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Jiménez-Romero C, Justo Alonso I, Caso Maestro O, Manrique Municio A, García-Sesma Á, Calvo Pulido J, Cambra Molero F, Loinaz Segurola C, Martín-Arriscado C, Nutu A, Marcacuzco Quinto A. Indications and Long-Term Outcomes of Using Mycophenolate Mofetil Monotherapy in Substitution for Calcineurin Inhibitors in Liver Transplantation. Transpl Int 2025; 38:13790. [PMID: 40060933 PMCID: PMC11886422 DOI: 10.3389/ti.2025.13790] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 01/27/2025] [Indexed: 05/13/2025]
Abstract
Switching the use of calcineurin inhibitors (CNIs), as basal immunosuppression in liver transplantation (LT) patients, for that of mycophenolate mofetil monotherapy (MMF-MT) is currently considered a good measure in recipients with chronic kidney disease (CKD) and other CNI-related adverse effects. We analyzed a retrospective cohort series of 324 LT patients who underwent long-term follow-up and were switched from CNI immunosuppression to MMF-MT due to CKD and other CNI-related adverse effects (diabetes, hypertension, infection). The median time on MMF-MT was 78 months. The indication for MMF-MT was CKD alone or associated with CNI-related adverse effects in 215 patients, diabetes in 61, hypertension in 42, and recurrent cholangitis in 6. Twenty-four (7.4%) patients developed non-resistant acute rejection post-MMF-MT, and 48 (14.8%) patients experienced MMF-related adverse effects, with MMF-MT withdrawn in only 8 (2.5%) patients. In the comparison between the pre-MMF-MT period and the last outpatient review, using a repeated measures model and taking each patient as its own comparator, we demonstrated a significant increase in GFR and significant decrease in creatinine and ALT values, remaining the other variables (diabetes, hypertension, and hematological and AST) within similar levels. Five-year survival post-MMF-MT conversion was 75.3%. MMF-MT significantly improved renal function, was well tolerated, and had a low rejection rate.
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Affiliation(s)
- Carlos Jiménez-Romero
- Unit of Hepato-Pancreato-Biliary Surgery and Abdominal Organ Transplantation, Doce de Octubre University Hospital, Madrid, Spain
- Department of Surgery, Faculty of Medicine, Complutense University, Madrid, Spain
| | - Iago Justo Alonso
- Unit of Hepato-Pancreato-Biliary Surgery and Abdominal Organ Transplantation, Doce de Octubre University Hospital, Madrid, Spain
- Department of Surgery, Faculty of Medicine, Complutense University, Madrid, Spain
| | - Oscar Caso Maestro
- Unit of Hepato-Pancreato-Biliary Surgery and Abdominal Organ Transplantation, Doce de Octubre University Hospital, Madrid, Spain
- Department of Surgery, Faculty of Medicine, Complutense University, Madrid, Spain
| | - Alejandro Manrique Municio
- Unit of Hepato-Pancreato-Biliary Surgery and Abdominal Organ Transplantation, Doce de Octubre University Hospital, Madrid, Spain
- Department of Surgery, Faculty of Medicine, Complutense University, Madrid, Spain
| | - Álvaro García-Sesma
- Unit of Hepato-Pancreato-Biliary Surgery and Abdominal Organ Transplantation, Doce de Octubre University Hospital, Madrid, Spain
- Department of Surgery, Faculty of Medicine, Complutense University, Madrid, Spain
| | - Jorge Calvo Pulido
- Unit of Hepato-Pancreato-Biliary Surgery and Abdominal Organ Transplantation, Doce de Octubre University Hospital, Madrid, Spain
- Department of Surgery, Faculty of Medicine, Complutense University, Madrid, Spain
| | - Félix Cambra Molero
- Unit of Hepato-Pancreato-Biliary Surgery and Abdominal Organ Transplantation, Doce de Octubre University Hospital, Madrid, Spain
- Department of Surgery, Faculty of Medicine, Complutense University, Madrid, Spain
| | - Carmelo Loinaz Segurola
- Unit of Hepato-Pancreato-Biliary Surgery and Abdominal Organ Transplantation, Doce de Octubre University Hospital, Madrid, Spain
- Department of Surgery, Faculty of Medicine, Complutense University, Madrid, Spain
| | | | - Anisa Nutu
- Unit of Hepato-Pancreato-Biliary Surgery and Abdominal Organ Transplantation, Doce de Octubre University Hospital, Madrid, Spain
- Department of Surgery, Faculty of Medicine, Complutense University, Madrid, Spain
| | - Alberto Marcacuzco Quinto
- Unit of Hepato-Pancreato-Biliary Surgery and Abdominal Organ Transplantation, Doce de Octubre University Hospital, Madrid, Spain
- Department of Surgery, Faculty of Medicine, Complutense University, Madrid, Spain
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2
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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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Jan MY, Patidar KR, Ghabril MS, Kubal CA. Optimization and Protection of Kidney Health in Liver Transplant Recipients: Intra- and Postoperative Approaches. Transplantation 2024:00007890-990000000-00916. [PMID: 39439013 DOI: 10.1097/tp.0000000000005252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Abstract
Postoperative acute kidney injury after liver transplant (LT) has long-term implications for kidney health. LT recipients are at risk of acute kidney injury due to a number of factors related to the donor liver, intraoperative factors including surgical technique, as well as recipient factors, such as pre-LT kidney function and postoperative complications. This review discusses these factors in detail and their impact on posttransplant kidney function. Long-term risk factors such as calcineurin inhibitors have also been discussed. Additionally, the impact of liver allocation policies on pre- and post-LT kidney health is discussed.
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Affiliation(s)
- Muhammad Y Jan
- Division of Transplant Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Kavish R Patidar
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX
| | - Marwan S Ghabril
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Chandrashekhar A Kubal
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
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Rudzik KN, Schonder KS, Humar A, Johnson HJ. Early Conversion to Everolimus Within 180 Days of Living Donor Liver Transplantation. Clin Transplant 2024; 38:e15402. [PMID: 39023099 DOI: 10.1111/ctr.15402] [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: 01/22/2024] [Revised: 06/06/2024] [Accepted: 06/24/2024] [Indexed: 07/20/2024]
Abstract
BACKGROUND Early conversion to Everolimus (EVR) post deceased donor liver transplant has been associated with improved renal function but increased rejection. Early EVR conversion has not been evaluated after living donor liver transplant (LDLT). A retrospective cohort study was conducted to compare the rate of rejection and renal function in patients converted to EVR early post-LDLT to patients on calcineurin inhibitors (CNIs). METHODS This was a single center retrospective cohort study of adult LDLT recipients between January 2012 and July 2019. Patients converted to EVR within 180 days of transplant were compared to patients on CNIs. The primary endpoint was biopsy proven acute rejection (BPAR) at 24 months posttransplant. Key secondary endpoints included eGFR at 24 months, change in eGFR, adverse events, and all-cause mortality. RESULTS From a total of 173 patients involved in the study: 58 were included in the EVR group and 115 in the CNI group. Median conversion to EVR was 26 days post-LDLT. At 24 months, there was no difference in BPAR (22.7% EVR vs. 19.1% CNI, p = 0.63). Median eGFR at 24 months posttransplant was not significantly different (68.6 [24.8 to 112.4] mL/min EVR vs. 75.9 [35.6-116.2] mL/min CNI, p = 0.103). Change in eGFR from baseline was worse in the EVR group (-13.0 [-39.9 to 13.9] mL/min EVR vs. -5.0 [-31.2 to 21.2] mL/min CNI, p = 0.047). Median change from conversion to 24 months posttransplant (EVR group only) was -3.43 mL/min/1.73 m2 (-21.0 to 9.6). CONCLUSIONS Early EVR conversion was not associated with increased risk of rejection among LDLT recipients. Renal function was not impacted. EVR may be considered as an alternative after LDLT in patients intolerant of CNIs.
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Affiliation(s)
| | - Kristine S Schonder
- Department of Pharmacy and Therapeutics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Abhinav Humar
- Thomas Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Heather J Johnson
- Department of Pharmacy and Therapeutics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Meganck S, Raevens S, Ferdinande K, Verhelst X, Hoorens A, Degroote H, Geerts A, Van Vlierberghe H. Recurrent rejections after liver transplantation for hepatocellular carcinoma with stem cell features in an adult patient. Acta Clin Belg 2024; 79:234-241. [PMID: 38961614 DOI: 10.1080/17843286.2024.2376304] [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: 04/08/2024] [Accepted: 07/01/2024] [Indexed: 07/05/2024]
Abstract
Patients with hepatoblastoma featuring carcinoma characteristics have better outcomes after liver transplantation, than after chemotherapy and resection. Possibly this should be extrapolated to aggressive subtypes of hepatocellular carcinomas in non-cirrhotic livers, where early liver transplantation might also be indicated. However, the risks associated with liver transplantation and immunosuppressive treatment after liver transplantation are once again demonstrated by this case of a 32-year-old women with a negative personal and familial history of liver diseases. She underwent transplantation (DBD) for a hepatocellular carcinoma with stem cell features (HCC-HS; an aggressive 'hepatoblast subtype' of hepatocellular carcinoma) after chemotherapeutical downstaging techniques failed to sufficiently downstage the tumor. Despite being on conventional immunosuppressive regimens (tacrolimus and mycophenolate mofetil with initial corticosteroids tapered), this patient still developed two severe rejection episodes, one of which necessitated retransplantation (DCD). Both episodes were preceded by alterations in tacrolimus trough levels, either intentionally, when tacrolimus was reduced within a nephroprotective regimen, or unintentionally, when rifampicin, a CYP3A4 inducer, significantly lowered the trough levels. Together, these episodes stress the importance of therapeutic drug monitoring of tacrolimus. Furthermore, the patient experienced an everolimus-linked drug-induced thrombotic microangiopathy, underwent multiple ERCPs for an anastomotic stricture and only one and a half year after the first liver transplantation she already suffers from long-term immunosuppressive-related side effects such as impaired glucose tolerance, hypertension and a potential cardiomyopathy. At present, she is still alive and experienced no recurrence of her primary tumor. Her case underscores the significant challenges in post-liver transplantation care.
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Affiliation(s)
- S Meganck
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Gent, Belgium
| | - S Raevens
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Gent, Belgium
| | - K Ferdinande
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Gent, Belgium
| | - X Verhelst
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Gent, Belgium
| | - A Hoorens
- Department of Pathology, Ghent University Hospital, Gent, Belgium
| | - H Degroote
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Gent, Belgium
| | - A Geerts
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Gent, Belgium
| | - H Van Vlierberghe
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Gent, Belgium
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Xiong Z, Yang Z, Wang Q, Li T. Global research hotspots and trends of acute rejection after liver transplantation from 1988 to 2022: a bibliometric analysis. Front Pharmacol 2024; 15:1357468. [PMID: 38694927 PMCID: PMC11061468 DOI: 10.3389/fphar.2024.1357468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 04/05/2024] [Indexed: 05/04/2024] Open
Abstract
Background: Acute rejection (AR) is the predominant form of rejection observed in liver transplantation and plays a crucial role in transplant immunology. This study aims to utilize bibliometric analysis to understand the status quo, hotspots, and future trends of research on AR after liver transplantation. Methods: We searched the Web of Science Core Collection (WoSCC) for studies on AR after liver transplantation published from 1988 to 2022. The Bibliometric Online Analysis Platform, VOSviewer, and CiteSpace were used for analysis of all extracted publications. Results: This study included 2,398 articles published in 456 journals by 12,568 authors from 1,965 institutions in 55 countries/regions. The United States and its affiliated institution, the University of Pittsburgh, were the most productive contributors. Transplantation (n = 12,435) was the most frequently cited journal. Neuhaus P (n = 38) was the highest output author, and Demetris AJ (n = 670) was the most co-cited author. The research hotspots of AR after liver transplantation include pathogenesis, immunosuppressive therapy, and prognosis. Emerging research directions include regulatory T cells, immunosuppression minimization, intra-patient variability (IPV) of tacrolimus, and novel non-invasive diagnostic markers. Conclusion: Our study utilized bibliometric methods to analyze the study of AR after liver transplantation over the past 35 years. With the prolonged survival of liver transplant recipients, the most active areas currently focus on individualized treatment and improving patient prognosis. Minimizing adverse reactions to immunosuppressive therapy while simultaneously avoiding an increase in the risk of AR remains a future research focus.
