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Vionnet J, Torres-Yaguana J, Miquel R, Abraldes JG, Wall J, Kodela E, Lozano JJ, Ruiz P, Navasa M, Marshall A, Nevens F, Gelson W, Leithead J, Masson S, Jaeckel E, Taubert R, Tachtatzis P, Eurich D, Simpson KJ, Bonaccorsi-Riani E, Ferguson J, Quaglia A, Demetris AJ, Lesniak AJ, Elstad M, Delord M, Douiri A, Rebollo-Mesa I, Martinez-Llordella M, Silva JAF, Markmann JF, Sánchez-Fueyo A. Randomized trial investigating the utility of a liver tissue transcriptional biomarker in identifying adult liver transplant recipients not requiring maintenance immunosuppression. Am J Transplant 2025; 25:1045-1058. [PMID: 39706366 DOI: 10.1016/j.ajt.2024.12.002] [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: 10/01/2024] [Revised: 11/23/2024] [Accepted: 12/03/2024] [Indexed: 12/23/2024]
Abstract
The maintenance of stable allograft status in the absence of immunosuppression (IS), known as operational tolerance, can be achieved in a small proportion of liver transplant recipients, but we lack reliable tools to predict its spontaneous development. We conducted a prospective, multicenter, biomarker-strategy design, IS withdrawal clinical trial to determine the utility of a predictive biomarker of operational tolerance. The biomarker test, originally identified in a patient cohort with high operational tolerance prevalence, consisted of a 5-gene transcriptional signature measured in liver tissue collected before initiating IS weaning. One hundred sixteen adult stable liver transplant recipients were randomized 1:1 to either arm A (IS withdrawal regardless of biomarker status) or arm B (IS withdrawal in biomarker-positive recipients). Immunosuppression withdrawal was initiated in 82 participants, rejection occurred in 54 (67.5%), and successful discontinuation of IS was achieved in 22 (27.5%), but only 13 (16.3%) met operational tolerance histologic criteria (10 in arm A; 3 in arm B). The biomarker test did not yield useful information in selecting patients able to successfully discontinue IS. Operational tolerance was associated with time posttransplant, recipient age, presence of circulating exhausted CD8+ T cells, and a reduced number of immune synapses within the graft.
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Affiliation(s)
- Julien Vionnet
- Institute of Liver Studies, School of Immunology and Microbial Sciences, King's College London University and King's College Hospital, London, UK; Transplantation Center, Service of Immunology and Allergy, and Servide of Gastroenterology and Hepatology, University Hospital of Lausanne, Lausanne, Switzerland
| | - Jorge Torres-Yaguana
- Institute of Liver Studies, School of Immunology and Microbial Sciences, King's College London University and King's College Hospital, London, UK
| | - Rosa Miquel
- Institute of Liver Studies, School of Immunology and Microbial Sciences, King's College London University and King's College Hospital, London, UK; Liver Histopathology Laboratory, King's College Hospital, London, UK
| | - Juan G Abraldes
- Liver Unit, Division of Gastroenterology, University of Alberta, Edmonton, Canada; Centre of Excellence for Gastrointestinal Inflammation and Immunity Research, University of Alberta, Edmonton, Canada
| | - Jurate Wall
- Institute of Liver Studies, School of Immunology and Microbial Sciences, King's College London University and King's College Hospital, London, UK
| | - Elisavet Kodela
- Institute of Liver Studies, School of Immunology and Microbial Sciences, King's College London University and King's College Hospital, London, UK
| | - Juan-Jose Lozano
- Bioinformatic Platform, Biomedical Research Center in Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III, Barcelona, Spain
| | - Pablo Ruiz
- Hospital Clinic Barcelona, Instituto de Investigaciones Biomédicas August Pi Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Miguel Navasa
- Hospital Clinic Barcelona, Instituto de Investigaciones Biomédicas August Pi Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Aileen Marshall
- Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London, UK
| | - Frederik Nevens
- Department of Hepatology, University Hospital Leuven, Leuven, Belgium
| | - Will Gelson
- Cambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Joanna Leithead
- Cambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Steven Masson
- Newcastle National Institute for Health and Care Research (NIHR) Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | | | | | | | | | - James Ferguson
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust and National Institute for Health and Social Care Research (NIHR) Birmingham Biomedical Research Centre (BRC), Centre for Liver and Gastrointestinal Research, University of Birmingham, Birmingham B15 2TT, UK
| | - Alberto Quaglia
- Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London, UK
| | - Anthony J Demetris
- Department of Pathology, Division of Transplantation, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Andrew J Lesniak
- Department of Pathology, Division of Transplantation, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Maria Elstad
- School of Population Health and Environmental Sciences, King's College London, London, UK
| | - Marc Delord
- School of Population Health and Environmental Sciences, King's College London, London, UK
| | - Abdel Douiri
- School of Population Health and Environmental Sciences, King's College London, London, UK
| | - Irene Rebollo-Mesa
- School of Population Health and Environmental Sciences, King's College London, London, UK
| | - Marc Martinez-Llordella
- Institute of Liver Studies, School of Immunology and Microbial Sciences, King's College London University and King's College Hospital, London, UK; Quell Therapeutics Ltd, London, UK
| | - Juliete A F Silva
- Immune Tolerance Network, Seattle, Washington, USA; Emory University, School of Medicine, Department of Surgery, Division of Transplantation, Atlanta, USA
| | - James F Markmann
- Penn Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Alberto Sánchez-Fueyo
- Institute of Liver Studies, School of Immunology and Microbial Sciences, King's College London University and King's College Hospital, London, UK.
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Tanimine N, Markmann JF, Wood-Trageser MA, Demetris AJ, Mason K, Silva JAF, Levitsky J, Feng S, Humar A, Emond JC, Shaked A, Klintmalm G, Sanchez-Fueyo A, Lesniak D, Breeden CP, Nepom GT, Bridges ND, Goldstein J, Larsen CP, DesMarais M, Gaile G, Chandran S. Donor-specific immune senescence as a candidate biomarker of operational tolerance following liver transplantation in adults: Results of a prospective, multicenter cohort study. Am J Transplant 2025; 25:1030-1044. [PMID: 39505152 DOI: 10.1016/j.ajt.2024.10.022] [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: 05/10/2024] [Revised: 10/16/2024] [Accepted: 10/28/2024] [Indexed: 11/08/2024]
Abstract
Immunosuppression can be withdrawn from selected liver transplant recipients, although robust clinical predictors of tolerance remain elusive. The Immune Tolerance Network ITN056ST study (OPTIMAL; NCT02533180) assessed clinical outcomes and mechanistic correlates of phased immunosuppression withdrawal (ISW) in nonautoimmune, nonviral adult liver transplant recipients. Enrolled subjects were ≥3 years posttransplant with minimal/absent inflammation or fibrosis on a screening liver biopsy. The primary end point was operational tolerance at 52 weeks following complete ISW. Of 61 subjects who initiated ISW, 34 failed during ISW and 10 restarted immunosuppression after completing ISW due to clinically manifest acute rejection. Only 10 of 17 clinically stable subjects remaining off immunosuppression at 1 year were ultimately deemed tolerant by biopsy. There were no cases of chronic rejection or graft loss; 28.3% developed de novo donor-specific antibody during ISW, which persisted in 11.3%. The majority of subjects (78.6%), including those who experienced rejection, ended the study on same or less calcineurin inhibitor than at baseline. A minority (16.4%) of histologically and clinically stable long-term adult liver transplant recipients can successfully discontinue and remain off immunosuppression. Increased frequency of donor-specific T cell senescence, C4d deposition, and higher density of immune synapses on the screening liver biopsy emerged as potential candidate biomarkers for operational tolerance.
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Affiliation(s)
- Naoki Tanimine
- Department of Gastroenterological and Transplant Surgery, Hiroshima University, Higashihiroshima, Japan
| | | | | | - Anthony J Demetris
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | | | - Juliete A F Silva
- Emory Transplant Center, Emory University, Atlanta, Georgia, USA; Immune Tolerance Network, Seattle, Washington, USA
| | - Josh Levitsky
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Sandy Feng
- Department of Surgery, University of California-San Francisco, San Francisco, California, USA
| | - Abhinav Humar
- Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Jean C Emond
- Department of Surgery, Columbia University Irving Medical Center, New York, New York, USA
| | - Abraham Shaked
- Department of Gastroenterological and Transplant Surgery, Hiroshima University, Higashihiroshima, Japan
| | - Goran Klintmalm
- Department of Surgery, Baylor University Medical Center, Dallas, Texas, USA
| | - Alberto Sanchez-Fueyo
- Institute of Liver Studies, King's College Hospital, Medical Research Council (MRC) Centre for Transplantation, King's College London University, London, UK
| | - Drew Lesniak
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Cynthia P Breeden
- Emory Transplant Center, Emory University, Atlanta, Georgia, USA; Immune Tolerance Network, Seattle, Washington, USA
| | | | - Nancy D Bridges
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Julia Goldstein
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Christian P Larsen
- Emory Transplant Center, Emory University, Atlanta, Georgia, USA; Immune Tolerance Network, Seattle, Washington, USA
| | | | - Geo Gaile
- Immune Tolerance Network, Seattle, Washington, USA
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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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Chu J, Bucuvalas J. Progress and challenges in assessing allograft health in liver transplantation. Liver Transpl 2025; 31:267-268. [PMID: 39466042 DOI: 10.1097/lvt.0000000000000527] [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: 10/22/2024] [Accepted: 10/22/2024] [Indexed: 10/29/2024]
Affiliation(s)
- Jaime Chu
- Icahn School of Medicine at Mount Sinai, Recanati/Miller Transplantation Institute, New York, New York, USA
| | - John Bucuvalas
- Jack and Lucy Clark Department of Pediatrics, Mount Sinai Kravis Children's Hospital, Recanati/Miller Transplantation Institute, New York, New York, USA
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Xia Q, Feng MX. Challenges for pediatric liver transplantation in the mainland of China: Where we are and where to go. Reflections from worldwide largest pediatric liver transplantation program. Hepatobiliary Pancreat Dis Int 2025; 24:35-38. [PMID: 39643582 DOI: 10.1016/j.hbpd.2024.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 11/12/2024] [Indexed: 12/09/2024]
Abstract
In China pediatric liver transplantation (PLT) has become a safe and standardized procedure. Innovations and measures to further improve long-term survival and quality of life for children should be the next focus. In particular better strategies related to the surgical treatment of high-risk recipients as well as the long-term follow-up of pediatric liver recipients have to be addressed. A particular attention should be given to children presenting significant co-morbidities and those needing retransplantation. A tight multidisciplinary follow-up system addressing both short- and long-term issues of pediatric liver recipients is still a challenge for the Chinese pediatric transplant community.
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Affiliation(s)
- Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200000, China.
| | - Ming-Xuan Feng
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200000, China
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Thompson JC, Levis Rabi M, Novoa M, Nash KR, Joly-Amado A. Evaluating the Efficacy of Levetiracetam on Non-Cognitive Symptoms and Pathology in a Tau Mouse Model. Biomedicines 2024; 12:2891. [PMID: 39767797 PMCID: PMC11727630 DOI: 10.3390/biomedicines12122891] [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: 11/18/2024] [Revised: 12/13/2024] [Accepted: 12/15/2024] [Indexed: 01/16/2025] Open
Abstract
Background/Objectives: Alzheimer's disease (AD) is marked by amyloid-β plaques and hyperphosphorylated tau neurofibrillary tangles (NFTs), leading to cognitive decline and debilitating non-cognitive symptoms. This study aimed to evaluate compounds from four different classes in a short-term (7-day) study using transgenic tau mice to assess their ability to reduce non-cognitive symptoms. The best candidate was then evaluated for longer exposure to assess non-cognitive symptoms, cognition, and pathology. Methods: Tg4510 mice, expressing mutated human tau (P301L), were administered with levetiracetam, methylphenidate, diazepam, and quetiapine for 7 days at 6 months old, when pathology and cognitive deficits are established. Drugs were given in the diet, and non-cognitive symptoms were evaluated using metabolic cages. Levetiracetam was chosen for longer exposure (3 months) in 3-month-old Tg4510 mice and non-transgenic controls to assess behavior and pathology. Results: After 3 months of diet, levetiracetam mildly reduced tau pathology in the hippocampus but did not improve cognition in Tg4510 mice. Interestingly, it influenced appetite, body weight, anxiety-like behavior, and contextual fear memory in non-transgenic animals but not in Tg4510 mice. Conclusions: While levetiracetam has shown benefits in amyloid deposition models, it had limited effects on tau pathology and behavior in an animal model of tau deposition, which is crucial for AD context. The differential effects on non-transgenic versus Tg4510 mice warrant further investigation.
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Affiliation(s)
| | | | | | | | - Aurelie Joly-Amado
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA; (J.C.T.); (M.L.R.); (M.N.); (K.R.N.)
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7
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Chichelnitskiy E, Goldschmidt I, Ruhl L, Rübsamen N, Jaeger VK, Karch A, Beushausen K, Keil J, Götz JK, D'Antiga L, Debray D, Hierro L, Kelly D, McLin V, Pawlowska J, Mikolajczyk RT, Bravi M, Klaudel-Dreszler M, Demir Z, Lloyd C, Korff S, Baumann U, Falk CS. Plasma immune signatures can predict rejection-free survival in the first year after pediatric liver transplantation. J Hepatol 2024; 81:862-871. [PMID: 38821361 DOI: 10.1016/j.jhep.2024.05.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 05/06/2024] [Accepted: 05/17/2024] [Indexed: 06/02/2024]
Abstract
BACKGROUND & AIMS After pediatric liver transplantation (pLT), children undergo life-long immunosuppression since reliable biomarkers for the assessment of rejection probability are scarce. In the multicenter (n = 7) prospective clinical cohort "ChilSFree" study, we aimed to characterize longitudinal dynamics of soluble and cellular immune mediators during the first year after pLT and identify early biomarkers associated with outcome. METHODS Using a Luminex-based multiplex technique paired with flow cytometry, we characterized longitudinal dynamics of soluble immune mediators (SIMs, n = 50) and immune cells in the blood of 244 patients at eight visits over 1 year: before, and 7/14/21/28 days and 3/6/12 months after pLT. RESULTS The unsupervised clustering of patients based on SIM profiles revealed six unique SIM signatures associated with clinical outcome. From three signatures linked to improved outcome, one was associated with 1-year-long rejection-free survival and stable graft function and was characterized by low levels of pro-inflammatory SIMs (CXCL8/9/10/12, CCL7, SCGF-β, sICAM-1), and high levels of regenerative (SCF, TNF-β) and pro-apoptotic (TRAIL) SIMs (all, p <0.001, fold change >100). Of note, this SIM signature appeared 2 weeks after pLT and remained stable over the entire year, pointing towards its potential as a novel early biomarker for minimizing or weaning immunosuppression. In the blood of these patients, a higher frequency of CD56bright natural killer cells (p <0.01), a known hallmark also associated with operationally tolerant pLT patients, was detected. The concordance of the model for prediction of rejection based on identified SIM signatures was 0.715, and 0.795, in combination with living-related transplantation as a covariate, respectively. CONCLUSIONS SIM blood signatures may enable the non-invasive and early assessment of rejection risks in the first year after pLT, paving the way for improved clinical management. IMPACT AND IMPLICATIONS ChilSFree represents the largest pediatric liver transplant (pLT) cohort with paired longitudinal data on soluble immune mediators (SIMs) and immune phenotyping in the first year after pLT. SIM signatures allow for the selection of rejection-free patients 2 weeks after pLT independently of patient diagnosis, sex, or age. The SIM signatures may enable the non-invasive and early assessment of rejection risks, paving the way for minimization or withdrawal of immunosuppression after pLT.
