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Delignette MC, Riff A, Antonini T, Soustre T, Bodinier M, Peronnet E, Venet F, Gossez M, Pantel S, Mabrut JY, Muller X, Mohkam K, Villeret F, Erard D, Dumortier J, Zoulim F, Heyer L, Guichon C, Blet A, Aubrun F, Monneret G, Lebossé F. Individual mHLA-DR trajectories in the ICU as predictors of early infections following liver transplantation: a prospective observational study. Crit Care 2025; 29:79. [PMID: 39966934 PMCID: PMC11834174 DOI: 10.1186/s13054-025-05305-x] [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: 11/14/2024] [Accepted: 01/30/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Infections are a leading cause of early mortality after liver transplantation (LT). Prior to transplantation, cirrhosis-associated immune dysfunction significantly increases the risk of infection. This study investigated the potential of immune monitoring, with a focus on monocytic HLA-DR (mHLA-DR) expression, as a predictor of post-LT complications. METHODS We conducted a prospective study on 130 patients awaiting LT at Lyon University Hospital to assess mHLA-DR expression, lymphocyte subsets, and T-cell function before and after LT. Multivariate analysis and K-means longitudinal clustering were performed to explore the relationships between immune trajectories and clinical outcomes. RESULTS Among the 99 patients who underwent LT, 35.4% experienced infections early post-LT. No difference in outcome was found regarding lymphocyte count or function. Delayed mHLA-DR recovery (Day 7 < 11,000 AB/C) and pre-LT MELD scores > 30 emerged as independent infection risk factors, with ORs of 12.1 [4.4-38.2], p < 0.0001 and 4.9 [1.4-18.4], p = 0.01, respectively. Patients with delayed mHLA-DR restoration also had reduced one-year survival (77.8% versus 98.3%, p = 0.003). K-means clustering revealed three distinct mHLA-DR recovery profiles, with the slowest recovery group showing the poorest outcomes. CONCLUSIONS Our findings highlight mHLA-DR as an early predictor of post-LT infections. Monitoring post-LT immune function through mHLA-DR expression could guide individualized management strategies to improve outcomes. Trial registration The study was registered in the ClinicalTrials.gov registry: NCT03995537, date: June 20, 2019.
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Affiliation(s)
- M C Delignette
- Anesthesiology and Intensive Care Department, Croix Rousse Hospital, Hospices Civils of Lyon, Lyon, France
- The Lyon Liver Institute, Everest IHU, Lyon, France
- EA 7426 Pathophysiology of Injury-Induced Immunosuppression (PI3), Lyon 1 University, Hospices Civils of Lyon, bioMérieux, Edouard Herriot Hospital, Lyon, France
- Claude Bernard Lyon 1 University, Lyon, France
| | - A Riff
- The Lyon Liver Institute, Everest IHU, Lyon, France
- EA 7426 Pathophysiology of Injury-Induced Immunosuppression (PI3), Lyon 1 University, Hospices Civils of Lyon, bioMérieux, Edouard Herriot Hospital, Lyon, France
- Claude Bernard Lyon 1 University, Lyon, France
- Hepatology Department, Croix Rousse Hospital, Hospices Civils of Lyon, 103 Grande Rue de la Croix Rousse, 69004, Lyon, France
| | - T Antonini
- The Lyon Liver Institute, Everest IHU, Lyon, France
- Hepatology Department, Croix Rousse Hospital, Hospices Civils of Lyon, 103 Grande Rue de la Croix Rousse, 69004, Lyon, France
| | - T Soustre
- Anesthesiology and Intensive Care Department, Croix Rousse Hospital, Hospices Civils of Lyon, Lyon, France
- The Lyon Liver Institute, Everest IHU, Lyon, France
| | - M Bodinier
- EA 7426 Pathophysiology of Injury-Induced Immunosuppression (PI3), Lyon 1 University, Hospices Civils of Lyon, bioMérieux, Edouard Herriot Hospital, Lyon, France
| | - E Peronnet
- EA 7426 Pathophysiology of Injury-Induced Immunosuppression (PI3), Lyon 1 University, Hospices Civils of Lyon, bioMérieux, Edouard Herriot Hospital, Lyon, France
| | - F Venet
- EA 7426 Pathophysiology of Injury-Induced Immunosuppression (PI3), Lyon 1 University, Hospices Civils of Lyon, bioMérieux, Edouard Herriot Hospital, Lyon, France
- Claude Bernard Lyon 1 University, Lyon, France
- Immunology Department, Edouard Herriot Hospital, Hospices Civils of Lyon, Lyon, France
- Centre International de Recherche en Infectiologie (CIRI), INSERM U1111, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Lyon 1 University, Lyon, France
| | - M Gossez
- EA 7426 Pathophysiology of Injury-Induced Immunosuppression (PI3), Lyon 1 University, Hospices Civils of Lyon, bioMérieux, Edouard Herriot Hospital, Lyon, France
- Claude Bernard Lyon 1 University, Lyon, France
- Immunology Department, Edouard Herriot Hospital, Hospices Civils of Lyon, Lyon, France
- Centre International de Recherche en Infectiologie (CIRI), INSERM U1111, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Lyon 1 University, Lyon, France
| | - S Pantel
- The Lyon Liver Institute, Everest IHU, Lyon, France
- Clinical Research Center, Croix Rousse Hospital, Hospices Civils of Lyon, Lyon, France
| | - J Y Mabrut
- The Lyon Liver Institute, Everest IHU, Lyon, France
- Claude Bernard Lyon 1 University, Lyon, France
- INSERM 1350 UMR PaThLiv, Pathobiology and Therapy of Liver diseases, Lyon, France
- Liver Transplantation Department, Croix Rousse Hospital, Hospices Civils of Lyon, Lyon, France
| | - X Muller
- The Lyon Liver Institute, Everest IHU, Lyon, France
- Claude Bernard Lyon 1 University, Lyon, France
- INSERM 1350 UMR PaThLiv, Pathobiology and Therapy of Liver diseases, Lyon, France
- Liver Transplantation Department, Croix Rousse Hospital, Hospices Civils of Lyon, Lyon, France
| | - K Mohkam
- The Lyon Liver Institute, Everest IHU, Lyon, France
- Claude Bernard Lyon 1 University, Lyon, France
- INSERM 1350 UMR PaThLiv, Pathobiology and Therapy of Liver diseases, Lyon, France
- Liver Transplantation Department, Croix Rousse Hospital, Hospices Civils of Lyon, Lyon, France
| | - F Villeret
- The Lyon Liver Institute, Everest IHU, Lyon, France
- Claude Bernard Lyon 1 University, Lyon, France
- Hepatology Department, Croix Rousse Hospital, Hospices Civils of Lyon, 103 Grande Rue de la Croix Rousse, 69004, Lyon, France
- INSERM 1350 UMR PaThLiv, Pathobiology and Therapy of Liver diseases, Lyon, France
| | - D Erard
- The Lyon Liver Institute, Everest IHU, Lyon, France
- Claude Bernard Lyon 1 University, Lyon, France
- Hepatology Department, Croix Rousse Hospital, Hospices Civils of Lyon, 103 Grande Rue de la Croix Rousse, 69004, Lyon, France
- INSERM 1350 UMR PaThLiv, Pathobiology and Therapy of Liver diseases, Lyon, France
| | - J Dumortier
- The Lyon Liver Institute, Everest IHU, Lyon, France
- Claude Bernard Lyon 1 University, Lyon, France
- Gastroenterology and Hepatology Unit, Edouard Herriot Hospital, Hospices Civils of Lyon, Lyon, France
| | - F Zoulim
- The Lyon Liver Institute, Everest IHU, Lyon, France
- Claude Bernard Lyon 1 University, Lyon, France
- Hepatology Department, Croix Rousse Hospital, Hospices Civils of Lyon, 103 Grande Rue de la Croix Rousse, 69004, Lyon, France
- INSERM 1350 UMR PaThLiv, Pathobiology and Therapy of Liver diseases, Lyon, France
| | - L Heyer
- Anesthesiology and Intensive Care Department, Croix Rousse Hospital, Hospices Civils of Lyon, Lyon, France
| | - C Guichon
- Anesthesiology and Intensive Care Department, Croix Rousse Hospital, Hospices Civils of Lyon, Lyon, France
- The Lyon Liver Institute, Everest IHU, Lyon, France
| | - A Blet
- Anesthesiology and Intensive Care Department, Croix Rousse Hospital, Hospices Civils of Lyon, Lyon, France
- The Lyon Liver Institute, Everest IHU, Lyon, France
- Claude Bernard Lyon 1 University, Lyon, France
- INSERM 1350 UMR PaThLiv, Pathobiology and Therapy of Liver diseases, Lyon, France
| | - F Aubrun
- Anesthesiology and Intensive Care Department, Croix Rousse Hospital, Hospices Civils of Lyon, Lyon, France
- The Lyon Liver Institute, Everest IHU, Lyon, France
- Claude Bernard Lyon 1 University, Lyon, France
| | - G Monneret
- The Lyon Liver Institute, Everest IHU, Lyon, France
- EA 7426 Pathophysiology of Injury-Induced Immunosuppression (PI3), Lyon 1 University, Hospices Civils of Lyon, bioMérieux, Edouard Herriot Hospital, Lyon, France
- Claude Bernard Lyon 1 University, Lyon, France
- Immunology Department, Edouard Herriot Hospital, Hospices Civils of Lyon, Lyon, France
| | - F Lebossé
- The Lyon Liver Institute, Everest IHU, Lyon, France.
