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1
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Yataco ML, Keaveny AP. Immunosuppression Post-Liver Transplant: End of the Calcineurin Era? Clin Liver Dis 2025; 29:287-302. [PMID: 40287272 DOI: 10.1016/j.cld.2024.12.006] [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: 04/29/2025]
Abstract
The introduction of calcineurin inhibitors (CNIs) as the primary form of immunosuppression (IS) for liver transplantation (LT) in the late 1970s was a key in increasingly successful outcomes for transplantation over the past 3 decades. Despite the side effects of CNI which directly contribute to the long-term morbidity and mortality post-LT, they will remain the cornerstone of IS in the near future. Efforts to minimize exposure to CNI will require the application of blood and tissue biomarkers that accurately identify the extent of IS and risk of rejection for individual patients.
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Affiliation(s)
- Maria L Yataco
- Department of Transplantation, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
| | - Andrew P Keaveny
- Department of Transplantation, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
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2
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Jang SC, Kim GA, Lim YS, Kim HL, Lee EK. Association between everolimus combination therapy and cancer risk after liver transplantation: A nationwide population-based quasi-cohort study. Am J Transplant 2025:S1600-6135(25)00005-X. [PMID: 39826891 DOI: 10.1016/j.ajt.2025.01.005] [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: 06/03/2024] [Revised: 12/30/2024] [Accepted: 01/06/2025] [Indexed: 01/22/2025]
Abstract
The potential of everolimus (EVR) in reducing hepatocellular carcinoma (HCC) among recipients following liver transplantation has been reported. This nationwide population-based quasi-cohort study investigated whether combining EVR with calcineurin inhibitor therapy affects the risk of HCC and extrahepatic cancers compared to a time duration-matched cohort of recipients not receiving EVR. Using data covering the entire population from Korea, liver transplant recipients who had initiated immunosuppressants between June 2015 and February 2020 were included, and divided into 2 groups: the EVR combination and noncombination groups. We calculated adjusted hazard ratios (aHRs) and absolute risk reduction for the risk of HCC and extrahepatic cancer with EVR combination therapy using a Cox regression model. A time duration-matched retrospective cohort of 932 recipients in both of the groups was identified. The EVR combination group showed a lower risk of HCC (aHR, 0.53; 95% confidence interval, 0.30-0.94) and extrahepatic cancers (aHR, 0.30; 95% confidence interval, 0.14-0.63) compared to the noncombination group. The absolute risk reduction was 0.004 for HCC and 0.012 for extrahepatic cancer. The findings suggest that adding EVR to calcineurin inhibitor therapy reduces cancer risk in liver transplant recipients, highlighting the importance of considering cancer risk when choosing immunosuppressive therapies.
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Affiliation(s)
- Suk-Chan Jang
- School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea
| | - Gi-Ae Kim
- Department of Internal Medicine, Kyung Hee University College of Medicine, Seoul, Republic of Korea
| | - Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hye-Lin Kim
- College of Pharmacy, Sahmyook University, Seoul, Republic of Korea.
| | - Eui-Kyung Lee
- School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea.
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3
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Lee J, Kim IW, Hong SK, Han N, Suh KS, Oh JM. Development and Clinical Validation of Model-Informed Precision Dosing for Everolimus in Liver Transplant Recipients. ACS Pharmacol Transl Sci 2025; 8:216-224. [PMID: 39816805 PMCID: PMC11729436 DOI: 10.1021/acsptsci.4c00581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 11/24/2024] [Accepted: 11/28/2024] [Indexed: 01/18/2025]
Abstract
Everolimus presents significant dosing challenges due to between- and within-patient pharmacokinetic variabilities. This study aimed to develop and validate a model-informed precision dosing strategy for everolimus in liver transplant recipients. The dosing strategy was initially developed using retrospective data, employing nonlinear mixed-effects modeling. The model included readily measurable covariates, body surface area, albumin, and tacrolimus trough concentration. The dosing strategy was subsequently validated in a prospective trial, recommending 1 to 1.75 mg dosages every 12 h, depending on covariates. Lower dosages were recommended for patients with lower body surface area and albumin with adjustments based on tacrolimus trough concentration. The estimated pharmacokinetic parameters (typical value ± standard error), apparent clearance (CL/F: 15.0 ± 0.5 L/h), and apparent volume of distribution (Vd/F: 862 ± 79.3 L) were refined using prospective clinical data from 20 patients, reducing interindividual variations. This research successfully developed and validated a population pharmacokinetic model for everolimus. The developed "dosE" web-based platform translates our pharmacokinetic model into a practical tool for healthcare providers, exemplifying the application of pharmaceutical research in clinical practice and potentially improving therapeutic outcomes in liver transplantation.
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Affiliation(s)
- Jeayoon Lee
- College
of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - In-Wha Kim
- College
of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Suk Kyun Hong
- Department
of Surgery, Seoul National University College
of Medicine, Seoul 03080, Republic
of Korea
| | - Nayoung Han
- College
of Pharmacy and Research Institute of Pharmaceutical Sciences, Jeju National University, Jeju, Special Self-Governing Province 63243, Republic
of Korea
| | - Kyung-Suk Suh
- Department
of Surgery, Seoul National University College
of Medicine, Seoul 03080, Republic
of Korea
| | - Jung Mi Oh
- College
of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
- College
of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of Korea
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4
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Berg T, Aehling NF, Bruns T, Welker MW, Weismüller T, Trebicka J, Tacke F, Strnad P, Sterneck M, Settmacher U, Seehofer D, Schott E, Schnitzbauer AA, Schmidt HH, Schlitt HJ, Pratschke J, Pascher A, Neumann U, Manekeller S, Lammert F, Klein I, Kirchner G, Guba M, Glanemann M, Engelmann C, Canbay AE, Braun F, Berg CP, Bechstein WO, Becker T, Trautwein C. [Not Available]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:1397-1573. [PMID: 39250961 DOI: 10.1055/a-2255-7246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
Affiliation(s)
- Thomas Berg
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Niklas F Aehling
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Tony Bruns
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martin-Walter Welker
- Medizinische Klinik I Gastroent., Hepat., Pneum., Endokrin. Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Tobias Weismüller
- Klinik für Innere Medizin - Gastroenterologie und Hepatologie, Vivantes Humboldt-Klinikum, Berlin, Deutschland
| | - Jonel Trebicka
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Deutschland
| | - Frank Tacke
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Pavel Strnad
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martina Sterneck
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Hamburg, Hamburg, Deutschland
| | - Utz Settmacher
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Jena, Deutschland
| | - Daniel Seehofer
- Klinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Eckart Schott
- Klinik für Innere Medizin II - Gastroenterologie, Hepatologie und Diabetolgie, Helios Klinikum Emil von Behring, Berlin, Deutschland
| | | | - Hartmut H Schmidt
- Klinik für Gastroenterologie und Hepatologie, Universitätsklinikum Essen, Essen, Deutschland
| | - Hans J Schlitt
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg, Regensburg, Deutschland
| | - Johann Pratschke
- Chirurgische Klinik, Charité Campus Virchow-Klinikum - Universitätsmedizin Berlin, Berlin, Deutschland
| | - Andreas Pascher
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Münster, Münster, Deutschland
| | - Ulf Neumann
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Essen, Essen, Deutschland
| | - Steffen Manekeller
- Klinik und Poliklinik für Allgemein-, Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Bonn, Bonn, Deutschland
| | - Frank Lammert
- Medizinische Hochschule Hannover (MHH), Hannover, Deutschland
| | - Ingo Klein
- Chirurgische Klinik I, Universitätsklinikum Würzburg, Würzburg, Deutschland
| | - Gabriele Kirchner
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg und Innere Medizin I, Caritaskrankenhaus St. Josef Regensburg, Regensburg, Deutschland
| | - Markus Guba
- Klinik für Allgemeine, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie, Universitätsklinikum München, München, Deutschland
| | - Matthias Glanemann
- Klinik für Allgemeine, Viszeral-, Gefäß- und Kinderchirurgie, Universitätsklinikum des Saarlandes, Homburg, Deutschland
| | - Cornelius Engelmann
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Ali E Canbay
- Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum, Bochum, Deutschland
| | - Felix Braun
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
| | - Christoph P Berg
- Innere Medizin I Gastroenterologie, Hepatologie, Infektiologie, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - Wolf O Bechstein
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Thomas Becker
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
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5
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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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6
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Cillo U, Carraro A, Avolio AW, Cescon M, Di Benedetto F, Giannelli V, Magistri P, Nicolini D, Vivarelli M, Lanari J. Immunosuppression in liver transplant oncology: position paper of the Italian Board of Experts in Liver Transplantation (I-BELT). Updates Surg 2024; 76:725-741. [PMID: 38713396 DOI: 10.1007/s13304-024-01845-z] [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: 07/13/2023] [Accepted: 07/31/2023] [Indexed: 05/08/2024]
Abstract
Liver transplant oncology (TO) represents an area of increasing clinical and scientific interest including a heterogeneous group of clinical-pathological settings. Immunosuppressive management after LT is a key factor relevantly impacting result. However, disease-related guidance is still lacking, and many open questions remain in the field. Based on such a substantial lack of solid evidences, the Italian Board of Experts in Liver Transplantation (I-BELT) (a working group including representatives of all national transplant centers), unprecedently promoted a methodologically sound consensus conference on the topic, based on the GRADE approach. The group final recommendations are herein presented and commented. The 18 PICOs and Statements and their levels of evidence and grades of recommendation are reported and grouped into seven areas: (1) risk stratification by histopathological and bio-molecular parameters and role of mTORi post-LT; (2) steroids and HCC recurrence; (3) management of immunosuppression when HCC recurs after LT; (4) mTORi monotherapy; (5) machine perfusion and HCC recurrence after LT; (6) physiopathology of tumor-infiltrating lymphocytes and immunosuppression, the role of inflammation; (7) immunotherapy in liver transplanted patients. The interest in mammalian targets of rapamycin inhibitors (mTORi), for steroid avoidance and the need for a reduction to CNI exposure emerged from the consensus process. A selected list of unmet needs prompting further investigations have also been developed. The so far heterogeneous and granular approach to immunosuppression in oncologic patients deserves greater efforts for a more standardized therapeutic response to the different clinical scenarios. This consensus process makes a first unprecedented step in this direction, to be developed on a larger scale.