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Affiliation(s)
- Evgeny Chichelnitskiy
- Institute of Transplant Immunology, Hannover Medical School (MHH), Hannover, Germany
| | - Imeke Goldschmidt
- Division of Pediatric Gastroenterology and Hepatology, MHH, Hannover, Germany; European Pediatric Liver Transplantation Network, Germany
| | - Louisa Ruhl
- Institute of Transplant Immunology, Hannover Medical School (MHH), Hannover, Germany
| | - Nicole Rübsamen
- Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany
| | - Veronika K Jaeger
- Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany
| | - Andre Karch
- Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany
| | - Kerstin Beushausen
- Institute of Transplant Immunology, Hannover Medical School (MHH), Hannover, Germany
| | - Jana Keil
- Institute of Transplant Immunology, Hannover Medical School (MHH), Hannover, Germany
| | - Juliane K Götz
- Division of Pediatric Gastroenterology and Hepatology, MHH, Hannover, Germany
| | - Lorenzo D'Antiga
- Pediatric Department, Hospital Papa Giovanni XXIII Bergamo, Italy; European Pediatric Liver Transplantation Network, Germany; Department of Medicine and Surgery, University of Milano - Bicocca, 20126 Milan, Italy
| | - Dominique Debray
- Pediatric liver unit, Hôpital Necker-Enfants Malades, Paris, France; European Pediatric Liver Transplantation Network, Germany
| | - Loreto Hierro
- Hospital Infantil Universitario La Paz, Madrid, Spain; European Pediatric Liver Transplantation Network, Germany
| | - Deirdre Kelly
- Birmingham Women's & Children's Hospital, and University of Birmingham, UK; European Pediatric Liver Transplantation Network, Germany
| | - Valerie McLin
- Swiss Pediatric Liver Center, Department of Pediatrics, Gynecology, and Obstetrics, University Hospitals Geneva, University of Geneva, Geneva, Switzerland; European Pediatric Liver Transplantation Network, Germany
| | - Joanna Pawlowska
- Department of Gastroenterology, Hepatology, Nutritional Disorders, and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Rafael T Mikolajczyk
- Institute of Medical Epidemiology, Biostatistics and Medical Informatics, University of Halle, Halle, Germany
| | - Michela Bravi
- Pediatric Department, Hospital Papa Giovanni XXIII Bergamo, Italy; European Pediatric Liver Transplantation Network, Germany
| | - Maja Klaudel-Dreszler
- Department of Gastroenterology, Hepatology, Nutritional Disorders, and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Zeynep Demir
- Pediatric liver unit, Hôpital Necker-Enfants Malades, Paris, France; European Pediatric Liver Transplantation Network, Germany
| | - Carla Lloyd
- Birmingham Women's & Children's Hospital, and University of Birmingham, UK; European Pediatric Liver Transplantation Network, Germany
| | - Simona Korff
- Swiss Pediatric Liver Center, Department of Pediatrics, Gynecology, and Obstetrics, University Hospitals Geneva, University of Geneva, Geneva, Switzerland; European Pediatric Liver Transplantation Network, Germany
| | - Ulrich Baumann
- Division of Pediatric Gastroenterology and Hepatology, MHH, Hannover, Germany; European Pediatric Liver Transplantation Network, Germany
| | - Christine S Falk
- Institute of Transplant Immunology, Hannover Medical School (MHH), Hannover, Germany; German Centre for Infection Research, TTU-IICH Hannover, Hannover, Germany.
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8
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Wang B, Zhou A, Wu Y, Pan Q, Wei X, Gao Y, Xiao W, Jin J, Zhou T, Luo Y, Zhan Z, Liu Y, Gao W, Liu Y, Xia Q. Establishment and validation of a predictive model of immune tolerance after pediatric liver transplantation: a multicenter cohort study. Int J Surg 2024; 110:5615-5626. [PMID: 38833360 PMCID: PMC11392161 DOI: 10.1097/js9.0000000000001671] [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: 01/25/2024] [Accepted: 05/09/2024] [Indexed: 06/06/2024]
Abstract
Background: Side-effect of life-long immunosuppressants (IS) administration is a major obstacle for the long-term survival of pediatric liver transplantation (LT) recipients. Immunotolerance is the status that recipients discontinued IS with normal liver function and intrahepatic histology. So far, only a few clinical parameters were identified related with tolerance but failed to accurately discriminate tolerant recipients in clinical practice. Here, the authors aimed to provide a comprehensive view of pre-LT and post-LT risk factors associated with the achievement of tolerance after pediatric LT and established a tolerance predictive nomogram (ITPLT) with high accuracy and specificity. Methods: The authors enrolled 2228 pediatric recipients who received LT in Renji Hospital between October 2006 and December 2020. All participants survived over 3 years after transplantation with comprehensive and intact medical history and follow-up data. They were randomly assigned to training and validation cohorts in accordance with a ratio of 1:1. Univariate and multivariable Logistic regression were used to identify clinical factors associated with post-LT immune tolerance and establish a predictive model. The model was further validated in an independent external validation cohort from Tianjin First Central Hospital. Results: Among all participants, 6% recipients successfully tapered IS with intact allograft function. The most common reason for IS discontinuity was pneumonia. Univariate analysis identified 15 clinical factors associated with tolerance achievement, including age at LT, follow-up time, preoperative total bilirubin, creatinine, INR, CYP polymorphism, types of transplantation, massive postoperative ascites, episodes of acute rejection, and the severity of EBV and CMV infection. Using multivariable Logistic regression, the authors established the predictive ITPLT model for post-LT tolerance, which included seven easily accessible clinical factors (age at LT, CYP3A5 genotype, types of transplantation, post-LT massive ascites, preoperative INR, creatinine, and total bilirubin levels). Then, the authors visualized the model using nomogram. The c -statistics for predicting tolerance achievement in the training, internal validation, and external validation cohorts were 0.854, 0.787, and 0.746, respectively. Conclusion: Multiple pre-LT and post-LT clinical factors affected the process of immune remodeling after pediatric LT. The predictive ITPLT model, composed of seven easily accessible clinical factors, could comprehensively reveal the effect of these clinical parameters on immune remodeling and accurately identify tolerant recipients after pediatric LT. The application of ITPLT could facilitate the individualized IS strategy in the future.
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Affiliation(s)
- Bingran Wang
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Aiwei Zhou
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Yichi Wu
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Qi Pan
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Xinzhe Wei
- Department of Pediatric Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin
| | - Yunmu Gao
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Wanglong Xiao
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Jing Jin
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Tao Zhou
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Yi Luo
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | | | - Yongbo Liu
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
- Shanghai Institute of Transplantation
| | - Wei Gao
- Department of Pediatric Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin
| | - Yuan Liu
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
- Shanghai Immune Therapy Institute
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
- Shanghai Institute of Transplantation
- Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai, People’s Republic of China
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9
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Chapin CA, Whitehead B, Shakhin V, Taylor SA, Kriegermeier A, Mohammad S, Alonso EM. Immunosuppression minimization is safe and associated with good long-term success in pediatric recipients of liver transplant. Liver Transpl 2024; 30:707-716. [PMID: 37934051 DOI: 10.1097/lvt.0000000000000300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 11/02/2023] [Indexed: 11/08/2023]
Abstract
Immunosuppression reduction after liver transplant is an important strategy to mitigate long-term medication side effects. We describe our center's experience with immunosuppression minimization to once-daily calcineurin inhibitor dosing. Success was defined as continuing daily calcineurin inhibitor monotherapy with normal transaminases and no rejection. We performed a retrospective review of eligible children who received a liver transplant between 2009 and 2016, had a surveillance biopsy, and were on twice-daily calcineurin inhibitor monotherapy. Twenty-eight of 51 eligible patients were minimized to daily calcineurin inhibitor with goal 12-hour trough detectable. Nineteen patients (68%) had 1-year success, and 17 (61%) had long-term success at a median follow-up of 5.0 years (interquartile range (IQR): 2.9-6.6). Minimization failure occurred at a median of 0.6 years (IQR: 0.3-1.0) after dose reduction. Patients with long-term success had lower aspartate aminotransferase levels prior to minimization compared to those who failed with a median of 28.0 IU/L (IQR: 20.5-32.0) versus 32.0 IU/L (IQR: 30.0-37.0), p = 0.047. The long-term success group demonstrated a trend toward greater recipients of liver transplant from living donors (53% vs. 18%, p = 0.07). At the time of the last follow-up at a median of 5.0 years (IQR: 2.9-6.1) after surveillance biopsy, most (73%) patients who failed had returned to twice-daily calcineurin inhibitor monotherapy, all had liver enzymes <2 times the upper limit of normal, and there were no patient deaths or graft losses. In conclusion, immunosuppression minimization is safe in pediatric recipients of liver transplant and should be considered to reduce long-term medication side effects and improve patient quality of life. Future studies are necessary to follow long-term outcomes and develop biomarkers to predict minimization success.
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Affiliation(s)
- Catherine A Chapin
- Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
| | - Bridget Whitehead
- Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
| | - Victoria Shakhin
- Department of Pediatrics, University of Michigan Health System, University of Michigan, C.S. Mott Children's Hospital, Ann Arbor, Michigan, USA
| | - Sarah A Taylor
- Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Alyssa Kriegermeier
- Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
| | - Saeed Mohammad
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Estella M Alonso
- Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
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10
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Diamond T, Rand EB. "Not too much, not too little, just right"-Finding the Goldilocks point in pediatric immunosuppression minimization. Liver Transpl 2024; 30:676-677. [PMID: 38270574 DOI: 10.1097/lvt.0000000000000334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 01/18/2024] [Indexed: 01/26/2024]
Affiliation(s)
- Tamir Diamond
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Elizabeth B Rand
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
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11
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Bellamy COC, O'Leary JG, Adeyi O, Baddour N, Batal I, Bucuvalas J, Del Bello A, El Hag M, El-Monayeri M, Farris AB, Feng S, Fiel MI, Fischer SE, Fung J, Grzyb K, Guimei M, Haga H, Hart J, Jackson AM, Jaeckel E, Khurram NA, Knechtle SJ, Lesniak D, Levitsky J, McCaughan G, McKenzie C, Mescoli C, Miquel R, Minervini MI, Nasser IA, Neil D, O'Neil MF, Pappo O, Randhawa P, Ruiz P, Fueyo AS, Schady D, Schiano T, Sebagh M, Smith M, Stevenson HL, Taner T, Taubert R, Thung S, Trunecka P, Wang HL, Wood-Trageser M, Yilmaz F, Zen Y, Zeevi A, Demetris AJ. Banff 2022 Liver Group Meeting report: Monitoring long-term allograft health. Am J Transplant 2024; 24:905-917. [PMID: 38461883 DOI: 10.1016/j.ajt.2024.03.008] [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: 09/12/2023] [Revised: 02/27/2024] [Accepted: 03/06/2024] [Indexed: 03/12/2024]
Abstract
The Banff Working Group on Liver Allograft Pathology met in September 2022. Participants included hepatologists, surgeons, pathologists, immunologists, and histocompatibility specialists. Presentations and discussions focused on the evaluation of long-term allograft health, including noninvasive and tissue monitoring, immunosuppression optimization, and long-term structural changes. Potential revision of the rejection classification scheme to better accommodate and communicate late T cell-mediated rejection patterns and related structural changes, such as nodular regenerative hyperplasia, were discussed. Improved stratification of long-term maintenance immunosuppression to match the heterogeneity of patient settings will be central to improving long-term patient survival. Such personalized therapeutics are in turn contingent on a better understanding and monitoring of allograft status within a rational decision-making approach, likely to be facilitated in implementation with emerging decision-support tools. Proposed revisions to rejection classification emerging from the meeting include the incorporation of interface hepatitis and fibrosis staging. These will be opened to online testing, modified accordingly, and subject to consensus discussion leading up to the next Banff conference.
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Affiliation(s)
- Christopher O C Bellamy
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland and Department of Pathology, Edinburgh Royal Infirmary, Edinburgh, Scotland.
| | - Jacqueline G O'Leary
- Dallas VA Medical Center & University of Texas, Southwestern, Department of Medicine, Dallas Texas, USA
| | - Oyedele Adeyi
- University of Minnesota Medical School, Department of Pathology, Minneapolis, Minnesota, USA
| | - Nahed Baddour
- Faculty of Medicine, University of Alexandria, Egypt
| | - Ibrahim Batal
- Pathology, Columbia University Irving Medical Center, New York, New York, USA
| | | | | | | | | | - Alton B Farris
- Pathology, Emory University Hospital, Atlanta, Georgia, USA
| | - Sandy Feng
- UCSF Health, Department of Surgery, San Francisco, California, USA
| | - Maria Isabel Fiel
- Pathology, Icahn School of Medicine, Mount Sinai, New York, New York, USA
| | | | - John Fung
- Uchicago Medicine, Department of Surgery, Chicago, Illinois, USA
| | | | - Maha Guimei
- Armed Forces College of Medicine, Cairo, Egypt
| | | | - John Hart
- Uchicago Medicine, Department of Pathology, Chicago, Illinois, USA
| | | | | | - Nigar A Khurram
- University of Pittsburgh Medical Center, Department of Pathology, Pittsburgh, Pennsylvania, USA
| | | | - Drew Lesniak
- University of Pittsburgh Medical Center, Department of Pathology, Pittsburgh, Pennsylvania, USA
| | | | | | | | | | - Rosa Miquel
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Marta I Minervini
- University of Pittsburgh Medical Center, Department of Pathology, Pittsburgh, Pennsylvania, USA
| | - Imad Ahmad Nasser
- Beth Israel Deaconess Medical Center, Harvard, Boston, Massachusetts, USA
| | - Desley Neil
- University Hospitals Birmingham NHS Foundation Trust, United Kingdom
| | - Maura F O'Neil
- University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Orit Pappo
- Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Parmjeet Randhawa
- University of Pittsburgh Medical Center, Department of Pathology, Pittsburgh, Pennsylvania, USA
| | - Phillip Ruiz
- University of Miami Hospital, Miami, Florida, USA
| | | | | | - Thomas Schiano
- Recanati/Miller Transplantation Institute, Mount Sinai Medical Center, New York, New York, USA
| | | | - Maxwell Smith
- Pathology, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | | | - Timucin Taner
- Division of Transplantation Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Richard Taubert
- Dept. of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Swan Thung
- Pathology, Icahn School of Medicine, Mount Sinai, New York, New York, USA
| | - Pavel Trunecka
- Institute for Clinical and Experimental Medicine (IKEM), Prague, Czechia
| | - Hanlin L Wang
- Pathology, UCLA Health, Los Angeles, California, USA
| | - Michelle Wood-Trageser
- University of Pittsburgh Medical Center, Department of Pathology, Pittsburgh, Pennsylvania, USA
| | - Funda Yilmaz
- Pathology, University of Ege, Imir, Bornova, Turkey
| | - Yoh Zen
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Adriana Zeevi
- University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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12
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Perito ER, McQueen M, Lau J, Krise-Confair C, Hillenburg JP, Mazariegos G, Squires JE. Patient-centered research in pediatric transplant: Engaging families and recipients. Am J Transplant 2024; 24:857-864. [PMID: 38325768 DOI: 10.1016/j.ajt.2024.01.030] [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: 09/06/2023] [Revised: 01/09/2024] [Accepted: 01/30/2024] [Indexed: 02/09/2024]
Abstract
Pediatric liver transplant (LT) recipients navigate a lifelong journey that includes constant monitoring and challenges. Research priorities and questions in LT have traditionally been provider-driven. This project was a novel partnership between a learning health system dedicated to pediatric LT (Starzl Network for Excellence in Pediatric Transplantation) and a parent-led advocacy group (Transplant Families) that aimed to prepare families and providers for collaborative patient-centered outcomes research (PCOR). We developed 5 virtual modules to (1) teach participants about PCOR, and (2) elicit ideas for PCOR priorities and processes in pediatric LT. Parents and providers participated via self-guided online modules or focus groups. Participants included 240 patient partners and 133 pediatric LT providers from 16 centers over 2 years. We held 20 focus groups, including 5 to amplify underrepresented voices: young adults, Spanish speakers, and African Americans. Feedback was summarized to create a PCOR Roadmap, a guide for future PCOR in the Starzl Network, which was disseminated back to participants online and via webinars. Feedback from a diverse group of stakeholders allowed us to develop PCOR priorities and processes for the pediatric LT community. Our engagement strategies could be adapted by other transplant communities to facilitate patient and provider research partnerships.