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Affiliation(s)
- Zhiwei Xiong
- Department of Liver Transplantation, The Second Xiang-ya Hospital, Central South University, Changsha, China
| | - Zhen Yang
- The Intractable Diseases Diagnosis and Treatment Center for Liver, Gallbladder, Pancreas and Intestine, Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Qiuguo Wang
- Department of Cardiovascular Surgery, The Second Xiang-ya Hospital, Central South University, Changsha, China
| | - Ting Li
- Department of Liver Transplantation, The Second Xiang-ya Hospital, Central South University, Changsha, China
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Adjei M, Kim IK. Current Use of Immunosuppression in Liver Transplantation. Surg Clin North Am 2024; 104:11-25. [PMID: 37953030 DOI: 10.1016/j.suc.2023.08.004] [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] [Indexed: 11/14/2023]
Abstract
Since the first successful liver transplant in 1967, immunosuppression has allowed liver transplantation to become the standard treatment of end-stage liver disease. Over the decades, the rates of rejection have decreased, and patient survival outcomes have significantly improved in large part due to the introduction and advancements of immunosuppression medications. However, the adverse effects associated with long-term immunosuppression have created new challenges facing liver transplantation and added significantly to posttransplantation morbidity. This review presents the data and rationale for immunosuppression approaches, addresses the main controversies related to immunosuppression in liver transplantation, and explores some of the newer advancements in immunosuppressive drug therapy.
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Affiliation(s)
- Michie Adjei
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, 8900 Beverly Boulevard, Los Angeles, CA 90048, USA
| | - Irene K Kim
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, 8900 Beverly Boulevard, Los Angeles, CA 90048, USA.
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8
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Gonzalez SA, Farfan Ruiz AC, Ibrahim RM, Wadei HM. Essentials of Liver Transplantation in the Setting of Acute Kidney Injury and Chronic Kidney Disease. ADVANCES IN KIDNEY DISEASE AND HEALTH 2023; 30:356-367. [PMID: 37657882 DOI: 10.1053/j.akdh.2023.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 06/06/2023] [Accepted: 06/26/2023] [Indexed: 09/03/2023]
Abstract
Kidney dysfunction is common among liver transplant candidates with decompensated cirrhosis and has a major impact on pre- and post-liver transplant survival. Updated definitions of acute kidney injury and criteria for the diagnosis of hepatorenal syndrome allow for early recognition and intervention, including early initiation of vasoconstrictor therapy for hepatorenal syndrome. The rise of the metabolic syndrome and nonalcoholic fatty liver disease as a cause of cirrhosis has coincided with an increase in intrinsic chronic kidney disease recognized in transplant candidates and recipients. Ultimately, the ability to accurately assess kidney function and associated risk is essential to decision-making in the context of transplantation, including selection of candidates for simultaneous liver and kidney transplantation.
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Affiliation(s)
- Stevan A Gonzalez
- Division of Hepatology, Annette C. and Harold C. Simmons Transplant Institute, Baylor Scott & White All Saints Medical Center Fort Worth and Baylor University Medical Center Dallas, TX; Department of Medicine, Burnett School of Medicine at TCU, Fort Worth, TX.
| | - Ana Cecilia Farfan Ruiz
- Division of Transplant Nephrology, Department of Transplant, Mayo Clinic College of Medicine and Science, Jacksonville, FL
| | - Ramez M Ibrahim
- Division of Transplant Nephrology, Department of Transplant, Mayo Clinic College of Medicine and Science, Jacksonville, FL
| | - Hani M Wadei
- Division of Transplant Nephrology, Department of Transplant, Mayo Clinic College of Medicine and Science, Jacksonville, FL
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9
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Todeschini L, Cristin L, Martinino A, Mattia A, Agnes S, Giovinazzo F. The Role of mTOR Inhibitors after Liver Transplantation for Hepatocellular Carcinoma. Curr Oncol 2023; 30:5574-5592. [PMID: 37366904 DOI: 10.3390/curroncol30060421] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 06/06/2023] [Accepted: 06/07/2023] [Indexed: 06/28/2023] Open
Abstract
Liver transplantation is a treatment option for nonresectable patients with early-stage HCC, with more significant advantages when Milan criteria are fulfilled. An immunosuppressive regimen is required to reduce the risk of graft rejection after transplantation, and CNIs represent the drugs of choice in this setting. However, their inhibitory effect on T-cell activity accounts for a higher risk of tumour regrowth. mTOR inhibitors (mTORi) have been introduced as an alternative immunosuppressive approach to conventional CNI-based regimens to address both immunosuppression and cancer control. The PI3K-AKT-mTOR signalling pathway regulates protein translation, cell growth, and metabolism, and the pathway is frequently deregulated in human tumours. Several studies have suggested the role of mTORi in reducing HCC progression after LT, accounting for a lower recurrence rate. Furthermore, mTOR immunosuppression controls the renal damage associated with CNI exposure. Conversion to mTOR inhibitors is associated with stabilizing and recovering renal dysfunction, suggesting an essential renoprotective effect. Limitations in this therapeutic approach are related to their negative impact on lipid and glucose metabolism as well as on proteinuria development and wound healing. This review aims to summarize the roles of mTORi in managing patients with HCC undergoing LT. Strategies to overcome common adverse effects are also proposed.
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Affiliation(s)
- Letizia Todeschini
- Faculty of Medicine and Surgery, University of Verona, 37134 Verona, Italy
| | - Luca Cristin
- Faculty of Medicine and Surgery, University of Verona, 37134 Verona, Italy
| | | | - Amelia Mattia
- General Surgery and Liver Transplantation Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Salvatore Agnes
- General Surgery and Liver Transplantation Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Francesco Giovinazzo
- General Surgery and Liver Transplantation Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
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10
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Montano-Loza AJ, Rodríguez-Perálvarez ML, Pageaux GP, Sanchez-Fueyo A, Feng S. Liver transplantation immunology: Immunosuppression, rejection, and immunomodulation. J Hepatol 2023; 78:1199-1215. [PMID: 37208106 DOI: 10.1016/j.jhep.2023.01.030] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/30/2022] [Accepted: 01/30/2023] [Indexed: 05/21/2023]
Abstract
Outcomes after liver transplantation have continuously improved over the past decades, but long-term survival rates are still lower than in the general population. The liver has distinct immunological functions linked to its unique anatomical configuration and to its harbouring of a large number of cells with fundamental immunological roles. The transplanted liver can modulate the immunological system of the recipient to promote tolerance, thus offering the potential for less aggressive immunosuppression. The selection and adjustment of immunosuppressive drugs should be individualised to optimally control alloreactivity while mitigating toxicities. Routine laboratory tests are not accurate enough to make a confident diagnosis of allograft rejection. Although several promising biomarkers are being investigated, none of them is sufficiently validated for routine use; hence, liver biopsy remains necessary to guide clinical decisions. Recently, there has been an exponential increase in the use of immune checkpoint inhibitors due to the unquestionable oncological benefits they provide for many patients with advanced-stage tumours. It is expected that their use will also increase in liver transplant recipients and that this might affect the incidence of allograft rejection. Currently, the evidence regarding the efficacy and safety of immune checkpoint inhibitors in liver transplant recipients is limited and cases of severe allograft rejection have been reported. In this review, we discuss the clinical relevance of alloimmune disease, the role of minimisation/withdrawal of immunosuppression, and provide practical guidance for using checkpoint inhibitors in liver transplant recipients.
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Affiliation(s)
- Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, AB, Canada.
| | - Manuel L Rodríguez-Perálvarez
- Department of Hepatology and Liver Transplantation, Hospital Universitario Reina Sofía, Universidad de Córdoba, IMIBIC, Córdoba, Spain; CIBER de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - George-Philippe Pageaux
- Liver Transplantation Unit, Digestive Department, Saint Eloi University Hospital, University of Montpellier, 34295, Montpellier Cedex 5, France
| | - Alberto Sanchez-Fueyo
- Institute of Liver Studies, King's College London University and King's College Hospital, London, United Kingdom
| | - Sandy Feng
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
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11
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Fuochi E, Anastasio L, Lynch EN, Campani C, Dragoni G, Milani S, Galli A, Innocenti T. Main factors influencing long-term outcomes of liver transplantation in 2022. World J Hepatol 2023; 15:321-352. [PMID: 37034235 PMCID: PMC10075010 DOI: 10.4254/wjh.v15.i3.321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/24/2022] [Accepted: 02/22/2023] [Indexed: 04/11/2023] Open
Abstract
Liver transplant (LT) outcomes have markedly improved in the recent decades, even if long-term morbidity and mortality are still considerable. Most of late deaths are independent from graft function and different comorbidities, including complications of metabolic syndrome and de novo neoplasms, seem to play a key role in determining long-term outcomes in LT recipients. This review discusses the main factors associated with late mortality and suggests possible strategies to improve long-term management and follow-up after liver transplantation. In particular, the reduction of drug toxicity, the use of tools to identify high-risk patients, and setting up a multidisciplinary team also for long-term management of LT recipients may further improve survival after liver transplantation.
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Affiliation(s)
- Elisa Fuochi
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Lorenzo Anastasio
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Erica Nicola Lynch
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Claudia Campani
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Gabriele Dragoni
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
- Department of Medical Biotechnologies, University of Siena, Siena 53100, Italy
| | - Stefano Milani
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Andrea Galli
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Tommaso Innocenti
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
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12
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Jiang J, Huang H, Chen R, Lin Y, Ling Q. Immunotherapy for hepatocellular carcinoma recurrence after liver transplantation, can we harness the power of immune checkpoint inhibitors? Front Immunol 2023; 14:1092401. [PMID: 36875077 PMCID: PMC9978931 DOI: 10.3389/fimmu.2023.1092401] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 02/03/2023] [Indexed: 02/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death globally and liver transplantation (LT) can serve as the best curative treatment option. However, HCC recurrence after LT remains the major obstacle to the long-term survival of recipients. Recently, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many cancers and provided a new treatment strategy for post-LT HCC recurrence. Evidence has been accumulated with the real-world application of ICIs in patients with post-LT HCC recurrence. Notably, the use of these agents as immunity boosters in recipients treated with immunosuppressors is still controversial. In this review, we summarized the immunotherapy for post-LT HCC recurrence and conducted an efficacy and safety evaluation based on the current experience of ICIs for post-LT HCC recurrence. In addition, we further discussed the potential mechanism of ICIs and immunosuppressive agents in regulating the balance between immune immunosuppression and lasting anti-tumor immunity.
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Affiliation(s)
- Jingyu Jiang
- Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission (NHC) Key Laboratory of Combined Multi-Organ Transplantation, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Haitao Huang
- Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission (NHC) Key Laboratory of Combined Multi-Organ Transplantation, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Ruihan Chen
- Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission (NHC) Key Laboratory of Combined Multi-Organ Transplantation, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Yimou Lin
- Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission (NHC) Key Laboratory of Combined Multi-Organ Transplantation, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Qi Ling
- Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission (NHC) Key Laboratory of Combined Multi-Organ Transplantation, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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13
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Coupier A, Gallien Y, Boillot O, Walter T, Guillaud O, Vallin M, Thimonier E, Erard D, Dumortier J. Antineoplastic chemotherapy and immunosuppression in liver transplant recipients: Squaring the circle? Clin Transplant 2023; 37:e14841. [PMID: 36394373 PMCID: PMC10078502 DOI: 10.1111/ctr.14841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 09/27/2022] [Accepted: 10/08/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND Malignancies are a major cause of late death after liver transplantation (LT). In LT recipients presenting a malignancy, antineoplastic chemotherapy is central part of the therapeutic arsenal, but management of both immunosuppressive and antineoplastic chemotherapy can be very challenging. The aim of the present retrospective study was to describe a recent single center cohort of LT recipients treated with antineoplastic cytotoxic chemotherapy. METHODS All LT recipients who received antineoplastic chemotherapy in our center between 2005 and 2021 were included. RESULTS The study population included 72 antineoplastic chemotherapy courses in 69 patients. There was a majority of men (81.9%); median age at LT was 54.9 (range 1-68) and was 63.0 (18-79) at the diagnosis of malignancy. Lung carcinomas (23.6%), head and neck carcinomas (20.8%), lymphomas (16.7%), and recurrent hepatocellular carcinoma (HCC) (8.3%) were the most frequent malignancies. Neoadjuvant (30.6%), adjuvant (12.5%) or palliative (54.2%) chemotherapy was performed. Immunosuppressive regimen was modified from a calcineurin inhibitor (CNI)-based to an everolimus-based regimen (63.5% of CNI discontinuation). Median survival after diagnosis of malignancy was 22.5 months and 5-year survival was 30.1%. Chemotherapy regimen was considered optimal in 81.9% of the cases. Multivariate analysis disclosed that non-PTLD N+ stage malignancy (HR = 5.52 95%CI [1.40;21.69], p = .014), non-PTLD M+ stage malignancy (HR = 10.55 95%CI [3.20;34.73], p = .0001), and suboptimal chemotherapy (HR = 2.73 95%CI [1.34;5.56], p = .005) were significantly associated with poorer prognosis. No rejection episode occurred during chemotherapy. CONCLUSIONS The present study is the first one focused on antineoplastic chemotherapy in LT recipients. Our results suggest that immunosuppressive drugs and antineoplastic chemotherapy can be managed satisfactorily in most cases but this needs confirmation from larger cohorts.
