06/2023] Open
Abstract
In recent years, the use of mammalian target of rapamycin inhibitors has gained traction in their use as alternative or adjunct immunosuppressants in the post-liver transplantation (LT) setting. The efficacy of everolimus (EVR) in de novo LT is established and a reasonable time to initiate EVR is 30 d from LT surgery. Initiating EVR early post-LT allows for calcineurin inhibitor (CNI) reduction, thus reducing nephrotoxicity in LT recipients. However, data is inadequate on the appropriate timing for conversion from CNI to EVR maintenance in order to achieve optimal renoprotective effect without compromising drug efficacy. Adverse effects of proteinuria, hypercholesterolemia and hyperlipidemia are significantly higher as compared to standard CNI and long-term implications on graft and patient survival in LT is still unclear. Future research to explore strategies to minimise EVR adverse effects will be crucial for the success of EVR as an important alternative or adjunct immunosuppressive therapy in LT.
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Affiliation(s)
- Mei-Ling Yee
- Department of Pharmacy, Singapore General Hospital, Singapore 169608, Singapore.
| | - Hui-Hui Tan
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore 169608, Singapore
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30
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Rubín Suárez A, Bilbao Aguirre I, Fernández-Castroagudin J, Pons Miñano JA, Salcedo Plaza M, Varo Pérez E, Prieto Castillo M. Recommendations of everolimus use in liver transplant. GASTROENTEROLOGIA Y HEPATOLOGIA 2017; 40:629-640. [PMID: 28743539 DOI: 10.1016/j.gastrohep.2017.05.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 05/23/2017] [Accepted: 05/23/2017] [Indexed: 01/26/2023]
Abstract
Mammalian target of rapamycin (mTOR) inhibitors, everolimus (EVL) and sirolimus are immunosuppressive agents with a minor nephrotoxic effect, limited to the development of proteinuria in some cases. The combination of EVL and low-dose tacrolimus has proven to be as safe and effective as standard therapy with tacrolimus for the prevention of acute cellular rejection. Early initiation of EVL-based immunosuppressive regimens with reduced exposure to calcineurin inhibitors has been shown to significantly improve renal function of LT recipients during induction and maintenance phases, with comparable efficacy and safety profiles. In patients with established kidney failure, initiating EVL may enable clinicians to reduce calcineurin inhibitors exposure, thereby contributing to the improved renal function of these patients. Although there is not sufficient evidence to recommend their use to prevent the recurrence of hepatocellular carcinoma and the progression of de novo tumours, they are used in this context in routine clinical practice.
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Affiliation(s)
- Angel Rubín Suárez
- Unidad de Hepatología, Servicio de Medicina Digestiva, Área de Enfermedades Digestivas, Hospital Universitari i Politècnic La Fe, CIBERehd, Valencia, España.
| | - Itxarone Bilbao Aguirre
- Servicio de Cirugía HBP y Trasplantes Digestivos, Hospital Universitario Vall d'Hebrón. Grupos de investigación VHIR y CIBERehd, Barcelona, España
| | - Javier Fernández-Castroagudin
- Servicio de Medicina Digestiva, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, España
| | - José Antonio Pons Miñano
- Unidad de Hepatología y Trasplante Hepático, IMIB. Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, España
| | - Magdalena Salcedo Plaza
- Unidad de Trasplante Hepático, Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón IISGM. CIBERehd, Madrid, España
| | - Evaristo Varo Pérez
- Unidad de Trasplante Abdominal, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, España
| | - Martín Prieto Castillo
- Unidad de Hepatología, Servicio de Medicina Digestiva, Área de Enfermedades Digestivas, Hospital Universitari i Politècnic La Fe, CIBERehd, Valencia, España
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Tchero H, Herlin C, Bekara F, Kangambega P, Sergiu F, Teot L. Failure rates of artificial dermis products in treatment of diabetic foot ulcer: A systematic review and network meta-analysis. Wound Repair Regen 2017; 25:691-696. [PMID: 28597935 DOI: 10.1111/wrr.12554] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 05/23/2017] [Indexed: 11/28/2022]
Abstract