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Affiliation(s)
- Emily R Perito
- Department of Pediatrics, Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA.
| | | | - Jennifer Lau
- Transplant Families, Phoenix, Arizona, USA; Starzl Network for Excellence in Pediatric Transplantation Patient and Family Voice, Pittsburgh PA; Transplant Families, Phoenix, Arizona, USA
| | - Cassandra Krise-Confair
- Starzl Network for Excellence in Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | | | - George Mazariegos
- Department of Surgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - James E Squires
- Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
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13
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Shaji Mathew J, Shingina A, Khan MQ, Wilson E, Syn N, Rammohan A, Alconchel F, Hakeem AR, Shankar S, Patel D, Keskin O, Liu J, Nasralla D, Mazzola A, Patel MS, Tanaka T, Victor D, Yoon U, Yoon YI, Vinaixa C, Kirchner V, De Martin E, Ghobrial RM, Chadha R. Proceedings of the 28th Annual Congress of the International Liver Transplantation Society. Liver Transpl 2024; 30:544-554. [PMID: 38240602 DOI: 10.1097/lvt.0000000000000330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 12/09/2023] [Indexed: 02/16/2024]
Abstract
The 2023 Joint International Congress of the International Liver Transplantation Society (ILTS), the European Liver and Intestine Transplant Association (ELITA), and the Liver Intensive Care Group of Europe (LICAGE) held in Rotterdam, the Netherlands, marked a significant recovery milestone for the liver transplant community after COVID-19. With 1159 participants and a surge in abstract submissions, the event focused on "Liver Disorders and Transplantation: Innovations and Evolving Indications." This conference report provides a comprehensive overview of the key themes discussed during the event, encompassing Hepatology, Anesthesia and Critical Care, Acute Liver Failure, Infectious Disease, Immunosuppression, Pediatric Liver Transplantation, Living Donor Liver Transplantation, Transplant Oncology, Surgical Approaches, and Machine Perfusion. The congress provided a platform for extensive discussions on a wide range of topics, reflecting the continuous advancements and collaborative efforts within the liver transplant community.
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Affiliation(s)
- Johns Shaji Mathew
- Department of GI, HPB & Multi-Organ Transplant Surgery, Rajagiri Hospital, Kochi, Kerala, India
| | - Alexandra Shingina
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Mohammad Qasim Khan
- Division of Gastroenterology, Department of Medicine, University of Western Ontario, London, Ontario, Canada
| | - Elizabeth Wilson
- Department of Anesthesiology, Emory University Hospital, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Nicholas Syn
- Division of Biomedical Informatics, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ashwin Rammohan
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Centre, Bharath Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | | | - Abdul Rahman Hakeem
- Department of Hepatobiliary and Liver Transplant Surgery, St James's University Hospital NHS Trust, Leeds, UK
| | - Sadhana Shankar
- Institute of Liver Studies, King's College Hospital, London, UK
| | | | - Onur Keskin
- Department of Gastroenterology, Hacettepe University Medical School, Ankara, Turkey
| | - Jiang Liu
- Hepato-Pancreato-Biliary Center, Department of Medicine, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - David Nasralla
- Department of HPB and Liver Transplant Surgery, The Royal Free Hospital, London, UK
| | - Alessandra Mazzola
- Sorbonne Université, Unité médicale de transplantation hépatique, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France
| | - Madhukar S Patel
- Division of Surgical Transplantation, Department of Surgery, University of Texas, Southwestern Medical Center, Dallas, Texas, USA
| | - Tomohiro Tanaka
- Department of Internal Medicine, Gastroenterology and Hepatology, University of Iowa, Iowa City, Iowa, USA
| | - David Victor
- Sherrie and Alan Conover Center for Liver Disease and Transplantation. Houston Methodist Hospital, Houston, Texas, USA
| | - Uzung Yoon
- Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, USA
| | | | - Carmen Vinaixa
- Hepatology Unit, Digestive Diseases Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Varvara Kirchner
- Department of Surgery, Division of Abdominal Transplantation, Stanford University, Stanford, California, USA
| | - Eleonora De Martin
- AP-HP, Hôpital Paul-Brousse, Centre Hépato- Biliaire, Unité INSERM 1193, Villejuif, France
| | - R Mark Ghobrial
- J.C. Walter Jr, Transplant Center, Department of Surgery, Weill Cornell Medical College, Houston Methodist Institute for Academic Medicine, Houston, Texas, USA
| | - Ryan Chadha
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Jacksonville, Florida, USA
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14
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Zhou AW, Jin J, Liu Y. Cellular strategies to induce immune tolerance after liver transplantation: Clinical perspectives. World J Gastroenterol 2024; 30:1791-1800. [PMID: 38659486 PMCID: PMC11036497 DOI: 10.3748/wjg.v30.i13.1791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 02/03/2024] [Accepted: 03/14/2024] [Indexed: 04/03/2024] Open
Abstract
Liver transplantation (LT) has become the most efficient treatment for pediatric and adult end-stage liver disease and the survival time after transplantation is becoming longer due to the development of surgical techniques and perioperative management. However, long-term side-effects of immunosuppressants, like infection, metabolic disorders and malignant tumor are gaining more attention. Immune tolerance is the status in which LT recipients no longer need to take any immunosuppressants, but the liver function and intrahepatic histology maintain normal. The approaches to achieve immune tolerance after transplantation include spontaneous, operational and induced tolerance. The first two means require no specific intervention but withdrawing immunosuppressant gradually during follow-up. No clinical factors or biomarkers so far could accurately predict who are suitable for immunosuppressant withdraw after transplantation. With the understanding to the underlying mechanisms of immune tolerance, many strategies have been developed to induce tolerance in LT recipients. Cellular strategy is one of the most promising methods for immune tolerance induction, including chimerism induced by hematopoietic stem cells and adoptive transfer of regulatory immune cells. The safety and efficacy of various cell products have been evaluated by prospective preclinical and clinical trials, while obstacles still exist before translating into clinical practice. Here, we will summarize the latest perspectives and concerns on the clinical application of cellular strategies in LT recipients.
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Affiliation(s)
- Ai-Wei Zhou
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Jing Jin
- Department of Nursing, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Yuan Liu
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
- Department of Liver Transplantation, Shanghai Immune Therapy Institute, Shanghai 200127, China
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15
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Peters AL, DePasquale EA, Begum G, Roskin KM, Woodle ES, Hildeman DA. Defining the T cell transcriptional landscape in pediatric liver transplant rejection at single cell resolution. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.26.582173. [PMID: 38464256 PMCID: PMC10925238 DOI: 10.1101/2024.02.26.582173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
Acute cellular rejection (ACR) affects >80% of pediatric liver transplant recipients within 5 years, and late ACR is associated with graft failure. Traditional anti-rejection therapy for late ACR is ineffective and has remained unchanged for six decades. Although CD8+ T cells promote late ACR, little has been done to define their specificity and gene expression. Here, we used single-cell sequencing and immune repertoire profiling (10X Genomics) on 30 cryopreserved 16G liver biopsies from 14 patients (5 pre-transplant or with no ACR, 9 with ACR). We identified expanded intragraft CD8+ T cell clonotypes (CD8EXP) and their gene expression profiles in response to anti-rejection treatment. Notably, we found that expanded CD8+ clonotypes (CD8EXP) bore markers of effector and CD56hiCD161- 'NK-like' T cells, retaining their clonotype identity and phenotype in subsequent biopsies from the same patients despite histologic ACR resolution. CD8EXP clonotypes localized to portal infiltrates during active ACR, and persisted in the lobule after histologic ACR resolution. CellPhoneDB analysis revealed differential crosstalk between KC and CD8EXP during late ACR, with activation of the LTB-LTBR pathway and downregulation of TGFß signaling. Therefore, persistently-detected intragraft CD8EXP clones remain active despite ACR treatment and may contribute to long-term allograft fibrosis and failure of operational tolerance.
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Affiliation(s)
- Anna L. Peters
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Erica A.K. DePasquale
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - Gousia Begum
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - Krishna M. Roskin
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - E. Steve Woodle
- Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - David A. Hildeman
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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16
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Kortbeek S, Anderson SG, Alonso EM, Rand EB, Bucuvalas J, Mazariegos GV, Campbell KM, Lobritto SJ, Feldman AG, Mysore KR, Anand R, Selzner N, Ng VL. Immunosuppression-Free Life after Pediatric Liver Transplant: A Case-Control Study from the Society of Pediatric Liver Transplant (SPLIT) Registry. J Pediatr 2024; 264:113744. [PMID: 37726087 DOI: 10.1016/j.jpeds.2023.113744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 08/29/2023] [Accepted: 09/13/2023] [Indexed: 09/21/2023]
Abstract
OBJECTIVE To compare long-term outcomes of pediatric liver transplant (LT) recipients off immunosuppression (IS) with matched controls on IS using data from the Society of Pediatric Liver Transplant (SPLIT) registry. STUDY DESIGN This was a retrospective case-control study. SPLIT participants <18 years of age, ≥4 years after isolated LT, and off IS for ≥1 year (cases) were age- and sex-matched 1:2 to patients with the same primary diagnosis and post-LT follow-up duration (controls). Primary outcomes included retransplantation, allograft rejection, IS comorbidities, and prevalence of SPLIT-derived composite ideal outcome (c-IO) achieved at the end of the follow-up period. Differences were compared using multiple linear regression for continuous outcomes and logistic regression for dichotomous data. RESULTS The study cohort was composed of 33 cases (42.4% male, 60.6% biliary atresia, median age at LT of 0.7 [P25, P75, 0.5, 1.6] years, median IS withdrawal time of 9 [P25, P75, 6, 12] years after LT) and 66 age- and sex-matched controls. No cases required retransplantation. Cases and controls had similar growth parameters, laboratory values, calculated glomerular filtration rates, rates of post-transplant lymphoproliferative disease, graft rejection, and attainment of c-IO. CONCLUSIONS No differences in allograft rejection rates, IS complications, or c-IO prevalence were seen between SPLIT patients off IS and age- and sex-matched controls remaining on IS. Discontinuation of IS most commonly occurred in the context of rigorously designed IS withdrawal trials. The available sample size was small, affecting generalizability to the broader pediatric LT population.
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Affiliation(s)
- Simone Kortbeek
- Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Alberta Children's Hospital, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | | | - Estella M Alonso
- Division of Gastroenterology, Hepatology, and Nutrition, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Elizabeth B Rand
- Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA
| | - John Bucuvalas
- Division of Pediatric Hepatology, Icahn School of Medicine at Mount Sinai, New York, NY
| | - George V Mazariegos
- Division of Transplantation Surgery, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Kathleen M Campbell
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Steven J Lobritto
- Division of Gastroenterology, Hepatology, and Nutrition, Columbia University Irving Medical Center, New York, NY
| | - Amy G Feldman
- Division of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Digestive Health Institute, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO
| | - Krupa R Mysore
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX
| | | | - Nazia Selzner
- Ajmera Transplant Center, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Vicky L Ng
- Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Transplant and Regenerative Medicine Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
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17
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Yao M, Henriksson J, Fahlander H, Guisti Coitinho P, Lundgren T, Ågren N, Ericzon BG, Kumagai-Braesch M. Evaluation of Methods to Obtain Peripheral Blood Mononuclear Cells From Deceased Donors for Tolerance-Induction Protocols. Cell Transplant 2024; 33:9636897241256462. [PMID: 38808671 PMCID: PMC11143843 DOI: 10.1177/09636897241256462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 05/01/2024] [Accepted: 05/06/2024] [Indexed: 05/30/2024] Open
Abstract
Regulatory cell therapies have shown promise in tolerance-induction protocols in living donor organ transplantation. These protocols should be pursued in deceased donor transplantation. Donor peripheral mononuclear cells (PBMCs) are an optimal source of donor antigens for the induction of donor-specific regulatory cells. During the development of a regulatory cell tolerance-induction protocol with organs from deceased donors, we compared 3 methods of obtaining PBMCs from deceased donors focusing on cell yield, viability, and contamination of unwanted cell types. PBMC procurement methods: 1. During organ procurement at the time of cold perfusion, blood was collected from the vena cava and placed into a 10-liter blood collection bag, and thereafter transported to Karolinska University Hospital, where leukapheresis was performed (BCL). 2. Blood was collected via the vena cava into blood donation bags before cold perfusion. The bags underwent buffy coat separation and thereafter automated leukocyte isolation system (BCS). 3. To collect PBMCs, leukapheresis was performed via a central dialysis catheter on deceased donors in the intensive care unit (ICU) prior to the organ procurement procedure (LEU).All 3 methods to obtain PBMC from deceased donors were safe and did not affect the procurement of organs. BCL contained around 50% of NK cells in lymphocytes population. LEU had a highest yield of donor PBMC among 3 groups. LEU had the lower amount of granulocyte contamination, compared to BCS and BCL. Based on these results, we choose LEU as the preferred method to obtain donor PBMC in the development of our tolerance-induction protocol.