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Affiliation(s)
- Antoine Coupier
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | | | - Olivier Boillot
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France
| | - Thomas Walter
- Université Claude Bernard Lyon 1, Lyon, France.,Service d'Oncologie Digestive, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Olivier Guillaud
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Mélanie Vallin
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Elsa Thimonier
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Domitille Erard
- Service d'Hépato-gastroentérologie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France
| | - Jérôme Dumortier
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France
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14
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Franke F, Renders L, Linecker M, Braun F. Immunsuppression nach Organtransplantation:
Essentials. TRANSFUSIONSMEDIZIN 2022. [DOI: 10.1055/a-1952-6749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Dieser Artikel soll einen Überblick über den Einsatz und
mögliche Probleme der immunsuppressiven Therapie nach solider
Organtransplantation (SOT) geben. Für einige Immunsuppressiva sind
andere Empfehlungen bezüglich der angestrebten Talblutspiegel angegeben,
als dies in der Fachinformation empfohlen ist. Wir möchten
ausdrücklich darauf hinweisen, dass es sich hierbei um die
persönliche Meinung der Autor*innen handelt.
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15
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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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16
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Nelson J, Alvey N, Bowman L, Schulte J, Segovia M, McDermott J, Te HS, Kapila N, Levine DJ, Gottlieb RL, Oberholzer J, Campara M. Consensus recommendations for use of maintenance immunosuppression in solid organ transplantation: Endorsed by the American College of Clinical Pharmacy, American Society of Transplantation, and the International Society for Heart and Lung Transplantation. Pharmacotherapy 2022; 42:599-633. [DOI: 10.1002/phar.2716] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/29/2022] [Accepted: 04/08/2022] [Indexed: 12/17/2022]
Affiliation(s)
- Joelle Nelson
- Department of Pharmacotherapy and Pharmacy Services University Health San Antonio Texas USA
- Pharmacotherapy Education and Research Center University of Texas Health San Antonio San Antonio Texas USA
- Department of Pharmacy, Pharmacotherapy Division, College of Pharmacy The University of Texas at Austin Austin Texas USA
| | - Nicole Alvey
- Department of Pharmacy Rush University Medical Center Chicago Illinois USA
- Science and Pharmacy Roosevelt University College of Health Schaumburg Illinois USA
| | - Lyndsey Bowman
- Department of Pharmacy Tampa General Hospital Tampa Florida USA
| | - Jamie Schulte
- Department of Pharmacy Services Thomas Jefferson University Hospital Philadelphia Pennsylvania USA
| | | | - Jennifer McDermott
- Richard DeVos Heart and Lung Transplant Program, Spectrum Health Grand Rapids Michigan USA
- Department of Medicine, Michigan State University College of Human Medicine Grand Rapids Michigan USA
| | - Helen S. Te
- Liver Transplantation, Center for Liver Diseases, Department of Medicine University of Chicago Medical Center Chicago Illinois USA
| | - Nikhil Kapila
- Department of Transplant Hepatology Duke University Hospital Durham North Carolina USA
| | - Deborah Jo Levine
- Division of Critical Care Medicine, Department of Medicine The University of Texas Health Science Center at San Antonio San Antonio Texas USA
| | - Robert L. Gottlieb
- Baylor University Medical Center and Baylor Scott and White Research Institute Dallas Texas USA
| | - Jose Oberholzer
- Department of Surgery/Division of Transplantation University of Virginia Charlottesville Virginia USA
| | - Maya Campara
- Department of Surgery University of Illinois Chicago Chicago Illinois USA
- Department of Pharmacy Practice University of Illinois Chicago Chicago Illinois USA
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17
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Kim DG, Hwang S, Kim JM, Ryu JH, You YK, Choi D, Kim BW, Kim DS, Nah YW, Kim TS, Cho JY, Hong G, Yang JD, Han J, Suh SW, Kim KW, Jung YK, Moon JI, Lee JY, Kim SH, Lee JG, Kim MS, Lee KW, Joo DJ. Non-Renal Risk Factors for Chronic Kidney Disease in Liver Recipients with Functionally Intact Kidneys at 1 Month. J Clin Med 2022; 11:4203. [PMID: 35887972 PMCID: PMC9315935 DOI: 10.3390/jcm11144203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/14/2022] [Accepted: 07/18/2022] [Indexed: 01/27/2023] Open
Abstract
Chronic kidney disease (CKD) is a critical complication of liver transplants, of which non-renal risk factors are not fully understood yet. This study aimed to reveal pre- and post-transplant risk factors for CKD (<60 mL/min/1.73 m2), examining liver recipients with functionally intact kidneys one month after grafting using nationwide cohort data. Baseline risk factors were analyzed with multivariable Cox regression analyses and post-transplant risk factors were investigated with the time-dependent Cox model and matched analyses of time-conditional propensity scores. Of the 2274 recipients with a one-month eGFR ≥ 60 mL/min/1.73 m2, 494 (22.3%) developed CKD during a mean follow-up of 36.6 ± 14.4 months. Age, female sex, lower body mass index, pre-transplant diabetes mellitus, and lower performance status emerged as baseline risk factors for CKD. Time-dependent Cox analyses revealed that recurrent hepatocellular carcinoma (HR = 1.93, 95% CI 1.06−3.53) and infection (HR = 1.44, 95% CI 1.12−1.60) were significant post-transplant risk factors for CKD. Patients who experienced one of those factors showed a significantly higher risk of subsequent CKD compared with the matched controls who lacked these features (p = 0.013 for recurrent hepatocellular carcinoma, and p = 0.003 for infection, respectively). This study clarifies pre- and post-transplant non-renal risk factors, which lead to renal impairment after LT independently from patients’ renal functional reserve.
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Affiliation(s)
- Deok-Gie Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Korea; (D.-G.K.); (J.G.L.); (M.S.K.)
| | - Shin Hwang
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
| | - Jong Man Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea;
| | - Je Ho Ryu
- Department of Surgery, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Busan 49241, Korea;
| | - Young Kyoung You
- Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Donglak Choi
- Department of Surgery, Catholic University of Daegu, Daegu 42472, Korea;
| | - Bong-Wan Kim
- Department of Liver Transplantation and Hepatobiliary Surgery, Ajou University School of Medicine, Suwon 16499, Korea;
| | - Dong-Sik Kim
- Department of Surgery, Korea University College of Medicine, Seoul 02841, Korea;
| | - Yang Won Nah
- Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea;
| | - Tae-Seok Kim
- Department of Surgery, Dongsan Medical Center, Keimyung University School of Medicine, Daegu 42601, Korea;
| | - Jai Young Cho
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam 13620, Korea;
| | - Geun Hong
- Department of Surgery, EWHA Womans University College of Medicine, Seoul 07804, Korea;
| | - Jae Do Yang
- Department of Surgery, Jeonbuk National University Hospital, Jeonju 54896, Korea;
| | - Jaryung Han
- Department of Surgery, Kyungpook National University Hospital, Daegu 41944, Korea;
| | - Suk-Won Suh
- Department of Surgery, College of Medicine, Chung-Ang University, Seoul 06974, Korea;
| | - Kwan Woo Kim
- Department of Surgery, Dong-A University Hospital, Busan 49201, Korea;
| | - Yun Kyung Jung
- Department of Surgery, Hanyang University, Seoul 04764, Korea;
| | - Ju Ik Moon
- Department of Surgery, Konyang University Hospital, Daejeon 35365, Korea;
| | - Jun Young Lee
- Department of Nephrology, Yonsei University Wonju College of Medicine, Wonju 26426, Korea;
| | - Sung Hwa Kim
- Department of Biostatistics, Yonsei University Wonju College of Medicine, Wonju 26426, Korea;
| | - Jae Geun Lee
- Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Korea; (D.-G.K.); (J.G.L.); (M.S.K.)
| | - Myoung Soo Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Korea; (D.-G.K.); (J.G.L.); (M.S.K.)
| | - Kwang-Woong Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul 03087, Korea
| | - Dong Jin Joo
- Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Korea; (D.-G.K.); (J.G.L.); (M.S.K.)
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18
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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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19
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Kim DG, Kim SH, Hwang S, Hong SK, Ryu JH, Kim BW, You YK, Choi D, Kim DS, Nah YW, Cho JY, Kim TS, Hong G, Joo DJ, Kim MS, Kim JM, Lee JG. Safety of Tacrolimus Monotherapy within 12 Months after Liver Transplantation in the Era of Reduced Tacrolimus and Mycophenolate Mofetil: National Registry Study. J Clin Med 2022; 11:2806. [PMID: 35628939 PMCID: PMC9145025 DOI: 10.3390/jcm11102806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 05/13/2022] [Accepted: 05/14/2022] [Indexed: 02/05/2023] Open
Abstract
Tacrolimus monotherapy is accepted as a feasible option during early post-liver transplantation as per current international consensus guidelines. However, its effects in the recent era of reduced tacrolimus (TAC) and mycophenolate mofetil (MMF) remain unclear. Liver recipients who either received TAC monotherapy from the treatment onset or switched from TAC/MMF to TAC-mono within 12 months (TAC-mono group; n = 991) were chronologically matched to patients who continued to receive TAC/MMF (TAC/MMF group; n = 991) at the corresponding time points on time-conditional propensity scores. Outcomes within 12 months after matched time points were compared. Biopsy-proven rejection (TAC/MMF: 3.5% vs. TAC-mono: 2.6%; p = 0.381) and graft failure (0.2% vs. 0.7%; p = 0.082) were similar in both groups. However, the decline in eGFR was 3.1 mL/min/1.73 m2 (95% CI: 0.8-5.3) greater at six months (p = 0.008) and 2.4 mL/min/1.73 m2 (95% CI: -0.05-4.9) greater at 12 months (p = 0.048) after the matched time points in TAC-mono group than that in TAC/MMF group. TAC trough levels were also higher in the TAC-mono group throughout the study period. TAC-mono within 12 months after liver transplantation is immunologically safe. However, it can increase the required TAC dose and the decline in renal function than that in TAC/MMF combination therapy.
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Affiliation(s)
- Deok Gie Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Korea; (D.G.K.); (D.J.J.); (M.S.K.)
| | - Sung Hwa Kim
- Department of Biostatistics, Yonsei University Wonju College of Medicine, Wonju 26426, Korea;
| | - Shin Hwang
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
| | - Suk Kyun Hong
- Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Korea;
| | - Je Ho Ryu
- Department of Surgery, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Busan 49241, Korea;
| | - Bong-Wan Kim
- Department of Liver Transplantation and Hepatobiliary Surgery, Ajou University School of Medicine, Suwon 16499, Korea;
| | - Young Kyoung You
- Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Donglak Choi
- Department of Surgery, Catholic University of Daegu, Daegu 42472, Korea;
| | - Dong-Sik Kim
- Department of Surgery, Korea University College of Medicine, Seoul 02841, Korea;
| | - Yang Won Nah
- Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea;
| | - Jai Young Cho
- Department of Surgery, Seoul National University College of Medicine, Bundang Hospital, Seongnam 13620, Korea;
| | - Tae-Seok Kim
- Department of Surgery, Dongsan Medical Center, Keimyung University School of Medicine, Daegu 42601, Korea;
| | - Geun Hong
- Department of Surgery, EWHA Womans University College of Medicine, Seoul 07804, Korea;
| | - Dong Jin Joo
- Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Korea; (D.G.K.); (D.J.J.); (M.S.K.)
| | - Myoung Soo Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Korea; (D.G.K.); (D.J.J.); (M.S.K.)
| | - Jong Man Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06531, Korea
| | - Jae Geun Lee
- Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Korea; (D.G.K.); (D.J.J.); (M.S.K.)