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Affiliation(s)
- Umberto Cillo
- Department of Surgical, Oncological and Gastroenterological Sciences, General Surgery 2 Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Padua University Hospital, Via Giustiniani 2, 34128, Padua, PD, Italy.
| | - Amedeo Carraro
- Liver Transplant Unit, Department of Surgery and Oncology, University Hospital Trust of Verona, Verona, Italy
| | - Alfonso W Avolio
- Department of General Surgery and Liver Transplantation, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Matteo Cescon
- General Surgery and Transplantation Unit, Department of Medical and Surgical Sciences, Azienda Ospedaliero-Universitaria-Policlinico S.Orsola-Malpighi, Bologna, Italy
| | - Fabrizio Di Benedetto
- Hepatopancreatobiliary Surgery and Liver Transplantation Unit, University of Modena and Reggio Emilia, Modena, Italy
| | - Valerio Giannelli
- Liver Unit, Department of Liver Transplant, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy
| | - Paolo Magistri
- Hepatopancreatobiliary Surgery and Liver Transplantation Unit, University of Modena and Reggio Emilia, Modena, Italy
| | - Daniele Nicolini
- Hepatobiliary and Abdominal Transplantation Surgery, Department of Experimental and Clinical Medicine, Riuniti Hospital, Polytechnic University of Marche, Ancona, Italy
| | - Marco Vivarelli
- Hepatobiliary and Abdominal Transplantation Surgery, Department of Experimental and Clinical Medicine, Riuniti Hospital, Polytechnic University of Marche, Ancona, Italy
| | - Jacopo Lanari
- Department of Surgical, Oncological and Gastroenterological Sciences, General Surgery 2 Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Padua University Hospital, Via Giustiniani 2, 34128, Padua, PD, Italy
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7
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Raja K, Panackel C. Post Liver Transplant Renal Dysfunction-Evaluation, Management and Immunosuppressive Practice. J Clin Exp Hepatol 2024; 14:101306. [PMID: 38274509 PMCID: PMC10806298 DOI: 10.1016/j.jceh.2023.101306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 11/21/2023] [Indexed: 01/27/2024] Open
Abstract
Liver transplantation (LT) is an effective and lifesaving treatment for patients with end-stage liver disease and hepatocellular carcinoma. Significant improvement in intermediate and long-term survival has been possible due to advancements in immunosuppressive therapy, perioperative care, and surgical techniques. Despite these advances, metabolic complications, including diabetes mellitus, cardiovascular diseases, malignancies, and renal dysfunction, are challenging issues after LT. Acute kidney injury (AKI) and chronic kidney disease (CKD) after LT are common and result in significant morbidity and mortality. Early diagnosis of kidney injury after LT is challenging, and no technique has yet proven effective in prediction of renal dysfunction. The methods for assessing renal function range from formulas that predict glomerular filtration rate to non-invasive biomarkers. The universal adoption of the model for end-stage liver disease has a direct impact on the incidence of peri-transplant AKI and development of CKD in the long-term. Post-LT renal dysfunction is multifactorial and is usually a result of pre-transplantation comorbidities, occurrence of renal dysfunction on the waiting list, perioperative events, and post-transplant nephrotoxic immunosuppressive medication use. Early identification of patients at risk for renal dysfunction and adoption of preventive measures are crucial in the pre-transplant period. No data are currently available to suggest a surgical technique that reliably demonstrates renal protection. Nephroprotective strategies during LT follow accepted surgical practice guidelines, such as maintenance of intravascular volume and mean arterial pressure. The management of kidney disease following LT is challenging, as by the time the serum creatinine is significantly elevated, few interventions impact the course of progression. Early nephroprotective measures are strongly advised and they mostly center on delaying the administration of calcineurin inhibitors (CNIs) during the initial postoperative period, lowering CNI dosage and combining CNI with mycophenolate mofetil and everolimus. The reasons for renal failure following LT, the techniques used to diagnose it, and the therapies designed to preserve renal function both immediately and late after LT are all critically evaluated in this review.
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Affiliation(s)
- Kaiser Raja
- Department of Gastroenterology and Hepatology, King's College Hospital London, Dubai, United Arab Emirates
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8
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Cabeza Rivera FH, Concepcion BP, Levea SLL. Chronic Kidney Disease After Liver Transplantation. ADVANCES IN KIDNEY DISEASE AND HEALTH 2023; 30:368-377. [PMID: 37657883 DOI: 10.1053/j.akdh.2023.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/03/2023]
Abstract
Chronic kidney disease among liver transplant recipients is common and associated with an increased mortality risk. Several risk factors and causes for the development of chronic kidney disease have been identified. They can be divided into perioperative factors, such as unresolved acute kidney injury; donor-related factors, such as the use of extended criteria liver allografts; and recipient-related factors, such as the use of calcineurin inhibitors and the presence of metabolic syndrome, diabetes, and obesity. There is a bimodal progression, more prominent during the initial post-transplant months, followed by a gradual but progressive decline over the subsequent years. Management strategies to prevent and treat chronic kidney disease in the general population can be reasonably applied to the liver transplant population and include addressing comorbidities such as hypertension and diabetes. Strategies to minimize or withdraw calcineurin inhibitors from the immunosuppressive regimen can slow progression of kidney dysfunction. Patients with advanced chronic kidney disease should be considered for kidney transplantation due to its survival advantage. Allocation policy in the United States confers safety-net allocation priority for liver transplant recipients who develop advanced chronic kidney disease within the first year of liver transplantation.
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Affiliation(s)
- Franco H Cabeza Rivera
- Katz Family Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, Miami, FL
| | | | - Swee-Ling L Levea
- Division of Nephrology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX
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9
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Three-year results of renal function in liver transplant recipients on low-dose sirolimus and tacrolimus: a multicenter, randomized, controlled trial. Liver Transpl 2023; 29:184-195. [PMID: 36668691 DOI: 10.1097/lvt.0000000000000003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 09/15/2022] [Indexed: 01/22/2023]
Abstract
The aim of this study was to investigate whether the combination of low-dose sirolimus (SRL) and low-dose extended-release tacrolimus (TAC) compared to normal-dose extended-release TAC results in a difference in the renal function and comparable rates of rejection, graft and patient survival at 36 months after transplantation. This study was an open-label, multicenter randomized, controlled trial. Patients were randomized to once-daily normal-dose extended-release TAC (control group) or once-daily combination therapy of SRL and low-dose extended-release TAC (interventional group). The primary endpoint was the cumulative incidence of chronic kidney disease (CKD) defined as grade ≥3 (estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2) at 36 months after transplantation. In total, 196 patients were included. CKD at 36 months was not different between the control and interventional group (50.8%, 95% CI: 39.7%-59.9%) vs. 43.7%, 95% CI: 32.8%-52.8%). Only at 6 months after transplantation, the eGFR was higher in the interventional group compared to the control group (mean eGFR 73.1±15 vs. 67.6±16 mL/min/1.73 m2, p=0.02) in the intention-to-treat population. No differences in the secondary endpoints and the number of serious adverse events were found between the groups. Once daily low-dose SRL combined with low-dose extended-release TAC does ultimately not provide less CKD grade ≥3 at 36 months compared to normal-dose extended-release TAC.
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10
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Xu X. State of the art and perspectives in liver transplantation. Hepatobiliary Pancreat Dis Int 2023; 22:1-3. [PMID: 36528548 DOI: 10.1016/j.hbpd.2022.12.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Accepted: 12/02/2022] [Indexed: 02/04/2023]
Affiliation(s)
- Xiao Xu
- Institute of Organ Transplantation, Zhejiang University, Hangzhou 310003, China.
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11
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Shah T, Manas DM, Ford SJ, Dasari BVM, Gibbs P, Venkataraman H, Moore J, Hughes S, Elshafie M, Karkhanis S, Smith S, Hoti E, O'Toole D, Caplin ME, Isaac J, Mazzafero V, Thorburn D. Where Are We Now with Liver Transplantation in Neuroendocrine Neoplasms? The Place of Liver Transplantation for Grades 1 and 2 Well-Differentiated Unresectable Liver Metastatic Neuroendocrine Tumours. Curr Oncol Rep 2023; 25:135-144. [PMID: 36648705 DOI: 10.1007/s11912-022-01343-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/15/2022] [Indexed: 01/18/2023]
Abstract
PURPOSE OF REVIEW This review outlines the role of liver transplantation in selected patients with unresectable neuroendocrine tumour liver metastases. It discusses the international consensus on eligibility criteria and outlines the efforts taking place in the UK and Ireland to develop effective national liver transplant programmes for neuroendocrine tumour patients. RECENT FINDINGS In the early history of liver transplantation, indications included cancer metastases to the liver as well as primaries of liver origin. Often, liver transplantation was a salvage procedure. The early results were disappointing, including in patients with neuroendocrine tumours. These data discouraged the widespread adoption of liver transplantation for neuroendocrine tumour liver metastases (NET LM). A few centres persisted in performing liver transplantation for patients with NET LM and in determining parameters predictive of good outcomes. Their work has provided evidence for benefit of liver transplantation in a selected group of patients with NET LM. Liver transplantation for NET LM is now accepted as a valid indication by many professional bodies, including the European Neuroendocrine Tumour Society (ENETS) and the United Network for Organ Sharing (UNOS). It is nevertheless rarely utilised. The UK and the Republic of Ireland are commencing a pilot programme of liver transplantation in selected patients. This programme will help develop the expertise and infrastructure to make liver transplantation for NET LM a routine procedure.
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Affiliation(s)
- Tahir Shah
- Queen Elizabeth Hospital Birmingham, Birmingham, UK.
| | | | | | | | | | | | | | - Simon Hughes
- Queen Elizabeth Hospital Birmingham, Birmingham, UK
| | | | | | - Stacey Smith
- Queen Elizabeth Hospital Birmingham, Birmingham, UK
| | - Emir Hoti
- St Vincent's University Hospital, Dublin, UK
| | | | | | - John Isaac
- Queen Elizabeth Hospital Birmingham, Birmingham, UK
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12
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Zhang G, Duan B, Li G. mTORi-based immunosuppression reduces HCC recurrence at the expense of increased adverse side effects: A systematic review and meta-analysis. Clin Transplant 2022; 36:e14823. [PMID: 36124430 DOI: 10.1111/ctr.14823] [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: 03/05/2022] [Revised: 08/13/2022] [Accepted: 09/10/2022] [Indexed: 12/27/2022]
Abstract
Sirolimus and everolimus are mammalian target of rapamycin inhibitors (mTORi) that can reduce relapse rates following liver transplantation (LT) for hepatocellular carcinoma (HCC). Herein, we performed a systematic review and meta-analysis to investigate the efficacy of mTORi and calcineurin inhibitors (CNI) in reducing HCC recurrence and survival adverse effects (AEs) in HCC patients after LT. Systematic literature searches were conducted using MEDLINE, EMBASE, and Cochrane Library databases up to October 2021. The primary outcomes of interest were tumor recurrence rates and overall survival. The secondary outcomes were the characterization and incidence of AEs. A total of 38 trials involving 10,607 participants was included in the analysis. The incidence of recurrence and overall mortality was significantly lower in the mTORi than in the CNI group (relative ratio [RR]: .78, 95% confidence interval [CI]: .68-.89 and RR: .76, 95% CI: .67-.86, respectively). The incidence of some AEs and complications such as acne, anemia, abnormal healing, dyslipidemia, depression, diarrhea, edema, headache/migraine, hypercholesterolemia, incisional hernia, infection, leukopenia, mouth ulceration, pyrexia, proteinuria, pruritis, rash, and thrombocytopenia were higher in the mTORi than in the CNI group. mTORi reduced the recurrence incidence and overall 5-year mortality rate but increased many other incidences of AEs compared with that by CNI. Therefore, clinicians should be aware of the risks and benefits of mTORi use when managing patients undergoing LT for HCC.