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Affiliation(s)
- Ming Yao
- Division of Transplantation Surgery, CLINTEC, Karolinska Institutet, and Department of Transplantation Surgery, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - Jarmo Henriksson
- Centre for Apheresis and Stem Cell Laboratory, KITM, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden
| | - Henrik Fahlander
- Centre for Apheresis and Stem Cell Laboratory, KITM, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden
| | - Pablo Guisti Coitinho
- Centre for Apheresis and Stem Cell Laboratory, KITM, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden
| | - Torbjörn Lundgren
- Division of Transplantation Surgery, CLINTEC, Karolinska Institutet, and Department of Transplantation Surgery, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - Nils Ågren
- Division of Transplantation Surgery, CLINTEC, Karolinska Institutet, and Department of Transplantation Surgery, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - Bo-Göran Ericzon
- Division of Transplantation Surgery, CLINTEC, Karolinska Institutet, and Department of Transplantation Surgery, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - Makiko Kumagai-Braesch
- Division of Transplantation Surgery, CLINTEC, Karolinska Institutet, and Department of Transplantation Surgery, Karolinska University Hospital, Huddinge, Stockholm, Sweden
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18
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Appenzeller-Herzog C, Rosat A, Mathes T, Baroja-Mazo A, Chruscinski A, Feng S, Herrero I, Londono MC, Mazariegos G, Ohe H, Pons JA, Sanchez-Fueyo A, Waki K, Vionnet J. Time since liver transplant and immunosuppression withdrawal outcomes: Systematic review and individual patient data meta-analysis. Liver Int 2024; 44:250-262. [PMID: 37905605 DOI: 10.1111/liv.15764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 09/22/2023] [Accepted: 10/08/2023] [Indexed: 11/02/2023]
Abstract
BACKGROUND & AIMS Successful immunosuppression withdrawal (ISW) is possible for a subfraction of liver transplant (LT) recipients but the factors that define the risk of ISW failure are largely unknown. One candidate prognostic factor for ISW success or operational tolerance (OT) is longer time between LT and ISW which we term "pre-withdrawal time". To clarify the impact of pre-withdrawal time span on subsequent ISW success or failure, we conducted a systematic review with meta-analysis. METHODS We systematically interrogated the literature for LT recipient ISW studies reporting pre-withdrawal time. Eligible articles from Embase, Medline, and the Cochrane Central Register of Controlled Trials were used for backward and forward citation searching. Pre-withdrawal time individual patient data (IPD) was requested from authors. Pooled mean differences and time-response curves were calculated using random-effects meta-analyses. RESULTS We included 17 studies with 691 patients, 15 of which (620 patients) with IPD. Study-level risk of bias was heterogeneous. Mean pre-withdrawal time was greater by 427 days [95% confidence interval (CI) 67-788] in OT compared to non-OT patients. This increase was potentiated to 799 days (95% CI 369-1229) or 1074 days (95% CI 685-1463) when restricting analysis to adult or European study participants. In time-response meta-analysis for adult or European ISW candidates, likelihood of OT increased by 7% (95% CI 4-10%) per year after LT (GRADE low- and moderate-certainty of evidence, respectively). CONCLUSIONS Our data support the impact of pre-withdrawal time in ISW decision-making for adult and European LT recipients. PROSPERO REGISTRATION CRD42021272995.
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Affiliation(s)
| | - Aurélie Rosat
- Service of Gastroenterology and Hepatology, University of Lausanne, Lausanne, Switzerland
| | - Tim Mathes
- Department for Medical Statistics, University Medical Centre Goettingen, Goettingen, Germany
| | - Alberto Baroja-Mazo
- Digestive and Endocrine Surgery and Transplantation of Abdominal Organs, Biomedical Research Institute of Murcia (Instituto Murciano de Investigación Biosanitaria-Arrixaca), Murcia, Spain
| | | | - Sandy Feng
- School of Medicine, University of California, San Francisco, California, USA
| | - Ignacio Herrero
- Liver Unit, Clinica Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra, Centro de investigación Biomédica en Red, Navarra, Spain
- Enfermedades Hepáticas y Digestivas, Pamplona, Spain
| | - Maria-Carlota Londono
- Liver Unit, Hospital Clinic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de investigación Biomédica en Red, Barcelona, Spain
- Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona, Spain
| | - George Mazariegos
- UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Hidenori Ohe
- Department of Surgery, Kyoto University, Kyoto, Japan
| | - José A Pons
- Hepatology and Liver Transplant Unit, University Clinical Hospital Virgen de la Arrixaca, Murcia, Spain
| | - Alberto Sanchez-Fueyo
- Institute of Liver Studies, King's College London University and King's College Hospital, London, UK
| | - Kayo Waki
- Department of Biomedical Informatics, The University of Tokyo, Tokyo, Japan
- Department of Diabetes and Metabolic Diseases, The University of Tokyo, Tokyo, Japan
| | - Julien Vionnet
- Service of Gastroenterology and Hepatology, University of Lausanne, Lausanne, Switzerland
- Institute of Liver Studies, King's College London University and King's College Hospital, London, UK
- Transplantation Centre, University Hospital of Lausanne and University of Lausanne, Lausanne, Switzerland
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19
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Antala S, DiNorcia J, Bucuvalas J. Balancing immunosuppression in pediatric liver transplantation: Playing the long game. Pediatr Transplant 2023; 27:e14575. [PMID: 37439035 DOI: 10.1111/petr.14575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 07/03/2023] [Indexed: 07/14/2023]
Abstract
The overarching goal in the care of pediatric liver transplant recipients is to optimize allograft and patient health. Balancing immunosuppression to maintain allograft health while avoiding medication side effects is essential for long-term survival and optimal quality of life in pediatric liver transplant recipients. Utilizing precision medicine to personalize immunosuppression, which includes minimization and withdrawal, is core to this effort. The unique anatomy and physiology of the liver make it more tolerant to immune-mediated injury and a more favorable organ for immunosuppression minimization and withdrawal. However, several challenges exist. Standard biochemical values and histologic features may not reliably predict allograft health after a reduction in immunosuppression. Additionally, biochemical values alone do not reliably identify which patients can successfully develop operational tolerance, as there may be occult allograft injury despite normal liver enzymes. Finally, the durability of tolerance after successful reduction in immunosuppression remains uncertain over time. Innovative tools show promise in circumventing these challenges, but more research is needed to determine actual clinical utility. While immunosuppression-free transplant may not be a current reality for most pediatric liver transplant recipients, strategies to safely minimize immunosuppression without compromising allograft health are within reach. Each liver allograft and recipient pair requires a different degree of immune modulation, and through a structured process of minimization and withdrawal, immunosuppression can indeed be tailored in a precise, personalized way to optimize outcomes. This review focuses on the progress that has been made to individualize immunosuppression in pediatric liver transplantation to ensure optimal allograft and recipient health.
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Affiliation(s)
- Swati Antala
- Department of Pediatrics, Icahn School of Medicine, Kravis Children's Hospital at Mount Sinai, New York City, New York, USA
| | - Joseph DiNorcia
- Recanati-Miller Transplantation Institute, Mount Sinai Hospital, New York City, New York, USA
| | - John Bucuvalas
- Department of Pediatrics, Icahn School of Medicine, Kravis Children's Hospital at Mount Sinai, New York City, New York, USA
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20
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Merola J, Emond JC, Levitsky J. Novel Noninvasive Biomarkers in Liver Transplantation: A Tool on the Doorstep of Clinical Utilization. Transplantation 2023; 107:2120-2125. [PMID: 37019173 DOI: 10.1097/tp.0000000000004580] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/07/2023]
Abstract
Biomarkers have the potential to transform the detection, treatment, and outcomes of liver transplant complications, though their application is limited because of the lack of prospective validation. Although many genetic, proteomic, and immune markers correlating with allograft rejection and graft dysfunction have been described, evaluation of these markers in combination and validation among a broad liver transplant recipient population remain understudied. In this review, we present evidence supporting biomarker applications in 5 clinical liver transplant scenarios: (i) diagnosis of allograft rejection, (ii) prediction of allograft rejection, (iii) minimization of immunosuppression, (iv) detection of fibrosis and recurrent disease, and (v) prediction of renal recovery following liver transplantation. Current limitations for biomarker utilization and opportunities for further investigation are discussed. Accurate risk assessment, diagnosis, and evaluation of treatment responses using such noninvasive tools will pave the way for a more personalized and precise approach to management of the liver transplant patients that has profound potential to reduce morbidity and improve graft and patient longevity.
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Affiliation(s)
- Jonathan Merola
- Center for Liver Disease and Transplantation, Columbia University Medical Center, New York, NY
| | - Jean C Emond
- Center for Liver Disease and Transplantation, Columbia University Medical Center, New York, NY
| | - Josh Levitsky
- Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, IL
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21
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Odenwald MA, Roth HF, Reticker A, Segovia M, Pillai A. Evolving challenges with long-term care of liver transplant recipients. Clin Transplant 2023; 37:e15085. [PMID: 37545440 DOI: 10.1111/ctr.15085] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 07/17/2023] [Accepted: 07/23/2023] [Indexed: 08/08/2023]
Abstract
The number of liver transplants (LT) performed worldwide continues to rise, and LT recipients are living longer post-transplant. This has led to an increasing number of LT recipients requiring lifelong care. Optimal care post-LT requires careful attention to both the allograft and systemic issues that are more common after organ transplantation. Common causes of allograft dysfunction include rejection, biliary complications, and primary disease recurrence. While immunosuppression prevents rejection and reduces incidences of some primary disease recurrence, it has detrimental systemic effects. Most commonly, these include increased incidences of metabolic syndrome, various malignancies, and infections. Therefore, it is of utmost importance to optimize immunosuppression regimens to prevent allograft dysfunction while also decreasing the risk of systemic complications. Institutional protocols to screen for systemic disease and heightened clinical suspicion also play an important role in providing optimal long-term post-LT care. In this review, we discuss these common complications of LT as well as unique considerations when caring for LT recipients in the years after transplant.
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Affiliation(s)
- Matthew A Odenwald
- Department of Medicine, Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medicine, Chicago, USA
| | - Hannah F Roth
- Department of Medicine, Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medicine, Chicago, USA
| | - Anesia Reticker
- Department of Pharmacy, University of Chicago Medicine, Chicago, USA
| | - Maria Segovia
- Department of Medicine, Section of Gastroenterology, Duke University School of Medicine, Durham, USA
| | - Anjana Pillai
- Department of Medicine, Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medicine, Chicago, USA
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22
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Dixon W, Perito ER, Bucuvalas J, Feng S. Mapping children by ALT 4-5 years after liver transplant: Potential individual and population applications. Pediatr Transplant 2023; 27:e14569. [PMID: 37458328 DOI: 10.1111/petr.14569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 05/25/2023] [Accepted: 06/30/2023] [Indexed: 08/26/2023]
Abstract
INTRODUCTION Although clinicians repeatedly measure ALT to assess allograft health in children with liver transplants, they generally make decisions based on single values or qualitative trends without quantitative aggregation or synthesis. We therefore aimed to derive and test a holistic ALT metric for the 5th post-transplant year (Yr 4-5) that may better guide clinical decision-making and/or population comparisons. METHODS We derived the "adjusted mean Yr 4-5 ALT" for children transplanted in 2005-2016 by averaging the median ALT from each month. Patients in quartiles (Q1-4) defined by the adjusted mean Yr 4-5 ALT were compared by clinical variables, Yr 5-8 outcomes, and tacrolimus standard deviation (MLVI). RESULTS For 97 children [49 male; 77 deceased donors; median (IQR) age at LT 2.5 (0.8-11.7) years], the 25th, 50th, and 75th percentile thresholds for adjusted mean Yr 4-5 ALT were 19, 28, and 47 U/L, respectively. Age, donor type, LT indication, rejection history, and mean tacrolimus levels did not differ between quartiles (Q). Children in Q4 had more Yr 4-5 acute rejection episodes (p < .01), higher Yr 4-5 MLVI (p < .01), and more Yr 5-8 for-cause liver biopsies (p < .01) than those in Q1 + Q2. Children in Q3 also had higher Yr 4-5 MLVI than Q1 + Q2 (p = .047). Rates of chronic rejection and therapeutic liver-related procedures were higher in Q4 but the difference did not reach significance. CONCLUSION An integrated ALT metric calculated utilizing all available ALT values correlates with MLVI and future for-cause biopsies. Further study of this novel ALT metric as a predictor of clinical outcomes and descriptor of populations is warranted.
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Affiliation(s)
- Wesley Dixon
- Division of Transplantation, Department of Surgery, University of California, San Francisco, San Francisco, California, USA
| | - Emily R Perito
- Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA
| | - John Bucuvalas
- Division of Hepatology, Department of Pediatrics, Mount Sinai Kravis Children's Hospital, Recanati/Miller Transplantation Institute, New York City, New York, USA
| | - Sandy Feng
- Division of Transplantation, Department of Surgery, University of California, San Francisco, San Francisco, California, USA
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23
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Algeri M, Velardi E, Spada M, Galaverna F, Carta R, Vinti L, Palumbo G, Gaspari S, Pietrobattista A, Boccieri E, Becilli M, Francalanci P, Bertaina V, Merli P, Locatelli F. Achievement of operational tolerance in a pediatric liver transplant recipient following successful hematopoietic stem cell transplantation from a different donor. Am J Transplant 2023; 23:1446-1450. [PMID: 37061187 DOI: 10.1016/j.ajt.2023.04.003] [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: 02/03/2023] [Revised: 04/03/2023] [Accepted: 04/03/2023] [Indexed: 04/17/2023]
Abstract
Hematopoietic stem cell transplantation (HSCT)-based approaches are increasingly investigated strategies to induce tolerance in recipients of solid allografts. However, in the majority of cases, these approaches rely on the infusion of hematopoietic stem cells recovered from the same solid organ donor. In this report, we describe the case of a boy who received liver transplantation from a deceased donor, who had successfully underwent allogeneic HSCT from an unrelated donor for hepatitis-associated aplastic anemia. In this patient, it was possible to permanently withdraw post-HSCT immune suppression without causing any sign of liver graft dysfunction. To the best of our knowledge, this is the first case of operational tolerance documented in a patient who received combined liver transplantation and HSCT from different donors.