- Claude Bernard Lyon 1 University, Lyon, France.
- Hepatology Department, Croix Rousse Hospital, Hospices Civils of Lyon, 103 Grande Rue de la Croix Rousse, 69004, Lyon, France.
- INSERM 1350 UMR PaThLiv, Pathobiology and Therapy of Liver diseases, Lyon, France.
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Costaguta AC, Costaguta GA, Rumbo C, Gondolesi G, D'Agostino D, Pallitto MB, Bottasso O, Álvarez F. Lack of differences in outcomes between 3 immunosuppression protocols in the first year after pediatric liver transplantation: A multicenter study. Liver Transpl 2025; 31:201-210. [PMID: 38949782 DOI: 10.1097/lvt.0000000000000427] [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: 01/23/2024] [Accepted: 06/17/2024] [Indexed: 07/02/2024]
Abstract
Advances in immunosuppression have extended patient and graft survival rates after solid organ transplantation; however, this is not free of side effects. Balancing safety and efficacy is of paramount importance, particularly in the pediatric setting. Current literature comparing different protocols is scarce, and decisions are mostly guided by physician preference. We aimed to compare 3 different protocols from 4 different centers to identify differences in outcomes after 1 year of follow-up. A retrospective analysis of the databases of the participating centers was performed. Consecutive patients aged <18 years with a first liver-only transplant and no other underlying congenital or acquired immunodeficiency were included. Patients were classified according to the immunosuppression protocol as follows: group A (prednisone + tacrolimus + basiliximab), group B (prednisone + tacrolimus + basiliximab + antithymocyte globulin), and group C (prednisone + tacrolimus). Differences in survival, frequency of rejection, infections, and other complications were analyzed in the entire group (n = 97) and the group with biliary atresia (n = 48). After 1 year of follow-up, no differences in patient or graft survival were observed when comparing either the entire group (n = 97) or patients with biliary atresia only (n = 48). The frequencies of rejection and episodes of infection were similar. Renal function showed no differences either before or after transplantation or between the groups. Immunosuppression protocols used in this study appeared to be equally safe and effective. This could offer the opportunity to tailor them to the patient's individual characteristics without compromising the outcome.
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Affiliation(s)
- Alejandro C Costaguta
- Liver Transplantation Unit of the Sanatorio de Niños de Rosario, Rosario, Santa Fe, Argentina
| | - Guillermo A Costaguta
- Department of Gastroenterology, Hepatology and Nutrition of CHU Sainte-Justine, Montreal, Quebec, Canada
| | - Carolina Rumbo
- Department Hepatology and Liver Transplantation Unit, University Hospital Fundación Favaloro, CABA, Buenos Aires, Argentina
| | - Gabriel Gondolesi
- Department Hepatology and Liver Transplantation Unit, University Hospital Fundación Favaloro, CABA, Buenos Aires, Argentina
| | - Daniel D'Agostino
- Department of Gastroenterology and Hepatology, Hospital Italiano, CABA, Buenos Aires, Argentina
| | - María Belén Pallitto
- Department of Gastroenterology and Hepatology, Hospital Italiano, CABA, Buenos Aires, Argentina
| | - Oscar Bottasso
- Immunology Department, IDICER-CONICET, Rosario, Argentina
| | - Fernando Álvarez
- Department of Gastroenterology, Hepatology and Nutrition of CHU Sainte-Justine, Montreal, Quebec, Canada
- Department of Pediatrics, Montreal's University, Montreal, Quebec, Canada
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Vasconcelos L, Grady J, Aristizabal S, Oliveira R, Urban MW, Chen S, Sanchez W, Greenleaf JF, Nenadic I. Attenuation Measuring Ultrasound Shearwave Elastography (AMUSE) as Noninvasive Imaging Biomarker for Liver Acute Cellular Rejection. ULTRASOUND IN MEDICINE & BIOLOGY 2025; 51:149-158. [PMID: 39414407 PMCID: PMC11573631 DOI: 10.1016/j.ultrasmedbio.2024.09.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 08/28/2024] [Accepted: 09/22/2024] [Indexed: 10/18/2024]
Abstract
OBJECTIVE There are over 9000 liver transplants in the United States per year, with acute cellular rejection (ACR) being a prevalent early post-transplant complication (20%-40%) treated using corticosteroids. Ischemia-reperfusion injury (IRI), another early post-transplant pathology, has similar laboratory results but typically resolves without therapy. ACR confirmation requires invasive liver biopsy, bearing risks like hemorrhage and pneumothorax. Attenuation Measuring Ultrasound Shearwave Elastography (AMUSE) assesses shear wave velocity (c) and attenuation (α) without rheological models and have shown potential for noninvasive tissue characterization. METHODS We analyzed 58 transplanted livers suspected for ACR by comparing AMUSE measurements to biopsy findings. Thirteen patients underwent longitudinal tracking from ACR diagnosis on day 7 to therapy initiation and repeat biopsy on day 14. Statistical methods and support vector machine (SVM) were used for performance analysis. RESULTS AMUSE measurements at 100, 200, and 300 Hz showed statistical significance (p < 0.001) for ACR presence, with 200 Hz exhibiting the highest Spearman correlation coefficients for c and α (0.68 and -0.83). High c (> 2.2 m/s) and low α (< 130 Np/m) at 200 Hz correlated with ACR diagnostic, while low c and high α indicated no ACR. Combining c and α into a single biomarker α/c improved patient differentiation, yielding an F1-score of 0.97. SVM was used to evaluate AMUSE ACR staging capabilities using all available frequencies, reaching 0.95 F1-score for categorical classification, with an AUROC of 0.99. When evaluating the presence of ACR the SVM reached 0.99 F1-score, with 1.00 sensitivity/recall. CONCLUSION These findings support the use of AMUSE potential for detection and staging of liver ACR.
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Affiliation(s)
| | - John Grady
- Department of Internal Medicine, University of Michigan Hospital, Ann Arbor, MI, USA
| | | | - Rebeca Oliveira
- Department of Earth and Environmental Sciences, University of Minnesota, Minneapolis, MN, USA
| | - Matthew W Urban
- Department of Radiology, Mayo Clinic, Rochester, MN, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - Shigao Chen
- Department of Radiology, Mayo Clinic, Rochester, MN, USA
| | - William Sanchez
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - James F Greenleaf
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - Ivan Nenadic
- Department of Radiology, Mayo Clinic, Rochester, MN, USA; Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
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Erdem Toslak I, Joyce C, Yacoub JH. Usefulness of Picture Archiving and Communication System-Based Quantitative Ultrasound Measurements in Evaluation of Allograft Dysfunction in Patients With Liver Transplantation. J Comput Assist Tomogr 2025; 49:34-41. [PMID: 39095062 DOI: 10.1097/rct.0000000000001647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/04/2024]
Abstract
OBJECTIVE The aim of this study was to assess the usefulness of picture archiving and communication system (PACS)-based quantitative grayscale ultrasonography (US) measurements in detecting allograft dysfunction in posttransplant patients. METHODS In this retrospective study, 116 patients with liver transplantation who underwent biopsy for allograft evaluation were recruited from the database. All participants had US images prior to procedure. Normal, acute cellular rejection (ACR), recurrent hepatitis (Hep), or combined (ACR/Hep) groups were generated based on pathology results. Region of interests were drawn for liver and rectus abdominus muscle to perform quantitative US analysis. The liver/muscle mean ratio (L/M) and heterogeneity index (HI; liver standard deviation/liver mean) were obtained. The ratios of groups were compared, and receiver-operating-characteristic analysis was performed. RESULTS There was a significant difference between normal (n = 16) and each of other groups (ACR, 39; Hep, 36; combined, 25) for L/M and HI ( P < 0.05). No significant difference was detected between ACR, Hep, and combined groups. The areas under the curve for L/M and HI were 0.755 (moderate) and 0.817 (good), respectively. To differentiate abnormal (ACR, Hep, and combined) from normal allografts sensitivity, specificity, PPV, and NPV were 50.0%, 87.5%, 96.2%, and 21.9% for cut point of L/M ≥1 and 84.0%, 68.8%, 94.4%, and 40.7% for cut point of HI ≥0.2 with odds ratios of 7.52 (for L/M ≥1) and 13.10 (for HI ≥0.2), respectively ( P < 0.01). CONCLUSIONS L/M has moderate and HI has good discrimination of normal from abnormal allograft in liver transplant patients. PACS-based quantitative US measurements is an objective, easy to use, noninvasive auxiliary tool to discriminate hepatic allograft dysfunction.