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20
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Meszaros M, Dubois V, Congy-Jolivet N, Hamada S, Thevenin C, Faure S, Boillot O, Kamar N, Pageaux GP, Del Bello A, Dumortier J. Impact of calcineurin inhibitor-free immunosuppression on de novo donor-specific antibody formation in liver transplant recipients. Liver Int 2022; 42:1132-1143. [PMID: 35184373 DOI: 10.1111/liv.15201] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 12/14/2021] [Accepted: 01/12/2022] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Low calcineurin inhibitor (CNI) levels expose liver transplant recipients to rejection episodes and potentially to antibody-mediated rejection. There are little data on the impact of CNI-free immunosuppression on de novo donor-specific HLA antibody (dnDSA) development. Here we evaluated the prevalence of dnDSA in liver transplant recipients on CNI-free maintenance regimens and their associations with histopathological abnormalities of allografts. METHODS Seven hundred and twenty-seven liver transplant recipients underwent a first liver transplant between 2000 and 2018 in three French transplant centres and had protocolized follow-up with dnDSA screening and allograft biopsy 1, 5 and 10 years after transplantation. RESULTS CNIs were withdrawn in 166 (22.8%) patients with or without conversion to mammalian target of rapamycin inhibitors and/or maintenance with mycophenolic acid. DSA were present after withdrawal in 30.1% (50/166) patients on CNI-free immunosuppression compared with 16% (90/561) on CNI maintenance therapy (p < 0.001). The cumulative incidence of dnDSA 10 years after transplant was 20% in the CNI group versus 28% in the CNI-free group (p < 0.01). dnDSAs were associated with histological graft abnormalities (significant allograft fibrosis or rejection) (HR 2.24, 95% CI 1.2-4.1; p = 0.01). In univariate Cox regression analysis, being on a CNI-free regimen did not impact graft histology. CONCLUSIONS Patients on a CNI-free IS regimen have a higher prevalence of dnDSA than patients on a standard IS regimen. dnDSAs but not CNI-free immunosuppression were associated with abnormal allograft histology.
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Affiliation(s)
- Magdalena Meszaros
- Département d'hépatologie et transplantation hépatique, CHU Saint Eloi, Montpellier, France
| | - Valérie Dubois
- Etablissement Français du Sang, Laboratoire d'Histocompatibilité, Lyon, France
| | | | - Sarah Hamada
- Etablissement Français du Sang, Laboratoire d'Histocompatibilité, Lyon, France
| | - Céline Thevenin
- Département d'Immunologie, CHU Montpellier, Montpellier, France
| | - Stephanie Faure
- Département d'hépatologie et transplantation hépatique, CHU Saint Eloi, Montpellier, France
| | - Olivier Boillot
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Unité de Transplantation hépatique, Lyon, France
| | - Nassim Kamar
- Département de Néphrologie et Transplantation d'Organes, CHU, Toulouse, France
| | | | - Arnaud Del Bello
- Département de Néphrologie et Transplantation d'Organes, CHU, Toulouse, France
| | - Jérôme Dumortier
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Unité de Transplantation hépatique, Lyon, France
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21
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Kitano Y, Pietrasz D, Fernandez-Sevilla E, Golse N, Vibert E, Sa Cunha A, Azoulay D, Cherqui D, Baba H, Adam R, Allard MA. Subjective Difficulty Scale in Liver Transplantation: A Prospective Observational Study. Transpl Int 2022; 35:10308. [PMID: 35387395 PMCID: PMC8977402 DOI: 10.3389/ti.2022.10308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 01/18/2022] [Indexed: 11/27/2022]
Abstract
The predictive value of a subjective difficulty scale (DS) after surgical procedures is unknown. The objective of this study was to evaluate the prognostic value of a DS after liver transplantation (LT) and to identify predictors of difficulty. Surgeons prospectively evaluated the difficulty of 441 consecutive liver transplantations from donation after brain death at the end of the surgery by using a DS from 0 to 10 (“the easiest to the hardest you can imagine”). DS was associated with severe morbidity. The risk of graft loss at 1 year remained unchanged from 0 to 6 but increased beyond 6. Graft survival and patient survival of group with DS 7–10 was significantly impaired compared to groups with DS: 0–3 or DS: 4–6 but were significantly impaired for the group with DS: 7–10. Independent predictors of difficult LT (DS ≥ 7) were annular segment 1, transjugular intrahepatic portosystemic shunt, retransplantation beyond 30 days, portal vein thrombosis, and ascites. Of them, ascites was a borderline non-significant covariate (p = .04). Vascular complications occurred more often after difficult LT (20.5% vs. 5.9%), whereas there was no difference in the other types of complications. DS can be used to tailor monitoring and anticipate early complications. External validation is needed.
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Affiliation(s)
- Yuki Kitano
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Université Paris Sud, Inserm U 935, Villejuif, France.,Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Daniel Pietrasz
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Université Paris Sud, Inserm U 935, Villejuif, France
| | - Elena Fernandez-Sevilla
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Université Paris Sud, Inserm U 935, Villejuif, France
| | - Nicolas Golse
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Université Paris Sud, Inserm U 935, Villejuif, France.,Unité INSERM 1193, Villejuif, France
| | - Eric Vibert
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Université Paris Sud, Inserm U 935, Villejuif, France.,Unité INSERM 1193, Villejuif, France
| | - Antonio Sa Cunha
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Université Paris Sud, Inserm U 935, Villejuif, France.,Équipe Chronothérapie, Cancers et Transplantation, Université Paris, Saclay, France
| | - Daniel Azoulay
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Université Paris Sud, Inserm U 935, Villejuif, France
| | - Daniel Cherqui
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Université Paris Sud, Inserm U 935, Villejuif, France.,Unité INSERM 1193, Villejuif, France
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - René Adam
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Université Paris Sud, Inserm U 935, Villejuif, France.,Équipe Chronothérapie, Cancers et Transplantation, Université Paris, Saclay, France
| | - Marc-Antoine Allard
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Université Paris Sud, Inserm U 935, Villejuif, France.,Équipe Chronothérapie, Cancers et Transplantation, Université Paris, Saclay, France
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22
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Sinakos E, Panas P, Fragkou N, Antoniadis N, Katsanos G, Tsakni E, Oikonomou T, Notopoulos A, Tsoulfas G, Goulis I, Akriviadis E. Tenofovir alafenamide prophylaxis post-liver transplantation: a real-world study in patients with chronic kidney disease. Acta Gastroenterol Belg 2022; 85:331-337. [PMID: 35709777 DOI: 10.51821/85.2.9577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
BACKGROUND & AIMS Tenofovir alafenamide fumarate (TAF) was shown equally efficacious in suppressing hepatitis B virus (HBV) but with less renal toxicity than tenofovir disoproxil fumarate (TDF). The aim of this real-world study was to evaluate renal function in post-liver transplantation (LT) patients that changed TDF with TAF. METHODS The TAF group (n=17) included patients who switched to TAF due to low (<60 ml/min/1.73m2) Glomerular Filtration Rate (GFR). The control group included patients that remained on TDF (n=30), although some (n= 14) had chronic kidney disease (CKD) (TDF-CKD group). GFR was assessed using: i) MDRD-6 variable; ii) CKD-EPI formula; iii) radionuclide technique (rGFR). RESULTS There were no significant differences between the two groups except for the presence of diabetes and follow-up period, which were more common and shorter, respectively, in the TAF group (35% vs. 10%, p=0.03; 13.7 vs. 35.5 months, p<0.001). At the end of follow-up there were no significant changes in renal function between the TAF and the TDF group or TDF-CKD group, although the numerical change in rGFR in the latter comparison was greater in the TAF group (ΔrGFR 3 vs. -2.14 ml/min, p=0.26). The use of everolimus was associated with improvement in renal function (ΔrGFR 2 vs. -7.75 ml/min, p=0.06 [TAF vs. TDF group]; 2 vs. -12 ml/min, p=0.01 [TAF vs. TDF-CKD group]). There were no TAF- related side effects or cases of HBV recurrence. CONCLUSION Conversion to TAF in post-LT patients who develop CKD does not lead to improvement of kidney function after a period of one year.
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Affiliation(s)
- E Sinakos
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Greece
| | - P Panas
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Greece
| | - N Fragkou
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Greece
| | - N Antoniadis
- Department of Transplant Surgery, Hippokratio Hospital, Aristotle University of Thessaloniki, Greece
| | - G Katsanos
- Department of Transplant Surgery, Hippokratio Hospital, Aristotle University of Thessaloniki, Greece
| | - E Tsakni
- Department of Transplant Surgery, Hippokratio Hospital, Aristotle University of Thessaloniki, Greece
| | - T Oikonomou
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Greece
| | - A Notopoulos
- Department of Nuclear Medicine, Hippokratio Hospital, Thessaloniki, Greece
| | - G Tsoulfas
- Department of Transplant Surgery, Hippokratio Hospital, Aristotle University of Thessaloniki, Greece
| | - I Goulis
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Greece
| | - E Akriviadis
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Greece
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23
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Toniutto P, Germani G, Ferrarese A, Bitetto D, Zanetto A, Fornasiere E, Fumolo E, Shalaby S, Burra P. An Essential Guide for Managing Post-Liver Transplant Patients: What Primary Care Physicians Should Know. Am J Med 2022; 135:157-166. [PMID: 34508700 DOI: 10.1016/j.amjmed.2021.08.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 08/11/2021] [Accepted: 08/11/2021] [Indexed: 12/16/2022]
Abstract
With long-term survival after liver transplantation becoming the rule, care for medical problems arising over time in liver-transplanted patients gained increasing importance. The most common causes of death occurring more than 1 year after liver transplantation are unrelated to liver diseases and facilitated by immunosuppressive treatments; examples are malignancies, renal failure, and cardiovascular, metabolic, and infectious diseases. Recipients receive life-long follow-up care at transplant centers, however, the increasing number of liver-transplanted patients is saturating the health care supply that transplant centers have to offer. Primary care physicians are increasingly exposed to liver-transplanted patients, even in the early periods after transplant, and an understanding of the most common risks and complications faced by these patients would enhance their care. This article reviews the long-term care of liver transplant recipients, emphasizing the key internal medicine-related issues that should be known by primary care physicians. A specific section is devoted to implementing strategies to involve these physicians in the long-term follow-up of liver-transplanted patients in close collaboration with transplant hepatologists.
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Affiliation(s)
- Pierluigi Toniutto
- Hepatology and Liver Transplantation Unit, Department of Specialized Medicine, Udine University Hospital, Udine, Italy;.
| | - Giacomo Germani
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Alberto Ferrarese
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Davide Bitetto
- Hepatology and Liver Transplantation Unit, Department of Specialized Medicine, Udine University Hospital, Udine, Italy
| | - Alberto Zanetto
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Ezio Fornasiere
- Hepatology and Liver Transplantation Unit, Department of Specialized Medicine, Udine University Hospital, Udine, Italy
| | - Elisa Fumolo
- Hepatology and Liver Transplantation Unit, Department of Specialized Medicine, Udine University Hospital, Udine, Italy
| | - Sarah Shalaby
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Patrizia Burra
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
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24
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Saunders EA, Engel B, Höfer A, Hartleben B, Vondran FWR, Richter N, Potthoff A, Zender S, Wedemeyer H, Jaeckel E, Taubert R. Outcome and safety of a surveillance biopsy guided personalized immunosuppression program after liver transplantation. Am J Transplant 2022; 22:519-531. [PMID: 34455702 DOI: 10.1111/ajt.16817] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 08/08/2021] [Accepted: 08/19/2021] [Indexed: 01/25/2023]
Abstract
Graft survival beyond year 1 has not changed after orthotopic liver transplantation (OLT) over the last decades. Likewise, OLT causes comorbidities such as infection, renal impairment and cancer. We evaluated our single-center real-world individualized immunosuppression program after OLT, based on 211 baseline surveillance biopsies (svLbx) without any procedural complications. Patients were classified as low, intermediate and high rejection risk based on graft injury in svLbx and anti-HLA donor-specific antibodies. While 32% of patients had minimal histological inflammation, 57% showed histological inflammation and 23% advanced fibrosis (>F2), which was not predicted by lab parameters. IS was modified in 79% of patients after svLbx. After immunosuppression reduction in 69 patients, only 5 patients showed ALT elevations and three of these patients had a biopsy-proven acute rejection, two of them related to lethal comorbidities. The rate of liver enzyme elevation including rejection was not significantly increased compared to a svLbx control cohort prior to the initiation of our structured program. Immunosuppression reduction led to significantly better kidney function compared to this control cohort. In conclusion, a biopsy guided personalized immunosuppression protocol after OLT can identify patients requiring lower immunosuppression or patients with graft injury in which IS should not be further reduced.