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Affiliation(s)
- Mattia Algeri
- Department of Pediatric Hematology and Oncology,Cell and Gene Therapy,Bambino Gesù Children's Hospital,IRCCS,Rome,Italy
| | - Enrico Velardi
- Department of Pediatric Hematology and Oncology,Cell and Gene Therapy,Bambino Gesù Children's Hospital,IRCCS,Rome,Italy
| | - Marco Spada
- Hepatobiliopancreatic Surgery, Liver and Kidney Transplantation Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Federica Galaverna
- Department of Pediatric Hematology and Oncology,Cell and Gene Therapy,Bambino Gesù Children's Hospital,IRCCS,Rome,Italy
| | - Roberto Carta
- Department of Pediatric Hematology and Oncology,Cell and Gene Therapy,Bambino Gesù Children's Hospital,IRCCS,Rome,Italy
| | - Luciana Vinti
- Department of Pediatric Hematology and Oncology,Cell and Gene Therapy,Bambino Gesù Children's Hospital,IRCCS,Rome,Italy
| | - Giuseppe Palumbo
- Department of Pediatric Hematology and Oncology,Cell and Gene Therapy,Bambino Gesù Children's Hospital,IRCCS,Rome,Italy; University Department of Pediatrics, Bambino Gesù Children's Hospital, University of Rome Tor Vergata, Rome, Italy
| | - Stefania Gaspari
- Department of Pediatric Hematology and Oncology,Cell and Gene Therapy,Bambino Gesù Children's Hospital,IRCCS,Rome,Italy
| | | | - Emilia Boccieri
- Department of Pediatric Hematology and Oncology,Cell and Gene Therapy,Bambino Gesù Children's Hospital,IRCCS,Rome,Italy
| | - Marco Becilli
- Department of Pediatric Hematology and Oncology,Cell and Gene Therapy,Bambino Gesù Children's Hospital,IRCCS,Rome,Italy
| | - Paola Francalanci
- Hepatology and Liver Transplant Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Valentina Bertaina
- Department of Pediatric Hematology and Oncology,Cell and Gene Therapy,Bambino Gesù Children's Hospital,IRCCS,Rome,Italy
| | - Pietro Merli
- Department of Pediatric Hematology and Oncology,Cell and Gene Therapy,Bambino Gesù Children's Hospital,IRCCS,Rome,Italy
| | - Franco Locatelli
- Department of Pediatric Hematology and Oncology,Cell and Gene Therapy,Bambino Gesù Children's Hospital,IRCCS,Rome,Italy; Department of Life Sciences and Public Health, Catholic University of the Sacred Heart, Rome, Italy.
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24
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Yeh H. Moving the Goalpost: From "Alive" to "Ideal". Transplantation 2023; 107:1667-1668. [PMID: 36814092 DOI: 10.1097/tp.0000000000004557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2023]
Affiliation(s)
- Heidi Yeh
- Department of Surgery, Massachusetts General Hospital, Boston, MA
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25
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Campos-Varela I, Rammohan A, Chadha R, Alconchel F, Hakeem AR, Mathew JS, Goldaracena N, Syn N, Shankar S, Patel D, Keskin O, Liu J, Nasralla D, Mazzola A, Shingina A, Spiro M, Patel MS, Tanaka T, Victor D, Yoon U, Yoon YI, Shaker T, Vinaixa C, Kirchner VA, De Martin E. Proceedings of the 27th Annual Congress of the International Liver Transplantation Society. Transplantation 2023; 107:1226-1231. [PMID: 37220340 DOI: 10.1097/tp.0000000000004637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
After a virtual congress in 2021 and a previous absence in 2020 because of the coronavirus disease 2019 pandemic, the 27th Annual Congress of the International Liver Transplantation Society was held from May 4 to 7, 2022, in a hybrid format in Istanbul, with 1123 (58% on-site) liver transplant professionals from 61 countries attending the meeting. The hybrid format successfully achieved a balance of much yearned-for "in-person interaction" and global online participation. Almost 500 scientific abstracts were presented. In this report, the Vanguard Committee aims to present a summary of key invited lectures and selected abstracts for the liver transplant community.
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Affiliation(s)
- Isabel Campos-Varela
- Liver Unit, Vall d'Hebron Hospital Universitari, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Ashwin Rammohan
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Centre, Bharath Institute of Higher Education and Research, Chennai, India
| | - Ryan Chadha
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Jacksonville, FL
| | | | - Abdul R Hakeem
- Department of Hepatobiliary and Liver Transplant Surgery, St James's University Hospital NHS Trust, Leeds, United Kingdom
| | | | - Nicolas Goldaracena
- Abdominal Organ Transplant and Hepatobiliary Surgery, University of Virginia Health System, Charlottesville, VA
| | | | - Sadhana Shankar
- The Liver Unit, King's College Hospital, London, United Kingdom
| | - Dhupal Patel
- Addenbrookes Hospital, Cambridge, United Kingdom
| | - Onur Keskin
- Department of Gastroenterology, Hacettepe University Medical School, Ankara, Turkey
| | - Jiang Liu
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - David Nasralla
- Department of HPB and Liver Transplant Surgery, The Royal Free Hospital, London, United Kingdom
| | - Alessandra Mazzola
- Sorbonne Université, Unité médicale de transplantation hépatique, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France
| | - Alexandra Shingina
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Michael Spiro
- Anesthesia and Intensive Care Medicine, Royal Free Hospital, London, United Kingdom
| | | | - Tomohiro Tanaka
- Department of Internal Medicine, Gastroenterology and Hepatology, University of Iowa, Iowa City, IA
| | - David Victor
- Sherrie and Alan Conover Center for Liver Disease and Transplantation. Houston Methodist Hospital, Houston, TX
| | - Uzung Yoon
- Thomas Jefferson University Hospital, Philadelphia, PA
| | | | - Tamer Shaker
- Division of Transplantation, Department of Surgery, University of Minnesota Medical School, Minneapolis, MN
| | - Carmen Vinaixa
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Hepatology and Liver Transplantation Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Varvara A Kirchner
- Division of Abdominal Transplantation, Department of Surgery, Stanford University, Stanford, CA
| | - Eleonora De Martin
- AP-HP, Hôpital Paul-Brousse, Centre Hépato- Biliaire, Unité INSERM 1193, Villejuif, France
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26
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Montano-Loza AJ, Rodríguez-Perálvarez ML, Pageaux GP, Sanchez-Fueyo A, Feng S. Liver transplantation immunology: Immunosuppression, rejection, and immunomodulation. J Hepatol 2023; 78:1199-1215. [PMID: 37208106 DOI: 10.1016/j.jhep.2023.01.030] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/30/2022] [Accepted: 01/30/2023] [Indexed: 05/21/2023]
Abstract
Outcomes after liver transplantation have continuously improved over the past decades, but long-term survival rates are still lower than in the general population. The liver has distinct immunological functions linked to its unique anatomical configuration and to its harbouring of a large number of cells with fundamental immunological roles. The transplanted liver can modulate the immunological system of the recipient to promote tolerance, thus offering the potential for less aggressive immunosuppression. The selection and adjustment of immunosuppressive drugs should be individualised to optimally control alloreactivity while mitigating toxicities. Routine laboratory tests are not accurate enough to make a confident diagnosis of allograft rejection. Although several promising biomarkers are being investigated, none of them is sufficiently validated for routine use; hence, liver biopsy remains necessary to guide clinical decisions. Recently, there has been an exponential increase in the use of immune checkpoint inhibitors due to the unquestionable oncological benefits they provide for many patients with advanced-stage tumours. It is expected that their use will also increase in liver transplant recipients and that this might affect the incidence of allograft rejection. Currently, the evidence regarding the efficacy and safety of immune checkpoint inhibitors in liver transplant recipients is limited and cases of severe allograft rejection have been reported. In this review, we discuss the clinical relevance of alloimmune disease, the role of minimisation/withdrawal of immunosuppression, and provide practical guidance for using checkpoint inhibitors in liver transplant recipients.
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Affiliation(s)
- Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, AB, Canada.
| | - Manuel L Rodríguez-Perálvarez
- Department of Hepatology and Liver Transplantation, Hospital Universitario Reina Sofía, Universidad de Córdoba, IMIBIC, Córdoba, Spain; CIBER de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - George-Philippe Pageaux
- Liver Transplantation Unit, Digestive Department, Saint Eloi University Hospital, University of Montpellier, 34295, Montpellier Cedex 5, France
| | - Alberto Sanchez-Fueyo
- Institute of Liver Studies, King's College London University and King's College Hospital, London, United Kingdom
| | - Sandy Feng
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
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27
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Goto R, Fukasaku Y, Ganchiku Y, Kawamura N, Watanabe M, Ota T, Hatanaka KC, Suzuki T, Shimamura T, Taketomi A. Post-transplant donor-specific anti-HLA antibodies with a higher mean fluorescence intensity are associated with graft fibrosis in pediatric living donor liver transplantation. Front Pediatr 2023; 11:1172516. [PMID: 37181419 PMCID: PMC10168538 DOI: 10.3389/fped.2023.1172516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 04/07/2023] [Indexed: 05/16/2023] Open
Abstract
The roles of post-transplant anti-HLA donor specific antibody (DSA) in pediatric liver transplantation (LT), including therapeutic strategies, remain controversial. This study aimed to identify the risks of post-transplant DSA for graft fibrosis progression in pediatric living donor LT (LDLT). We retrospectively evaluated 88 LDLT pediatric cases between December 1995 and November 2019. DSAs were assessed with single antigen bead test. Graft fibrosis was histopathologically scored with METAVIR and the centrilobular sinusoidal fibrosis system. Post-transplant DSAs were detected in 37 (52.9%) cases at 10.8 (1.3-26.9) years post-LDLT. The histopathological examination of 32 pediatric cases with post-transplant DSA revealed that 7 (21.9%) with a high DSA-MFI (≥9,378) showed graft fibrosis progression (≥F2). No graft fibrosis was observed in the subjects with a low DSA-MFI. The risk factors for developing graft fibrosis in pediatric cases with post-transplant DSA were an older graft age (>46.5 years old), lower platelet count (<10.7 × 104/ml) and higher Fib4 index (>0.7807, recipient age; >1.8952, donor age). Limited efficacy of additional immunosuppressants was observed in DSA positive pediatric cases. In conclusion, pediatric cases with a high DSA-MFI and risk factors should undergo a histological examination. The appropriate treatment for post-transplant DSA in pediatric LT needs to be determined.
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Affiliation(s)
- Ryoichi Goto
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Yasutomo Fukasaku
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Yoshikazu Ganchiku
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Norio Kawamura
- Department of Transplant Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Masaaki Watanabe
- Department of Transplant Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Takuji Ota
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Kanako C. Hatanaka
- Center for Development of Advanced Diagnostics, Hokkaido University Hospital, Sapporo, Japan
| | - Tomomi Suzuki
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Tsuyoshi Shimamura
- Division of Organ Transplantation, Hokkaido University Hospital, Sapporo, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan
- Department of Transplant Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
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28
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Bosselmann EA, Dranicki F, Campos-Murguia A, Hartleben B, Wedemeyer H, Jaeckel E, Taubert R. Combination of everolimus and low-dose tacrolimus controls histological liver allograft injury as sufficiently as high-dose tacrolimus. FRONTIERS IN TRANSPLANTATION 2023; 2:1168163. [PMID: 38993848 PMCID: PMC11235273 DOI: 10.3389/frtra.2023.1168163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 03/21/2023] [Indexed: 07/13/2024]
Abstract
Introduction The combination of everolimus (EVR) and low-dose tacrolimus (lowTAC) prevents T cell-mediated rejection of liver grafts as sufficiently as high-dose tacrolimus (highTAC) and mycophenolate, but is associated with a preserved kidney function within the first years after orthotopic liver transplantation (OLT). However, none of the available studies assessed the histological pattern of graft injury or fibrosis in surveillance biopsies (svLbx). Methods All svLbx taken under at least one month of stable immunosuppression with either EVR (aim 3-8 ng/ml) combined with lowTAC (aim 3-5 ng/ml) or highTAC (aim 5-8 ng/ml) combined with mycophenolate (500-1500 mg/day) within the first three to four years after OLT at our center were included. Patients who were switched to EVR because of insufficient control of alloreactivity were excluded. Results Reasons for switches to EVR were mainly malignancies before or after OLT, or chronic kidney injury. We were able to include 20 svLbx with EVR/lowTAC and 49 with highTAC/mycophenolate. Both groups had similar liver enzymes and similar kidney function. The EVR/lowTAC group exhibited lower TAC trough levels at svLbx (4.4 vs. 6.6 ng/ml; p<.001) in comparison to highTAC/mycophenolate. Histological graft injury quantified by the rejection activity index and hepatitis activity index (Ishak), as well as fibrosis were not significantly different between the EVR/lowTAC and highTAC/mycophenolate groups. Likewise, subclinical TCMR, histological criteria justifying immunosuppression minimization, and steatosis had equal prevalence in both regimens. Immunosuppression was adjusted according to the svLbx findings. Immunosuppression regimens had similarly low rates of rejection after immunosuppression reduction, when relevant graft injury was absent in the biopsy. Discussion In conclusion, EVR/lowTAC seems to control alloreactivity and histological graft injury as sufficiently as highTAC/mycophenolate within the first 3-4 years after OLT.
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Affiliation(s)
- Emily A Bosselmann
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Fabian Dranicki
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Alejandro Campos-Murguia
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Björn Hartleben
- Institute for Pathology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
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Shamsaeefar A, Kazemi K, Nikoupour H, Moosavi SA, Mashhadiagha A, Sayadi M, Gholami S, Motazedian N, Nikeghbalian S, Malekhosseini SA. Prope tolerance after pediatric liver transplantation: Experience at Shiraz Organ Transplant Center. Transpl Immunol 2023; 78:101827. [PMID: 37003498 DOI: 10.1016/j.trim.2023.101827] [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: 12/06/2022] [Revised: 03/18/2023] [Accepted: 03/19/2023] [Indexed: 04/03/2023]
Abstract
BACKGROUND Children receive transplants at a younger age, and the period of immunosuppression therapy may extend over decades. However, immunosuppression seems to be responsible for long-term mortality and morbidity. Pediatric liver transplant recipients can benefit from achieving immune tolerance and the opportunity of freedom from lifelong immunosuppression. This study aimed to investigate the frequency of prope tolerance among pediatric liver transplant recipients and the characteristics of these patients. METHODS In this retrospective cohort study of pediatric liver transplant recipients, the medical records of transplant recipients treated at Shiraz Organ Transplant Center between 1994 and 2017 were reviewed. Prope tolerance was defined as normal laboratory values and stable clinical status on low-dose monotherapy. Children treated with low-dose monotherapy were categorized as the prope tolerant group. We compared the characteristics of prope tolerant recipients on low-dose monotherapy with patients on standard immunosuppression, i.e. full-dose tacrolimus plus steroids and mycophenolate mofetil. The data were analyzed with the t-test, chi-squared test, and a Cox proportional hazard model at a 5% significance level in SPSS software version 16. RESULTS A total of 585 children with a mean age of 8.32 ± 5.23 years were enrolled. 341 patients were categorized as prope tolerant and 244 comprised the full immunosuppression regimen group. Mean age at transplantation and rejection frequency were lower in the prope tolerant group (p < 0.001, p < 0.001). Based on the underlying diseases, metabolic/genetic, biliary tract, and cryptogenic liver diseases were significantly more prevalent in the prope tolerant group (p < 0.001). However, autoimmune liver disease was found to be more prevalent in the full immunosuppression regimen group. Also, those who received living organs (p = 0.001) and recipients of organs from female donors had a greater likelihood of achieving prope tolerant. According to the multiple Cox regression results, age at transplantation (p = 0.022), rejection frequency (p < 0.001), and autoimmune liver diseases (p = 0.028) had a prognostic effect on prope tolerance. CONCLUSION Factors as underlying disease, age at transplantation, and rejection frequency were factors that were predictive of prope tolerance in this sample of children. However, the risk of rejection should be considered during the tapering period.