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Affiliation(s)
- Gongming Zhang
- Beijing You'an Hospital, Capital Medical University, Beijing, China
| | - Binwei Duan
- Beijing You'an Hospital, Capital Medical University, Beijing, China
| | - Guangming Li
- Beijing You'an Hospital, Capital Medical University, Beijing, China
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13
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Panackel C, Mathew JF, Fawas N M, Jacob M. Immunosuppressive Drugs in Liver Transplant: An Insight. J Clin Exp Hepatol 2022; 12:1557-1571. [PMID: 36340316 PMCID: PMC9630030 DOI: 10.1016/j.jceh.2022.06.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 06/16/2022] [Indexed: 12/12/2022] Open
Abstract
Liver transplantation (LT) is the standard of care for end-stage liver failure and hepatocellular carcinoma. Over the years, immunosuppression regimens have improved, resulting in enhanced graft and patient survival. At present, the side effects of immunosuppressive agents are a significant threat to post-LT quality of life and long-term outcome. The role of personalized immunosuppression is to reach a delicate balance between optimal immunosuppression and minimal side effects. Today, immunosuppression in LT is more of an art than a science. There are no validated markers for overimmunosuppression and underimmunosuppression, only a few drugs have therapeutic drug monitoring and immunosuppression regimens vary from center to center. The immunosuppressive agents are broadly classified into biological agents and pharmacological agents. Most regimens use multiple agents with different modes of action to reduce the dosage and minimize the toxicities. The calcineurin inhibitor (CNI)-related toxicities are reduced by antibody induction or using mTOR inhibitor/antimetabolites as CNI sparing or CNI minimization strategies. Post-liver transplant immunosuppression has an intensive phase in the first three months when alloreactivity is high, followed by a maintenance phase when immunosuppression minimization protocols are implemented. Over time some patients achieve "tolerance," defined as the successful stopping of immunosuppression with good graft function and no indication of rejection. Cell-based therapy using immune cells with tolerogenic potential is the future and may permit complete withdrawal of immunosuppressive agents.
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Key Words
- AMR, Antibody-mediated rejection
- APCs, Antigen-presenting cells
- ATG, Anti-thymocyte globulin
- CNI, Calcineurin inhibitors
- CsA, Cyclosporine A
- EVR, Everolimus
- IL-2R, Interleukin 2 Receptor
- LT, Liver transplantation
- MMF, Mycophenolate mofetil
- MPA, Mycophenolic acid
- SRL, Sirolimus
- TAC, Tacrolimus
- TCMR, T-cell-mediated rejection
- antimetabolites
- basiliximab
- calcineurin inhibitors
- cyclosporine
- everolimus
- immunosuppression
- liver transplantation
- mTORi, mammalian targets of rapamycin inhibitor
- mycophenolate mofetil
- tacrolimus
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Affiliation(s)
- Charles Panackel
- Aster Integrated Liver Care, Aster Medcity, Kochi, Kerala, 682027, India
| | - Joe F Mathew
- Aster Integrated Liver Care, Aster Medcity, Kochi, Kerala, 682027, India
| | - Mohamed Fawas N
- Aster Integrated Liver Care, Aster Medcity, Kochi, Kerala, 682027, India
| | - Mathew Jacob
- Aster Integrated Liver Care, Aster Medcity, Kochi, Kerala, 682027, India
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14
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Galeev SR, Gautier SV. Risks and ways of preventing kidney dysfunction in drug-induced immunosuppression in solid organ recipients. RUSSIAN JOURNAL OF TRANSPLANTOLOGY AND ARTIFICIAL ORGANS 2022. [DOI: 10.15825/1995-1191-2022-4-24-38] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Immunosuppressive therapy (IMT) is the cornerstone of treatment after transplantation. The goal of immunosuppression is to prevent acute and chronic rejection while maximizing patient survival and long-term graft function. However, the expected effects of IMT must be balanced against the major adverse effects of these drugs and their toxicity. The purpose of this review is to summarize world experience on current immunosuppressive strategies and to assess their effects on renal function.
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Affiliation(s)
- Sh. R. Galeev
- Shumakov National Medical Research Center of Transplantology and Artificial Organs
| | - S. V. Gautier
- Shumakov National Medical Research Center of Transplantology and Artificial Organs; Sechenov University
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15
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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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16
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De Simone P, Bronzoni J, Martinelli C. Everolimus versus mycophenolate mofetil in liver transplantation: every improvement in renal function matters. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2022; 114:312-313. [PMID: 35545915 DOI: 10.17235/reed.2022.8902/2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2025]
Abstract
The current edition of the journal features a Spanish, nationwide, multi-institutional study by Gomez Bravo MA et al. exploring the advantages of everolimus (EVR)-facilitated tacrolimus (TAC) minimization versus TAC in combination with mycophenolate mofetil (MMF) after liver transplantation (LT).
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Affiliation(s)
- Paolo De Simone
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Italia
| | - Jessica Bronzoni
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Italia
| | - Caterina Martinelli
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Italia
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17
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Zorzetti N, Lauro A, Khouzam S, Marino IR. Immunosuppression, Compliance, and Tolerance After Orthotopic Liver Transplantation: State of the Art. EXP CLIN TRANSPLANT 2022; 20:3-9. [PMID: 35384800 DOI: 10.6002/ect.mesot2021.l13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Orthotopic liver transplantation is the treatment of choice for several otherwise irreversible forms of acute and chronic liver diseases. Early implemented immunosuppressant regimens have had disappointing results with high rejection rates. However, new drugs have reduced the daily immunosuppression requirements, thereby improving graft and patient survival as well as kidney function. Liver rejection is a T-cell-driven immune response and is the active target of immunosuppressive agents. Immunosuppressants can be divided into pharmacological or biological drugs: the gold standard is the calcineurin inhibitors, steroids, mycophenolate mofetil, and mechanistic target of rapamycin inhibitors. Compliance with these agents is essential, although they can increase the risk of infections and neoplastic diseases. In some patients, graft tolerance can be achieved. Graft tolerance is defined as the absence of acute and chronic rejection in a graft, with normal function and histology in an immunosuppression-free, fully immunocompetent host, usually as the final result of a successful attempt at immunosuppression withdrawal. The occurrence of immunosuppressive-related complications has led to new protocols aimed at protecting renal function and preventing de novo cancer and dysmetabolic syndrome. The backbone of immunosuppression remains calcineurin inhibitors in association with other drugs, mainly over the short-term period. To avoid rejection and the side effects on renal dysfunction, de novo cancer, and cardiovascular syndrome, optimal long-term immunosuppressive therapy should be tailored in liver transplant recipients.
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Affiliation(s)
- Noemi Zorzetti
- From the Department of General Surgery, Ospedale A. Costa, Porretta Terme-Bologna, Italy
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18
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[Kidney failure after liver transplantation]. Nephrol Ther 2022; 18:89-103. [PMID: 35151596 DOI: 10.1016/j.nephro.2021.11.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 05/11/2021] [Accepted: 11/06/2021] [Indexed: 02/06/2023]
Abstract
One third of cirrhotic patients present impaired kidney function. It has multifactorial causes and has a harmful effect on patients' morbi-mortality before and after liver transplant. Kidney function does not improve in all patients after liver transplantation and liver-transplant recipients are at high risk of developing chronic kidney disease. Causes for renal dysfunction can be divided in three groups: preoperative, peroperative and postoperative factors. To date, there is no consensus for the modality of evaluation the risk for chronic kidney disease after liver transplantation, and for its prevention. In the present review, we describe the outcome of kidney function after liver transplantation, and the prognostic factors of chronic kidney disease to determine a risk stratification for each patient. Furthermore, we discuss therapeutic options to prevent kidney dysfunction in this setting, and highlight the indications of combined liver-kidney transplantation.
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19
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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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20
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Pacheco MP, Carneiro-D'Albuquerque LA, Mazo DF. Current aspects of renal dysfunction after liver transplantation. World J Hepatol 2022; 14:45-61. [PMID: 35126839 PMCID: PMC8790396 DOI: 10.4254/wjh.v14.i1.45] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 10/24/2021] [Accepted: 01/06/2022] [Indexed: 02/06/2023] Open
Abstract
The development of chronic kidney disease (CKD) after liver transplantation (LT) exerts a severe effect on the survival of patients. The widespread adoption of the model for end-stage liver disease score strongly impacted CKD incidence after the procedure, as several patients are transplanted with previously deteriorated renal function. Due to its multifactorial nature, encompassing pre-transplantation conditions, perioperative events, and nephrotoxic immunosuppressor therapies, the accurate identification of patients under risk of renal disease, and the implementation of preventive approaches, are extremely important. Methods for the evaluation of renal function in this setting range from formulas that estimate the glomerular filtration rate, to non-invasive markers, although no option has yet proved efficient in early detection of kidney injury. Considering the nephrotoxicity of calcineurin inhibitors (CNI) as a factor of utmost importance after LT, early nephroprotective strategies are highly recommended. They are based mainly on delaying the application of CNI during the immediate postoperative-period, reducing their dosage, and associating them with other less nephrotoxic drugs, such as mycophenolate mofetil and everolimus. This review provides a critical assessment of the causes of renal dysfunction after LT, the methods of its evaluation, and the interventions aimed at preserving renal function early and belatedly after LT.
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Affiliation(s)
- Mariana P Pacheco
- Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo School of Medicine, Sao Paulo 05403-900, Sao Paulo, Brazil
| | - Luiz Augusto Carneiro-D'Albuquerque
- Division of Digestive Organs Transplant, Department of Gastroenterology, University of São Paulo School of Medicine, Sao Paulo 05403-900, Sao Paulo, Brazil
| | - Daniel F Mazo
- Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo School of Medicine, Sao Paulo 05403-900, Sao Paulo, Brazil
- Division of Gastroenterology, Department of Internal Medicine, School of Medical Sciences of University of Campinas, Campinas 13083-878, Sao Paulo, Brazil
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21
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Gómez-Bravo M, Prieto Castillo M, Navasa M, Sánchez-Antolín G, Lladó L, Otero A, Serrano T, Jiménez Romero C, García González M, Valdivieso A, González-Diéguez ML, de la Mata M, Pons JA, Salcedo M, Rodrigo JM, Cuervas-Mons V, González Rodríguez A, Caralt M, Pardo F, Varo Pérez E, Crespo G, Rubin Á, Guilera M, Aldea A, Santoyo J. Everolimus plus minimized tacrolimus on kidney function in liver transplantation: REDUCE, a prospective, randomized controlled study. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2022; 114:335-342. [DOI: 10.17235/reed.2022.8549/2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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22
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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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23
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Abstract
One-third of patients with cirrhosis present kidney failure (AKI and CKD). It has multifactorial causes and a harmful effect on morbidity and mortality before and after liver transplantation. Kidney function does not improve in all patients after liver transplantation, and liver transplant recipients are at a high risk of developing chronic kidney disease. The causes of renal dysfunction can be divided into three groups: pre-operative, perioperative and post-operative factors. To date, there is no consensus on the modality to evaluate the risk of chronic kidney disease after liver transplantation, or for its prevention. In this narrative review, we describe the outcome of kidney function after liver transplantation, and the prognostic factors of chronic kidney disease in order to establish a risk categorization for each patient. Furthermore, we discuss therapeutic options to prevent kidney dysfunction in this context, and highlight the indications of combined liver–kidney transplantation.
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24
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Bzeizi KI, Smith R, Albenmousa A, Dama M, Aba-Alkhail F, Jalan R, Broering D. Long-Term Outcomes of Everolimus Therapy in De Novo Liver Transplantation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Transplant Proc 2021; 53:148-158. [PMID: 33390288 DOI: 10.1016/j.transproceed.2020.09.021] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 09/22/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Risk of nephrotoxicity in liver transplant patients on calcineurin inhibitors (CnIs) is a concern. Several controlled trials reported benefit of everolimus (EVR) in minimizing this risk when combined with a reduced CnI dose. BACKGROUND To systematically review the efficacy and safety of EVR, alone or with reduced CnI dose, as compared to CnI alone post-liver transplantation. METHODS We searched MEDLINE, Scopus, and the Cochrane Library for randomized controlled trials comparing EVR- and CnI-based regimens post-liver transplantation. Assessment of studies and data extraction were undertaken independently. RESULTS Eight studies were selected, describing 769 patients. Cockcroft-Gault GFR was higher at one (P = .05), 3, and 5 years (P = .030) in patients on EVR compared to those receiving CnI therapy. The composite endpoint of efficacy failure was similar between the 2 arms after 1, 3, and 5 years of study. More patients discontinued EVR due to adverse effects in 1 year; however, no difference was noted after 3 or 5 years. A higher rates of proteinuria, peripheral edema, and incisional hernia occurred in patients on EVR. CONCLUSIONS The analysis confirms noninferiority of EVR and reduced CnI combination. Combination regimen resulted in better renal function compared to standard CnI therapy.