Diabetic foot ulcer (DFU) is a frequent complication in diabetic patients, occurring in up to 25% of those affected. Among the treatments available to clinicians, the use of bioengineered skin substitutes is an attractive alternative. Artificial dermis functions as a matrix, covering the wound and supporting healing and reconstruction of the lost tissue. This study was aimed at reviewing the use of five regeneration matrices (namely, Integra, Nevelia, Matriderm, Pelnac, and Renoskin) as reported by clinical trials. We searched Medline, Embase, ISI Web of Science, Scopus, and Cochrane Central Register of Controlled Trials databases for relevant studies. Risk of failure rates was analysed by relative risk ratio method and complete ulcer healing was studied using network meta-analysis. Thirteen studies (12 randomized clinical trials and one cohort study) were eligible for analysis. The network meta-analysis based on a single study for Matriderm and 12 studies for other products showed that Matriderm was statistically inferior in achieving complete ulcer healing, as compared to all other products combined. In the second phase analysis, which was limited to three studies using artificial dermis products, there was a 57% reduction in the risk of reepithelialization failure for DFU patients who used Matriderm or Pelnac, compared to those who used Pelnac with basic fibroblast growth factor spray or skin grafting. The data showed an overall low failure rate suggesting that these bioengineered skin products provide a suitable support and microenvironment for healing of DFUs with low ulcer recurrence rates. This systematic review with meta-analysis highlights the pressing need for more studies investigating the safety, efficacy and failure rates of regeneration matrices in the treatment of DFUs.
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Affiliation(s)
- Huidi Tchero
- Department of Trauma and Orthopedic Surgery, CH Saint Martin, Guadeloupe, France
| | - Christian Herlin
- Department of Reconstructive and Plastic Surgery, Montpellier, France
| | - Farid Bekara
- Department of Reconstructive and Plastic Surgery, Montpellier, France
| | - Pauline Kangambega
- Department of Division of Diabetes, Endocrinology and Metabolism, CHRU de Pointe-A-Pitre, Pointe-A-Pitre, Guadeloupe, France
| | - Fluieraru Sergiu
- Department of Reconstructive and Plastic Surgery, Montpellier, France
| | - Luc Teot
- Department of Reconstructive and Plastic Surgery, Montpellier, France
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Effect of Early Everolimus-Facilitated Reduction of Tacrolimus on Efficacy and Renal Function in De Novo Liver Transplant Recipients: 24-Month Results for the North American Subpopulation. Transplantation 2017; 101:341-349. [PMID: 28121741 PMCID: PMC5265688 DOI: 10.1097/tp.0000000000001524] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Background A recent randomized phase III study of 719 de novo liver transplant recipients showed that early everolimus plus reduced-dose tacrolimus (EVR + rTAC) led to significantly better kidney function than standard TAC (TAC-C), without compromising efficacy. In that study, patients from North America (n = 211) had increased risk factors for posttransplant renal insufficiency at study start, relative to patients from Europe and rest of world (eg, worse renal function, more diabetes, older age). Methods A post hoc analysis was performed to assess whether these regional disparities affected study outcomes in North American patients. Results In this subpopulation, estimated glomerular filtration rates at randomization were higher in TAC-C over EVR + rTAC (76.4 vs 69.3 mL/min per 1.73 m2). Mean changes in estimated glomerular filtration rate values (mL/min per 1.73 m2) favored EVR + rTAC over TAC-C at months 12 (+3.7 vs −4.5; P = 0.032), 24 (+2.7 vs −6.6; P = 0.042), and 36 (+4.3 vs −8.1; P = 0.059). The composite efficacy endpoint of treated biopsy-proven acute rejection, graft loss, or death was 10.9%, 14.1%, and 14.1% for EVR + rTAC and 13.1%, 17.2%, and 19.3% for TAC-C at months 12, 24, and 36, respectively. Conclusions Although the North American cohort had more comorbidities, results were consistent with the overall population for efficacy and renal function. In order to reduce nephrotoxicity in liver transplantation, several strategies are being explored including early everolimus-facilitated tacrolimus dose reduction, which in a recent multicenter study led to better kidney function versus standard TAC without compromising efficacy. In this North American cohort sub-analysis, results are similar despite higher baseline comorbidities.