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Affiliation(s)
- Alireza Shamsaeefar
- Abu Ali Sina Organ Transplant Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Kourosh Kazemi
- Abu Ali Sina Organ Transplant Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hamed Nikoupour
- Abu Ali Sina Organ Transplant Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Ali Moosavi
- Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amirali Mashhadiagha
- Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mehrab Sayadi
- Cardiovascular Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sivash Gholami
- Abu Ali Sina Organ Transplant Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nasrin Motazedian
- Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Saman Nikeghbalian
- Abu Ali Sina Organ Transplant Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Meeting Report: The Fifth International Samuel Strober Workshop on Clinical Immune Tolerance. Transplantation 2023; 107:564-569. [PMID: 36808845 DOI: 10.1097/tp.0000000000004473] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/23/2023]
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Zhang Z, Zhao S, Si Z, Wang Z, Dong C, Sun C, Zheng W, Kai W, Zhang W, Song Z, Gao W, Shen Z. Incidence and risk factors of subclinical rejection after pediatric liver transplantation, and impact on allograft fibrosis. Clin Transplant 2023; 37:e14894. [PMID: 36581321 DOI: 10.1111/ctr.14894] [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: 09/29/2022] [Revised: 12/12/2022] [Accepted: 12/24/2022] [Indexed: 12/31/2022]
Abstract
INTRODUCTION Subclinical rejection (SCR) is a common injury in protocol biopsy after pediatric liver transplantation (pLT), but its effect on the recipient is not clearly understood. We herein investigated the incidence and risk factors involved in SCR and analyzed the relationship between SCR and allograft fibrosis (AF). METHODS We retrospectively reviewed the biopsy results from 507 children between May 2013 and May 2019, and 352 patients underwent protocol biopsy 2 years after pLT, 203 underwent protocol biopsy 5 years after pLT, and 48 underwent protocol biopsy both 2 and 5 years after pLT. RESULTS The incidence of SCR in the 5-year group was higher than that in the 2-year group (20.2% vs.13.4%, respectively, p = .033). The number of patients with mild and moderate SCR in the 5-year group was also higher than that in the 2-year group (p = .039). Logistic regression analysis showed that acute rejection before liver biopsy and deceased donor liver transplantation (DDLT) were independent risk factors for SCR in the two groups, and that the incidence and severity of AF in protocol biopsies at both periods in the SCR group were higher than those in the non-SCR group (p < .05). CONCLUSIONS The incidence and severity of SCR increased with the prolongation of protocol biopsy time. We postulate that acute rejection and DDLT are independent risk factors for SCR after transplantation. As the occurrence of SCR also augmented the incidence and severity of AF.
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Affiliation(s)
- Zhixin Zhang
- First Central Clinic Institute, Tianjin Medical University, Tianjin, China
| | - Shengqiao Zhao
- First Central Clinic Institute, Tianjin Medical University, Tianjin, China
| | - Zhuyuan Si
- First Central Clinic Institute, Tianjin Medical University, Tianjin, China
| | - Zhenglu Wang
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Chong Dong
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Chao Sun
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Weiping Zheng
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Wang Kai
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Wei Zhang
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Zhuolun Song
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Wei Gao
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Zhongyang Shen
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
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Wood-Trageser MA, Lesniak D, Gambella A, Golnoski K, Feng S, Bucuvalas J, Sanchez-Fueyo A, Demetris AJ. Next-generation pathology detection of T cell-antigen-presenting cell immune synapses in human liver allografts. Hepatology 2023; 77:355-366. [PMID: 35819312 PMCID: PMC9834436 DOI: 10.1002/hep.32666] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 06/27/2022] [Accepted: 07/01/2022] [Indexed: 01/28/2023]
Abstract
BACKGROUND AND AIMS In otherwise near-normal appearing biopsies by routine light microscopy, next-generation pathology (NGP) detected close pairings (immune pairs; iPAIRs) between lymphocytes and antigen-presenting cells (APCs) that predicted immunosuppression weaning failure in pediatric liver transplant (LTx) recipients (Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients [iWITH], NCT01638559). We hypothesized that NGP-detected iPAIRs enrich for true immune synapses, as determined by nuclear shape metrics, intercellular distances, and supramolecular activation complex (SMAC) formation. APPROACH AND RESULTS Intralobular iPAIRs (CD45 high lymphocyte-major histocompatibility complex II + APC pairs; n = 1167, training set) were identified at low resolution from multiplex immunohistochemistry-stained liver biopsy slides from several multicenter LTx immunosuppression titration clinical trials (iWITH; NCT02474199 (Donor Alloantigen Reactive Tregs (darTregs) for Calcineurin Inhibitor (CNI) Reduction (ARTEMIS); Prospective Longitudinal Study of iWITH Screen Failures Secondary to Histopathology). After excluding complex multicellular aggregates, high-resolution imaging was used to examine immune synapse formation ( n = 998). By enriching for close intranuclear lymphocyte-APC distance (mean: 0.713 μm) and lymphocyte nuclear flattening (mean ferret diameter: 2.1), SMAC formation was detected in 29% of iPAIR-engaged versus 9.5% of unpaired lymphocytes. Integration of these morphometrics enhanced NGP detection of immune synapses (ai-iSYN). Using iWITH preweaning biopsies from eligible patients ( n = 53; 18 tolerant, 35 nontolerant; testing set), ai-iSYN accurately predicted (87.3% accuracy vs. 81.4% for iPAIRs; 100% sensitivity, 75% specificity) immunosuppression weaning failure. This confirmed the presence and importance of intralobular immune synapse formation in liver allografts. Stratification of biopsy mRNA expression data by immune synapse quantity yielded the top 20 genes involved in T cell activation and immune synapse formation and stability. CONCLUSIONS NGP-detected immune synapses (subpathological rejection) in LTx patients prior to immunosuppression reduction suggests that NGP-detected (allo)immune activity usefulness for titration of immunosuppressive therapy in various settings.
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Affiliation(s)
- Michelle A Wood-Trageser
- Division of Liver and Transplant Pathology , University of Pittsburgh , Pittsburgh , Pennsylvania , USA
| | - Drew Lesniak
- Division of Liver and Transplant Pathology , University of Pittsburgh , Pittsburgh , Pennsylvania , USA
| | - Alessandro Gambella
- Division of Liver and Transplant Pathology , University of Pittsburgh , Pittsburgh , Pennsylvania , USA
- Pathology Unit, Department of Medical Sciences , University of Turin , Torino , Italy
| | - Kayla Golnoski
- Division of Liver and Transplant Pathology , University of Pittsburgh , Pittsburgh , Pennsylvania , USA
| | - Sandy Feng
- Division of Transplantation, Department of Surgery , University of California San Francisco , San Francisco , California , USA
| | - John Bucuvalas
- Mount Sinai Kravis Children's Hospital and Recanati/Miller Transplantation Institute , Mount Sinai Health System , New York , New York , USA
| | | | - A Jake Demetris
- Division of Liver and Transplant Pathology , University of Pittsburgh , Pittsburgh , Pennsylvania , USA
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Pérez-Escobar J, Jimenez JV, Rodríguez-Aguilar EF, Servín-Rojas M, Ruiz-Manriquez J, Safar-Boueri L, Carrillo-Maravilla E, Navasa M, García-Juárez I. Immunotolerance in liver transplantation: a primer for the clinician. Ann Hepatol 2023; 28:100760. [PMID: 36179797 DOI: 10.1016/j.aohep.2022.100760] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 09/08/2022] [Indexed: 02/04/2023]
Abstract
The use of immunosuppressive medications for solid organ transplantation is associated with cardiovascular, metabolic, and oncologic complications. On the other hand, the development of graft rejection is associated with increased mortality and graft dysfunction. Liver transplant recipients can withdraw from immunosuppression without developing graft injury while preserving an adequate antimicrobial response - a characteristic known as immunotolerance. Immunotolerance can be spontaneously or pharmacologically achieved. Contrary to the classic dogma, clinical studies have elucidated low rates of true spontaneous immunotolerance (no serologic or histological markers of immune injury) among liver transplant recipients. However, clinical, serologic, and tissue biomarkers can aid in selecting patients in whom immunosuppression can be safely withdrawn. For those who failed an immunosuppression withdrawal trial or are at high risk of rejection, pharmacological interventions for immunotolerance induction are under development. In this review, we provide an overview of the mechanisms of immunotolerance, the clinical studies investigating predictors and biomarkers of spontaneous immunotolerance, as well as the potential pharmacological interventions for inducing it.
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Affiliation(s)
- Juanita Pérez-Escobar
- Department of Hepatology and Liver Transplant, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Jose Victor Jimenez
- Department of Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Erika Faride Rodríguez-Aguilar
- Department of Hepatology and Liver Transplant, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Maximiliano Servín-Rojas
- Department of Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Jesus Ruiz-Manriquez
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Luisa Safar-Boueri
- Comprehensive Transplant Center, Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Eduardo Carrillo-Maravilla
- Department of Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Miquel Navasa
- Liver Transplant Unit, Hepatology Service, Hospital Clínic de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Ignacio García-Juárez
- Department of Hepatology and Liver Transplant, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
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Shi B, Liu Y, Liu D, Yuan L, Guo W, Wen P, Su Z, Wang J, Xu S, Xia J, An W, Wang R, Wen P, Xing T, Zhang J, Gu H, Wang Z, Zhong L, Fan J, Li H, Zhang W, Peng Z. Genotype-guided model significantly improves accuracy of tacrolimus initial dosing after liver transplantation. EClinicalMedicine 2023; 55:101752. [PMID: 36444212 PMCID: PMC9700266 DOI: 10.1016/j.eclinm.2022.101752] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 10/31/2022] [Accepted: 11/01/2022] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND The initial dose of tacrolimus after liver transplantation (LT) is critical for rapidly achieving the steady state of the drug concentration, minimizing the potential adverse reactions and warranting long-term patient prognosis. We aimed to develop and validate a genotype-guided model for determining personalized initial dose of tacrolimus. METHODS By combining pharmacokinetic modeling, pharmacogenomic analysis and multiple statistical methods, we developed a genotype-guided model to predict individualized tacrolimus initial dose after LT in the discovery (n = 150) and validation cohorts (n = 97) respectively. This model was further validated in a prospective, randomized and single-blind clinical trial from August, 2021 to February, 2022 (n = 40, ChiCTR2100050288). FINDINGS Our model included donor's and recipient's genotypes, recipient's weight and total bilirubin, which achieved an area under the curve of receiver operating characteristic curve (AUC of ROC) of 0.88 and 0.79 in the discovery and validation cohorts, respectively. We found that patients who were given tacrolimus within the recommended concentration range (RCR) (4-10 ng/mL), the new-onset metabolic syndromes are lower, especially for new-onset diabetes (p = 0.043). In the clinical trial, compared to those in experience-based (EB) group, patients in the model-based (MB) group were more likely to achieving the RCR (75% vs 40%, p = 0.025) with a more variable individualized dose (0.023-0.096 mg/kg/day vs 0.045-0.057 mg/kg/day). Moreover, significantly fewer medication adjustments were required for the MB group than the EB group (2.75 ± 2.01 vs 6.05 ± 3.35, p = 0.001). INTERPRETATION Our genotype-based model significantly improved the initial dosing accuracy of tacrolimus and reduced the number of medication adjustments, which are critical for improving the prognosis of LT patients. FUNDING National Natural Science Foundation of China, Shanghai three-year action plan, National Science and Technology Major Project of China.
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Affiliation(s)
- Baojie Shi
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of Organ Transplantation, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
- Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
| | - Yuan Liu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University, 200080, Shanghai, China
| | - Dehua Liu
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of Organ Transplantation, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
- Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
| | - Liyun Yuan
- Bio-Med Big Data Center, Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China
| | - Wenzhi Guo
- Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, China
| | - Peihao Wen
- Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, China
| | - Zhaojie Su
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of Organ Transplantation, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
- Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
| | - Jie Wang
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of Organ Transplantation, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
- Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
| | - Shiquan Xu
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of Organ Transplantation, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
- Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
| | - Junjie Xia
- Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
| | - Wenbin An
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of Organ Transplantation, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
- Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
| | - Rui Wang
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of Organ Transplantation, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
- Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
| | - Peizhen Wen
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of Organ Transplantation, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
- Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
| | - Tonghai Xing
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University, 200080, Shanghai, China
| | - Jinyan Zhang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University, 200080, Shanghai, China
| | - Haitao Gu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University, 200080, Shanghai, China
| | - Zhaowen Wang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University, 200080, Shanghai, China
| | - Lin Zhong
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University, 200080, Shanghai, China
| | - Junwei Fan
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University, 200080, Shanghai, China
- Corresponding author.
| | - Hao Li
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of Organ Transplantation, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
- Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
- Corresponding author.
| | - Weituo Zhang
- Hongqiao International Institute of Medicine, Shanghai Tong Ren Hospital and Clinical Research Institute, Shanghai Jiao Tong University School of Medicine, 200050, Shanghai, China
- Corresponding author.
| | - Zhihai Peng
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of Organ Transplantation, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
- Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
- Corresponding author.
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Sood V, Lal BB, Ashwini N, Khanna R, Pamecha V, Trehanpati N, Alam S. Operational Tolerance after Liver Transplantation: First Report from India. J Clin Exp Hepatol 2023; 13:178-181. [PMID: 36647413 PMCID: PMC9840074 DOI: 10.1016/j.jceh.2022.09.002] [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: 07/25/2022] [Accepted: 09/08/2022] [Indexed: 01/19/2023] Open
Abstract
Operational tolerance after liver transplantation is an ideal goal to avoid long-term morbidities associated with chronic immunosuppressive medication use. It is achievable in a highly selected group of post-transplant recipients but requires long-term follow-up and strict monitoring. We hereby report a post-transplant case who achieved spontaneous operational tolerance after inadvertent immunosuppression withdrawal.
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Affiliation(s)
- Vikrant Sood
- Department of Pediatric Hepatology, New Delhi 110070, India
| | - Bikrant B. Lal
- Department of Pediatric Hepatology, New Delhi 110070, India
| | - N.S. Ashwini
- Department of Hepatopathology, New Delhi 110070, India
| | - Rajeev Khanna
- Department of Pediatric Hepatology, New Delhi 110070, India
| | - Viniyendra Pamecha
- Department of Hepato-pancreato-biliary Surgery and Liver Transplantation, New Delhi 110070, India
| | - Nirupama Trehanpati
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi 110070, India
| | - Seema Alam
- Department of Pediatric Hepatology, New Delhi 110070, India
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Barbetta A, Rocque B, Sarode D, Bartlett JA, Emamaullee J. Revisiting transplant immunology through the lens of single-cell technologies. Semin Immunopathol 2023; 45:91-109. [PMID: 35980400 PMCID: PMC9386203 DOI: 10.1007/s00281-022-00958-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 07/06/2022] [Indexed: 11/03/2022]
Abstract
Solid organ transplantation (SOT) is the standard of care for end-stage organ disease. The most frequent complication of SOT involves allograft rejection, which may occur via T cell- and/or antibody-mediated mechanisms. Diagnosis of rejection in the clinical setting requires an invasive biopsy as there are currently no reliable biomarkers to detect rejection episodes. Likewise, it is virtually impossible to identify patients who exhibit operational tolerance and may be candidates for reduced or complete withdrawal of immunosuppression. Emerging single-cell technologies, including cytometry by time-of-flight (CyTOF), imaging mass cytometry, and single-cell RNA sequencing, represent a new opportunity for deep characterization of pathogenic immune populations involved in both allograft rejection and tolerance in clinical samples. These techniques enable examination of both individual cellular phenotypes and cell-to-cell interactions, ultimately providing new insights into the complex pathophysiology of allograft rejection. However, working with these large, highly dimensional datasets requires expertise in advanced data processing and analysis using computational biology techniques. Machine learning algorithms represent an optimal strategy to analyze and create predictive models using these complex datasets and will likely be essential for future clinical application of patient level results based on single-cell data. Herein, we review the existing literature on single-cell techniques in the context of SOT.