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Affiliation(s)
- Khalid Ibrahim Bzeizi
- Department of Liver Transplantation, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
| | - Richard Smith
- Department of Medicine, Ipswich Hospital Trust, Heath Rd, Ipswich, UK
| | - Ali Albenmousa
- Department of Liver Transplantation, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | | | - Faisal Aba-Alkhail
- Department of Liver Transplantation, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; Multi Organ Transplant, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Rajiv Jalan
- Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Campus, London, UK
| | - Dieter Broering
- Department of Liver Transplantation, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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25
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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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Immunosuppressive regimens for adult liver transplant recipients in real-life practice: consensus recommendations from an Italian Working Group. Hepatol Int 2020; 14:930-943. [PMID: 33099753 PMCID: PMC7803715 DOI: 10.1007/s12072-020-10091-5] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 09/06/2020] [Indexed: 02/07/2023]
Abstract
It is a well-recognized fact that implementing new guidelines in clinical practice may be difficult; therefore the Italian Society for Organ and Tissue Transplantation (SITO) set out to define practical immunosuppression tools for the management of liver transplantation patients. In 2017, an Italian Working Group of liver transplant experts and hepatologists issued a set of consensus statements along with evidence-based recommendations on the use of everolimus after liver transplantation. This article presents the evidence- and consensus-based algorithms developed within the Italian Working Group, which are aimed towards guiding clinicians in the selection of immunosuppressive regimens for the management of adult liver transplant recipients in real-life practice. The liver transplant recipient population, typically managed in clinical practice, was divided into the following categories: (1) standard patients; (2) critically ill patients; (3) patients with a specific etiology; (4) patients with hepatocellular carcinoma; (5) and patients with de novo malignancies. The algorithms are divided into two parts, according to the time from transplantation (0-3 months and > 3 months) and are discussed here along with relevant supporting literature, when available. Ultimately, it is hoped that the evidence- and consensus-based algorithms developed within the Italian Working Group, and presented here, contribute to simplify, personalize, and optimize immunosuppression of liver transplantation recipients in clinical practice.
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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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Kim NG, Sharma A, Saab S. Cardiovascular and metabolic disease in the liver transplant recipient. Best Pract Res Clin Gastroenterol 2020; 46-47:101683. [PMID: 33158470 DOI: 10.1016/j.bpg.2020.101683] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 08/31/2020] [Indexed: 01/31/2023]
Abstract
Liver transplantation has led to great improvements in long-term survival in patients with decompensated liver disease and hepatocellular carcinoma. Cardiovascular disease is the leading cause of non-graft-related deaths and has increased prevalence in liver allograft recipients. This is partly secondary to higher post-transplant rates of metabolic risk factors-notably obesity, hypertension, dyslipidemia, and diabetes mellitus, which comprise metabolic syndrome. Post-transplantation metabolic syndrome is expected to be a growing factor in morbidity and mortality as transplant candidates trend older, the rates of metabolic risk factors in the general population increase, non-alcoholic steatohepatitis grows disproportionally as an indication for transplantation, and post-transplantation survival lengthens. This review discusses the incidence and contributory factors for post-transplant increases in metabolic disease, as well as the burden of cardiovascular disease in the liver allograft recipient. Patients with pre-transplant diabetes or obesity are at particularly high risk for post-transplant metabolic syndrome, and would likely benefit from closer surveillance and more aggressive medical management of risk factors. In metabolic disease resistant to initial medical therapies, tailoring of immunosuppressive regimens may further assist in minimizing long-term cardiovascular disease, although this must be done with caution to avoid worsening the risk of graft failure.
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Affiliation(s)
- Nathan G Kim
- Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
| | - Avneesh Sharma
- Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Sammy Saab
- Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA; Department of Surgery, University of California at Los Angeles, Los Angeles, CA, USA.
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29
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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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30
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Ferrín G, Guerrero M, Amado V, Rodríguez-Perálvarez M, De la Mata M. Activation of mTOR Signaling Pathway in Hepatocellular Carcinoma. Int J Mol Sci 2020; 21:1266. [PMID: 32070029 PMCID: PMC7072933 DOI: 10.3390/ijms21041266] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 02/10/2020] [Accepted: 02/11/2020] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and occurs mainly in patients with liver cirrhosis. The mammalian target of rapamycin (mTOR) signaling pathway is involved in many hallmarks of cancer including cell growth, metabolism re-programming, proliferation and inhibition of apoptosis. The mTOR pathway is upregulated in HCC tissue samples as compared with the surrounding liver cirrhotic tissue. In addition, the activation of mTOR is more intense in the tumor edge, thus reinforcing its role in HCC proliferation and spreading. The inhibition of the mTOR pathway by currently available pharmacological compounds (i.e., sirolimus or everolimus) is able to hamper tumor progression both in vitro and in animal models. The use of mTOR inhibitors alone or in combination with other therapies is a very attractive approach, which has been extensively investigated in humans. However, results are contradictory and there is no solid evidence suggesting a true benefit in clinical practice. As a result, neither sirolimus nor everolimus are currently approved to treat HCC or to prevent tumor recurrence after curative surgery. In the present comprehensive review, we analyzed the most recent scientific evidence while providing some insights to understand the gap between experimental and clinical studies.
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Affiliation(s)
- Gustavo Ferrín
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain; (G.F.); (M.G.); (V.A.); (M.D.l.M.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 14004 Córdoba, Spain
| | - Marta Guerrero
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain; (G.F.); (M.G.); (V.A.); (M.D.l.M.)
- Department of Hepatology and Liver Transplantaton, Hospital Universitario Reina Sofía, 14004 Córdoba, Spain
| | - Víctor Amado
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain; (G.F.); (M.G.); (V.A.); (M.D.l.M.)
- Department of Hepatology and Liver Transplantaton, Hospital Universitario Reina Sofía, 14004 Córdoba, Spain
| | - Manuel Rodríguez-Perálvarez
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain; (G.F.); (M.G.); (V.A.); (M.D.l.M.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 14004 Córdoba, Spain
- Department of Hepatology and Liver Transplantaton, Hospital Universitario Reina Sofía, 14004 Córdoba, Spain
| | - Manuel De la Mata
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain; (G.F.); (M.G.); (V.A.); (M.D.l.M.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 14004 Córdoba, Spain
- Department of Hepatology and Liver Transplantaton, Hospital Universitario Reina Sofía, 14004 Córdoba, Spain
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31
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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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32
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Bedreli S, Straub K, Achterfeld A, Willuweit K, Katsounas A, Saner F, Wedemeyer H, Herzer K. The Effect of Immunosuppression on Coagulation After Liver Transplantation. Liver Transpl 2019; 25:1054-1065. [PMID: 31021493 DOI: 10.1002/lt.25476] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 03/30/2019] [Indexed: 12/24/2022]
Abstract
Everolimus (EVR) is a mammalian target of rapamycin (mTOR) inhibitor commonly used for immunosuppression (IS) after liver transplantation (LT). However, there are concerns about whether mTOR inhibitors may move the hemostatic balance toward a higher likelihood of thrombosis. The present study aimed to investigate potential coagulation disorders after the administration of EVR. We evaluated 54 patients after conversion to an EVR-based IS regimen (n = 26) and compared those patients with patients who were switched to extended-release tacrolimus (TAC) but had never received EVR (n = 28). At baseline and again at 1 month and 6 months after conversion, we measured international normalized ratio, activated partial thromboplastin time, and anticoagulation and fibrinolysis factors, and we performed rotational thromboelastometry (ROTEM). Data were analyzed with a Mann-Whitney U test, a repeated-measure analysis of variance, and a Fisher's exact test. Statistical significance was set at the level of P ≤ 0.05. Plasma levels of von Willebrand factor, fibrinogen, and factor VIII were significantly higher than baseline levels at 1 month and 6 months after conversion of IS to EVR (P < 0.001); plasma levels of protein C, protein S, and plasminogen also increased significantly (P < 0.001). ROTEM confirmed a significant increase in maximum clot firmness in EXTEM, INTEM, and FIBTEM assays (P < 0.001). In all assays, maximum lysis was significantly lower than baseline levels at 1 month and 6 months after conversion to EVR. Patients converted to IS with extended-release TAC exhibited no significant changes in coagulation variables. Retrospective analysis showed a significantly higher incidence of thromboembolic complications among patients treated with EVR-based IS than among those treated with extended-release TAC (P < 0.01). In conclusion, the administration of EVR after LT seems to modify hemostasis to a procoagulant state. Thrombophilia screening before conversion may determine which patients will benefit from conversion to EVR-based IS.
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Affiliation(s)
- Sotiria Bedreli
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Katja Straub
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Anne Achterfeld
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Katharina Willuweit
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Antonios Katsounas
- Department of Gastroenterology, Hepatology and Infectious Diseases, University of Magdeburg, Magdeburg, Germany
| | - Fuat Saner
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Kerstin Herzer
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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33
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International Liver Transplantation Society Consensus Statement on Immunosuppression in Liver Transplant Recipients. Transplantation 2019; 102:727-743. [PMID: 29485508 DOI: 10.1097/tp.0000000000002147] [Citation(s) in RCA: 178] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Effective immunosupression management is central to achieving optimal outcomes in liver transplant recipients. Current immunosuppression regimens and agents are highly effective in minimizing graft loss due to acute and chronic rejection but can also produce a substantial array of toxicities. The utilization of immunosuppression varies widely, contributing to the wide disparities in posttransplant outcomes reported between transplant centers. The International Liver Transplantation Society (ILTS) convened a consensus conference, comprised of a global panel of expert hepatologists, transplant surgeons, nephrologists, and pharmacologists to review the literature and experience pertaining to immunosuppression management to develop guidelines on key aspects of immunosuppression. The consensus findings and recommendations of the ILTS Consensus guidelines on immunosuppression in liver transplant recipients are presented in this article.