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Affiliation(s)
- Iclal Erdem Toslak
- From the Department of Radiology, Health Sciences University Antalya Training and Research Hospital, Muratpaşa, Antalya, Türkiye
| | - Cara Joyce
- Clinical Research Office, Loyola University Chicago Health Sciences Division Maywood, IL
| | - Joseph H Yacoub
- Department of Radiology, Medstar Georgetown University Hospital, Washington, DC 20007, USA
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Laue T, Junge N, Leiskau C, Mutschler F, Ohlendorf J, Baumann U. Effectiveness of hepatitis A immunization after pediatric liver transplantation: A retrospective observational analysis. Am J Transplant 2024:S1600-6135(24)00761-5. [PMID: 39706367 DOI: 10.1016/j.ajt.2024.12.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Revised: 12/14/2024] [Accepted: 12/16/2024] [Indexed: 12/23/2024]
Abstract
This retrospective study aimed to investigate the response to hepatitis A virus (HAV) immunization following liver transplantation. We analyzed 234 vaccination records of 284 children who underwent liver transplantation between January 2003 and July 2021, including annual serologic results. Of the 120 HAV-naïve patients, approximately 71% and 83% showed seroconversion after receiving 1 and 2 vaccine doses, respectively. The third dose increased the seroconversion rate to 93%. In multivariable logistic regression analysis, the number of vaccine doses and age at first vaccine dose were independently associated with seroconversion. In contrast, additional immunosuppression with mycophenolate mofetil was negatively associated with seroconversion. In Cox regression analysis, of all 96 seroconverted children, younger age at first vaccination and additional immunosuppression with either mycophenolate mofetil or prednisolone were identified as independent risk factors for the early loss of HAV immunity. In summary, HAV immunization with the 3-dose vaccination series is recommended for pediatric liver transplant recipients. Antibody testing and booster vaccinations, if necessary, are recommended, especially for those living in endemic areas or with additional immunosuppressive treatments.
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Affiliation(s)
- Tobias Laue
- Division for Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver, and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
| | - Norman Junge
- Division for Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver, and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Christoph Leiskau
- Paediatric Gastroenterology, Department of Paediatrics and Adolescent Medicine, University Medical Centre Goettingen, Georg August University Goettingen, Goettingen, Germany
| | - Frauke Mutschler
- Division for Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver, and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Johanna Ohlendorf
- Division for Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver, and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Ulrich Baumann
- Division for Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver, and Metabolic Diseases, Hannover Medical School, Hannover, Germany
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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 2024:S1600-6135(24)00682-8. [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] [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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7
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Channaoui A, de Magnée C, Tambucci R, Bonaccorsi-Riani E, Pirotte T, Magasich-Airola N, Detaille T, Houtekie L, Menten R, Dumitriu D, van den Hove M, Baldin P, Smets F, Scheers I, Jannone G, Sokal E, Stephenne X, Reding R. Failure to Rescue Pediatric Recipients of Living Donor Liver Transplantation: A Single-Center Study of Technical Complications in 500 Primary Grafts. Pediatr Transplant 2024; 28:e14861. [PMID: 39320008 DOI: 10.1111/petr.14861] [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: 08/08/2024] [Revised: 08/28/2024] [Accepted: 09/08/2024] [Indexed: 09/26/2024]
Abstract
BACKGROUND The concept of failure to rescue (FTR) has been used to evaluate the quality of care in several surgical specialties but has not been well-studied after living donor liver transplantation (LDLT) in children. METHODS This study retrospectively reviewed 500 pediatric LDLT performed at a single center between 1993 and 2022. The recipient outcomes were assessed by means of patient and graft survival rates, retransplantation rates, and arterial/portal/biliary complication rates. Graft and patient losses secondary to these complications were calculated regarding FTR for patients (FTRp) and grafts (FTRg). RESULTS Overall 1- and 5-year patient survival rates were 94.5% and 92.1%, respectively, the corresponding figures for graft survival being 92.7% and 89.8%. One-year hepatic artery complication rate was 3.6% (n = 18 cases), the respective rates for portal vein complications and biliary complications being 5.7% (n = 57) and 15.6% (n = 101). One-year FTRp rates for hepatic artery thrombosis, portal vein thrombosis, anastomotic biliary stricture, and intrahepatic biliary stricture were 28.6%, 9.4%, 3.6%, and 0%, respectively. The corresponding FTRg rates being 21.4%, 6.3%, 0%, and 36.4%. CONCLUSION Such novel analytical method may offer valuable insights for optimizing quality of care in pediatric LDLT.
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Affiliation(s)
- Aniss Channaoui
- Pediatric Surgery and Transplant Unit, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | - Catherine de Magnée
- Pediatric Surgery and Transplant Unit, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | - Roberto Tambucci
- Pediatric Surgery and Transplant Unit, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | | | - Thierry Pirotte
- Department of Anesthesiology, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | - Natalia Magasich-Airola
- Department of Anesthesiology, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | - Thierry Detaille
- Pediatric Intensive Care Unit, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | - Laurent Houtekie
- Pediatric Intensive Care Unit, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | - Renaud Menten
- Pediatric Radiology Unit, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | - Dana Dumitriu
- Pediatric Radiology Unit, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | - Marguerite van den Hove
- Pediatric Surgery and Transplant Unit, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | - Pamela Baldin
- Department of Pathology, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | - Françoise Smets
- Division of Pediatric Gastroenterology and Hepatology, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | - Isabelle Scheers
- Division of Pediatric Gastroenterology and Hepatology, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | - Giulia Jannone
- Division of Pediatric Gastroenterology and Hepatology, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | - Etienne Sokal
- Division of Pediatric Gastroenterology and Hepatology, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | - Xavier Stephenne
- Division of Pediatric Gastroenterology and Hepatology, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | - Raymond Reding
- Pediatric Surgery and Transplant Unit, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium
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8
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Tang LCY, Chetwood JD, Lai MSM, Yip TCF, Cao R, Powter E, Salimi S, Wu R, Coulshed A, Bowen DG, Strasser SI, Valliani T, Crawford M, Pulitano C, McKenzie C, Kench J, McCaughan GW, Liu K. Incidence, epidemiology, and outcomes of acute allograft rejection following liver transplantation in Australia. Liver Transpl 2024; 30:1039-1049. [PMID: 38647419 DOI: 10.1097/lvt.0000000000000375] [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: 09/25/2023] [Accepted: 03/30/2024] [Indexed: 04/25/2024]
Abstract
Acute allograft rejection is a well-known complication of liver transplantation (LT). The incidence, epidemiology, and outcomes of acute rejection have not been well described in Australia. We retrospectively studied consecutive adults who underwent deceased donor LT at a single center between 2010 and 2020. Donor and recipient data at the time of LT and recipient outcomes were collected from a prospective LT database. Liver biopsy reports were reviewed, and only a graft's first instance of biopsy-proven acute rejection was analyzed. During the study period, 796 liver transplants were performed in 770 patients. Biopsy-proven rejection occurred in 34.9% of transplants. There were no significant changes in the incidence of rejection over time (linear trend p =0.11). The median time to the first episode of rejection was 71 days after LT: 2.2% hyperacute, 50.4% early (≤90 d), and 47.5% late rejection (>90 d). Independent risk factors for rejection were younger recipient age at transplant (aHR 0.98 per year increase, 95% CI: 0.97-1.00, p =0.01), and ABO-incompatible grafts (aHR 2.55 vs. ABO-compatible, 95% CI: 1.27-5.09, p <0.01) while simultaneous multiorgan transplants were protective (aHR 0.21 vs. LT only, 95% CI: 0.08-0.58, p <0.01). Development of acute rejection (both early and late) was independently associated with significantly reduced graft (aHR 3.13, 95% CI: 2.21-4.42, p <0.001) and patient survival (aHR 3.42, 95% CI: 2.35-4.98, p <0.001). In this 11-year Australian study, acute LT rejection occurred in 35%, with independent risk factors of younger recipient age and ABO-incompatible transplant, while having a simultaneous multiorgan transplant was protective. Acute rejection was independently associated with reduced graft and patient survival after adjustment for other factors.