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Affiliation(s)
- Arianna Barbetta
- Department of Surgery, Division of Abdominal Organ Transplant, University of Southern California, 1510 San Pablo St. Suite 412, Los Angeles, CA, 90033, USA
- University of Southern California, Los Angeles, CA, USA
| | - Brittany Rocque
- Department of Surgery, Division of Abdominal Organ Transplant, University of Southern California, 1510 San Pablo St. Suite 412, Los Angeles, CA, 90033, USA
- University of Southern California, Los Angeles, CA, USA
| | - Deepika Sarode
- Department of Surgery, Division of Abdominal Organ Transplant, University of Southern California, 1510 San Pablo St. Suite 412, Los Angeles, CA, 90033, USA
- University of Southern California, Los Angeles, CA, USA
| | - Johanna Ascher Bartlett
- Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital of Los Angeles, Los Angeles, CA, USA
| | - Juliet Emamaullee
- Department of Surgery, Division of Abdominal Organ Transplant, University of Southern California, 1510 San Pablo St. Suite 412, Los Angeles, CA, 90033, USA.
- University of Southern California, Los Angeles, CA, USA.
- Division of Hepatobiliary and Abdominal Organ Transplantation Surgery, Children's Hospital Los Angeles, Los Angeles, CA, USA.
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37
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Squires JE, Bilhartz J, Soltys K, Hafberg E, Mazariegos GV, Gupta NA, Anand R, Anderson SG, Miloh T. Factors associated with improved patient and graft survival beyond 1 year in pediatric liver transplantation. Liver Transpl 2022; 28:1899-1910. [PMID: 35555876 DOI: 10.1002/lt.26502] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 03/29/2022] [Accepted: 04/04/2022] [Indexed: 01/13/2023]
Abstract
With advances in surgical techniques, medical management, and more equitable allocation systems, children who receive a liver transplantation (LT) today can expect remarkable outcomes early after LT. However, beyond 1 year after transplant, attrition rates have not improved. We reviewed two separate eras (Era 1: January 1995-June 2004 vs. Era 2: July 2004-March 2018) of the Society of Pediatric Liver Transplantation registry to explore the evolution and associated factors contributing to late graft loss (LGL) and late mortality (LM). The fraction of long-term pediatric LT recipients surviving after 1 year with their first graft significantly improved (81.5% in Era 1 vs. 85.7% in Era 2; p < 0.0001). This improvement occurred despite significant changes in patient selection toward higher risk populations (p < 0.001) and without notable improvement in perioperative complications such as hepatic artery thrombosis (p = 0.24) and early posttransplant reoperation (p = 0.94) that have historically contributed to poor late-allograft outcomes. Improved outcomes were associated with changes in patient characteristics and perioperative practices, which subsequently impacted both early post-LT complications as well as other sequalae known to contribute to adverse events in long-term pediatric LT recipients. In conclusion, despite significant changes in patient selection toward higher risk populations, and without notable improvement in several perioperative complications known to contribute to poor late-allograft outcomes, significant improvements in LGL and a trend toward improvement in LM was seen in a more contemporary cohort of children receiving an LT.
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Affiliation(s)
- James E Squires
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Jacob Bilhartz
- C. S. Mott Children's Hospital, University of Michigan Health, Ann Arbor, Michigan, USA
| | - Kyle Soltys
- Hillman Center for Pediatric Transplantation, Thomas E. Starzl Transplantation Institute, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Einar Hafberg
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - George V Mazariegos
- Hillman Center for Pediatric Transplantation, Thomas E. Starzl Transplantation Institute, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Nitika A Gupta
- Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia, USA
| | | | | | - Tamir Miloh
- Department of Pediatrics, University of Miami, Miami, Florida, USA
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38
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Baumann AK, Beck J, Kirchner T, Hartleben B, Schütz E, Oellerich M, Wedemeyer H, Jaeckel E, Taubert R. Elevated fractional donor-derived cell-free DNA during subclinical graft injury after liver transplantation. Liver Transpl 2022; 28:1911-1919. [PMID: 35429207 DOI: 10.1002/lt.26479] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 03/18/2022] [Accepted: 04/05/2022] [Indexed: 02/07/2023]
Abstract
Personalized immunosuppression (IS) promises to improve the balance of necessary control of alloreactivity and dose-dependent adverse effects of long-term IS such as kidney insufficiency, infections, and malignancies. The majority of liver transplantation (LT) recipients exhibit graft injuries (graft inflammation and/or fibrosis) that are not eligible for an IS reduction according to current Banff criteria, even when liver enzymes are normal or only marginally elevated. This cross-sectional study evaluated the noninvasive prediction of such subclinical graft injuries in surveillance liver biopsies via donor-derived cell-free DNA (dd-cfDNA). Absolute and fractional dd-cfDNA increased stepwise from patients without histological signs of rejection (n = 26) over subclinical graft injury (n = 61), including subclinical T cell-mediated rejection to clinical overt T cell-mediated rejection (n = 21). Thus, fractional plasma dd-cfDNA was significantly elevated paired to surveillance biopsies with relevant subclinical graft injury according to 2016 Banff criteria compared with those with minimal or absent histological graft injury. In contrast, the presence of donor-specific anti-human leukocyte antigen antibodies was not associated with the amount of dd-cfDNA. The sensitivity and specificity of fractional dd-cfDNA to noninvasively predict relevant subclinical graft injury was rather limited with 73% and 52% at the cutoff value of 2.1% fractional dd-cfDNA. The positive predictive value of fractional dd-cfDNA above 2.1% was 76% to noninvasively predict subclinical graft injury, calculated on the prevalence of graft injury in our prospective surveillance biopsy program, whereas the negative predictive values was not predictive (47%). In conclusion, dd-cfDNA has a rather limited diagnostic fidelity in addition to other noninvasive markers for the assessment of subclinical graft injury in personalized IS approaches after LT in a cross-sectional setting.
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Affiliation(s)
- Anna K Baumann
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | | | - Theresa Kirchner
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Björn Hartleben
- Institute for Pathology, Hannover Medical School, Hannover, Germany
| | | | - Michael Oellerich
- Department of Clinical Pharmacology, University Medical Center Goettingen, Goettingen, 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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39
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Feng H, Xi ZF, Kasahara M, Xia Q. Pediatric liver transplantation: progress in optimizing long-term outcomes and directions for future research. Sci Bull (Beijing) 2022; 67:1929-1931. [PMID: 36546196 DOI: 10.1016/j.scib.2022.09.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Affiliation(s)
- Hao Feng
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China; Shanghai Engineering Research Centre of Transplantation and Immunology, Shanghai 200127, China; Shanghai Institute of Transplantation, Shanghai 200127, China
| | - Zhi-Feng Xi
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China; Shanghai Engineering Research Centre of Transplantation and Immunology, Shanghai 200127, China
| | - Mureo Kasahara
- Transplantation Center, National Center for Child Health and Development, Tokyo 157-8535, Japan
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China; Shanghai Engineering Research Centre of Transplantation and Immunology, Shanghai 200127, China; Shanghai Institute of Transplantation, Shanghai 200127, China.
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40
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Taner T, Bruner J, Emaumaullee J, Bonaccorsi-Riani E, Zarrinpar A. New Approaches to the Diagnosis of Rejection and Prediction of Tolerance in Liver Transplantation. Transplantation 2022; 106:1952-1962. [PMID: 35594482 PMCID: PMC9529763 DOI: 10.1097/tp.0000000000004160] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Immunosuppression after liver transplantation is essential for preventing allograft rejection. However, long-term drug toxicity and associated complications necessitate investigation of immunosuppression minimization and withdrawal protocols. Development of such protocols is hindered by reliance on current paradigms for monitoring allograft function and rejection status. The current standard of care for diagnosis of rejection is histopathologic assessment and grading of liver biopsies in accordance with the Banff Rejection Activity Index. However, this method is limited by cost, sampling variability, and interobserver variation. Moreover, the invasive nature of biopsy increases the risk of patient complications. Incorporating noninvasive techniques may supplement existing methods through improved understanding of rejection causes, hepatic spatial architecture, and the role of idiopathic fibroinflammatory regions. These techniques may also aid in quantification and help integrate emerging -omics analyses with current assessments. Alternatively, emerging noninvasive methods show potential to detect and distinguish between different types of rejection while minimizing risk of adverse advents. Although biomarkers have yet to replace biopsy, preliminary studies suggest that several classes of analytes may be used to detect rejection with greater sensitivity and in earlier stages than traditional methods, possibly when coupled with artificial intelligence. Here, we provide an overview of the latest efforts in optimizing the diagnosis of rejection in liver transplantation.
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Affiliation(s)
- Timucin Taner
- Departments of Surgery & Immunology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Julia Bruner
- Department of Surgery, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Juliet Emaumaullee
- Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Eliano Bonaccorsi-Riani
- Abdominal Transplant Unit, Cliniques Universitaires Saint Luc, Université Catholique de Louvain, Brussels, Belgium
| | - Ali Zarrinpar
- Department of Surgery, College of Medicine, University of Florida, Gainesville, FL, USA
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41
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Wozniak LJ, Venick RS, Naini BV, Scapa J, Hickey MJ, Rossetti M, Korin Y, Reed EF, Farmer DG, Busuttil RW, Vargas JH, McDiarmid SV. Operational tolerance is not always permanent: A 10-year prospective study in pediatric liver transplantation recipients. Liver Transpl 2022; 28:1640-1650. [PMID: 35395132 DOI: 10.1002/lt.26474] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 02/03/2022] [Accepted: 03/02/2022] [Indexed: 12/25/2022]
Abstract
Immunosuppression withdrawal can be safely performed in select liver transplantation recipients, but the long-term outcomes and sustainability of tolerance have not been well studied. We completed a 10-year prospective, observational study of 18 pediatric liver transplantation recipients with operational tolerance to (1) assess the sustainability of tolerance over time, (2) compare the clinical characteristics of patients who maintained versus lost tolerance, (3) characterize liver histopathology findings in surveillance liver biopsies; and (4) describe immunologic markers in patients with tolerance. Comparator patients from two clinical phenotype groups termed "stable" and "nontolerant" patients were used as controls. Of the 18 patients with operational tolerance, the majority of patients were males (n = 14, 78%) who were transplanted for cholestatic liver disease (n = 12, 67%). Median age at transplantation was 1.9 (range, 0.6-8) years. Median time after transplantation that immunosuppression had been discontinued was 13.1 (range, 2.9-22.1) years. As many as 11 (61%) maintained tolerance for a median of 10.4 (range, 1.9-22.1) years, whereas 7 (39%) lost tolerance after a median of 3.2 (range, 1.5-18.6) years. Populations of T regulatory cells (%CD4+ CD25hi CD127lo ) were significantly higher in patients with tolerance (p = 0.02). Our results emphasize that spontaneous operational tolerance is a dynamic and nonpermanent state. It is therefore essential for patients who are clinically stable off immunosuppression to undergo regular follow-up and laboratory monitoring, as well as surveillance biopsies to rule out subclinical rejection.
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Affiliation(s)
- Laura J Wozniak
- Pediatric Gastroenterology, Hepatology, and Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Robert S Venick
- Pediatric Gastroenterology, Hepatology, and Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.,Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Bita V Naini
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Jason Scapa
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Michelle J Hickey
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.,Immunogenetics Center, University of California, Los Angeles (UCLA), Los Angeles, California, USA
| | - Maura Rossetti
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.,Immunogenetics Center, University of California, Los Angeles (UCLA), Los Angeles, California, USA
| | - Yael Korin
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.,Immunogenetics Center, University of California, Los Angeles (UCLA), Los Angeles, California, USA
| | - Elaine F Reed
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.,Immunogenetics Center, University of California, Los Angeles (UCLA), Los Angeles, California, USA
| | - Douglas G Farmer
- Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Ronald W Busuttil
- Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Jorge H Vargas
- Pediatric Gastroenterology, Hepatology, and Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Sue V McDiarmid
- Pediatric Gastroenterology, Hepatology, and Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.,Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
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42
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Duizendstra AA, De Knegt RJ, Nagtzaam NMA, Betjes MGH, Dik WA, Litjens NHR, Kwekkeboom J. Minimal Development of Liver Fibrosis in Adult Tolerant Liver Transplant Recipients Late After Immunosuppressive Drug Weaning and Transplantation. Transplant Proc 2022; 54:1874-1880. [PMID: 36100485 DOI: 10.1016/j.transproceed.2022.04.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 04/13/2022] [Indexed: 10/14/2022]
Abstract
BACKGROUND Operationally tolerant liver transplant (LTx)-recipients can be weaned off immunosuppressive (IS) drugs without development of graft rejection. However, it is feared that liver fibrosis might develop after complete IS weaning. The purpose of this small single-center study was to assess liver fibrosis in adult tolerant LTx recipients long after LTx and IS weaning. METHODS Liver fibrosis was assessed in adult tolerant LTx-recipients (n = 9) using noninvasive transient elastography and measurements of multiple pro- and antifibrotic serum markers associated with liver fibrosis. The data was collected for 2 subsequent years; 8 and 9 years after IS weaning and 19 and 20 years after transplantation. Healthy individuals (n = 9) matched for age and sex were included as a reference for fibrosis-related serum markers. This study was conducted in accordance with the Declaration of Helsinki and approved by the medical ethics committee of our institution. RESULTS Transient elastography indicated that 7 of 9 tolerant LTx recipients had no or minimal liver fibrosis (F0-F1), whereas 2 recipients had moderate or severe liver fibrosis (F2-F3). Most fibrosis-related serum markers in tolerant LTx recipients were within or close to the range obtained for healthy individuals. CONCLUSIONS The results from this small, single-center study indicated that most adult tolerant LTx recipients have no or minimal liver graft fibrosis long after transplantation and IS weaning, and their fibrosis-related serum marker profile indicates an absence of a profibrotic status.