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34
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Liu J, Ma B, Cao W, Li M, Bramer WM, Peppelenbosch MP, Pan Q. Direct-acting antiviral agents for liver transplant recipients with recurrent genotype 1 hepatitis C virus infection: Systematic review and meta-analysis. Transpl Infect Dis 2019; 21:e13047. [PMID: 30615227 PMCID: PMC6850617 DOI: 10.1111/tid.13047] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 12/18/2018] [Accepted: 12/23/2018] [Indexed: 12/15/2022]
Abstract
Background Comprehensive evaluation of safety and efficacy of different combinations of direct‐acting antivirals (DAAs) in liver transplant recipients with genotype 1 (GT1) hepatitis C virus (HCV) recurrence remains limited. Therefore, we performed this systematic review and meta‐analysis in order to evaluate the clinical outcome of DAA treatment in liver transplant patients with HCV GT1 recurrence. Methods Studies were included if they contained information of 12 weeks sustained virologic response (SVR12) after DAA treatment completion as well as treatment related complications for liver transplant recipients with GT1 HCV recurrence. Results We identified 16 studies comprising 885 patients. The overall pooled estimate proportion of SVR12 was 93% (95% confidence interval (CI): 0.89, 0.96), with moderate heterogeneity observed (τ2 = 0.01, P < 0.01, I2=75%). High tolerability was observed in liver transplant recipients reflected by serious adverse events (sAEs) with pooled estimate proportion of 4% (95% CI: 0.01, 0.07; τ2 = 0.02, P < 0.01, I2 = 81%). For subgroup analysis, a total of five different DAA regimens were applied for treating these patients. Sofosbuvir/Ledipasvir (SOF/LDV) led the highest pooled estimate SVR12 proportion, followed by Paritaprevir/Ritonavir/Ombitasivir/Dasabuvir (PrOD), Daclatasvir (DCV)/Simeprevir (SMV) ± Ribavirin (RBV), and SOF/SMV ± RBV, Asunaprevir (ASV)/DCV. There was a tendency for favoring a higher pooled SVR12 proportion in patients with METAVIR Stage F0‐F2 of 97% (95% CI: 0.93, 0.99) compared to 85% (95% CI: 0.79, 0.90) for stage F3‐F4 (P < 0.01). There was no significant difference between LT recipients treated with or without RBV (P = 0.23). Conclusions Direct‐acting antiviral treatment is highly effective and well‐tolerated in liver transplant recipients with recurrent GT1 HCV infection.
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Affiliation(s)
- Jiaye Liu
- Biomedical Research Center, Northwest Minzu University, Lanzhou, China.,Erasmus MC Cancer Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Buyun Ma
- Erasmus MC Cancer Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Wanlu Cao
- Erasmus MC Cancer Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Meng Li
- Erasmus MC Cancer Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Wichor M Bramer
- Department of Medical Library, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Maikel P Peppelenbosch
- Erasmus MC Cancer Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Qiuwei Pan
- Biomedical Research Center, Northwest Minzu University, Lanzhou, China.,Erasmus MC Cancer Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
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35
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Abstract
The standard therapy for decompensated end-stage chronic liver disease of any etiology and acute fulminant hepatic failure is liver transplantation (LT). Advances in immunosuppressive therapy decreased the rates of acute and chronic rejections. Thus, graft and patient survivals have significantly improved. However, long-term adverse effects of prolonged use of immunosuppressive agents such as malignancies, opportunistic infections, metabolic disorders, and other organ toxicities have now become a major concern. Consequently, alternative approaches are needed to deescalate the customary drugs and their side effects. Therapy must be individualized and additional preventive measures should be taken by patients with particular risk factors or predisposed to certain adverse effects. Current opinion favors a combination of agents with different mechanism of actions and toxicity profiles. Corticosteroids are employed in immediate and early postoperative period. Although they have a pronounced side effect profile, calcineurin inhibitors (CNIs) are still the backbone of early and late phase immunosuppressive regimens because of their proved efficacy. Antimetabolites are frequent choices for steroid and/or CNI-sparing strategies. Studies also have established a role for mammalian target of rapamycin (mTOR) inhibitors in specific groups of recipients. Biologic agents are a hot topic of interest and made their way into current strategies for induction. Agents extrapolated from other transplantation or immunologic experience are being evaluated.
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Affiliation(s)
- Burcak E Tasdogan
- Department of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Michelle Ma
- Department of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Cem Simsek
- Department of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Behnam Saberi
- Department of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Ahmet Gurakar
- Department of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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36
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Abstract
Liver transplantation has become an important treatment modality for patients with end-stage liver disease/cirrhosis, acute liver failure, and hepatocellular carcinoma. Although surgical techniques and immunosuppressive regimens for liver transplantation have improved significantly over the past 20 years, infectious complications continue to contribute to the morbidity and mortality in this patient population. The use of standardized screening protocols for both donors and recipients, coupled with targeted prophylaxis against specific pathogens, has helped to mitigate the risk of infection in liver transplant recipients. Patients with chronic liver disease and cirrhosis have immunological deficits that place them at increased risk for infection while awaiting liver transplantation. The patient undergoing liver transplantation is prone to develop healthcare-acquired infections due to multidrug-resistant organisms that could potentially affect patient outcomes after transplantation. The complex nature of liver transplant surgery that involves multiple vascular and hepatobiliary anastomoses further increases the risk of infection after liver transplantation. During the early post-transplantation period, healthcare-acquired bacterial and fungal infections are the most common types of infection encountered in liver transplant recipients. The period of maximal immunosuppression that occurs at 1–6 months after transplantation can be complicated by opportunistic infections due to both primary infection and reactivation of latent infection. Severe community-acquired infections can complicate the course of liver transplantation beyond 12 months after transplant surgery. This chapter provides an overview of liver transplantation including indications, donor-recipient selection criteria, surgical procedures, and immunosuppressive therapies. A focus on infections in patients with chronic liver disease/cirrhosis and an overview of the specific infectious complications in liver transplant recipients are presented.
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37
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Rodríguez-Perálvarez M, Guerrero M, Barrera L, Ferrín G, Álamo JM, Ayllón MD, Artacho GS, Montero JL, Briceño J, Bernal C, Padillo J, Marín-Gómez LM, Pascasio JM, Poyato A, Gómez-Bravo MA, De la Mata M. Impact of Early Initiated Everolimus on the Recurrence of Hepatocellular Carcinoma After Liver Transplantation. Transplantation 2018; 102:2056-2064. [PMID: 29757893 DOI: 10.1097/tp.0000000000002270] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Many centers implement everolimus-based immunosuppression in liver transplant patients with hepatocellular carcinoma. We aimed to explore the potential impact of early initiated everolimus on tumor recurrence after liver transplantation. METHODS This study included 192 patients with hepatocellular carcinoma undergoing liver transplantation among who 64 individuals were prospectively enrolled (2012-2015) and received early initiated everolimus (ie, started between postoperative day 15 to 21), whereas the remaining 128 patients acted as historical controls without everolimus. Propensity score matching was performed to ensure comparability. Multivariate Cox regression and competing risks analysis were used to control for potential confounders. RESULTS Patients with and without everolimus were comparable in terms of number of nodules (P = 0.37), total tumor diameter (P = 0.44), Milan criteria fulfillment (P = 0.56), and histological differentiation (P = 0.61), but there were increased microvascular invasion rates in the everolimus group (26.5% vs 13.3%; P = 0.026). Tumor recurrence rates were similar with and without everolimus (10.9% vs 9.9% at 36 months respectively; P = 0.18). After controlling for microvascular invasion among other potential confounders, everolimus had no significant impact on tumor recurrence, neither in the multivariate Cox regression (relative risk = 3.23; P = 0.09), nor in the competing risks analysis for tumor recurrence-death (relative risk = 1.02; P = 0.94). Patients receiving everolimus had reduced tacrolimus trough concentrations and lower serum creatinine within the first 18 months postliver transplantation. CONCLUSION Everolimus may not be universally prescribed to prevent tumor recurrence in liver transplant patients with hepatocellular carcinoma. Future randomized trials should be focused on patients with histological features of increased tumor aggressiveness, in whom the potential benefit would be higher.
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Affiliation(s)
- Manuel Rodríguez-Perálvarez
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain
| | - Marta Guerrero
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain
| | - Lydia Barrera
- General Surgery and Transplantation, Hospital Virgen del Rocío, IBIS, Sevilla, Spain
| | - Gustavo Ferrín
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain
| | - Jose M Álamo
- General Surgery and Transplantation, Hospital Virgen del Rocío, IBIS, Sevilla, Spain
| | - María D Ayllón
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain
| | | | - José L Montero
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain
| | - Javier Briceño
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain
| | - Carmen Bernal
- General Surgery and Transplantation, Hospital Virgen del Rocío, IBIS, Sevilla, Spain
| | - Javier Padillo
- General Surgery and Transplantation, Hospital Virgen del Rocío, IBIS, Sevilla, Spain
| | - Luis M Marín-Gómez
- General Surgery and Transplantation, Hospital Virgen del Rocío, IBIS, Sevilla, Spain
| | - Juan M Pascasio
- General Surgery and Transplantation, Hospital Virgen del Rocío, IBIS, Sevilla, Spain
| | - Antonio Poyato
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain
| | - Miguel A Gómez-Bravo
- General Surgery and Transplantation, Hospital Virgen del Rocío, IBIS, Sevilla, Spain
| | - Manuel De la Mata
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain
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Abstract
The evidence base concerning use of mammalian target of rapamycin (mTOR) inhibitor therapy after liver transplantation is evolving rapidly, clarifying their benefits and disadvantages in different clinical scenarios. The H2304 trial showed that starting everolimus at 1 month posttransplant, with reduced tacrolimus, achieves a sustained improvement in renal function versus standard tacrolimus-based therapy, with at least equivalent immunosuppressive efficacy. Randomized studies evaluating early discontinuation of calcineurin inhibitor (CNI) therapy after introduction of an mTOR inhibitor consistently demonstrated a substantial improvement in renal function versus standard CNI therapy. However, concomitant mycophenolic acid is advisable to avoid an increase in mild biopsy-proven acute rejection, and induction with an interleukin-2 receptor antagonist may also be helpful. High-quality robust data regarding prevention of posttransplant malignancies under mTOR inhibitors is lacking in liver transplantation, although there are some indications of benefit. In maintenance patients, robust data are limited regarding mTOR inhibitor initiation in response to deteriorating renal function or other indications but late conversion (>1 year) appears ineffective. Rates of mTOR inhibitor discontinuation due to adverse events are high, affecting at least a quarter of patients. In conclusion, the evidence base for use of mTOR inhibitors early posttransplant to support CNI reduction now convincingly demonstrates a renal advantage, but adequate adjunctive immunosuppression is essential to preserve efficacy.
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Dumortier J, Maucort-Boulch D, Poinsot D, Thimonier E, Chambon-Augoyard C, Ducroux E, Vallin M, Walter T, Robinson P, Guillaud O, Boillot O. Immunosuppressive regimen and risk for de novo malignancies after liver transplantation for alcoholic liver disease. Clin Res Hepatol Gastroenterol 2018; 42:427-435. [PMID: 29861393 DOI: 10.1016/j.clinre.2018.04.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 04/18/2018] [Accepted: 04/24/2018] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Long-term prognosis after liver transplantation for alcoholic liver disease is impaired because of the occurrence of de novo malignancies and recurrent disease on liver graft. The aim of the present retrospective study was to evaluate the risk of de novo malignancy and to identify the predictive factors in a large cohort of liver-transplanted patients with a long follow-up in the setting of alcoholic liver disease. METHODS All patients who underwent a first liver transplantation for alcoholic liver disease in our centre, from December 1985 to October 2010, and who survived more than 6 months were included. Survival, incidence of de novo malignancies and several clinical and biological parameters were studied. RESULTS The study population consisted in 368 patients (284 males, median age 52.6 years). The cumulative incidence of a first solid organ de novo malignancy after LT was 8.7% at 5 years, 22.3% at 10 years, 31.5% at 15 years, and 33.1% at 20 years. Tobacco use (both past and current) was associated with a significant increased risk of de novo solid organ malignancy (HR 3.35 and 4.62, respectively), whereas immunosuppressive regimen including mTOR inhibitors (mTORi) was associated with a decreased risk (post-transplant time under mTORi-including immunosuppressive regimen was significantly longer in patients who did not present de novo malignancy (10.6% vs. 2.3%, P=1.4×10-5)). CONCLUSIONS Our study provides additional evidence that de novo malignancies in alcoholic liver disease liver transplant patients is a major long-term complication, and that conversion from to an mTORi-including immunosuppressive regimen could reduce this risk.