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33
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Modification of immunosuppressive therapy as risk factor for complications after liver transplantation. Best Pract Res Clin Gastroenterol 2017. [PMID: 28624108 DOI: 10.1016/j.bpg.2017.03.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Management of complications post-liver transplantation (LT) includes immunosuppressive manipulations with the aim to reduce the overall burden of immunologic suppression and compensate for renal, cardiovascular, metabolic toxicities, and for the increased oncologic risk. Two approaches can be implemented to reduce immunosuppression-related adverse events: upfront schedules tailored to the pretransplant individual patient's risk profile versus downstream modifications in the event of immunosuppression-related complications. Upfront strategies are supported by evidence originating from prospective randomized trials and consist of triple/quadruple schedules whereby calcineurin inhibitors (CNI)-exposure is reduced with combination of anti-CD25 monoclonal antibodies, antimetabolites and corticosteroids. Quadruple regimens allow for staggering of CNI introduction and higher renal function in the early term, but their superiority in the long term has not yet been established. A more recent upfront schedule contemplates early (4 weeks) introduction of mammalian target of rapamycin inhibitor (mTORi) everolimus and allows for reduction of CNI up to 4 years posttransplantation. Incorporation of mTORi has the potential to prolong time to recurrence for patients with hepatocellular carcinoma. However, as suggested by the available evidence, downstream immunosuppressive manipulations are more frequently adopted in clinical practice. These encompass CNI replacement and immunosuppression withdrawal. Switching CNI to mTORi monotherapy is the option most commonly adopted to relieve renal function and compensate for posttransplant malignancies. Its impact is dependent on interval from transplantation and underlying severity of renal impairment. Introduction of mTORi is associated with longer overall survival for patients with extrahepatic posttransplant malignancies, but results are awaited for recurrences of hepatocellular carcinoma. Immunosuppression withdrawal seems feasible (70%) in very long term survivors (>10 years), but is not associated with reversal of immunosuppression-related complications. Awaiting novel immunosuppressive drug categories, integration of upfront strategies with the aim to reduce CNI-exposure and a low threshold for adjustment in the posttransplant course are both advisable to improve long-term outcomes of LT.
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Rodríguez‐Perálvarez M, Guerrero‐Misas M, Thorburn D, Davidson BR, Tsochatzis E, Gurusamy KS. Maintenance immunosuppression for adults undergoing liver transplantation: a network meta-analysis. Cochrane Database Syst Rev 2017; 3:CD011639. [PMID: 28362060 PMCID: PMC6464256 DOI: 10.1002/14651858.cd011639.pub2] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND As part of liver transplantation, immunosuppression (suppressing the host immunity) is given to prevent graft rejections resulting from the immune response of the body against transplanted organ or tissues from a different person whose tissue antigens are not compatible with those of the recipient. The optimal maintenance immunosuppressive regimen after liver transplantation remains uncertain. OBJECTIVES To assess the comparative benefits and harms of different maintenance immunosuppressive regimens in adults undergoing liver transplantation through a network meta-analysis and to generate rankings of the different immunosuppressive regimens according to their safety and efficacy. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until October 2016 to identify randomised clinical trials on immunosuppression for liver transplantation. SELECTION CRITERIA We included only randomised clinical trials (irrespective of language, blinding, or publication status) in adult participants undergoing liver transplantation (or liver retransplantation) for any reason. We excluded trials in which participants had undergone multivisceral transplantation or participants with established graft rejections. We considered any of the various maintenance immunosuppressive regimens compared with each other. DATA COLLECTION AND ANALYSIS We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio, rate ratio, and hazard ratio (HR) with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. MAIN RESULTS We included a total of 26 trials (3842 participants) in the review, and 23 trials (3693 participants) were included in one or more outcomes in the review. The vast majority of the participants underwent primary liver transplantation. All of the trials were at high risk of bias, and all of the evidence was of low or very low quality. In addition, because of sparse data involving trials at high risk of bias, it is not possible to entirely rely on the results of the network meta-analysis. The trials included mainly participants undergoing primary liver transplantation of varied aetiologies. The follow-up in the trials