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Affiliation(s)
- Emily A Saunders
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Bastian Engel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Anne Höfer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Björn Hartleben
- Institute for Pathology, Hannover Medical School, Hannover, Germany
| | - Florian W R Vondran
- Department for General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Nicolas Richter
- Department for General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Andrej Potthoff
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Steffen Zender
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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25
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Pan F, Cao S, Li XL, Jia YN, Wang RL, He Q, Zhu JQ. The Model for End-Stage Liver Disease Score and the Follow-Up Period Can Cause the Shift of Circulating Lymphocyte Subsets in Liver Transplant Recipients. Front Med (Lausanne) 2022; 8:779443. [PMID: 35047528 PMCID: PMC8761724 DOI: 10.3389/fmed.2021.779443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Accepted: 11/30/2021] [Indexed: 11/13/2022] Open
Abstract
Little is known about the shift of lymphocytes under the condition of the model for end-stage liver disease score and the follow-up period. Then, we detected the peripheral blood from liver transplant recipients by flow cytometry and compared the results. The model for end-stage liver disease score affected the percentages of T-cell subsets and B cells during the short-term follow-up period, but failed to influence the lymphocyte subsets during the long-term follow-up period. In contrast, the follow-up period not only affected the absolute counts of T-cell subsets and natural killer (NK) cells in patients with the low model for end-stage liver disease scores, but also influenced the percentages and absolute counts of T-cell subsets in patients with the high model for end-stage liver disease scores. In the two-way ANOVA, we further revealed that the model for end-stage liver disease score was associated with the percentages of T cells and CD4+ T cells and the absolute numbers of T-cell subsets and B cells, while the follow-up period was associated with the percentages of T-cell subsets and the absolute numbers of lymphocyte subsets. Therefore, patients with either the low model for end-stage liver disease scores or the long-term follow-up period are in a relatively activated immune condition.
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Affiliation(s)
- Fei Pan
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Shuang Cao
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Xian-Liang Li
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Ya-Nan Jia
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Ruo-Lin Wang
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Qiang He
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Ji-Qiao Zhu
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
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26
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Faitot F, Artzner T, Michard B, Besch C, Schenck M, Herbrecht JE, Langenstein RJ, Maestraggi Q, Guillot M, Harlay ML, Castelain V, Addeo P, Ellero B, Woehl-Jaegle ML, Serfaty L, Bachellier P, Schneider F, Study Group OBOTSLTS. Immunosuppression in patients with Grade 3 Acute-On-Chronic Liver Failure at transplantation: A practice analysis study. Clin Transplant 2022; 36:e14580. [PMID: 34974638 DOI: 10.1111/ctr.14580] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 10/18/2021] [Accepted: 12/23/2021] [Indexed: 12/22/2022]
Abstract
Transplantation for patients with acute-on-chronic liver failure grade 3 (ACLF3) has encouraging results with one-year-survival of 80-90%. These patients with multiple organ failure meet the conditions for serious alterations of drug metabolism and increased toxicity. The goal of this study was to identify immunosuppression-dependent factors that affect survival. This retrospective monocentric study was conducted in patients with ACLF3 consecutively transplanted between 2007 and 2019. The primary endpoint was one-year survival. Secondary endpoints were overall survival, treated rejection and surgical complications. Immunosuppression was evaluated as to type of immunosuppression, post-transplant introduction timing, through levels and trough level intra-patient variability (IPV). One hundred patients were included. Tacrolimus IPV <40% (p=0.019), absence of early tacrolimus overdose (p=0.033), use of anti-IL2-receptor antibodies (p=0.034) and early mycophenolic acid introduction (p=0.038) predicted one-year survival. Treated rejection was an independent predictor of survival (p=0.001; HR 4.2 (CI 95%: 1.13-15.6)). Early everolimus introduction was neither associated with higher rejection rates nor with more surgical complications. Management of immunosuppression in ACLF3 critically ill patients undergoing liver transplantation is challenging. Occurrence and treatment of rejection impacts on survival. Early introduction of mTOR inhibitor seems safe and efficient in this situation. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Francois Faitot
- Hepatobiliopancreatic Surgery and Transplantation Department, Hopital de Hautepierre, Hopitaux Universitaires de Strasbourg, Strasbourg, France.,Laboratoire ICube, UMR7357, University of Strasbourg, Strasbourg, France
| | - Thierry Artzner
- Medecine Intensive-Reanimation, Hopital de Hautepierre, Hopitaux Universitaires de Strasbourg, Strasbourg, France
| | - Baptiste Michard
- Hepatobiliopancreatic Surgery and Transplantation Department, Hopital de Hautepierre, Hopitaux Universitaires de Strasbourg, Strasbourg, France
| | - Camille Besch
- Hepatobiliopancreatic Surgery and Transplantation Department, Hopital de Hautepierre, Hopitaux Universitaires de Strasbourg, Strasbourg, France
| | - Maleka Schenck
- Medecine Intensive-Reanimation, Hopital de Hautepierre, Hopitaux Universitaires de Strasbourg, Strasbourg, France
| | - Jean-Etienne Herbrecht
- Medecine Intensive-Reanimation, Hopital de Hautepierre, Hopitaux Universitaires de Strasbourg, Strasbourg, France
| | - Ralf Janssen Langenstein
- Medecine Intensive-Reanimation, Hopital de Hautepierre, Hopitaux Universitaires de Strasbourg, Strasbourg, France
| | - Quentin Maestraggi
- Medecine Intensive-Reanimation, Hopital de Hautepierre, Hopitaux Universitaires de Strasbourg, Strasbourg, France
| | - Max Guillot
- Medecine Intensive-Reanimation, Hopital de Hautepierre, Hopitaux Universitaires de Strasbourg, Strasbourg, France
| | - Marie-Line Harlay
- Medecine Intensive-Reanimation, Hopital de Hautepierre, Hopitaux Universitaires de Strasbourg, Strasbourg, France
| | - Vincent Castelain
- Medecine Intensive-Reanimation, Hopital de Hautepierre, Hopitaux Universitaires de Strasbourg, Strasbourg, France.,Federation Medicale Translationnelle Strasbourg, Université de Strasbourg, Strasbourg, France
| | - Pietro Addeo
- Hepatobiliopancreatic Surgery and Transplantation Department, Hopital de Hautepierre, Hopitaux Universitaires de Strasbourg, Strasbourg, France
| | - Bernard Ellero
- Hepatobiliopancreatic Surgery and Transplantation Department, Hopital de Hautepierre, Hopitaux Universitaires de Strasbourg, Strasbourg, France
| | - Marie-Lorraine Woehl-Jaegle
- Hepatobiliopancreatic Surgery and Transplantation Department, Hopital de Hautepierre, Hopitaux Universitaires de Strasbourg, Strasbourg, France
| | - Lawrence Serfaty
- Department of Hepatogastroenterology, Hopital de Hautepierre, Hopitaux Universitaires de Strasbourg, Strasbourg, France
| | - Philippe Bachellier
- Hepatobiliopancreatic Surgery and Transplantation Department, Hopital de Hautepierre, Hopitaux Universitaires de Strasbourg, Strasbourg, France
| | - Francis Schneider
- Medecine Intensive-Reanimation, Hopital de Hautepierre, Hopitaux Universitaires de Strasbourg, Strasbourg, France.,Federation Medicale Translationnelle Strasbourg, Université de Strasbourg, Strasbourg, France
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27
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Domínguez-Gil B, Moench K, Watson C, Serrano MT, Hibi T, Asencio JM, Van Rosmalen M, Detry O, Heimbach J, Durand F. Prevention and Management of Donor-transmitted Cancer After Liver Transplantation: Guidelines From the ILTS-SETH Consensus Conference. Transplantation 2022; 106:e12-e29. [PMID: 34905759 DOI: 10.1097/tp.0000000000003995] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
As with any other intervention in health, liver transplantation (LT) entails a variety of risks, including donor-transmitted cancers (DTCs). At present, 2%-4% of used deceased organ donors are known to have a current or past history of malignancy. The frequency of DTCs is consistently reported at 3-6 cases per 10 000 solid organ transplants, with a similar frequency in the LT setting. A majority of DTCs are occult cancers unknown in the donor at the time of transplantation. Most DTCs are diagnosed within 2 y after LT and are associated with a 51% probability of survival at 2 y following diagnosis. The probability of death is greatest for DTCs that have already metastasized at the time of diagnosis. The International Liver Transplantation Society-Sociedad Española de Trasplante Hepático working group on DTC has provided guidance on how to minimize the occurrence of DTCs while avoiding the unnecessary loss of livers for transplantation both in deceased and living donor LT. The group endorses the Council of Europe classification of risk of transmission of cancer from donor to recipient (minimal, low to intermediate, high, and unacceptable), classifies a range of malignancies in the liver donor into these 4 categories, and recommends when to consider LT, mindful of the risk of DTCs, and the clinical condition of patients on the waiting list. We further provide recommendations to professionals who identify DTC events, stressing the need to immediately alert all stakeholders concerned, so a coordinated investigation and management can be initiated; decisions on retransplantation should be made on a case-by-case basis with a multidisciplinary approach.
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Affiliation(s)
| | - Kerstin Moench
- Donor Transplant Coordination Unit, Westpfalz-Klinikum, Kaiserslautern, Germany
| | - Christopher Watson
- The Roy Calne Transplant Unit and Department of Surgery, University of Cambridge, Cambridge, United Kingdom
| | - M Trinidad Serrano
- Hepatology Section, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
| | - Taizo Hibi
- Department of Pediatric Surgery and Transplantation, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
| | - José M Asencio
- Liver Transplant Unit, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | | | - Olivier Detry
- Department of Abdominal Surgery and Transplantation, Centre Hospitalier Universitaire de Liege, University of Liege, Liege, Belgium
| | | | - François Durand
- Hepatology Department, Liver Intensive Care Unit, Hospital Beaujon, Clichy, France
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28
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Bhanji RA, Chow J, Ma M, Pannu N, Bain VG, Kneteman N, Montano-Loza AJ. Post-liver transplantation chronic kidney disease is associated with increased cardiovascular disease risk and poor survival. Transpl Int 2021; 34:2824-2833. [PMID: 34738667 DOI: 10.1111/tri.14154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 10/25/2021] [Accepted: 11/01/2021] [Indexed: 11/30/2022]
Abstract
Chronic kidney disease (CKD) is common following liver transplantation (LT). We aimed to investigate the frequency, risk factors, and impact of CKD on cardiovascular disease (CVD), graft, and patient survival. We analyzed 752 patients who received LT at the University of Alberta. Development of CKD was defined as eGFR <60 ml/min for greater than 3 months, intrinsic renal disease or presence of end-stage renal disease requiring renal replacement therapy. 240 patients were female (32%), and mean age at LT was 53 ± 11 years. CKD was diagnosed in 448 (60%) patients. On multivariable analysis, age (OR 1.3; P = 0.01), female sex (OR 3.3; P < 0.001), baseline eGFR (OR 0.83; P < 0.001), MELD (OR 1.03; P = 0.01), de novo metabolic syndrome (OR 2.3; P = 0.001), and acute kidney injury (OR 3.5; P < 0.001) were associated with CKD. A higher tacrolimus concentration to dose ratio was protective for CKD (OR 0.69; P < 0.001). CKD was associated with post-transplant CVD (26% vs. 16% P < 0.001), reduced graft (HR 1.4; P = 0.02), and patient survival (HR 1.3; P = 0.03). CKD is a frequent complication following LT and is associated with an increased risk of CVD and reduced graft and patient survival.
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Affiliation(s)
- Rahima A Bhanji
- Division of Gastroenterology & Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada
| | - Jessica Chow
- Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Mang Ma
- Division of Gastroenterology & Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada
| | - Neesh Pannu
- Division of Nephrology, University of Alberta Hospital, Edmonton, AB, Canada
| | - Vincent G Bain
- Division of Gastroenterology & Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada
| | - Norman Kneteman
- Department of Surgery & Liver Transplantation, University of Alberta Hospital, Edmonton, AB, Canada
| | - Aldo J Montano-Loza
- Division of Gastroenterology & Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada
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29
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Dong V, Nadim MK, Karvellas CJ. Post-Liver Transplant Acute Kidney Injury. Liver Transpl 2021; 27:1653-1664. [PMID: 33963666 DOI: 10.1002/lt.26094] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 04/19/2021] [Accepted: 04/26/2021] [Indexed: 12/13/2022]
Abstract
Acute kidney injury (AKI) is a common condition following liver transplantation (LT). It negatively impacts patient outcomes by increasing the chances of developing chronic kidney disease and reducing graft and patient survival rates. Multiple definitions of AKI have been proposed and used throughout the years, with the International Club of Ascites definition being the most widely now used for patients with cirrhosis. Multiple factors are associated with the development of post-LT AKI and can be categorized into pre-LT comorbidities, donor and recipient characteristics, operative factors, and post-LT factors. Many of these factors can be optimized in an attempt to minimize the risk of AKI occurring and to improve renal function if AKI is already present. A special consideration during the post-LT phase is needed for immunosuppression as certain immunosuppressive medications can be nephrotoxic. The calcineurin inhibitor tacrolimus (TAC) is the mainstay of immunosuppression but can result in AKI. Several strategies including use of the monoclonoal antibody basilixamab to allow for delayed initiation of tacrolimus therapy and minimization through combination and minimization or elimination of TAC through combination with mycophenolate mofetil or mammalian target of rapamycin inhibitors have been implemented to reverse and avoid AKI in the post-LT setting. Renal replacement therapy may ultimately be required to support patients until recovery of AKI after LT. Overall, by improving renal function in post-LT patients with AKI, outcomes can be improved.