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Affiliation(s)
- Jérôme Dumortier
- Fédération des spécialités digestives, hôpital Edouard-Herriot, hospices civils de Lyon, 69437 Lyon cedex 03, France; Université Claude-Bernard Lyon 1, 69437 Lyon cedex 03, France.
| | - Delphine Maucort-Boulch
- Université Claude-Bernard Lyon 1, 69437 Lyon cedex 03, France; Service de biostatistique-bioinformatique, centre hospitalier Lyon-Sud, hospices civils de Lyon, 69437 Lyon cedex 03, France
| | - Domitille Poinsot
- Fédération des spécialités digestives, hôpital Edouard-Herriot, hospices civils de Lyon, 69437 Lyon cedex 03, France; Université Claude-Bernard Lyon 1, 69437 Lyon cedex 03, France
| | - Elsa Thimonier
- Fédération des spécialités digestives, hôpital Edouard-Herriot, hospices civils de Lyon, 69437 Lyon cedex 03, France; Université Claude-Bernard Lyon 1, 69437 Lyon cedex 03, France
| | - Christine Chambon-Augoyard
- Fédération des spécialités digestives, hôpital Edouard-Herriot, hospices civils de Lyon, 69437 Lyon cedex 03, France
| | - Emilie Ducroux
- Service de dermatologie, hôpital Edouard-Herriot, hospices civils de Lyon, 69437 Lyon cedex 03, France
| | - Mélanie Vallin
- Fédération des spécialités digestives, hôpital Edouard-Herriot, hospices civils de Lyon, 69437 Lyon cedex 03, France
| | - Thomas Walter
- Fédération des spécialités digestives, hôpital Edouard-Herriot, hospices civils de Lyon, 69437 Lyon cedex 03, France; Université Claude-Bernard Lyon 1, 69437 Lyon cedex 03, France
| | - Philip Robinson
- Direction de la recherche clinique et de l'innovation, hospices civils de Lyon, 69437 Lyon cedex 03, France
| | - Olivier Guillaud
- Fédération des spécialités digestives, hôpital Edouard-Herriot, hospices civils de Lyon, 69437 Lyon cedex 03, France
| | - Olivier Boillot
- Fédération des spécialités digestives, hôpital Edouard-Herriot, hospices civils de Lyon, 69437 Lyon cedex 03, France; Université Claude-Bernard Lyon 1, 69437 Lyon cedex 03, France
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De Simone P, Carrai P, Coletti L, Ghinolfi D, Petruccelli S, Precisi A, Campani D, Marchetti P, Filipponi F. Everolimus vs Mycophenolate Mofetil in Combination With Tacrolimus: A Propensity Score-matched Analysis in Liver Transplantation. Transplant Proc 2018; 50:3615-3620. [PMID: 30577246 DOI: 10.1016/j.transproceed.2018.07.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Accepted: 07/04/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND No trial has investigated the long-term outcome of everolimus (EVR)-incorporating immunosuppression vs tacrolimus (TAC) and mycophenolate mofetil (MMF) after liver transplantation. MATERIALS AND METHODS With a propensity score methodology, 178 recipients on TAC and MMF were compared to 178 patients on TAC and EVR. RESULTS At a median (interquartile range) follow-up of 45 (46.3) months, the probability of treated biopsy-proven acute rejection, graft loss, and death was 36.6% for MMF and 28.1% for EVR (P = .0891). Treated biopsy-proven acute rejection was numerically lower for EVR (3.3% vs 7.3%, P = .09), while adverse events (70.2% vs 58.9%, P = .02) and drug discontinuations (21.3% vs 11.8%, P = .01) were significantly higher with regard to hypercholesterolemia (P = .001), thrombocytopenia (P = .0062), and edema (P = .0107). Patients on MMF showed more hypertension (P = .0315), tremor (P = .0006), cytomegalovirus infection (P = .0165), and malignancies (P = .0175). EVR was associated with lesser deterioration in mean (SD) renal function at the latest follow-up (-2.2 (1.8) vs -5.1 (3.2) mL/min/1.73 m2, t = 3.6, P = .005). CONCLUSIONS The efficacy of the combination of TAC and EVR is comparable to that of TAC and MMF. Drug discontinuations and adverse events were higher for patients on EVR, but these latter showed less hypertension, cytomegalovirus infection, and renal dysfunction. The observed reduction in posttransplant malignancies for EVR requires longer follow-up to be confirmed.
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Affiliation(s)
- P De Simone
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy.
| | - P Carrai
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - L Coletti
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - D Ghinolfi
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - S Petruccelli
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - A Precisi
- Laboratory, University of Pisa Medical School Hospital, Pisa, Italy
| | - D Campani
- Department of Pathology, University of Pisa Medical School Hospital, Pisa, Italy
| | - P Marchetti
- Department of Clinical and Experimental Medicine, University of Pisa Medical School Hospital, Pisa, Italy
| | - F Filipponi
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
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41
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Welker MW, Weiler N, Bechstein WO, Herrmann E, Betz C, Schöffauer M, Zeuzem S, Sarrazin C, Amann K, Jung O. Key role of renal biopsy in management of progressive chronic kidney disease in liver graft recipients. J Nephrol 2018; 32:129-137. [PMID: 29946864 DOI: 10.1007/s40620-018-0506-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 06/13/2018] [Indexed: 01/09/2023]
Abstract
AIMS Chronic kidney disease (CKD) is a common complication after liver transplantation (LT). The etiology of CKD is broad and may only be assessed accurately by renal histology. The current study aimed to analyze the safety of renal biopsy in daily clinical practice as well as its usefulness regarding management of CKD after LT. METHODS We performed a retrospective analysis of clinical data and renal biopsies obtained from patients with severe renal impairment (overt proteinuria, progressive deterioration of renal function) after LT with respect to safety, etiology of renal disease, and therapeutic consequences. RESULTS Renal biopsies were obtained from 14 patients at median (minimum-maximum) 3 (0.2-12) years after LT. No major complications associated with renal biopsy were observed. Histomorphological alterations were varied (nephrosclerosis, n = 5; IgA-glomerulonephritis, n = 4; tenofovir-associated nephropathy, membranoproliferative glomerulonephritis type 1, membranous glomerulonephritis, amyloid A amyloidosis, and calcineurin inhibitor nephropathy, n = 1, respectively). The diagnosis of specific renal diseases other than calcineurin-inhibitor nephrotoxicity facilitated specific treaments and avoided unnecessary modification of immunosuppression in the majority of patients. CONCLUSIONS Renal biopsy in patients with CKD after LT seems safe and may offer specific therapeutic options. Furthermore, unnecessary changes of immunosuppression can be avoided in a considerable number of patients.
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Affiliation(s)
- Martin-Walter Welker
- Medizinische Klinik I, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
| | - Nina Weiler
- Medizinische Klinik I, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
| | - Wolf Otto Bechstein
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
| | - Eva Herrmann
- Institut für Biostatistik und mathematische Modellierung, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
| | - Christoph Betz
- Medizinische Klinik III, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
| | - Mark Schöffauer
- Medizinische Klinik I, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.,Medizinische Klinik III, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
| | - Stefan Zeuzem
- Medizinische Klinik I, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
| | - Christoph Sarrazin
- Medizinische Klinik I, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.,St. Josefs-Hospital, Beethoven Str. 20, 65189, Wiesbaden, Germany
| | - Kerstin Amann
- Abteilung für Nephropathologie, Universitätsklinikum Erlangen, Krankenhausstraße 8-10, 91054, Erlangen, Germany
| | - Oliver Jung
- Medizinische Klinik III, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.,KfH Kuratorium für Dialyse und Nierentransplantation e.V., Standort Klinikum Frankfurt Höchst, Gotenstraße 6-8, 65929, Frankfurt am Main, Germany
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Jeng LB, Lee SG, Soin AS, Lee WC, Suh KS, Joo DJ, Uemoto S, Joh J, Yoshizumi T, Yang HR, Song GW, Lopez P, Kochuparampil J, Sips C, Kaneko S, Levy G. Efficacy and safety of everolimus with reduced tacrolimus in living-donor liver transplant recipients: 12-month results of a randomized multicenter study. Am J Transplant 2018; 18:1435-1446. [PMID: 29237235 DOI: 10.1111/ajt.14623] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 10/24/2017] [Accepted: 11/29/2017] [Indexed: 01/25/2023]
Abstract
In a multicenter, open-label, study, 284 living-donor liver transplant patients were randomized at 30 ± 5 days posttransplant to start everolimus+reduced tacrolimus (EVR+rTAC) or continue standard tacrolimus (TAC Control). EVR+rTAC was non-inferior to TAC Control for the primary efficacy endpoint of treated BPAR, graft loss or death at 12 months posttransplant: difference -0.7% (90% CI -5.2%, 3.7%); P < .001 for non-inferiority. Treated BPAR occurred in 2.2% and 3.6% of patients, respectively. The key secondary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, achieved non-inferiority (P < .001 for non-inferiority), but not superiority and was similar between groups overall (mean -8.0 vs. -12.1 mL/min/1.73 m2 , P = .108), and in patients continuing randomized treatment (-8.0 vs. -13.3 mL/min/1.73 m2 , P = .046). In the EVR+rTAC and TAC control groups, study drug was discontinued in 15.5% and 17.6% of patients, adverse events with suspected relation to study drug occurred in 57.0% and 40.4%, and proteinuria ≥1 g/24 h in 9.3% and 0%, respectively. Everolimus did not negatively affect liver regeneration. At 12 months, hepatocellular recurrence was only seen in the standard TAC-treated patients (5/62; 8.1%). In conclusion, early introduction of EVR+rTAC was non-inferior to standard tacrolimus in terms of efficacy and renal function at 12 months, with hepatocellular carcinoma recurrence only in TAC Control patients. ClinicalTrials.gov Identifier: NCT01888432.