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Affiliation(s)
- Lauren C Y Tang
- Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - John D Chetwood
- Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
| | - Mandy S M Lai
- Department of Medicine and Therapeutics, Medical Data Analytic Centre, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Terry C F Yip
- Department of Medicine and Therapeutics, Medical Data Analytic Centre, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Rena Cao
- Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Elizabeth Powter
- Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Shirin Salimi
- Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Rodger Wu
- Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Andrew Coulshed
- Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - David G Bowen
- Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
| | - Simone I Strasser
- Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
| | - Talal Valliani
- Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Michael Crawford
- Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
| | - Carlo Pulitano
- Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
| | - Catriona McKenzie
- Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
- New South Wales Health Pathology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - James Kench
- Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
- New South Wales Health Pathology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Geoffrey W McCaughan
- Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
- Liver Injury and Cancer Program, Centenary Institute, Sydney, New South Wales, Australia
| | - Ken Liu
- Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
- Liver Injury and Cancer Program, Centenary Institute, Sydney, New South Wales, Australia
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9
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Awad SM, El Batanony EH, Elmahdy SK, Allam ET, Rizk SK, Zaid AB, Taha M, Salem RH. Interleukin 6 and interleukin 17A serum levels and gene- polymorphisms in the development of early allograft rejection in living donor liver transplant recipients. Sci Rep 2024; 14:21687. [PMID: 39289412 PMCID: PMC11408691 DOI: 10.1038/s41598-024-71102-1] [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: 01/06/2024] [Accepted: 08/26/2024] [Indexed: 09/19/2024] Open
Abstract
The aim of this study is to evaluate the role of serum level of Interleukin 6(IL-6) and Interleukin 17 (IL-17) in liver transplantation outcome for living recipients, Analyze the relation between the gene polymorphism and the occurrence of rejection after liver transplantation and Study the relation between the gene polymorphism and the occurrence of different infectious complications. The study was conducted in March 2023 and included 60 healthy volunteers from the National Liver Institute (NLI) blood bank at Menoufia University and 120 live donation liver recipient patients at NLI. During one month of liver transplantation, the cytokine levels (IL-17, IL-6 proteins, IL-6 G-174C, and IL-17 A rs2275913 gene polymorphism) and CD4 levels for 60 patients of 120 live donation liver recipient patients whom early reject transplanted tissue and the same parameters were measured after 6 months follow up for non-reject group. The main finding of this study was that the post-transplant rejection group and the post-transplant non-rejection and control groups differed significantly in the genotype frequency (CC, CG, and GG) or alleles of IL-6 G-174C (p = 0.011). On the other hand IL-17A rs2275913 gene polymorphism and its alleles (p = 0.71) showed no statistically significant difference. We also observed that serum IL-17 levels, with 100% specificity and 100% sensitivity threshold, will be more sensitive and specific than serum IL-6 and CD4 count in differentiating post-transplant rejection from non-rejection patients. The results showed that there was no significant relationship between the genotypes and serum levels of interleukins and the type and degree of rejection. Proinflammatory cytokines might be useful indicators for distinguishing and early identifying unfavorable outcomes after transplantation, allowing for prompt and effective treatment intervention. To evaluate these findings, prospective clinical trials are required.
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Affiliation(s)
- Samah Mohammed Awad
- Clinical Microbiology and Immunology Department, National Liver Institute, Menoufia University, Shibin Elkom, 32511, Egypt
| | - Eman Helmy El Batanony
- Clinical Microbiology and Immunology Department, National Liver Institute, Menoufia University, Shibin Elkom, 32511, Egypt
| | - Shaimaa K Elmahdy
- Gastroenterology and Hepatology Department, National Liver Institute, Menoufia University, Shibin Elkom, 32511, Egypt
| | - Esraa Tawfik Allam
- Departments of Clinical Pathology, National Liver Institute, Menoufia University, Shibin Elkom, 32511, Egypt
| | - Sara Kamal Rizk
- Biochemistry department, Faculty of Medicine, Menoufia University, Shibin Elkom, 32511, Egypt
| | - Ahmed B Zaid
- Departments of Clinical Pathology, National Liver Institute, Menoufia University, Shibin Elkom, 32511, Egypt.
| | - Mohammad Taha
- Hepatopancreatobiliary and Liver Transplant Surgery, National Liver Institute, Shibin Elkom, 32511, Egypt
| | - Radwa H Salem
- Clinical Microbiology and Immunology Department, National Liver Institute, Menoufia University, Shibin Elkom, 32511, Egypt
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10
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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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11
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Vega-Abellaneda S, Dopazo C, Yañez F, Soler Z, Xie Z, Canalda-Baltrons A, Pons-Tarín M, Bilbao I, Manichanh C. Microbiome composition recovery after liver transplantation correlates with initial liver disease severity and antibiotics treatment. Am J Transplant 2024; 24:1623-1633. [PMID: 38556088 DOI: 10.1016/j.ajt.2024.03.038] [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: 12/20/2023] [Revised: 03/02/2024] [Accepted: 03/27/2024] [Indexed: 04/02/2024]
Abstract
Liver transplantation (LT) is crucial for end-stage liver disease, but it is linked to infection risks. Pathobionts, microorganisms potentially harmful under specific conditions, can cause complications posttransplant. Monitoring such pathogens in fecal samples can be challenging and therefore remains underexplored post-LT. This study aimed to analyze the gut microbiome before and after LT, tracking pathobionts and correlating clinical data. The study involved 17 liver transplant recipients, 17 healthy relatives (spouses), and 13 donors. Gut samples collected pretranplantation and posttransplantation underwent bacterial and fungal profiling through DNA sequencing. Quantitative polymerase chain reaction was used to assess microbial load. Statistical analyses included alpha and beta diversity measures, differential abundance analysis, and correlation tests between microbiome and clinical parameters. Microbiome analysis revealed dynamic changes in diversity posttransplant. Notably, high-severity patients showed persistent and greater dysbiosis during the first months post-LT compared with low-severity patients, partly due to an antibiotic treatment pre-LT. The analysis identified a higher proportion of pathogens such as Escherichia coli/Shigella flexneri in high-severity cases posttransplant. Furthermore, butyrate producers including Roseburia intestinalis, Anaerostipes hadrus, and Eubacterium coprostanoligenes were positively correlated with levels of albumin. This study offers valuable insights into post-LT microbiome changes, shedding light on the need for tailored prophylactic treatment post-LT.
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Affiliation(s)
- Sara Vega-Abellaneda
- Microbiome Lab, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Cristina Dopazo
- Department of HPB Surgery and Transplants, Vall d'Hebron Hospital Universitari, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autónoma de Barcelona, Barcelona, Spain; CIBER of Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Francisca Yañez
- Microbiome Lab, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Zaida Soler
- Microbiome Lab, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Zixuan Xie
- Microbiome Lab, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Aleix Canalda-Baltrons
- Microbiome Lab, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Marc Pons-Tarín
- Microbiome Lab, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Itxarone Bilbao
- Department of HPB Surgery and Transplants, Vall d'Hebron Hospital Universitari, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autónoma de Barcelona, Barcelona, Spain; CIBER of Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
| | - Chaysavanh Manichanh
- Microbiome Lab, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; CIBER of Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.
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12
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Hartjes K, Koo D, Al-Ibraheemi A, Sweeny KF, Wehrman A, Elisofon S, Lee CK, Cuenca AG, Kim HB, Lee EJ. Early Graft Loss With Suspected Seventh-Day Syndrome Following Pediatric Liver Transplantation. Pediatr Transplant 2024; 28:e14818. [PMID: 38940480 DOI: 10.1111/petr.14818] [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: 01/30/2024] [Revised: 06/10/2024] [Accepted: 06/14/2024] [Indexed: 06/29/2024]
Abstract
INTRODUCTION Allograft dysfunction within the first week posttransplant is an uncommon but known complication following liver transplantation. Seventh-Day Syndrome (7DS) is a rare complication of allograft dysfunction following liver transplantation characterized by the rapid clinical deterioration of a formerly well-functioning allograft within the first week posttransplant. The etiology of 7DS is unknown, and treatment options remain limited. While cases of graft survival have been reported, the risk of mortality remains exceedingly high without urgent retransplantation. METHODS Patient data was retrospectively analyzed and a literature review performed. RESULTS We present a unique case of split liver transplantation into two pediatric recipients in which one recipient developed rapidly progressive graft failure approximately 1 week postoperatively requiring urgent retransplantation while the other recipient had an unremarkable postoperative course. Upon clinical manifestation of progressive graft failure, the patient was treated with thymoglobulin, rituximab, intravenous immunoglobulin, and plasmapheresis. Despite this, the patient's clinical status continued to decline and she underwent retransplantation 11 days following her initial liver transplant. CONCLUSION Seventh-Day Syndrome is a rare complication following liver transplantation that is associated with a high risk of morbidity and mortality. Our case adds to the limited literature on 7DS in children and is the first to report a comparative posttransplant clinical course in two recipients who received split grafts from the same donor.