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Affiliation(s)
- Victor Dong
- Interdepartmental Division of Critical Care, University of Toronto, Toronto, Alberta, Canada.,Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Alberta, Canada
| | - Mitra K Nadim
- Division of Nephrology and Hypertension, University of Southern California, Los Angeles, CA
| | - Constantine J Karvellas
- Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Alberta, Canada.,Department of Critical Care Medicine, University of Alberta, Edmonton, Alberta, Canada
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30
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Immunosuppression in liver and intestinal transplantation. Best Pract Res Clin Gastroenterol 2021; 54-55:101767. [PMID: 34874848 DOI: 10.1016/j.bpg.2021.101767] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 10/08/2021] [Indexed: 02/07/2023]
Abstract
Immunosuppression handling plays a key role in the early and long-term results of transplantation. The development of multiple immunosuppressive drugs led to numerous clincial trials searching to reach the ideal regimen. Due to heterogeneity of the studied patient cohorts and flaws in many, even randomized controlled, study designs, the answer still stands out. Nowadays triple-drug immunosuppression containing a calcineurin inhibitor (preferentially tacrolimus), an antimetabolite (using mycophenolate moffettil or Azathioprine) and short-term steroids with or without induction therapy (using anti-IL2 receptor blocker or anti-lymphocytic serum) is the preferred option in both liver and intestinal transplantation. This chapter aims, based on a critical review of the definitions of rejection, corticoresistant rejection and standard immunosuppression to give some reflections on how to reach an optimal immunosuppressive status and to conduct trials allowing to draw solid conclusions. Endpoints of future trials should not anymore focus on biopsy proven, acute and chronic, rejection but also on graft and patient survival. Correlation between early- and long-term biologic, immunologic and histopathologic findings will be fundamental to reach in much more patients the status of operational tolerance.
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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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32
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Barjon C, Dahlqvist G, Ghazal K, Saliba F, Durand F, Duvoux C, Aoudjehane L, Conti F. Influence of everolimus-based treatment on circulating regulatory T cells after liver transplantation: Comparative study with tacrolimus-based therapy. Clin Res Hepatol Gastroenterol 2021; 45:101559. [PMID: 33191181 DOI: 10.1016/j.clinre.2020.10.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 10/13/2020] [Accepted: 10/14/2020] [Indexed: 02/04/2023]
Abstract
Liver transplantation remains the only treatment for terminal liver diseases. However, immunosuppressive drugs required for allograft acceptance are toxic and may be responsible for severe side effects. Modulating the immune system to induce tolerance is a promising approach to reduce immunosuppressive regimen. More particularly, promoting natural CD4+ CD25+ FoxP3+ Tregs could be crucial in achieving tolerance. Contrary to calcineurin inhibitors, reports indicate that mTOR inhibitors may have a positive impact on Tregs. Here we present the first randomized prospective clinical study where Tregs levels from liver transplanted patients receiving either tacrolimus or everolimus were monitored for 6 months, starting from the day of transplantation. A total of 30 patients from four centers were monitored. Blood samples were obtained at day 0, day 14, one month, three months and six months post-transplantation. Flow-cytometry immunophenotyping of Tregs (CD4+ CD25+ CD127- FoxP3+) and functional assays with Tregs were performed to assess their immunosuppressive capacity. Levels of Tregs were significantly reduced after one month of standard tacrolimus-based immunosuppressive regimen (p<0.05). Four months after conversion, levels of Tregs from patients treated with everolimus was significantly higher than patients under tacrolimus (p<0.02). Functional assays demonstrated that Tregs conserved their capacity to suppress the proliferation of activated PBMC.
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Affiliation(s)
- Clément Barjon
- UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France; De Duve Institute, UCLouvain, 1200 Brussels, Belgium
| | - Géraldine Dahlqvist
- UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France; Hepatogastroenterology Unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
| | | | - Faouzi Saliba
- Centre Hépato-Biliaire, Hôpital Paul Brousse, AP-HP, Villejuif, France
| | - François Durand
- Liver Intensive Care Unit, Hôpital Beaujon, Assistance Publique-Hopitaux de Paris and University of Paris, Paris, France
| | - Christophe Duvoux
- Department of Hepatology, Hôpital Henri Mondor, AP-HP, Créteil, France
| | | | - Filomena Conti
- UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France; Liver Transplantation Unit, AP-HP, Hôpital de la Pitié-Salpêtrière, 75012 Paris, France
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33
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Sung PS, Han JW, Seo C, Ahn J, Lee SK, Nam HC, Choi HJ, You YK, Jang JW, Choi JY, Yoon SK. Real-Life Experience of mTOR Inhibitors in Liver Transplant Recipients in a Region Where Living Donation Is Predominant. Front Pharmacol 2021; 12:685176. [PMID: 34326770 PMCID: PMC8314303 DOI: 10.3389/fphar.2021.685176] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 06/30/2021] [Indexed: 12/12/2022] Open
Abstract
Background: Mammalian target of rapamycin (mTOR) inhibitors, such as everolimus and sirolimus, may be efficacious in preserving renal function in liver transplantation (LT) recipients while preventing hepatocellular carcinoma (HCC) recurrence. Materials and Methods: In this study, we retrospectively evaluated the safety, efficacy, and renoprotective effects of mTOR inhibitors in LT recipients. Among the 84 patients enrolled, mTOR inhibitor was commenced during the first year after LT. Renal function was measured by estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease equation. Results: Regarding the type of mTOR inhibitor, everolimus was used in 71 patients and sirolimus in 13 patients. Concomitant tacrolimus was used in 63 patients (75.0%). For total enrolled patients, kidney function did not significantly change during 12 months after initiation of mTOR inhibitors, although tacrolimus-withdrawn patients (n = 21) showed better kidney function compared to tacrolimus-minimized patients (n = 63) after conversion. However, a significant improvement in kidney function was observed in the eGFR <60 ml/min/1.73 m2 group (n = 19) 12 months after initiation of mTOR inhibitors, for both patient groups with early + mid starters (n = 7, stating within 1 year after LT) and late starters (n = 12, starting over 1 year after LT). mTOR inhibitors were safely administered without serious adverse events that led to drug discontinuation. Conclusion: We demonstrated that patients with renal impairment showed significant improvement in renal function regardless of the timing of mTOR inhibitor start, suggesting that switch to mTOR inhibitors may be beneficial when renal function declines.
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Affiliation(s)
- Pil Soo Sung
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea
- The Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ji Won Han
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea
- The Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Changho Seo
- Department of Surgery, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea
| | - Joseph Ahn
- Department of Surgery, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea
| | - Soon Kyu Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea
- The Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hee Chul Nam
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea
- The Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ho Joong Choi
- Department of Surgery, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea
| | - Young Kyoung You
- Department of Surgery, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea
| | - Jeong Won Jang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea
- The Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jong Young Choi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea
- The Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung Kew Yoon
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea
- The Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
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34
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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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35
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Zhu JQ, Wang J, Li XL, Xu WL, Lv SC, Zhao X, Lang R, He Q. A combination of the percentages of IFN-γ +CD4 +T cells and granzyme B +CD19 +B cells is associated with acute hepatic rejection: a case control study. J Transl Med 2021; 19:187. [PMID: 33933100 PMCID: PMC8088570 DOI: 10.1186/s12967-021-02855-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Accepted: 04/21/2021] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND T cells and B cells play a key role in alloimmune responses. We aimed to characterize the shift of T cell subsets and B cell subsets during acute hepatic rejection, and further determine whether they could serve as a prognostic marker. METHODS Blood samples together with the clinical data from liver transplant recipients with and without acute hepatic rejection were collected and analyzed as well as from a validation cohort. RESULTS Upon activation the expression of TGF-β and granzyme B in CD19+B cells, and the expression of IL-2 and IFN-γ in CD4+T cells were higher in acute hepatic rejection. However, only the frequencies of granzyme B+CD19+B cells and IFN-γ+CD4+T cells correlated with liver function in addition to with each other. A combination of the two cell subsets as a novel marker could classify rejection versus non-rejection (area under the curve 0.811, p = 0.001) with the cut-off value of 62.93%, which was more sensitive for worse histological changes (p = 0.027). Moreover, the occurrence rate of acute rejection was higher in the group with the novel marker > 62.93% (p = 0.000). The role of the novel marker was further confirmed in a validation cohort, which was identified to be the only significant independent risk factor for acute rejection (odds ratio: 0.923; 95% CI confidence interval: 0.885-0.964; p = 0.000). CONCLUSIONS A combination of the percentages of IFN-γ+CD4+T cells and granzyme B+CD19+B cells can distinguish rejection from non-rejection, which can be used as a potential prognostic marker for acute rejection in liver transplant recipients.
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Affiliation(s)
- Ji-Qiao Zhu
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020 China
| | - Jing Wang
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020 China
| | - Xian-Liang Li
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020 China
| | - Wen-Li Xu
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020 China
| | - Shao-cheng Lv
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020 China
| | - Xin Zhao
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020 China
| | - Ren Lang
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020 China
| | - Qiang He
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020 China
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36
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Lee S, Kim JM, Kim S, Rhu J, Choi GS, Joh JW. Early use of everolimus improved renal function after adult deceased donor liver transplantation. KOREAN JOURNAL OF TRANSPLANTATION 2021; 35:8-14. [PMID: 35769619 PMCID: PMC9235327 DOI: 10.4285/kjt.20.0043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 10/29/2020] [Accepted: 10/29/2020] [Indexed: 11/04/2022] Open
Abstract
Background Tacrolimus (TAC) is a main therapy for liver transplantation (LT) patients, but it has side effects such as chronic nephrotoxicity that progressively aggravate renal function. The purpose of this study was to retrospectively compare the renal function between a TAC group and a combination of everolimus and reduced TAC (EVR-TAC) group after deceased donor liver transplantation (DDLT). Methods The study comprised 131 patients who underwent DDLT between January 2013 and April 2018 at our institution. They received TAC or EVR-TAC after DDLT. Everolimus (EVR) was introduced between 1 and 6 months after DDLT. Results Thirty-six of 131 patients (27.5%) received EVR-TAC. The incidence of chronic kidney disease (CKD; estimated glomerular filtration rate, <60 mL/1.73 m2) in the EVR-TAC group was higher than in the TAC group (25% vs. 8.4%; P=0.019). Increasing serum creatinine (n=23, 63.9%) was the most common cause for adding EVR to treatment of the posttransplant patients. There were no statistical differences in acute rejection and CKD between the two groups. The TAC trough level was significantly lower in the EVR-TAC group than in the TAC group, and the renal function of the EVR-TAC group was worse than that of the TAC group until 1 year after DDLT. However, the renal function of the EVR-TAC group improved and became similar to that of TAC group at 3 years posttransplant. Conclusions The present study suggests that EVR should be introduced as soon as possible after DDLT to reduce exposure to high doses of TAC to improve the renal function.
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Affiliation(s)
- Seohee Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jong Man Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sangjin Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jinsoo Rhu
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Gyu-Seong Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae-Won Joh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Long-Term Tacrolimus Blood Trough Level and Patient Survival in Adult Liver Transplantation. J Pers Med 2021; 11:jpm11020090. [PMID: 33535628 PMCID: PMC7912911 DOI: 10.3390/jpm11020090] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/25/2021] [Accepted: 01/29/2021] [Indexed: 12/30/2022] Open
Abstract
Tacrolimus is the most widely used immunosuppressant in liver transplant (LT) patients. However, the ideal long-term target level for these patients is unknown. This retrospective study aimed to investigate the impact of tacrolimus blood concentration five years after LT on long-term patient survival outcomes in adult LT recipients. Patients who underwent LT between January 2004 and July 2014 at a tertiary medical center were included in this study (n = 189). The mean tacrolimus blood concentrations of each patient during the fifth year after LT were recorded and the overall survival rate was determined. A multivariate analysis of factors associated with long-term survival was conducted using a Cox’s model. The median follow-up period was 9.63 years, and 144 patients (76.2%) underwent live donor LT. Sixteen patients died within 5 years of LT. In the Cox’s model, patients with a mean tacrolimus blood trough level of 4.6–10.2 ng/mL had significantly better long-term survival than those with a mean tacrolimus blood trough level outside this range (estimated hazard ratio = 4.76; 95% confidence interval: 1.34–16.9, p = 0.016). Therefore, a tacrolimus level no lower than 4.6 ng/mL would be recommended in adult LT patients.