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Affiliation(s)
| | | | | | - Wei-Chen Lee
- Chang Gung Memorial Hospital, Tao-Yuan, Lin-Ko, Taiwan
| | - Kyung-Suk Suh
- Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Dong Jin Joo
- Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea
| | | | - Jaewon Joh
- Samsung Medical Center, Seoul, Republic of Korea
| | | | | | - Gi-Won Song
- Asan Medical Center, Seoul, Republic of Korea
| | | | | | | | | | - Gary Levy
- University of Toronto, Toronto, Canada
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Fairfield C, Penninga L, Powell J, Harrison EM, Wigmore SJ. Glucocorticosteroid-free versus glucocorticosteroid-containing immunosuppression for liver transplanted patients. Cochrane Database Syst Rev 2018; 4:CD007606. [PMID: 29630730 PMCID: PMC6494590 DOI: 10.1002/14651858.cd007606.pub4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Liver transplantation is an established treatment option for end-stage liver failure. Now that newer, more potent immunosuppressants have been developed, glucocorticosteroids may no longer be needed and their removal may prevent adverse effects. OBJECTIVES To assess the benefits and harms of glucocorticosteroid avoidance (excluding intra-operative use or treatment of acute rejection) or withdrawal versus glucocorticosteroid-containing immunosuppression following liver transplantation. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded and Conference Proceedings Citation Index - Science, Literatura Americano e do Caribe em Ciencias da Saude (LILACS), World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.gov, and The Transplant Library until May 2017. SELECTION CRITERIA Randomised clinical trials assessing glucocorticosteroid avoidance or withdrawal versus glucocorticosteroid-containing immunosuppression for liver transplanted people. Our inclusion criteria stated that participants should have received the same co-interventions. We included trials that assessed complete glucocorticosteroid avoidance (excluding intra-operative use or treatment of acute rejection) versus short-term glucocorticosteroids, as well as trials that assessed short-term glucocorticosteroids versus long-term glucocorticosteroids. DATA COLLECTION AND ANALYSIS We used RevMan to conduct meta-analyses, calculating risk ratio (RR) for dichotomous variables and mean difference (MD) for continuous variables, both with 95% confidence intervals (CIs). We used a random-effects model and a fixed-effect model and reported both results where a discrepancy existed; otherwise we reported only the results from the fixed-effect model. We assessed the risk of systematic errors using 'Risk of bias' domains. We controlled for random errors by performing Trial Sequential Analysis. We presented our results in a 'Summary of findings' table. MAIN RESULTS We included 17 completed randomised clinical trials, but only 16 studies with 1347 participants provided data for the meta-analyses. Ten of the 16 trials assessed complete postoperative glucocorticosteroid avoidance (excluding intra-operative use or treatment of acute rejection) versus short-term glucocorticosteroids (782 participants) and six trials assessed short-term glucocorticosteroids versus long-term glucocorticosteroids (565 participants). One additional study assessed complete post-operative glucocorticosteroid avoidance but could only be incorporated into qualitative analysis of the results due to limited data published in an abstract. All trials were at high risk of bias. Only eight trials reported on the type of donor used. Overall, we found no statistically significant difference for mortality (RR 1.15, 95% CI 0.93 to 1.44; low-quality evidence), graft loss including death (RR 1.15, 95% CI 0.90 to 1.46; low-quality evidence), or infection (RR 0.88, 95% CI 0.73 to 1.05; very low-quality evidence) when glucocorticosteroid avoidance or withdrawal was compared with glucocorticosteroid-containing immunosuppression. Acute rejection and glucocorticosteroid-resistant rejection were statistically significantly more frequent when glucocorticosteroid avoidance or withdrawal was compared with glucocorticosteroid-containing immunosuppression (RR 1.33, 95% CI 1.08 to 1.64; low-quality evidence; and RR 2.14, 95% CI 1.13 to 4.02; very low-quality evidence). Diabetes mellitus and hypertension were statistically significantly less frequent when glucocorticosteroid avoidance or withdrawal was compared with glucocorticosteroid-containing immunosuppression (RR 0.81, 95% CI 0.66 to 0.99; low-quality evidence; and RR 0.76, 95% CI 0.65 to 0.90; low-quality evidence). We performed Trial Sequential Analysis for all outcomes. None of the outcomes crossed the monitoring boundaries or reached the required information size. Hence, we cannot exclude random errors from the results of the conventional meta-analyses. AUTHORS' CONCLUSIONS Many of the benefits and harms of glucocorticosteroid avoidance or withdrawal remain uncertain because of the limited number of published randomised clinical trials, limited numbers of participants and outcomes, and high risk of bias in the trials. Glucocorticosteroid avoidance or withdrawal appears to reduce diabetes mellitus and hypertension whilst increasing acute rejection, glucocorticosteroid-resistant rejection, and renal impairment. We could identify no other benefits or harms of glucocorticosteroid avoidance or withdrawal. Glucocorticosteroid avoidance or withdrawal may be of benefit in selected patients, especially those at low risk of rejection and high risk of hypertension or diabetes mellitus. The optimal duration of glucocorticosteroid administration remains unclear. More randomised clinical trials assessing glucocorticosteroid avoidance or withdrawal are needed. These should be large, high-quality trials that minimise the risk of random and systematic error.
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Affiliation(s)
- Cameron Fairfield
- Royal Infirmary Edinburgh ‐ NHS Lothian, Royal Infirmary EdinburghHepatobiliary‐Pancreatic Surgical Services and Edinburgh Transplant Unit51 Little France CrescentEdinburghMidlothianUKEH16 4SA
| | - Luit Penninga
- Rigshospitalet, Copenhagen University HospitalDepartment of Surgery and Transplantation C2122Blegdamsvej 9CopenhagenDenmarkDK‐2100
| | - James Powell
- NHS LothianScottish Liver Transplant UnitRoyal Infirmary of Edinburgh, 51 Little France CrescentEdinburghUKEH16 4SA
| | - Ewen M Harrison
- University of EdinburghClinical Surgery53 Little France CrescentEdinburghMidlothianUKEH16 4SA
| | - Stephen J Wigmore
- Royal Infirmary Edinburgh ‐ NHS Lothian, Royal Infirmary EdinburghHepatobiliary‐Pancreatic Surgical Services and Edinburgh Transplant Unit51 Little France CrescentEdinburghMidlothianUKEH16 4SA
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Manzia TM, Angelico R, Toti L, Grimaldi C, Sforza D, Vella I, Tariciotti L, Lenci I, Breshanaj G, Baiocchi L, Tisone G. Ab initio Everolimus-based Versus Standard Calcineurin Inhibitor Immunosuppression Regimen in Liver Transplant Recipients. Transplant Proc 2018; 50:175-183. [PMID: 29407305 DOI: 10.1016/j.transproceed.2017.12.018] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Revised: 11/13/2017] [Accepted: 12/12/2017] [Indexed: 02/05/2023]
Abstract
AIM We designed a retrospective case-control study to determine the efficacy and feasibility of everolimus (EVR) combined with low-dose tacrolimus (Tac) ab initio versus standard-dose Tac after liver transplantation (LT). METHODS Seventy-one adult LT patients, receiving EVR and low-dose Tac without corticosteroids or induction therapy from postoperative day 1 (EVR group) were compared with a well-matched control group of 61 recipients treated with standard-dose Tac in association with antimetabolite. RESULTS Baseline characteristics for the two groups were comparable. The overall patient and graft survival rates were similar (P = .908). Liver function was stable during the follow-up. In the EVR group, biopsy-proven acute rejection occurred in two cases (2.8%), whereas chronic rejection occurred in one (1.4%). The EVR group experienced a better renal function already after 2 weeks (estimated glomerular filtration rate: 89.85 [36.46 to 115.3] mL/min/1.73 m2 vs. 68.77 [16.11 to 115.42] mL/min/1.73 m2; P = .013), which was also observed after a median time of 27 months (range, 0 to 82 months) from LT (estimated glomerular filtration rate: 80 [45 to 118.3] mL/min/1.73 m2 vs. 70.9 [45 to 88.4] mL/min/1.73 m2; P = .04). After a median time of 27 months, the EVR group showed lower incidence of arterial hypertension and insulin-dependent diabetes mellitus. CONCLUSION Ab initio EVR-based immunosuppression could be a valid option immediately after surgery in recipients at high-risk for post-LT renal impairment.
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Affiliation(s)
- T M Manzia
- Department of Experimental Medicine and Surgery, Liver Unit, Tor Vergata University of Rome, Italy.
| | - R Angelico
- Department of Experimental Medicine and Surgery, Liver Unit, Tor Vergata University of Rome, Italy; Division of Abdominal Transplantation and Hepatobiliopancreatic Surgery, Bambino Gesu` Children's Research Hospital IRCCS, Rome, Italy
| | - L Toti
- Department of Experimental Medicine and Surgery, Liver Unit, Tor Vergata University of Rome, Italy
| | - C Grimaldi
- Division of Abdominal Transplantation and Hepatobiliopancreatic Surgery, Bambino Gesu` Children's Research Hospital IRCCS, Rome, Italy
| | - D Sforza
- Department of Experimental Medicine and Surgery, Liver Unit, Tor Vergata University of Rome, Italy
| | - I Vella
- Department of Experimental Medicine and Surgery, Liver Unit, Tor Vergata University of Rome, Italy
| | - L Tariciotti
- Department of Experimental Medicine and Surgery, Liver Unit, Tor Vergata University of Rome, Italy
| | - I Lenci
- Department of Hepatology and Gastroenterology, Liver Unit, Tor Vergata University of Rome, Italy
| | - G Breshanaj
- Department of Experimental Medicine and Surgery, Liver Unit, Tor Vergata University of Rome, Italy
| | - L Baiocchi
- Department of Hepatology and Gastroenterology, Liver Unit, Tor Vergata University of Rome, Italy
| | - G Tisone
- Department of Experimental Medicine and Surgery, Liver Unit, Tor Vergata University of Rome, Italy
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Yee ML, Tan HH. Use of everolimus in liver transplantation. World J Hepatol 2017; 9:990-1000. [PMID: 28878864 PMCID: PMC5569278 DOI: 10.4254/wjh.v9.i23.990] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 05/20/2017] [Accepted: 06/12/2017] [Indexed: 02/06/2023] Open
Abstract
In recent years, the use of mammalian target of rapamycin inhibitors has gained traction in their use as alternative or adjunct immunosuppressants in the post-liver transplantation (LT) setting. The efficacy of everolimus (EVR) in de novo LT is established and a reasonable time to initiate EVR is 30 d from LT surgery. Initiating EVR early post-LT allows for calcineurin inhibitor (CNI) reduction, thus reducing nephrotoxicity in LT recipients. However, data is inadequate on the appropriate timing for conversion from CNI to EVR maintenance in order to achieve optimal renoprotective effect without compromising drug efficacy. Adverse effects of proteinuria, hypercholesterolemia and hyperlipidemia are significantly higher as compared to standard CNI and long-term implications on graft and patient survival in LT is still unclear. Future research to explore strategies to minimise EVR adverse effects will be crucial for the success of EVR as an important alternative or adjunct immunosuppressive therapy in LT.
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Affiliation(s)
- Mei-Ling Yee
- Department of Pharmacy, Singapore General Hospital, Singapore 169608, Singapore.
| | - Hui-Hui Tan
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore 169608, Singapore
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Rubín Suárez A, Bilbao Aguirre I, Fernández-Castroagudin J, Pons Miñano JA, Salcedo Plaza M, Varo Pérez E, Prieto Castillo M. Recommendations of everolimus use in liver transplant. GASTROENTEROLOGIA Y HEPATOLOGIA 2017; 40:629-640. [PMID: 28743539 DOI: 10.1016/j.gastrohep.2017.05.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 05/23/2017] [Accepted: 05/23/2017] [Indexed: 01/26/2023]
Abstract
Mammalian target of rapamycin (mTOR) inhibitors, everolimus (EVL) and sirolimus are immunosuppressive agents with a minor nephrotoxic effect, limited to the development of proteinuria in some cases. The combination of EVL and low-dose tacrolimus has proven to be as safe and effective as standard therapy with tacrolimus for the prevention of acute cellular rejection. Early initiation of EVL-based immunosuppressive regimens with reduced exposure to calcineurin inhibitors has been shown to significantly improve renal function of LT recipients during induction and maintenance phases, with comparable efficacy and safety profiles. In patients with established kidney failure, initiating EVL may enable clinicians to reduce calcineurin inhibitors exposure, thereby contributing to the improved renal function of these patients. Although there is not sufficient evidence to recommend their use to prevent the recurrence of hepatocellular carcinoma and the progression of de novo tumours, they are used in this context in routine clinical practice.