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Affiliation(s)
- Kayla Hartjes
- Division of Gastroenterology, Hepatology, & Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Donna Koo
- Department of Surgery, Pediatric Transplant Center, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Alyaa Al-Ibraheemi
- Department of Pathology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Katherine F Sweeny
- Division of Gastroenterology, Hepatology, & Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Andrew Wehrman
- Division of Gastroenterology, Hepatology, & Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Scott Elisofon
- Division of Gastroenterology, Hepatology, & Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Christine K Lee
- Division of Gastroenterology, Hepatology, & Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Alex G Cuenca
- Department of Surgery, Pediatric Transplant Center, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Heung Bae Kim
- Department of Surgery, Pediatric Transplant Center, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Eliza J Lee
- Department of Surgery, Pediatric Transplant Center, Boston Children's Hospital, Boston, Massachusetts, USA
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13
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Soares ME, Costa G, Guerra L, Morais MC, Vaz N, Codes L, Bittencourt PL. Influence of Tacrolimus Intrapatient Variability on Allograft Rejection Frequency and Survival Following Liver Transplantation. Ther Drug Monit 2024; 46:456-459. [PMID: 38648652 DOI: 10.1097/ftd.0000000000001192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Accepted: 01/26/2024] [Indexed: 04/25/2024]
Abstract
BACKGROUND Tacrolimus is the primary calcineurin inhibitor used in immunosuppressive regimens to prevent allograft rejection (AR) after organ transplantation. Recent studies have linked intrapatient variability (IPV) of tacrolimus with AR occurrence and reduced survival, especially in kidney transplant recipients. However, limited data are available on the impact of tacrolimus IPV on adverse outcomes after liver transplantation (LT). AIMS The aim of this study was to assess the association between tacrolimus IPV using various methodologies with acute AR and long-term patient survival after LT. METHODS All patients who underwent LT from January 2010 to July 2021 were retrospectively evaluated. Tacrolimus IPV was calculated for each patient using the mean and SD, mean absolute deviation (MAD), coefficient of variation (CV), and time in therapeutic range (TTR). These measures were then compared with AR within the first 24 months after LT and to long-term survival. RESULTS Out of 234 patients, 32 (13.7%) developed AR and 183 (78.2%) survived, with a mean follow-up of 101 ± 43 months. Tacrolimus IPV, assessed by mean, SD, MAD, and CV, was 8.3 ± 2.1, 2.7 ± 1.3, 32.0% ± 11.7%, and 39.4% ± 15.4%, respectively. There was no statistically significant correlation between Tacrolimus IPV and AR or survival post-LT. CONCLUSIONS In a large cohort of patients from diverse racial backgrounds, tacrolimus IPV was not associated with clinically relevant outcomes such as AR and survival after LT.
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Affiliation(s)
| | - Gabriela Costa
- Bahiana School of Medicine and Public Health, Salvador, Bahia, Brazil ; and
| | - Laura Guerra
- Bahiana School of Medicine and Public Health, Salvador, Bahia, Brazil ; and
| | - Maria Clara Morais
- Bahiana School of Medicine and Public Health, Salvador, Bahia, Brazil ; and
| | - Nayana Vaz
- Unit of Gastroenterology and Hepatology, Portuguese Hospital, Salvador, Bahia, Brazil
| | - Liana Codes
- Bahiana School of Medicine and Public Health, Salvador, Bahia, Brazil ; and
- Unit of Gastroenterology and Hepatology, Portuguese Hospital, Salvador, Bahia, Brazil
| | - Paulo Lisboa Bittencourt
- Bahiana School of Medicine and Public Health, Salvador, Bahia, Brazil ; and
- Unit of Gastroenterology and Hepatology, Portuguese Hospital, Salvador, Bahia, Brazil
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14
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Maddur H, Wilson N, Patil P, Asrani S. Rejection in Liver Transplantation Recipients. J Clin Exp Hepatol 2024; 14:101363. [PMID: 38495462 PMCID: PMC10943490 DOI: 10.1016/j.jceh.2024.101363] [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: 07/27/2023] [Accepted: 02/09/2024] [Indexed: 03/19/2024] Open
Abstract
Rejection following liver transplantation continues to impact transplant recipients although rates have decreased over time with advances in immunosuppression management. The diagnosis of rejection remains challenging with liver biopsy remaining the reference standard for diagnosis. Proper classification of rejection type and severity is imperative as this guides management and ultimately graft preservation. Future areas of promise include non-invasive testing for detection of rejection to reduce the morbidity associated with invasive testing and further advances in immunosuppression management to reduce toxicities associated with immunosuppression while minimizing rejection related morbidity.
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15
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Deininger KM, Anderson HD, Patrinos GP, Mitropoulou C, Aquilante CL. Cost-effectiveness analysis of CYP3A5 genotype-guided tacrolimus dosing in solid organ transplantation using real-world data. THE PHARMACOGENOMICS JOURNAL 2024; 24:14. [PMID: 38750044 DOI: 10.1038/s41397-024-00334-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 04/05/2024] [Accepted: 04/23/2024] [Indexed: 06/15/2024]
Abstract
The objective of this study was to estimate the cost-effectiveness of CYP3A5 genotype-guided tacrolimus dosing in kidney, liver, heart, and lung transplant recipients relative to standard of care (SOC) tacrolimus dosing, from a US healthcare payer perspective. We developed decision-tree models to compare economic and clinical outcomes between CYP3A5 genotype-guided and SOC tacrolimus therapy in the first six months post-transplant. We derived inputs for CYP3A5 phenotype frequencies and physician use of genotype test results to inform clinical care from literature; tacrolimus exposure [high vs low tacrolimus time in therapeutic range using the Rosendaal algorithm (TAC TTR-Rosendaal)] and outcomes (incidences of acute tacrolimus nephrotoxicity, acute cellular rejection, and death) from real-world data; and costs from the Medicare Fee Schedule and literature. We calculated cost per avoided event and performed sensitivity analyses to evaluate the robustness of the results to changes in inputs. Incremental costs per avoided event for CYP3A5 genotype-guided vs SOC tacrolimus dosing were $176,667 for kidney recipients, $364,000 for liver recipients, $12,982 for heart recipients, and $93,333 for lung recipients. The likelihood of CYP3A5 genotype-guided tacrolimus dosing leading to cost-savings was 19.8% in kidney, 32.3% in liver, 51.8% in heart, and 54.1% in lung transplant recipients. Physician use of genotype results to guide clinical care and the proportion of patients with a high TAC TTR-Rosendaal were key parameters driving the cost-effectiveness of CYP3A5 genotype-guided tacrolimus therapy. Relative to SOC, CYP3A5 genotype-guided tacrolimus dosing resulted in a slightly greater benefit at a higher cost. Further economic evaluations examining intermediary outcomes (e.g., dose modifications) are needed, particularly in populations with higher frequencies of CYP3A5 expressers.
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Affiliation(s)
- Kimberly M Deininger
- Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA
| | - Heather D Anderson
- Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA
| | - George P Patrinos
- Department of Pharmacy, University of Patras School of Health Sciences, Patras, Greece
- Department of Genetics and Genomics, United Arab Emirates University, College of Medicine and Health Sciences, Al-Ain, Abu Dhabi, UAE
- Zayed Center for Health Sciences, United Arab Emirates University, Al-Ain, Abu Dhabi, UAE
| | - Christina Mitropoulou
- Department of Genetics and Genomics, United Arab Emirates University, College of Medicine and Health Sciences, Al-Ain, Abu Dhabi, UAE
- The Golden Helix Foundation, London, UK
| | - Christina L Aquilante
- Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA.
- Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
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16
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Romano P, Cano L, Pietrasz D, Beghdadi N, Allard MA, Salloum C, Blandin F, Ciacio O, Pittau G, Adam R, Azoulay D, Sa Cunha A, Vibert E, De Carlis L, Vitale A, Cillo U, Cherqui D, Golse N. Liver Transplantation from Elderly Donors (≥85 Years Old). Cancers (Basel) 2024; 16:1803. [PMID: 38791881 PMCID: PMC11119999 DOI: 10.3390/cancers16101803] [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: 04/04/2024] [Revised: 04/29/2024] [Accepted: 05/06/2024] [Indexed: 05/26/2024] Open
Abstract
BACKGROUND Despite the ongoing trend of increasing donor ages in liver transplantation (LT) setting, a notable gap persists in the availability of comprehensive guidelines for the utilization of organs from elderly donors. This study aimed to evaluate the viability of livers grafts from donors aged ≥85 years and report the post-LT outcomes compared with those from "ideal" donors under 40 years old. METHODS Conducted retrospectively at a single center from 2005 to 2023, this study compared outcomes of LTs from donors aged ≥85 y/o and ≤40 y/o, with the propensity score matching to the recipient's gender, age, BMI, MELD score, redo-LT, LT indication, and cause of donor death. RESULTS A total of 76 patients received grafts from donors ≥85 y/o and were compared to 349 liver grafts from donors ≤40 y/o. Prior to PSM, the 5-year overall survival was 63% for the elderly group and 77% for the young group (p = 0.002). After PSM, the 5-year overall survival was 63% and 73% (p = 0.1). A nomogram, developed at the time of graft acceptance and including HCC features, predicted 10-year survival after LT using a graft from a donor aged ≥85. CONCLUSIONS In the context of organ scarcity, elderly donors emerge as a partial solution. Nonetheless, without proper selection, LT using very elderly donors yields inferior long-term outcomes compared to transplantation from very young donors ≤40 y/o. The resulting nomogram based on pre-transplant criteria allows for the optimization of elderly donor/recipient matching to achieve satisfactory long-term results, in addition to traditional matching methods.
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Affiliation(s)
- Pierluigi Romano
- Department of Hepato-Biliary and Pancreatic Surgery, and Liver Transplantation, Paul Brousse Hospital, AP-HP, 94800 Villejuif, France; (P.R.); (N.B.); (O.C.); (G.P.); (R.A.)
- Department of Surgical, Oncological and Gastroenterological Sciences (DiSCOG), Second General Surgical Unit, University of Padova, 35122 Padua, Italy (U.C.)