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38
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Lassailly G, Dumortier J, Saint-Marcoux F, El Amrani M, Boulanger J, Boleslawski E, Millet G, Ningarhari M, Truant S, Canva V, Goria O, Boillot O, Louvet A, Mathurin P, Lebuffe G, Pruvot FR, Marquet P, Dharancy S. Real life experience of mycophenolate mofetil monotherapy in liver transplant patients. Clin Res Hepatol Gastroenterol 2021; 45:101451. [PMID: 32536555 DOI: 10.1016/j.clinre.2020.04.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 04/23/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Mycophenolate mofetil (MMF) monotherapy following liver transplantation (LT) remains controversial due to a risk of acute rejection. The aim of this study was to report the largest multicenter experience of the use a MMF monotherapy guided by therapeutic drug monitoring using pharmacoslope modeling and Bayesian estimations of the MPA inter-dose AUC (BEAUCMPA) before withdrawing calcineurin inhibitors (CNI) and to evaluate the benefit of MMF monotherapy. METHODS MMF daily doses were adjusted to reach the BEAUCMPA target of 45μg.h/mL. Then CNI were withdrawn and patients were followed on liver test and clinical outcomes. MAIN FINDINGS From 2000-2014, in 2 transplantation centers, 94 liver transplant recipients received MMF monotherapy 6.5±4 years after LT. The mean BEAUCMPA was 45.5±16μg.h/mL. During follow-up, 4 patients experienced acute rejection (4%). During the first year, estimated glomerular filtration rate (eGFR) improved from 46.2±10.5 to 49.1±11.5mL/kg/min (P=0.025). Benefit persisted at year 5. In patients with metabolic syndrome, eGFR did not improve. CONCLUSION MMF monotherapy regimen appears usually safe and beneficial, with low risk of acute rejection and eGFR improvement. Therapeutic drug monitoring strategy seemed useful by identifying 14% of patients with low MMF exposure.
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Affiliation(s)
- Guillaume Lassailly
- Maladies Appareil Digestif, pole médico-chirurgical, Hôpital Huriez CHU Lille, Inserm U995, Université de Lille, France
| | - Jerome Dumortier
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices civils de Lyon, Université Claude Bernard Lyon 1, Lyon, France
| | - Franck Saint-Marcoux
- Département de Pharmacologie Toxicologie, CHU Limoges, Limoges, Inserm UMR 850, Université Limoges, Limoges, France
| | - Medhi El Amrani
- Département de Chirurgie Digestive et de Transplantation, pole médico-chirurgical, Hôpital Huriez CHU Lille, Université de Lille, Lille, France
| | - Juliette Boulanger
- Maladies Appareil Digestif, pole médico-chirurgical, Hôpital Huriez CHU Lille, Inserm U995, Université de Lille, France
| | - Emmanuel Boleslawski
- Département de Chirurgie Digestive et de Transplantation, pole médico-chirurgical, Hôpital Huriez CHU Lille, Université de Lille, Lille, France
| | - Guillaume Millet
- Département de Chirurgie Digestive et de Transplantation, pole médico-chirurgical, Hôpital Huriez CHU Lille, Université de Lille, Lille, France
| | - Massih Ningarhari
- Maladies Appareil Digestif, pole médico-chirurgical, Hôpital Huriez CHU Lille, Inserm U995, Université de Lille, France
| | - Stephanie Truant
- Département de Chirurgie Digestive et de Transplantation, pole médico-chirurgical, Hôpital Huriez CHU Lille, Université de Lille, Lille, France
| | - Valérie Canva
- Maladies Appareil Digestif, pole médico-chirurgical, Hôpital Huriez CHU Lille, Inserm U995, Université de Lille, France
| | - Odile Goria
- Département d'Hépato-gastroentérologie, Hôpital Charles Nicolle, CHU Rouen, Rouen, France
| | - Olivier Boillot
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices civils de Lyon, Université Claude Bernard Lyon 1, Lyon, France
| | - Alexandre Louvet
- Maladies Appareil Digestif, pole médico-chirurgical, Hôpital Huriez CHU Lille, Inserm U995, Université de Lille, France
| | - Philippe Mathurin
- Maladies Appareil Digestif, pole médico-chirurgical, Hôpital Huriez CHU Lille, Inserm U995, Université de Lille, France
| | - Gilles Lebuffe
- Département d'Hépato-gastroentérologie, Hôpital Charles Nicolle, CHU Rouen, Rouen, France
| | - François-René Pruvot
- Département de Chirurgie Digestive et de Transplantation, pole médico-chirurgical, Hôpital Huriez CHU Lille, Université de Lille, Lille, France
| | - Pierre Marquet
- Département de Pharmacologie Toxicologie, CHU Limoges, Limoges, Inserm UMR 850, Université Limoges, Limoges, France
| | - Sébastien Dharancy
- Maladies Appareil Digestif, pole médico-chirurgical, Hôpital Huriez CHU Lille, Inserm U995, Université de Lille, France.
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Immune and gene expression profiling during tacrolimus to everolimus conversion early after liver transplantation. Hum Immunol 2020; 82:81-88. [PMID: 33213941 DOI: 10.1016/j.humimm.2020.10.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 10/25/2020] [Accepted: 10/31/2020] [Indexed: 01/08/2023]
Abstract
Early elimination of tacrolimus in favor of everolimus can improve renal function in liver transplant recipients. However, as this approach increases the risk of acute rejection, it may benefit from predictive biomarkers guiding weaning. We enrolled 20 recipients on stable tacrolimus + everolimus to undergo tacrolimus withdrawal early post-liver transplant. Blood samples were collected at month 3 (withdrawal initiation), 4 (withdrawal completion), 4.5 and 6 (both everolimus alone). 15 patients did not reject and 5 had mild rejection responding to tacrolimus resumption. Before tacrolimus withdrawal, eventual rejecters had higher percentages of CD56+ NK cells and CD19+CD27+CD24+ memory B cells, and lower levels of T cells expressing the exhaustion marker PD-1. Over time, memory B cells, Ki-67+CD3+ (proliferating) cells and CD4+CD127-CD25HIGH FOXP3+ Tregs increased in rejecters. Tregs also increased in non-rejecters over time. The number of differentially expressed genes progressively increased in rejecters, particularly in mTOR, Eukaryotic Initiation Factor 2, and Neuroinflammation signaling pathways. There was no difference in anti-HLA antibodies between the groups. In summary, blood mononuclear cell and gene expression may predict successful vs. failed early tacrolimus withdrawal in liver transplant recipients. While needing validation, these preliminary findings highlight the potential for cellular and molecular biomarkers to guide decision-making during tacrolimus weaning.
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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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Incidence, Predictors, and Impact on Survival of Long-term Cardiovascular Events After Liver Transplantation. Transplantation 2020; 104:317-325. [PMID: 31335770 DOI: 10.1097/tp.0000000000002852] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Information on the risk factors, particularly kidney function, and impact of long-term cardiovascular events (CVE) after liver transplantation (LT) remains scarce. METHODS This is a retrospective, single-center study that included consecutive LT recipients between 2007 and 2017. The incidence of CVE, their risk factors, and their impact on patient survival were investigated. RESULTS We included 627 LT recipients. The incidence of CVE was 8% and 20% at 12 and 60 months after LT, respectively. The independent risk factors of long-term (beyond 12 mo) CVE were age at LT (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.01-1.07), male gender (HR, 2.48; 95% CI, 1.21-5.05), history of pre-LT cardiovascular disease (HR, 2.19; 95% CI, 1.2-3.98), and immunosuppression with cyclosporine A (HR, 1.93; 95% CI, 1.14-3.3). In patients with pre-LT cardiovascular disease, creatinine levels 12 months after LT significantly impacted the risk of long-term CVE. Long-term CVE (HR, 2.12; 95% CI, 1.24-3.61), hepatitis C as the etiology of liver disease (HR, 2.18; 95% CI, 1.29-3.67), cytomegalovirus infection (HR, 1.89; 95% CI, 1.08-3.3), and donor age (HR, 1.02; 95% CI, 1.01-1.04) were independent factors associated with post-LT patient death. CONCLUSIONS Age, male gender, cardiovascular disease before LT, and cyclosporine A were associated with the risk of long-term CVE. The impact of serum creatinine was restricted to patients with pre-LT cardiovascular disease. In these patients, preservation of kidney function early after LT may lessen the incidence of CVE, which are an independent predictor of post-LT death.
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Xiong XF, Chen DD, Zhu HJ, Ge WH. Prognostic value of endogenous and exogenous metabolites in liver transplantation. Biomark Med 2020; 14:1165-1181. [PMID: 32969246 DOI: 10.2217/bmm-2020-0073] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Liver transplantation has been widely accepted as an effective intervention for end-stage liver diseases and early hepatocellular carcinomas. However, a variety of postoperative complications and adverse reactions have baffled medical staff and patients. Currently, transplantation monitoring relies primarily on nonspecific biochemical tests, whereas diagnosis of multiple complications depends on invasive pathological examination. Therefore, a noninvasive monitoring method with high selectivity and specificity is desperately needed. This review summarized the potential of endogenous small-molecule metabolites as biomarkers for assessing graft function, ischemia-reperfusion injury and liver rejection. Exogenous metabolites, mainly those immunosuppressive agents with high intra- and inter-individual variability, were also discussed for transplantation monitoring.
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Affiliation(s)
- Xiao-Fu Xiong
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu, China.,College of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China
| | - Ding-Ding Chen
- College of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China
| | - Huai-Jun Zhu
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu, China.,Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Wei-Hong Ge
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu, China
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Tanimine N, Ohira M, Tahara H, Ide K, Tanaka Y, Onoe T, Ohdan H. Strategies for Deliberate Induction of Immune Tolerance in Liver Transplantation: From Preclinical Models to Clinical Application. Front Immunol 2020; 11:1615. [PMID: 32849546 PMCID: PMC7412931 DOI: 10.3389/fimmu.2020.01615] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 06/17/2020] [Indexed: 12/12/2022] Open
Abstract
The liver exhibits intrinsic immune regulatory properties that maintain tolerance to endogenous and exogenous antigens, and provide protection against pathogens. Such an immune privilege contributes to susceptibility to spontaneous acceptance despite major histocompatibility complex mismatch when transplanted in animal models. Furthermore, the presence of a liver allograft can suppress the rejection of other solid tissue/organ grafts from the same donor. Despite this immune privilege of the livers, to control the undesired alloimmune responses in humans, most liver transplant recipients require long-term treatment with immune-suppressive drugs that predispose to cardiometabolic side effects and renal insufficiency. Understanding the mechanism of liver transplant tolerance and crosstalk between a variety of hepatic immune cells, such as dendritic cells, Kupffer cells, liver sinusoidas endothelial cells, hepatic stellate cells and so on, and alloreactive T cells would lead to the development of strategies for deliberate induction of more specific immune tolerance in a clinical setting. In this review article, we focus on results derived from basic studies that have attempted to elucidate the immune modulatory mechanisms of liver constituent cells and clinical trials that induced immune tolerance after liver transplantation by utilizing the immune-privilege potential of the liver.
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Affiliation(s)
- Naoki Tanimine
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masahiro Ohira
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Medical Center for Translational and Clinical Research Hiroshima University Hospital, Hiroshima, Japan
| | - Hiroyuki Tahara
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kentaro Ide
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuka Tanaka
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takashi Onoe
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Kure Medical Center and Chugoku Cancer Center, National Hospital Organization, Kure, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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Chadha R, De Martin E, Kabacam G, Kirchner V, Kalisvaart M, Goldaracena N, Tanaka T, Spiro M, Sapisochin G, Vinaixa C, Hessheimer A, Campos Varela I, Rammohan A, Yoon YI, Victor D, Scalera I, Chan A, Bhangui P. Proceedings of the 25th Annual Congress of the International Liver Transplantation Society. Transplantation 2020; 104:1560-1565. [PMID: 32732832 DOI: 10.1097/tp.0000000000003160] [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: 11/26/2022]
Abstract
The 25th Annual Congress of the International Liver Transplantation Society was held in Toronto, Canada, from May 15 to 18, 2019. Surgeons, hepatologists, anesthesiologists, critical care intensivists, radiologists, pathologists, and research scientists from all over the world came together with the common aim of improving care and outcomes for liver transplant recipients and living donors. Some of the featured topics at this year's conference included multidisciplinary perioperative care in liver transplantation, worldwide approaches to organ allocation, donor steatosis, and updates in pediatrics, immunology, and radiology. This report presents excerpts and highlights from invited lectures and select abstracts, reviewed and compiled by the Vanguard Committee of International Liver Transplantation Society. This will hopefully contribute to further advances in clinical practice and research in liver transplantation.