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Affiliation(s)
- Angel Rubín Suárez
- Unidad de Hepatología, Servicio de Medicina Digestiva, Área de Enfermedades Digestivas, Hospital Universitari i Politècnic La Fe, CIBERehd, Valencia, España.
| | - Itxarone Bilbao Aguirre
- Servicio de Cirugía HBP y Trasplantes Digestivos, Hospital Universitario Vall d'Hebrón. Grupos de investigación VHIR y CIBERehd, Barcelona, España
| | - Javier Fernández-Castroagudin
- Servicio de Medicina Digestiva, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, España
| | - José Antonio Pons Miñano
- Unidad de Hepatología y Trasplante Hepático, IMIB. Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, España
| | - Magdalena Salcedo Plaza
- Unidad de Trasplante Hepático, Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón IISGM. CIBERehd, Madrid, España
| | - Evaristo Varo Pérez
- Unidad de Trasplante Abdominal, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, España
| | - Martín Prieto Castillo
- Unidad de Hepatología, Servicio de Medicina Digestiva, Área de Enfermedades Digestivas, Hospital Universitari i Politècnic La Fe, CIBERehd, Valencia, España
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Abstract
Immunosuppression after liver transplantation (LT) is presently based on use of calcineurin inhibitors (CNI), although they are associated with an increased incidence of renal dysfunction, cardiovascular complications, and de novo and recurrent malignancies. Over the past decade, mammalian target of rapamycin inhibitors have received considerable attention as immunosuppressants because they are associated with a more favorable renal profile versus CNI, as well as antiproliferative activity in clinical studies. Comprehensive guidelines on use of everolimus (EVR) in LT are still lacking. In Italy, a project, named Everolimus: the road to long-term functioning, was initiated to collect the experience on EVR after LT with the aim of providing guidance for transplant clinicians. Herein, recommendations by this national consensus group, based on Delphi methodology, are presented. Consensus was reached on 20 of the 23 statements proposed, and their level of evidence, grade of recommendation, and percent of agreement are reported. Statements are grouped into 4 areas: (A) renal function; (B) time of EVR introduction, CNI reduction and elimination, and risk for graft rejection; (C) antiproliferative effects of EVR; and (D) management of EVR-related adverse events. The high level of consensus shows that there is good agreement on the routine use of EVR in predefined clinical scenarios, especially in light of posttransplant nephrotoxicity and other adverse events associated with long-term administration of CNIs. The authors summarize the recommendations reached by an Italian National Consensus group using the Delphi methodology on the use of everolimus in liver transplantation, particularly its role in renal function, antiproliferative effects, adverse events, timing of introduction, and rejection risk.
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Wong TC, Lo CM, Fung JY. Emerging drugs for prevention of T-cell mediated rejection in liver and kidney transplantation. Expert Opin Emerg Drugs 2017; 22:123-136. [PMID: 28503959 DOI: 10.1080/14728214.2017.1330884] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Acute and chronic graft rejection continues to be an important problem after solid organ transplantation. With the introduction of potent immunosuppressive agents such as calcineurin inhibitors, the risk of rejection has been significantly reduced. However, the adverse effects of life-long immunosuppression remain a concern, and there exist a fine balance between over-immunosuppression and risk of rejection. Areas covered: In this review, the current standard of care in immunosuppressive therapy, including the use of steroids, calcineurin inhibitors, mycophenolate prodrugs and mammalian target of rapamycin inhibitors, will be discussed. Newer immunosuppressive agents showing promising early data after liver and kidney transplantation will also be explored. Expert Opinion: Currently, calcineurin inhibitors continue to be a vital component of immunosuppressive therapy after solid organ transplantation. Although minimization and avoidance strategies have been developed, the ultimate goal of inducing tolerance remains elusive. Newer emerging agents should have potent and specific immunosuppressive activity, with minimal associated side effects. An individualized approach should be adopted to tailor immunosuppression according to the different needs of recipients.
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Affiliation(s)
- Tiffany Cl Wong
- a Department of Surgery, Department of Medicine , Queen Mary Hospital, The University of Hong Kong , Hong Kong , Hong Kong S.A.R
| | - Chung-Mau Lo
- a Department of Surgery, Department of Medicine , Queen Mary Hospital, The University of Hong Kong , Hong Kong , Hong Kong S.A.R
| | - James Yy Fung
- a Department of Surgery, Department of Medicine , Queen Mary Hospital, The University of Hong Kong , Hong Kong , Hong Kong S.A.R
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Modification of immunosuppressive therapy as risk factor for complications after liver transplantation. Best Pract Res Clin Gastroenterol 2017. [PMID: 28624108 DOI: 10.1016/j.bpg.2017.03.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Management of complications post-liver transplantation (LT) includes immunosuppressive manipulations with the aim to reduce the overall burden of immunologic suppression and compensate for renal, cardiovascular, metabolic toxicities, and for the increased oncologic risk. Two approaches can be implemented to reduce immunosuppression-related adverse events: upfront schedules tailored to the pretransplant individual patient's risk profile versus downstream modifications in the event of immunosuppression-related complications. Upfront strategies are supported by evidence originating from prospective randomized trials and consist of triple/quadruple schedules whereby calcineurin inhibitors (CNI)-exposure is reduced with combination of anti-CD25 monoclonal antibodies, antimetabolites and corticosteroids. Quadruple regimens allow for staggering of CNI introduction and higher renal function in the early term, but their superiority in the long term has not yet been established. A more recent upfront schedule contemplates early (4 weeks) introduction of mammalian target of rapamycin inhibitor (mTORi) everolimus and allows for reduction of CNI up to 4 years posttransplantation. Incorporation of mTORi has the potential to prolong time to recurrence for patients with hepatocellular carcinoma. However, as suggested by the available evidence, downstream immunosuppressive manipulations are more frequently adopted in clinical practice. These encompass CNI replacement and immunosuppression withdrawal. Switching CNI to mTORi monotherapy is the option most commonly adopted to relieve renal function and compensate for posttransplant malignancies. Its impact is dependent on interval from transplantation and underlying severity of renal impairment. Introduction of mTORi is associated with longer overall survival for patients with extrahepatic posttransplant malignancies, but results are awaited for recurrences of hepatocellular carcinoma. Immunosuppression withdrawal seems feasible (70%) in very long term survivors (>10 years), but is not associated with reversal of immunosuppression-related complications. Awaiting novel immunosuppressive drug categories, integration of upfront strategies with the aim to reduce CNI-exposure and a low threshold for adjustment in the posttransplant course are both advisable to improve long-term outcomes of LT.
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Rodríguez‐Perálvarez M, Guerrero‐Misas M, Thorburn D, Davidson BR, Tsochatzis E, Gurusamy KS. Maintenance immunosuppression for adults undergoing liver transplantation: a network meta-analysis. Cochrane Database Syst Rev 2017; 3:CD011639. [PMID: 28362060 PMCID: PMC6464256 DOI: 10.1002/14651858.cd011639.pub2] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND As part of liver transplantation, immunosuppression (suppressing the host immunity) is given to prevent graft rejections resulting from the immune response of the body against transplanted organ or tissues from a different person whose tissue antigens are not compatible with those of the recipient. The optimal maintenance immunosuppressive regimen after liver transplantation remains uncertain. OBJECTIVES To assess the comparative benefits and harms of different maintenance immunosuppressive regimens in adults undergoing liver transplantation through a network meta-analysis and to generate rankings of the different immunosuppressive regimens according to their safety and efficacy. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until October 2016 to identify randomised clinical trials on immunosuppression for liver transplantation. SELECTION CRITERIA We included only randomised clinical trials (irrespective of language, blinding, or publication status) in adult participants undergoing liver transplantation (or liver retransplantation) for any reason. We excluded trials in which participants had undergone multivisceral transplantation or participants with established graft rejections. We considered any of the various maintenance immunosuppressive regimens compared with each other. DATA COLLECTION AND ANALYSIS We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio, rate ratio, and hazard ratio (HR) with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. MAIN RESULTS We included a total of 26 trials (3842 participants) in the review, and 23 trials (3693 participants) were included in one or more outcomes in the review. The vast majority of the participants underwent primary liver transplantation. All of the trials were at high risk of bias, and all of the evidence was of low or very low quality. In addition, because of sparse data involving trials at high risk of bias, it is not possible to entirely rely on the results of the network meta-analysis. The trials included mainly participants undergoing primary liver transplantation of varied aetiologies. The follow-up in the trials ranged from 3 to 144 months. The most common maintenance immunosuppression used as a control was tacrolimus. There was no evidence of difference in mortality (21 trials; 3492 participants) or graft loss (15 trials; 2961 participants) at maximal follow-up between the different maintenance immunosuppressive regimens based on the network meta-analysis. In the direct comparison, based on a single trial including 222 participants, tacrolimus plus sirolimus had increased mortality (HR 2.76, 95% CrI 1.30 to 6.69) and graft loss (HR 2.34, 95% CrI 1.28 to 4.61) at maximal follow-up compared with tacrolimus. There was no evidence of differences in the proportion of people with serious adverse events (1 trial; 719 participants), proportion of people with any adverse events (2 trials; 940 participants), renal impairment (8 trials; 2233 participants), chronic kidney disease (1 trial; 100 participants), graft rejections (any) (16 trials; 2726 participants), and graft rejections requiring treatment (5 trials; 1025 participants) between the different immunosuppressive regimens. The network meta-analysis showed that the number of adverse events was lower with cyclosporine A than with many other immunosuppressive regimens (12 trials; 1748 participants), and the risk of retransplantation (13 trials; 1994 participants) was higher with cyclosporine A than with tacrolimus (HR 3.08, 95% CrI 1.13 to 9.90). None of the trials reported number of serious adverse events, health-related quality of life, or costs. FUNDING 14 trials were funded by pharmaceutical companies who would benefit from the results of the trial; two trials were funded by parties who had no vested interest in the results of the trial; and 10 trials did not report the source of funding. AUTHORS' CONCLUSIONS Based on low-quality evidence from a single small trial from direct comparison, tacrolimus plus sirolimus increases mortality and graft loss at maximal follow-up compared with tacrolimus. Based on very low-quality evidence from network meta-analysis, we found no evidence of difference between different immunosuppressive regimens. We found very low-quality evidence from network meta-analysis and low-quality evidence from direct comparison that cyclosporine A causes more retransplantation compared with tacrolimus. Future randomised clinical trials should be adequately powered; performed in people who are generally seen in the clinic rather than in highly selected participants; employ blinding; avoid postrandomisation dropouts or planned cross-overs; and use clinically important outcomes such as mortality, graft loss, renal impairment, chronic kidney disease, and retransplantation. Such trials should use tacrolimus as one of the control groups. Moreover, such trials ought to be designed in such a way as to ensure low risk of bias and low risks of random errors.
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Affiliation(s)
- Manuel Rodríguez‐Perálvarez
- Reina Sofía University Hospital, IMIBIC, CIBERehdHepatology and Liver TransplantationAvenida Menéndez Pidal s/nCórdobaSpain14004
| | - Marta Guerrero‐Misas
- Reina Sofía University Hospital, IMIBIC, CIBERehdHepatology and Liver TransplantationAvenida Menéndez Pidal s/nCórdobaSpain14004
| | - Douglas Thorburn
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetLondonUKNW3 2QG
| | - Brian R Davidson
- Royal Free Campus, UCL Medical SchoolDepartment of SurgeryPond StreetLondonUKNW3 2QG
| | - Emmanuel Tsochatzis
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetLondonUKNW3 2QG
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