- Department of General and Transplant Surgery, Grande Ospedale Metropolitano Niguarda, School of Medicine and Surgery, University of Milan-Bicocca, 20126 Milan, Italy;
| | - Luis Cano
- INRAE, CHU Pontchaillou, UMR 1241 NUMECAN, Université de Rennes, 35033 Rennes, France
| | - Daniel Pietrasz
- Department of Hepato-Biliary and Pancreatic Surgery, and Liver Transplantation, Paul Brousse Hospital, AP-HP, 94800 Villejuif, France; (P.R.); (N.B.); (O.C.); (G.P.); (R.A.)
- INSERM, Physiopathogénèse et Traitement des Maladies du Foie, UMR-S 1193, Université Paris-Saclay, 94805 Villejuif, France
| | - Nassiba Beghdadi
- Department of Hepato-Biliary and Pancreatic Surgery, and Liver Transplantation, Paul Brousse Hospital, AP-HP, 94800 Villejuif, France; (P.R.); (N.B.); (O.C.); (G.P.); (R.A.)
| | - Marc-Antoine Allard
- Department of Hepato-Biliary and Pancreatic Surgery, and Liver Transplantation, Paul Brousse Hospital, AP-HP, 94800 Villejuif, France; (P.R.); (N.B.); (O.C.); (G.P.); (R.A.)
- INSERM, Physiopathogénèse et Traitement des Maladies du Foie, UMR-S 1193, Université Paris-Saclay, 94805 Villejuif, France
| | - Chady Salloum
- Department of Hepato-Biliary and Pancreatic Surgery, and Liver Transplantation, Paul Brousse Hospital, AP-HP, 94800 Villejuif, France; (P.R.); (N.B.); (O.C.); (G.P.); (R.A.)
| | - Frédérique Blandin
- Department of Hepato-Biliary and Pancreatic Surgery, and Liver Transplantation, Paul Brousse Hospital, AP-HP, 94800 Villejuif, France; (P.R.); (N.B.); (O.C.); (G.P.); (R.A.)
| | - Oriana Ciacio
- Department of Hepato-Biliary and Pancreatic Surgery, and Liver Transplantation, Paul Brousse Hospital, AP-HP, 94800 Villejuif, France; (P.R.); (N.B.); (O.C.); (G.P.); (R.A.)
| | - Gabriella Pittau
- Department of Hepato-Biliary and Pancreatic Surgery, and Liver Transplantation, Paul Brousse Hospital, AP-HP, 94800 Villejuif, France; (P.R.); (N.B.); (O.C.); (G.P.); (R.A.)
| | - René Adam
- Department of Hepato-Biliary and Pancreatic Surgery, and Liver Transplantation, Paul Brousse Hospital, AP-HP, 94800 Villejuif, France; (P.R.); (N.B.); (O.C.); (G.P.); (R.A.)
| | - Daniel Azoulay
- Department of Hepato-Biliary and Pancreatic Surgery, and Liver Transplantation, Paul Brousse Hospital, AP-HP, 94800 Villejuif, France; (P.R.); (N.B.); (O.C.); (G.P.); (R.A.)
- INSERM, Physiopathogénèse et Traitement des Maladies du Foie, UMR-S 1193, Université Paris-Saclay, 94805 Villejuif, France
| | - Antonio Sa Cunha
- Department of Hepato-Biliary and Pancreatic Surgery, and Liver Transplantation, Paul Brousse Hospital, AP-HP, 94800 Villejuif, France; (P.R.); (N.B.); (O.C.); (G.P.); (R.A.)
- INSERM, Physiopathogénèse et Traitement des Maladies du Foie, UMR-S 1193, Université Paris-Saclay, 94805 Villejuif, France
| | - Eric Vibert
- Department of Hepato-Biliary and Pancreatic Surgery, and Liver Transplantation, Paul Brousse Hospital, AP-HP, 94800 Villejuif, France; (P.R.); (N.B.); (O.C.); (G.P.); (R.A.)
- INSERM, Physiopathogénèse et Traitement des Maladies du Foie, UMR-S 1193, Université Paris-Saclay, 94805 Villejuif, France
| | - Luciano De Carlis
- Department of General and Transplant Surgery, Grande Ospedale Metropolitano Niguarda, School of Medicine and Surgery, University of Milan-Bicocca, 20126 Milan, Italy;
| | - Alessandro Vitale
- Department of Surgical, Oncological and Gastroenterological Sciences (DiSCOG), Second General Surgical Unit, University of Padova, 35122 Padua, Italy (U.C.)
| | - Umberto Cillo
- Department of Surgical, Oncological and Gastroenterological Sciences (DiSCOG), Second General Surgical Unit, University of Padova, 35122 Padua, Italy (U.C.)
| | - Daniel Cherqui
- Department of Hepato-Biliary and Pancreatic Surgery, and Liver Transplantation, Paul Brousse Hospital, AP-HP, 94800 Villejuif, France; (P.R.); (N.B.); (O.C.); (G.P.); (R.A.)
- INSERM, Physiopathogénèse et Traitement des Maladies du Foie, UMR-S 1193, Université Paris-Saclay, 94805 Villejuif, France
| | - Nicolas Golse
- Department of Hepato-Biliary and Pancreatic Surgery, and Liver Transplantation, Paul Brousse Hospital, AP-HP, 94800 Villejuif, France; (P.R.); (N.B.); (O.C.); (G.P.); (R.A.)
- INSERM, Physiopathogénèse et Traitement des Maladies du Foie, UMR-S 1193, Université Paris-Saclay, 94805 Villejuif, France
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17
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Xiong Z, Yang Z, Wang Q, Li T. Global research hotspots and trends of acute rejection after liver transplantation from 1988 to 2022: a bibliometric analysis. Front Pharmacol 2024; 15:1357468. [PMID: 38694927 PMCID: PMC11061468 DOI: 10.3389/fphar.2024.1357468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 04/05/2024] [Indexed: 05/04/2024] Open
Abstract
Background: Acute rejection (AR) is the predominant form of rejection observed in liver transplantation and plays a crucial role in transplant immunology. This study aims to utilize bibliometric analysis to understand the status quo, hotspots, and future trends of research on AR after liver transplantation. Methods: We searched the Web of Science Core Collection (WoSCC) for studies on AR after liver transplantation published from 1988 to 2022. The Bibliometric Online Analysis Platform, VOSviewer, and CiteSpace were used for analysis of all extracted publications. Results: This study included 2,398 articles published in 456 journals by 12,568 authors from 1,965 institutions in 55 countries/regions. The United States and its affiliated institution, the University of Pittsburgh, were the most productive contributors. Transplantation (n = 12,435) was the most frequently cited journal. Neuhaus P (n = 38) was the highest output author, and Demetris AJ (n = 670) was the most co-cited author. The research hotspots of AR after liver transplantation include pathogenesis, immunosuppressive therapy, and prognosis. Emerging research directions include regulatory T cells, immunosuppression minimization, intra-patient variability (IPV) of tacrolimus, and novel non-invasive diagnostic markers. Conclusion: Our study utilized bibliometric methods to analyze the study of AR after liver transplantation over the past 35 years. With the prolonged survival of liver transplant recipients, the most active areas currently focus on individualized treatment and improving patient prognosis. Minimizing adverse reactions to immunosuppressive therapy while simultaneously avoiding an increase in the risk of AR remains a future research focus.
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Affiliation(s)
- Zhiwei Xiong
- Department of Liver Transplantation, The Second Xiang-ya Hospital, Central South University, Changsha, China
| | - Zhen Yang
- The Intractable Diseases Diagnosis and Treatment Center for Liver, Gallbladder, Pancreas and Intestine, Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Qiuguo Wang
- Department of Cardiovascular Surgery, The Second Xiang-ya Hospital, Central South University, Changsha, China
| | - Ting Li
- Department of Liver Transplantation, The Second Xiang-ya Hospital, Central South University, Changsha, China
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18
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Chiang HJ, Chuang YH, Li CW, Lin CC, Eng HL, Chen CL, Cheng YF, Chou MC. Usefulness of Diffusion-Weighted Imaging in Evaluating Acute Cellular Rejection and Monitoring Treatment Response in Liver Transplant Recipients. Diagnostics (Basel) 2024; 14:807. [PMID: 38667453 PMCID: PMC11049147 DOI: 10.3390/diagnostics14080807] [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: 02/26/2024] [Revised: 03/29/2024] [Accepted: 04/10/2024] [Indexed: 04/28/2024] Open
Abstract
Acute cellular rejection (ACR) is a significant immune issue among recipients following liver transplantation. Although diffusion-weighted magnetic resonance imaging (DWI) is widely used for diagnosing liver disease, it has not yet been utilized for monitoring ACR in patients after liver transplantation. Therefore, the aim of this study was to evaluate the efficacy of DWI in monitoring treatment response among recipients with ACR. This study enrolled 25 recipients with highly suspected ACR rejection, and all subjects underwent both biochemistry and DWI scans before and after treatment. A pathological biopsy was performed 4 to 24 h after the first MRI examination to confirm ACR and degree of rejection. All patients were followed up and underwent a repeated MRI scan when their liver function returned to the normal range. After data acquisition, the DWI data were post-processed to obtain the apparent diffusion coefficient (ADC) map on a voxel-by-voxel basis. Five regions of interest were identified on the liver parenchyma to measure the mean ADC values from each patient. Finally, the mean ADC values and biochemical markers were statistically compared between ACR and non-ACR groups. A receiver operating characteristic (ROC) curve was constructed to evaluate the performance of the ADC and biochemical data in detecting ACR, and correlation analysis was used to understand the relationship between the ADC values, biochemical markers, and the degree of rejection. The histopathologic results revealed that 20 recipients had ACR, including 10 mild, 9 moderate, and 1 severe rejection. The results demonstrated that the ACR patients had significantly lower hepatic ADC values than those in patients without ACR. After treatment, the hepatic ADC values in ACR patients significantly increased to levels similar to those in non-ACR patients with treatment. The ROC analysis showed that the sensitivity and specificity for detecting ACR were 80% and 95%, respectively. Furthermore, the correlation analysis revealed that the mean ADC value and alanine aminotransferase level had strong and moderate negative correlation with the degree of rejection, respectively (r = -0.72 and -0.47). The ADC values were useful for detecting hepatic ACR and monitoring treatment response after immunosuppressive therapy.