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Affiliation(s)
- Ryan Chadha
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Jacksonville, FL
| | - Eleonora De Martin
- Department of Hepatology, AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, INSERM 1193, Villejuif, France
| | - Gokhan Kabacam
- Department of Gastroenterology, Ankara Guven Hospital, Ankara, Turkey
| | - Varvara Kirchner
- Department of Surgery, University of Minnesota Medical School and Masonic Children's Hospital, Minneapolis, MN
| | | | - Nicolas Goldaracena
- Department of Abdominal Organ Transplant and Hepatobiliary Surgery, University of Virginia Health System, Charlottesville, VA
| | - Tomohiro Tanaka
- Department of Hepatology, University of Iowa Hospitals and Clinics and Iowa City VA Medical Center, Iowa City, IA
| | - Michael Spiro
- Department of Anaesthesia and Intensive Care Medicine, Royal Free Hospital, London, United Kingdom
| | - Gonzalo Sapisochin
- Department of Abdominal Transplant and HPB Surgical Oncology, University Health Network, University of Toronto, Toronto, Canada
| | - Carmen Vinaixa
- Hepatology and Liver Transplantation Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Amelia Hessheimer
- Hepatopancreatobiliary Surgery and Transplantation, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Isabel Campos Varela
- Liver Unit, Department of Internal Medicine, Hospital Universitario Vall D'Hebrón, Institut de Recerca, Barcelona, Spain
| | | | - Young-In Yoon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of South Korea
| | - David Victor
- Houston Methodist Hospital, Sherrie and Alan Conover Center for Liver Disease and Transplantation, Methodist University Hospital, Houston, TX
| | - Irene Scalera
- Hepatobiliary and Liver Transplant Unit, A. Cardarelli Hospital, Liver Unit, Cardarelli Hospital, Naples, Italy
| | - Albert Chan
- Division of Liver Transplantation, The University of Hong Kong, Hong-Kong
| | - Prashant Bhangui
- Medanta Institute of Liver Transplantation and Regenerative Medicine, Medanta-The Medicity, Gurugram, Delhi NCR, India
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Gilad O, Rabinowich L, Levy S, Gotlieb N, Lubezky N, Goykhman Y, Nachmany I, Katz P, Shibolet O, Katchman H. Metabolic and Renal Effects of Mammalian Target of Rapamycin Inhibitors Treatment After Liver Transplantation: Real-Life Single-Center Experience. Transplant Proc 2020; 53:221-227. [PMID: 32650991 DOI: 10.1016/j.transproceed.2020.05.021] [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: 01/20/2020] [Accepted: 05/12/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND Mammalian target of rapamycin (mTOR) inhibitors following liver transplantation (LT) are used to minimize calcineurin inhibitor (CNI)-related nephrotoxicity. Data about metabolic effects of mTOR inhibitors are still limited. AIM This study aims to determine the renal and metabolic effects of different mTOR inhibitor-based protocols in real-life LT patients. METHODS This is a retrospective cohort study of patients treated with mTOR inhibitors after LT. Demographics, treatment protocols, glomerular filtration rate (GFR), and metabolic parameters were collected over a period of 4 years. Initiation of blood pressure (BP), diabetes mellitus, and lipid medications was also noted. RESULTS Fifty-two LT recipients received mTOR inhibitors. GFR improved significantly (by 1.96 mL/min/year), with greater improvement in patients with baseline renal dysfunction (+13.3 mL/min vs +4.5 mL/min at 3 years). Conversion to an mTOR inhibitor during the first post-transplant year resulted in a more durable improvement in GFR (for 4 years vs only 1 year for later conversion).No significant weight gain or new-onset diabetes mellitus was observed. However, there was some increase in total cholesterol (+7 mg/dL) and blood pressure (+2 mm Hg during the third year and +8 mm Hg in the fourth years), followed by initiation of lipid-lowering and BP medications in 25% and 13% of patients, respectively. CONCLUSIONS Treatment with an mTOR inhibitor following LT resulted in improved kidney functions without significant negative metabolic effects such as weight gain or new-onset diabetes mellitus. This makes mTOR inhibitors a valuable immunosuppressive option in the face of the growing incidence of nonalcoholic steatohepatitis as a leading cause for LT.
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Affiliation(s)
- O Gilad
- Liver Unit, Department of Gastroenterology, Tel Aviv Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - L Rabinowich
- Liver Unit, Department of Gastroenterology, Tel Aviv Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - S Levy
- Liver Unit, Department of Gastroenterology, Tel Aviv Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - N Gotlieb
- Liver Unit, Department of Gastroenterology, Tel Aviv Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - N Lubezky
- Devision of Surgery, Tel Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Y Goykhman
- Devision of Surgery, Tel Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - I Nachmany
- Devision of Surgery, Tel Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - P Katz
- Devision of Surgery, Tel Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - O Shibolet
- Liver Unit, Department of Gastroenterology, Tel Aviv Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - H Katchman
- Liver Unit, Department of Gastroenterology, Tel Aviv Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Tejedor-Tejada J, Alonso-Martín C, Almohalla-Álvarez C, Valenzuela EF, Muñoz RN, Delgado LS, Martín CM, Sánchez-Martín F, García-Pajares F, Sánchez-Antolín G. Immunosuppressive Treatment With mTOR Inhibitors for Malignancies After Liver Transplantation: Long-Term Survival Retrospective Analysis. Transplant Proc 2020; 52:1507-1510. [PMID: 32213292 DOI: 10.1016/j.transproceed.2020.02.058] [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: 01/22/2020] [Accepted: 02/05/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Immunosuppressive calcineurin inhibitors have been associated with an increased risk of post-transplant malignancies. The mammalian target of rapamycin inhibitors (mTORi) is an alternative immunosuppressive regimen with an antineoplastic effect. The aim of the study was to determine the long-term survival of mTORi-treated recipients with de novo or recurring tumors after liver transplantation (LT). METHODS This retrospective analysis included mTORi-treated LT recipients between March 2013 and March 2019. We analyzed long-term survival and mTORi indications in an oncology setting in patients with de novo and recurrent malignancies after LT. Overall survival (OS) rate was compared from the Spanish Liver Transplant Registry (SLTR) data using the Kaplan-Meier method. High-risk hepatocellular carcinoma (HCC) was defined as microvascular invasion or satellite lesions as described in the liver explant. RESULTS A total of 237 patients underwent LT during the study period; 111 patients underwent mTORi-based immunosuppression (48%, cancer was the main indication): 24.5% high-risk HCC; 24.4% HCC recurrence; 14.3% cholangiocarcinoma; and 36.7% de novo malignancies. The 1- and 5-year OS rates after LT in the mTORi group were 83% and 65%, respectively (SLTR group, 85% and 72.6%, respectively); 30.6% patients received mTORi monotherapy, and 38.7% patients had an early switch to mTORi in the first 3 months after oncologic diagnosis. mTORi monotherapy or oncologic treatment strategies had a nonsignificant association with prognosis. The OS rate was higher when the mTORi switch occurred early, 83% and 67%, respectively. CONCLUSIONS mTORi-based immunosuppression may be a preferred option in patients transplanted with tumors. The OS rate was comparable to data from the SLTR. An mTORi early switch improves OS rate.
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Affiliation(s)
- Javier Tejedor-Tejada
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Hospital Universitario Rio Hortega, Valladolid, Spain.
| | - Carmen Alonso-Martín
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Hospital Universitario Rio Hortega, Valladolid, Spain
| | - Carolina Almohalla-Álvarez
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Hospital Universitario Rio Hortega, Valladolid, Spain
| | - Esteban Fuentes Valenzuela
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Hospital Universitario Rio Hortega, Valladolid, Spain
| | - Rodrigo Nájera Muñoz
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Hospital Universitario Rio Hortega, Valladolid, Spain
| | - Laura Sánchez Delgado
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Hospital Universitario Rio Hortega, Valladolid, Spain
| | - Carlos Maroto Martín
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Hospital Universitario Rio Hortega, Valladolid, Spain
| | - Fátima Sánchez-Martín
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Hospital Universitario Rio Hortega, Valladolid, Spain
| | - Félix García-Pajares
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Hospital Universitario Rio Hortega, Valladolid, Spain
| | - Gloria Sánchez-Antolín
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Hospital Universitario Rio Hortega, Valladolid, Spain
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Thude H, Onken L, Kappauf J, Dworak M, Sterneck M, Peine S, Nashan B, Koch M. Ectonucleoside triphosphate diphosphohydrolase 1 and 5'-nucleotidase ecto gene polymorphisms and acute cellular rejection after liver transplantation. HLA 2020; 96:64-69. [PMID: 32248630 DOI: 10.1111/tan.13892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 04/02/2020] [Indexed: 11/28/2022]
Abstract
The single nucleotide polymorphisms (SNPs) rs11188513, rs7071836, rs10748643, rs9450279, rs4458647, and rs6922 map in the genes of ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) and 5'-nucleotidase ecto. We investigated whether these SNPs and haplotypes of these SNPs are associated with an acute cellular rejection after liver transplantation. A total of 69 recipients with an acute cellular rejection and 138 recipients without an acute cellular rejection were analyzed. Analyzed individually, no SNP demonstrates an association, but the haplotype rs11188513T-rs7071836G-rs10748643A of the ENTPD1 gene appeared more frequently in recipients without rejection and conversely, the haplotype rs11188513T-rs7071836G-rs10748643G of the ENTPD1 gene was more often represented in recipients with rejection. These two haplotypes seem to be important for the susceptibility of an acute cellular rejection after liver transplantation.
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Affiliation(s)
- Hansjörg Thude
- Institute of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Lena Onken
- Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Julia Kappauf
- Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Markus Dworak
- Clinical and Regulatory Affairs, Novartis Pharma GmbH, Nürnberg, Germany
| | - Martina Sterneck
- Transplantation-Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sven Peine
- Institute of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Björn Nashan
- Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Martina Koch
- Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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48
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Sirolimus and mTOR Inhibitors: A Review of Side Effects and Specific Management in Solid Organ Transplantation. Drug Saf 2020; 42:813-825. [PMID: 30868436 DOI: 10.1007/s40264-019-00810-9] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Inhibitors of mechanistic target of rapamycin (mTOR inhibitors) are used as antiproliferative immunosuppressive drugs and have many clinical applications in various drug combinations. Experience in transplantation studies has been gained regarding the side effect profile of these drugs and the potential benefits and limitations compared with other immunosuppressive agents. This article reviews the adverse effects of mTOR inhibitors in solid organ transplantation, with special attention given to mechanisms hypothesized to cause adverse events and their management strategies.
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49
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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, Leroy V, Hardwigsen J, Gharbi H, Masson C, Tindel M, Conti F. Early Switch From Tacrolimus to Everolimus After Liver Transplantation: Outcomes at 2 Years. Liver Transpl 2019; 25:1822-1832. [PMID: 31631501 PMCID: PMC7383505 DOI: 10.1002/lt.25664] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 08/14/2019] [Indexed: 12/12/2022]
Abstract
The observational CERTITUDE study follows liver transplant patients who completed the SIMCER trial. SIMCER randomized patients at month 1 after transplant to everolimus (EVR) with stepwise tacrolimus (TAC) withdrawal or to standard TAC, both with basiliximab induction and mycophenolic acid ± steroids. After completing SIMCER at 6 months after transplant, 65 EVR-treated patients and 78 TAC-treated patients entered CERTITUDE. At month 24 after transplant, 34/65 (52.3%) EVR-treated patients remained calcineurin inhibitor (CNI) free. Mean estimated glomerular filtration rate (eGFR) was significantly higher with EVR versus TAC during months 3-12. At month 24, eGFR values were 83.6 versus 75.3 mL/minute/1.73 m2 , respectively (P = 0.90) and adjusted mean change in eGFR from randomization was -8.0 versus -13.5 mL/minute/1.73 m2 (P = 0.15). At month 24, 45.9%, 31.1%, and 23.0% of EVR-treated patients had chronic kidney disease stages 1, 2, and 3, respectively, versus 25.7%, 45.7%, and 28.6% of TAC-treated patients (P = 0.05). Treated biopsy-proven acute rejection affected 4 EVR-treated patients and 2 TAC patients during months 6-24. Adverse events led to study discontinuation in 15.4% and 7.7% of EVR-treated and TAC-treated patients, respectively. Grade 3 or 4 hematological events were rare in both groups. A CNI-free EVR-based maintenance regimen appears feasible in approximately half of liver transplant patients. It preserves renal function effectively with good efficacy without compromising safety or hematological tolerance.
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Affiliation(s)
- Faouzi Saliba
- Centre Hépato‐BiliaireHôpital Paul Brousse, AP‐HPVillejuifFrance
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50
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Mousa OY, Keaveny AP. Everolimus: Longer-Term CERTITUDE. Liver Transpl 2019; 25:1745-1746. [PMID: 31606937 DOI: 10.1002/lt.25659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 10/10/2019] [Indexed: 01/13/2023]
Affiliation(s)
- Omar Y Mousa
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.,Department of Medicine, Mayo Clinic Health System, Mankato, MN
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