ranged from 3 to 144 months. The most common maintenance immunosuppression used as a control was tacrolimus. There was no evidence of difference in mortality (21 trials; 3492 participants) or graft loss (15 trials; 2961 participants) at maximal follow-up between the different maintenance immunosuppressive regimens based on the network meta-analysis. In the direct comparison, based on a single trial including 222 participants, tacrolimus plus sirolimus had increased mortality (HR 2.76, 95% CrI 1.30 to 6.69) and graft loss (HR 2.34, 95% CrI 1.28 to 4.61) at maximal follow-up compared with tacrolimus. There was no evidence of differences in the proportion of people with serious adverse events (1 trial; 719 participants), proportion of people with any adverse events (2 trials; 940 participants), renal impairment (8 trials; 2233 participants), chronic kidney disease (1 trial; 100 participants), graft rejections (any) (16 trials; 2726 participants), and graft rejections requiring treatment (5 trials; 1025 participants) between the different immunosuppressive regimens. The network meta-analysis showed that the number of adverse events was lower with cyclosporine A than with many other immunosuppressive regimens (12 trials; 1748 participants), and the risk of retransplantation (13 trials; 1994 participants) was higher with cyclosporine A than with tacrolimus (HR 3.08, 95% CrI 1.13 to 9.90). None of the trials reported number of serious adverse events, health-related quality of life, or costs. FUNDING 14 trials were funded by pharmaceutical companies who would benefit from the results of the trial; two trials were funded by parties who had no vested interest in the results of the trial; and 10 trials did not report the source of funding. AUTHORS' CONCLUSIONS Based on low-quality evidence from a single small trial from direct comparison, tacrolimus plus sirolimus increases mortality and graft loss at maximal follow-up compared with tacrolimus. Based on very low-quality evidence from network meta-analysis, we found no evidence of difference between different immunosuppressive regimens. We found very low-quality evidence from network meta-analysis and low-quality evidence from direct comparison that cyclosporine A causes more retransplantation compared with tacrolimus. Future randomised clinical trials should be adequately powered; performed in people who are generally seen in the clinic rather than in highly selected participants; employ blinding; avoid postrandomisation dropouts or planned cross-overs; and use clinically important outcomes such as mortality, graft loss, renal impairment, chronic kidney disease, and retransplantation. Such trials should use tacrolimus as one of the control groups. Moreover, such trials ought to be designed in such a way as to ensure low risk of bias and low risks of random errors.
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Affiliation(s)
- Manuel Rodríguez‐Perálvarez
- Reina Sofía University Hospital, IMIBIC, CIBERehdHepatology and Liver TransplantationAvenida Menéndez Pidal s/nCórdobaSpain14004
| | - Marta Guerrero‐Misas
- Reina Sofía University Hospital, IMIBIC, CIBERehdHepatology and Liver TransplantationAvenida Menéndez Pidal s/nCórdobaSpain14004
| | - Douglas Thorburn
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetLondonUKNW3 2QG
| | - Brian R Davidson
- Royal Free Campus, UCL Medical SchoolDepartment of SurgeryPond StreetLondonUKNW3 2QG
| | - Emmanuel Tsochatzis
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetLondonUKNW3 2QG
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Thölking G, Gerth HU, Schuette-Nuetgen K, Reuter S. Influence of tacrolimus metabolism rate on renal function after solid organ transplantation. World J Transplant 2017; 7:26-33. [PMID: 28280692 PMCID: PMC5324025 DOI: 10.5500/wjt.v7.i1.26] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Revised: 11/22/2016] [Accepted: 01/14/2017] [Indexed: 02/05/2023] Open
Abstract
The calcineurin inhibitor (CNI) tacrolimus (TAC) is an integral part of the immunosuppressive regimen after solid organ transplantation. Although TAC is very effective in prevention of acute rejection episodes, its highly variable pharmacokinetic and narrow therapeutic window require frequent monitoring of drug levels and dose adjustments. TAC can cause CNI nephrotoxicity even at low blood trough levels (4-6 ng/mL). Thus, other factors besides the TAC trough level might contribute to CNI-related kidney injury. Unfortunately, TAC pharmacokinetic is determined by a whole bunch of parameters. However, for daily clinical routine a simple application strategy is needed. To address this problem, we and others have evaluated a simple calculation method in which the TAC blood trough concentration (C) is divided by the daily dose (D). Fast TAC metabolism (C/D ratio < 1.05) was identified as a potential risk factor for an inferior kidney function after transplantation. In this regard, we recently showed a strong association between fast TAC metabolism and CNI nephrotoxicity as well as BKV infection. Therefore, the TAC C/D ratio may assist transplant clinicians in a simple way to individualize the immunosuppressive regimen.
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