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Affiliation(s)
- Hsien-Jen Chiang
- Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (H.-J.C.); (Y.-H.C.)
- Department of Diagnostic Radiology, Kaohsiung Municipal Feng Shan Hospital—Under the Management of Chang Gung Medical Foundation, Kaohsiung 83062, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Yi-Hsuan Chuang
- Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (H.-J.C.); (Y.-H.C.)
| | - Chun-Wei Li
- Department of Medical Imaging and Radiological Sciences, College of Health Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Chih-Che Lin
- Liver Transplantation Center, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (C.-C.L.); (C.-L.C.)
- Department of Surgery, Kaohsiung Municipal Feng Shan Hospital—Under the Management of Chang Gung Medical Foundation, Kaohsiung 83062, Taiwan
| | - Hock-Liew Eng
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan;
| | - Chao-Long Chen
- Liver Transplantation Center, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (C.-C.L.); (C.-L.C.)
| | - Yu-Fan Cheng
- Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (H.-J.C.); (Y.-H.C.)
| | - Ming-Chung Chou
- Department of Medical Imaging and Radiological Sciences, College of Health Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
- Center for Big Data Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
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19
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De Simone P, Precisi A, Lai Q, Ducci J, Campani D, Marchetti P, Gitto S. Everolimus Mitigates the Risk of Hepatocellular Carcinoma Recurrence after Liver Transplantation. Cancers (Basel) 2024; 16:1243. [PMID: 38610921 PMCID: PMC11010831 DOI: 10.3390/cancers16071243] [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: 01/12/2024] [Revised: 03/10/2024] [Accepted: 03/19/2024] [Indexed: 04/14/2024] Open
Abstract
To obtain long-term data on the use of everolimus in patients who underwent liver transplantation for hepatocellular carcinoma, we conducted a retrospective, single-center analysis of adult recipients transplanted between 2013 and 2021. Patients on everolimus-incorporating immunosuppression were matched with those on tacrolimus using an inverse probability of treatment weighting methodology. Two propensity-matched groups of patients were thus compared: 233 (45.6%) receiving everolimus versus 278 (54.4%) on tacrolimus. At a median (interquartile range) follow-up of 4.4 (3.8) years after transplantation, everolimus patients showed a reduced risk of recurrence versus tacrolimus (7.7% versus 16.9%; RR = 0.45; p = 0.002). At multivariable analysis, microvascular infiltration (HR = 1.22; p < 0.04) and a higher tumor grading (HR = 1.27; p < 0.04) were associated with higher recurrence rate while being within Milan criteria at transplant (HR = 0.56; p < 0.001), a successful pre-transplant downstaging (HR = 0.63; p = 0.01) and use of everolimus (HR = 0.46; p < 0.001) had a positive impact on the risk of post-transplant recurrence. EVR patients with earlier drug introduction (≤30 days; p < 0.001), longer treatment duration (p < 0.001), and higher drug exposure (≥5.9 ng/mL; p < 0.001) showed lower recurrence rates versus TAC. Based on our experience, everolimus provides a reduction in the relative risk of hepatocellular carcinoma recurrence, especially for advanced-stage patients and those with earlier drug administration, higher drug exposure, and longer time on treatment. These data advocate for early everolimus introduction after liver transplantation to reduce the attrition rate consequent to chronic immunosuppression.
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Affiliation(s)
- Paolo De Simone
- Liver Transplant Program, University of Pisa Medical School Hospital, 56124 Pisa, Italy
- Department of Surgical, Medical, Biochemical Pathology and Intensive Care, University of Pisa, 56126 Pisa, Italy;
| | - Arianna Precisi
- Transplant Laboratory, University of Pisa Medical School Hospital, 56126 Pisa, Italy;
| | - Quirino Lai
- AOU Umberto I Policlinico of Rome, Sapienza University of Rome, 00161 Rome, Italy;
| | - Juri Ducci
- Azienda Ospedaliero Universitaria Pisana, 56124 Pisa, Italy;
| | - Daniela Campani
- Department of Surgical, Medical, Biochemical Pathology and Intensive Care, University of Pisa, 56126 Pisa, Italy;
- Department of Pathology, University of Pisa Medical School Hospital, 56124 Pisa, Italy
| | - Piero Marchetti
- Diabetology Unit, University of Pisa Medical School Hospital, 56124 Pisa, Italy;
| | - Stefano Gitto
- Internal Medicine and Liver Unit, University Hospital Careggi, 50134 Florence, Italy;
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
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20
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Chen F, Yong JK, Shen C, Zhou T, Feng M, Wan P, Luo Y, Lin H, Qian Y, Xia Q. High intra-patient variability of tacrolimus within post-operative 1 month predicted worse 1-year outcomes in pediatric liver transplant recipients. Eur J Clin Pharmacol 2024:10.1007/s00228-024-03663-z. [PMID: 38502358 DOI: 10.1007/s00228-024-03663-z] [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: 08/03/2023] [Accepted: 03/04/2024] [Indexed: 03/21/2024]
Abstract
BACKGROUND The pharmacokinetics of tacrolimus (TAC) show high intra-patient variability (IPV), which is associated with poor long-term outcomes following adult liver transplantation (LT). However, this relationship remains to be confirmed in pediatric liver transplant (PLT) recipients. The present study aimed to investigate the association between TAC IPV and grafts or patient outcomes after pediatric liver transplantion. METHODS This retrospective study included 848 PLT recipients (including infants) between January, 2016, and June, 2021. The IPV of TAC concentrations was estimated by calculating the coefficient of variation (CV) of trough concentrations in whole blood within 1 month after transplantation. Patients were categorized into two groups, low IPV (CV < 45%) and high IPV (CV ≥ 45%), based on the third quartile of the CV distribution. RESULTS A total of 848 patients were included in our study. The low CV group included 614 patients, with a mean TAC trough concentration of 8.59 ± 1.65 ng/ml and a median CV of 32.37%. In contrast, the high CV group included 214 patients, the mean TAC trough concentration and median CV were 8.81 ± 2.00 ng/ml and 54.88%, respectively. The median hospital duration was significantly higher in the high CV group (22 days vs. 20 days, P = 0.01). Univariate analysis was performed to evaluate the significant differences in 1-year recipient survival (P = 0.041) and 1-year graft survival (P = 0.005) between the high- and low-CV groups. Moreover, high CV (HR 2.316, 95%CI 1.026-5.231, P = 0.043) and persistent EBV viremia (HR 13.165, 95%CI 3.090-56.081, P < 0.001) were identified as independent risk factors for 1- year mortality after PLT. CONCLUSIONS PLT recipients with high TAC trough concentration of CV in the first month were associated with poor 1-year outcomes. This CV calculation provides a valuable strategy to monitor TAC exposure.
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Affiliation(s)
- Fang Chen
- Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, People's Republic of China
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, No. 1630 Dongfang Road, Shanghai, 200127, People's Republic of China
| | - June-Kong Yong
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, No. 1630 Dongfang Road, Shanghai, 200127, People's Republic of China
| | - Chuan Shen
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, No. 1630 Dongfang Road, Shanghai, 200127, People's Republic of China
| | - Tao Zhou
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, No. 1630 Dongfang Road, Shanghai, 200127, People's Republic of China
| | - Mingxuan Feng
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, No. 1630 Dongfang Road, Shanghai, 200127, People's Republic of China
| | - Ping Wan
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, No. 1630 Dongfang Road, Shanghai, 200127, People's Republic of China
| | - Yi Luo
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, No. 1630 Dongfang Road, Shanghai, 200127, People's Republic of China
| | - Houwen Lin
- Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, People's Republic of China
| | - Yongbing Qian
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, No. 1630 Dongfang Road, Shanghai, 200127, People's Republic of China.
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, No. 1630 Dongfang Road, Shanghai, 200127, People's Republic of China.