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Affiliation(s)
- Aafke A Duizendstra
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Robert J De Knegt
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Nicole M A Nagtzaam
- Laboratory of Medical Immunology, Department of Immunology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Michiel G H Betjes
- Erasmus MC Transplant Institute, Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Willem A Dik
- Laboratory of Medical Immunology, Department of Immunology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Nicolle H R Litjens
- Erasmus MC Transplant Institute, Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Jaap Kwekkeboom
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
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43
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Castle JT, Levy BE, Rodeberg DA. Abdominal Tumors. Surg Clin North Am 2022; 102:715-737. [DOI: 10.1016/j.suc.2022.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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44
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Andrade MS, Young JS, Pollard JM, Yin D, Alegre ML, Chong AS. Linked sensitization by memory CD4+ T cells prevents costimulation blockade–induced transplantation tolerance. JCI Insight 2022; 7:159205. [PMID: 35674134 PMCID: PMC9220839 DOI: 10.1172/jci.insight.159205] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 04/22/2022] [Indexed: 11/17/2022] Open
Abstract
Dominant infectious tolerance explains how brief tolerance-inducing therapies result in lifelong tolerance to donor antigens and “linked” third-party antigens, while recipient sensitization and ensuing immunological memory prevent the successful induction of transplant tolerance. In this study, we juxtapose these 2 concepts to test whether mechanisms of dominant infectious tolerance can control a limited repertoire of memory T and B cells. We show that sensitization to a single donor antigen is sufficient to prevent stable transplant tolerance, rendering it unstable. Mechanistic studies revealed that recall antibody responses and memory CD8+ T cell expansion were initially controlled, but memory CD4+Foxp3– T cell (Tconv) responses were not. Remarkably, naive donor-specific Tconvs at tolerance induction also acquired a resistance to tolerance, proliferating and acquiring a phenotype similar to memory Tconvs. This phenomenon of “linked sensitization” underscores the challenges of reprogramming a primed immune response toward tolerance and identifies a potential therapeutic checkpoint for synergizing with costimulation blockade to achieve transplant tolerance in the clinic.
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45
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Proceedings of the 26th Annual Virtual Congress of the International Liver Transplantation Society. Transplantation 2022; 106:1738-1744. [PMID: 35676871 DOI: 10.1097/tp.0000000000004183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
After a 1-y absence due to the coronavirus disease 2019 pandemic, the 26th Annual Congress of the International Liver Transplantation Society was held from May 15 to 18, 2021, in a virtual format. Clinicians and researchers from all over the world came together to share their knowledge on all the aspects of liver transplantation (LT). Apart from a focus on LT in times of coronavirus disease 2019, featured topics of this year's conference included infectious diseases in LT, living donation, machine perfusion, oncology, predictive scoring systems and updates in anesthesia/critical care, immunology, radiology, pathology, and pediatrics. This report presents highlights from invited lectures and a review of the select abstracts. The aim of this report, generated by the Vanguard Committee of International Liver Transplantation Society, is to provide a summary of the most recent developments in clinical practice and research in LT.
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46
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Perito ER, Persyn E, Bucuvalas J, Martinez M, Mohammad S, Squires JE, Demetris AJ, Feng S. Graft Fibrosis Over 10 to 15 Years in Pediatric Liver Transplant Recipients: Multicenter Study of Paired, Longitudinal Surveillance Biopsies. Liver Transpl 2022; 28:1051-1062. [PMID: 35029022 DOI: 10.1002/lt.26409] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 12/19/2021] [Accepted: 12/22/2021] [Indexed: 01/13/2023]
Abstract
Previous single-center, cross-sectional studies have reported a steep increase in the prevalence and severity of fibrosis through 10 to 15 years after pediatric liver transplantation. We report a multicenter study of paired surveillance biopsies in a contemporary cohort. Children who underwent liver transplant when younger than 6 years old and had paired surveillance liver biopsies were enrolled (n = 78, 35% girls, median 1.2 years old at transplant). A central pathologist graded inflammation, assessed rejection activity index, and staged fibrosis in the portal, sinusoidal, and perivenular compartments, allowing for calculation of the Liver Allograft Fibrosis Score (LAFSc). Analysis of variance tested associations between fibrosis progression and clinical parameters. The first biopsy, at a median 8.2 years (interquartile range, 5.9-11.6 years) after transplantation, showed absent to mild fibrosis (LAFSc 0-2) in 29%, moderate (LAFSc 3-5) in 56%, and severe (LAFSc 6-7) in 14% of patients. The second biopsy, at a median 4.7 years (IQR, 4.3-5.1 years) later, showed fibrosis progression (LAFSc increased by ≥3) in 10 (13%) and regression (LAFSc decreased by ≥3) in 4 (5%) patients. After adjusting for baseline LAFSc, younger age at transplant was the only risk factor for fibrosis progression. Although fibrosis prevalence and severity 6 to 12 years after transplant was similar to previous reports, fibrosis trajectory during the next 4 to 5 years was stable. Our data may be reassuring for children with consistently normal liver tests. A comprehensive understanding of factors determining allograft health during the very long term is essential to optimizing allograft and patient health.
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Affiliation(s)
- Emily R Perito
- Department of Pediatrics, Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA
| | - Elodie Persyn
- Institute of Liver Studies, King's College London, London, UK
| | - John Bucuvalas
- Department of Pediatrics, Mount Sinai Kravis Children's Hospital and Recanati/Miller Transplantation Institute, Mount Sinai Health System, New York, NY
| | - Mercedes Martinez
- Department of Surgery, Center for Liver Diseases and Transplantation, Columbia University Irving Medical Center, New York, NY
| | - Saeed Mohammad
- Department of Pediatrics, Siragusa Transplantation Center, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
| | - James E Squires
- Department of Pediatrics, University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh, Pittsburgh, PA
| | | | - Sandy Feng
- Department of Surgery, University of California San Francisco, San Francisco, CA
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47
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Shin S, Lee M, Dente E, Yazigi N, Khan KM, Kaufman SS, Ahn J, Timofeeva OA, Ekong UD. Mismatch epitope load predicts de novo-DSA-free survival in pediatric liver transplantation. Pediatr Transplant 2022; 26:e14251. [PMID: 35279919 DOI: 10.1111/petr.14251] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 01/28/2022] [Accepted: 02/03/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Our knowledge of de novo anti-HLA donor-specific antibodies (dnDSA) in liver transplantation continues to be defined. We hypothesized that differences of HLA-DR/DQ mismatches can improve precision in alloimmune risk categorization and be applied to tailor immunosuppression. METHODS A retrospective chart review of 244 pediatric patients consecutively transplanted at our center between 2003 and 2019 was performed to identify patients tested for dnDSA. Records were queried for: demographics, pre-transplant diagnosis, biopsy-proven T-cell-mediated rejection (TCMR), radiology proven biliary complications, tacrolimus trough levels, dnDSA characteristics, and HLA typing. The eplet mismatch analyses were performed using HLAMatchmaker™ 3.1. All statistical analyses were conducted using R software version 3.40. RESULTS There were 99 dnDSA-negative patients and 73 dnDSA-positive patients (n = 70 against class II and n = 3 against class I and II). ROC analysis identified optimal cutoff of eplet mismatch load for dnDSA and defined risk groups for an alloimmune outcome. Kaplan-Meier curves and log-rank tests showed high eplet mismatch load was associated with shorter dnDSA-free survival (log-rank p = .001). Multivariable Cox regression models showed that tacrolimus coefficient of variation and tacrolimus mean levels were significantly associated with dnDSA-free survival (p < .001 and p = .036). Fisher's exact test showed that dnDSA was associated with an increased likelihood of TCMR (OR 14.94; 95% CI 3.65 - 61.19; p < .001). Patients without TCMR were more likely to have dnDSA to HLA-DQ7 and less likely to have dnDSA to HLA-DQ2 (p = .03, p = .080). CONCLUSIONS Mismatched epitope load predicts dnDSA-free survival in pediatric liver transplant, while dnDSA specificity may determine alloimmune outcome.
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Affiliation(s)
- Stephanie Shin
- Georgetown University School of Medicine, Washington, District of Columbia, USA
| | - Margaret Lee
- Georgetown University School of Medicine, Washington, District of Columbia, USA
| | - Elizabeth Dente
- Georgetown University School of Medicine, Washington, District of Columbia, USA
| | - Nada Yazigi
- Georgetown University School of Medicine, Washington, District of Columbia, USA.,Medstar Georgetown Transplant Institute, Medstar Georgetown University Hospital, Washington, District of Columbia, USA
| | - Khalid M Khan
- Georgetown University School of Medicine, Washington, District of Columbia, USA.,Medstar Georgetown Transplant Institute, Medstar Georgetown University Hospital, Washington, District of Columbia, USA
| | - Stuart S Kaufman
- Georgetown University School of Medicine, Washington, District of Columbia, USA.,Medstar Georgetown Transplant Institute, Medstar Georgetown University Hospital, Washington, District of Columbia, USA
| | - Jaeil Ahn
- Department of Biostatistics, Bioinformatics, & Biomathematics, Georgetown University, Washington, District of Columbia, USA
| | - Olga A Timofeeva
- Georgetown University School of Medicine, Washington, District of Columbia, USA.,Histocompatibility Laboratory, Department of Pathology & Laboratory Medicine, Georgetown University, Washington, District of Columbia, USA
| | - Udeme D Ekong
- Georgetown University School of Medicine, Washington, District of Columbia, USA.,Medstar Georgetown Transplant Institute, Medstar Georgetown University Hospital, Washington, District of Columbia, USA
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Squires JE, Demetris AJ. Surveillance Biopsies in Pediatric Liver Transplantation: Is the Juice Worth the Squeeze? Liver Transpl 2022; 28:754-755. [PMID: 35092345 DOI: 10.1002/lt.26420] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 01/20/2022] [Indexed: 01/13/2023]
Affiliation(s)
- James E Squires
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, Pittsburgh, PA
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Barbetta A, Meeberg G, Rocque B, Barhouma S, Weaver C, Gilmour S, Faytrouni F, Guttman O, Zielsdorf S, Etesami K, Kwon Y, Yanni G, Campbell P, Shapiro J, Emamaullee J. Immunologic benefits of maternal living donor allografts in pediatric liver transplantation: fewer rejection episodes and no evidence of de novo allosensitization. Pediatr Transplant 2022; 26:e14197. [PMID: 34806273 PMCID: PMC9053650 DOI: 10.1111/petr.14197] [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: 08/27/2021] [Revised: 10/23/2021] [Accepted: 11/10/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Pediatric liver transplant (LT) recipients of maternal living liver donor (LLD) grafts have been reported to experience fewer rejection episodes. However, it is unclear whether this benefit translates to reduction in developing donor-specific antibody (DSA) among maternal-LLD recipients. The aim of this study was to compare immunologic outcomes among maternal-LLD, non-maternal-LLD, and deceased donor liver transplant (DDLT) recipients. METHODS Children (≤18 years) who underwent LT between 1/1998 and 12/2019 at two high-volume LT centers in North America were evaluated. Patients were divided into three groups by type of graft received (maternal-LLD, non-maternal LLD, and DDLT). Clinical variables and outcomes were compared according to each graft type. RESULTS A total of 450 pediatric primary LT were analyzed: 275 (61.1%) DDLT, 73 (16.2%) maternal-LLD, and 102 (22.6%) non-maternal-LLD. Children receiving LLD grafts were less likely to develop rejection when compared to the DDLT group (DDLT 46.9% vs. maternal-LLD 31.5% vs. non-maternal-LLD 28.4%, p = 0.001). There was no difference in rejection rates between maternal and non-maternal-LLD recipients. A higher percentage of maternal-LLD recipients were on immunosuppression monotherapy compared to non-maternal-LLD and DDLT recipients (6.7% vs. 1.2 vs. 2.4%, respectively). A subgroup of 68 patients were tested for DSA post-LT. Maternal-LLD recipients were less likely to develop de novo DSA (maternal-LLD 11.8% vs. non-maternal-LLD 19.3% vs. DDLT 43%, p = 0.018). None of the maternal-LLD recipients developed antibody-mediated rejection. CONCLUSIONS These data support the concept of immunologic benefit of maternal-LLD in pediatric LT, with lower rates of rejection and allosensitization post-LT when compared to DDLT recipients.
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Affiliation(s)
- Arianna Barbetta
- Department of Surgery, Division of Abdominal Organ Transplant, University of Southern California, Los Angeles, CA, USA
| | | | - Brittany Rocque
- Department of Surgery, Division of Abdominal Organ Transplant, University of Southern California, Los Angeles, CA, USA
| | | | - Carly Weaver
- Division of Hepatobiliary and Abdominal Organ Transplantation Surgery, Children’s Hospital-Los Angeles, Los Angeles, CA USA
| | | | - Farah Faytrouni
- Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
| | - Orlee Guttman
- Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
| | - Shannon Zielsdorf
- Department of Surgery, Division of Abdominal Organ Transplant, University of Southern California, Los Angeles, CA, USA,University of Southern California, Los Angeles, CA, USA,Division of Hepatobiliary and Abdominal Organ Transplantation Surgery, Children’s Hospital-Los Angeles, Los Angeles, CA USA
| | - Kambiz Etesami
- Department of Surgery, Division of Abdominal Organ Transplant, University of Southern California, Los Angeles, CA, USA,University of Southern California, Los Angeles, CA, USA,Division of Hepatobiliary and Abdominal Organ Transplantation Surgery, Children’s Hospital-Los Angeles, Los Angeles, CA USA
| | - Yong Kwon
- Department of Surgery, Division of Abdominal Organ Transplant, University of Southern California, Los Angeles, CA, USA,University of Southern California, Los Angeles, CA, USA,Division of Hepatobiliary and Abdominal Organ Transplantation Surgery, Children’s Hospital-Los Angeles, Los Angeles, CA USA
| | - George Yanni
- University of Southern California, Los Angeles, CA, USA,Department of Pediatrics, Children’s Hospital-Los Angeles, Los Angeles, CA USA
| | - Patricia Campbell
- Alberta Transplant Institute, Edmonton, AB, Canada,Departemtent of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
| | | | - Juliet Emamaullee
- Department of Surgery, Division of Abdominal Organ Transplant, University of Southern California, Los Angeles, CA, USA,University of Southern California, Los Angeles, CA, USA,Division of Hepatobiliary and Abdominal Organ Transplantation Surgery, Children’s Hospital-Los Angeles, Los Angeles, CA USA
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50
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Donor and recipient polygenic risk scores influence the risk of post-transplant diabetes. Nat Med 2022; 28:999-1005. [PMID: 35393535 DOI: 10.1038/s41591-022-01758-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 02/24/2022] [Indexed: 12/13/2022]
Abstract
Post-transplant diabetes mellitus (PTDM) reduces allograft and recipient life span. Polygenic risk scores (PRSs) show robust association with greater risk of developing type 2 diabetes (T2D). We examined the association of PTDM with T2D PRS in liver recipients (n = 1,581) and their donors (n = 1,555), and kidney recipients (n = 2,062) and their donors (n = 533). Recipient T2D PRS was associated with pre-transplant T2D and the development of PTDM. T2D PRS in liver donors, but not in kidney donors, was an independent risk factor for PTDM development. The inclusion of a combined liver donor and recipient T2D PRS significantly improved PTDM prediction compared with a model that included only clinical characteristics: the area under the curve (AUC) was 67.6% (95% confidence interval (CI) 64.1-71.1%) for the combined T2D PRS versus 62.3% (95% CI 58.8-65.8%) for the clinical characteristics model (P = 0.0001). Liver recipients in the highest quintile of combined donor and recipient T2D PRS had the greatest risk of PTDM, with an odds ratio of 3.22 (95% CI 2.07-5.00) (P = 1.92 × 10-7) compared with those in the lowest quintile. In conclusion, T2D PRS identifies transplant candidates with high risk of PTDM for which pre-emptive diabetes management and donor selection may be warranted.
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