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Wang X, Zhu W, Chen H, Li X, Zheng W, Zhang Y, Fan N, Chen X, Wang G. JNK signaling mediates acute rejection via activating autophagy of CD8 + T cells after liver transplantation in rats. Front Immunol 2024; 15:1359859. [PMID: 38562941 PMCID: PMC10982410 DOI: 10.3389/fimmu.2024.1359859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 03/04/2024] [Indexed: 04/04/2024] Open
Abstract
Background Acute rejection (AR) after liver transplantation (LT) remains an important factor affecting the prognosis of patients. CD8+ T cells are considered to be important regulatory T lymphocytes involved in AR after LT. Our previous study confirmed that autophagy mediated AR by promoting activation and proliferation of CD8+ T cells. However, the underlying mechanisms regulating autophagy in CD8+ T cells during AR remain unclear. Methods Human liver biopsy specimens of AR after orthotopic LT were collected to assess the relationship between JNK and CD8+ T cells autophagy. The effect of JNK inhibition on CD8+ T cells autophagy and its role in AR were further examined in rats. Besides, the underlying mechanisms how JNK regulated the autophagy of CD8+ T cells were further explored. Results The expression of JNK is positive correlated with the autophagy level of CD8+ T cells in AR patients. And similar findings were obtained in rats after LT. Further, JNK inhibitor remarkably inhibited the autophagy of CD8+ T cells in rat LT recipients. In addition, administration of JNK inhibitor significantly attenuated AR injury by promoting the apoptosis and downregulating the function of CD8+ T cells. Mechanistically, JNK may activate the autophagy of CD8+ T cells through upregulating BECN1 by inhibiting the formation of Bcl-2/BECN1 complex. Conclusion JNK signaling promoted CD8+ T cells autophagy to mediate AR after LT, providing a theoretical basis for finding new drug targets for the prevention and treatment of AR after LT.
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Affiliation(s)
- Xiaowen Wang
- Department of Hepatic Surgery, Liver Transplantation, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Wenfeng Zhu
- Department of Hepatic Surgery, Liver Transplantation, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Haoqi Chen
- Department of Hepatic Surgery, Liver Transplantation, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Xuejiao Li
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Wenjie Zheng
- Department of Hepatic Surgery, Liver Transplantation, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yuan Zhang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ning Fan
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaolong Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Genshu Wang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
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22
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Kosuta I, Kelava T, Ostojic A, Sesa V, Mrzljak A, Lalic H. Immunology demystified: A guide for transplant hepatologists. World J Transplant 2024; 14:89772. [PMID: 38576757 PMCID: PMC10989464 DOI: 10.5500/wjt.v14.i1.89772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 01/24/2024] [Accepted: 02/29/2024] [Indexed: 03/15/2024] Open
Abstract
Liver transplantation has become standard practice for treating end-stage liver disease. The success of the procedure relies on effective immunosuppressive medications to control the host's immune response. Despite the liver's inherent capacity to foster tolerance, the early post-transplant period is marked by significant immune reactivity. To ensure favorable outcomes, it is imperative to identify and manage various rejection types, encompassing T-cell-mediated, antibody-mediated, and chronic rejection. However, the approach to prescribing immunosuppressants relies heavily on clinical judgment rather than evidence-based criteria. Given that the majority of patients will require lifelong immuno suppression as the mechanisms underlying operational tolerance are still being investigated, healthcare providers must possess an understanding of immune responses, rejection mechanisms, and the pathways targeted by immunosuppressive drugs. This knowledge enables customization of treatments and improved patient care, even though a consensus on an optimal immunosuppressive regimen remains elusive.
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Affiliation(s)
- Iva Kosuta
- Department of Intensive Care Medicine, University Hospital Centre Zagreb, Zagreb 10000, Croatia
| | - Tomislav Kelava
- Department of Physiology, School of Medicine, Univeristy of Zagreb, Zagreb 10000, Croatia
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, Zagreb 10000, Croatia
| | - Ana Ostojic
- Department of Gastroenterology and Hepatology, Liver Transplant Center, University Hospital Centre Zagreb, Zagreb 10000, Croatia
| | - Vibor Sesa
- Department of Gastroenterology and Hepatology, Liver Transplant Center, University Hospital Centre Zagreb, Zagreb 10000, Croatia
| | - Anna Mrzljak
- Department of Gastroenterology and Hepatology, University Hospital Centre Zagreb, Zagreb 10000, Croatia
- Department of Medicine, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Hrvoje Lalic
- Department of Physiology, University of Zagreb School of Medicine, Zagreb 10000, Croatia
- Laboratory for Cell Biology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb 10000, Croatia
- Department of Laboratory Immunology, Clinical Department of Laboratory Diagnostics, University Hospital Center Zagreb, Zagreb 10000, Croatia
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Ashokkumar C, Ningappa M, Raghu V, Mazariegos G, Higgs BW, Morgan P, Remaley L, Fazzolare Martin T, Holzer P, Trostle K, Xu Q, Zeevi A, Squires J, Soltys K, Horslen S, Khanna A, Ganoza A, Sindhi R. Enhanced Donor Antigen Presentation by B Cells Predicts Acute Cellular Rejection and Late Outcomes After Transplantation. Transplant Direct 2024; 10:e1589. [PMID: 38414976 PMCID: PMC10898653 DOI: 10.1097/txd.0000000000001589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 10/16/2023] [Accepted: 11/11/2023] [Indexed: 02/29/2024] Open
Abstract
Background Enhanced B-cell presentation of donor alloantigen relative to presentation of HLA-mismatched reference alloantigen is associated with acute cellular rejection (ACR), when expressed as a ratio called the antigen presenting index (API) in an exploratory cohort of liver and intestine transplant (LT and IT) recipients. Methods To test clinical performance, we measured the API using the previously described 6-h assay in 84 LT and 54 IT recipients with median age 3.3 y (0.05-23.96). Recipients experiencing ACR within 60 d after testing were termed rejectors. Results We first confirmed that B-cell uptake and presentation of alloantigen induced and thus reflected the alloresponse of T-helper cells, which were incubated without and with cytochalasin and primaquine to inhibit antigen uptake and presentation, respectively. Transplant recipients included 76 males and 62 females. Rejectors were tested at median 3.6 d before diagnosis. The API was higher among rejectors compared with nonrejectors (2.2 ± 0.2 versus 0.6 ± 0.04, P value = 1.7E-09). In logistic regression and receiver-operating-characteristic analysis, API ≥1.1 achieved sensitivity, specificity, and positive and negative predictive values for predicting ACR in 99 training set samples. Corresponding metrics ranged from 80% to 88% in 32 independent posttransplant samples, and 73% to 100% in 20 independent pretransplant samples. In time-to-event analysis, API ≥1.1 predicted higher incidence of late donor-specific anti-HLA antibodies after API measurements in LT recipients (P = 0.011) and graft loss in IT recipients (P = 0.008), compared with recipients with API <1.1, respectively. Conclusions Enhanced donor antigen presentation by circulating B cells predicts rejection after liver or intestine transplantation as well as higher incidence of DSA and graft loss late after transplantation.
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Affiliation(s)
- Chethan Ashokkumar
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
| | - Mylarappa Ningappa
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
| | - Vikram Raghu
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital Pittsburgh, PA
| | - George Mazariegos
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
| | - Brandon W. Higgs
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
| | - Paul Morgan
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
| | - Lisa Remaley
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
| | - Tamara Fazzolare Martin
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
| | - Pamela Holzer
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
| | - Kevin Trostle
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
| | - Qingyong Xu
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Adriana Zeevi
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - James Squires
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital Pittsburgh, PA
| | - Kyle Soltys
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
| | - Simon Horslen
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital Pittsburgh, PA
| | - Ajai Khanna
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
| | - Armando Ganoza
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
| | - Rakesh Sindhi
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
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Liukkonen VH, Nordin AJ, Färkkilä MA, Mirtti TK, Arola JT, Åberg FO. Protocol liver biopsy predicts graft survival after liver transplantation. Clin Transplant 2024; 38:e15286. [PMID: 38504561 DOI: 10.1111/ctr.15286] [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: 11/23/2023] [Revised: 02/20/2024] [Accepted: 02/26/2024] [Indexed: 03/21/2024]
Abstract
BACKGROUND The use of protocol liver biopsy to monitor liver allograft status remains controversial. There is limited data from modern transplantation populations that includes protocol biopsies to evaluate its value in predicting clinical outcomes. METHODS All protocol liver biopsies were identified from 875 patients who underwent liver transplantation at Helsinki University Hospital between 2000 and 2019. Each histologic component was analyzed for its ability to predict long-term outcomes, especially graft survival. We determined the frequency of significant biopsy findings based on the Banff working group definition. Liver function tests (LFTs) and clinical markers were evaluated for their ability to predict significant biopsy findings. RESULTS In total, 867 protocol liver biopsies were analyzed. Significant findings were identified in 20.1% of the biopsies. In the first protocol biopsy, steatohepatitis (hazard ratio [HR] 3.504, p = .03) and moderate or severe congestion (HR 3.338, p = .04) predicted graft loss. The presence of cholangitis (HR 2.563, p = .04), necrosis (HR 7.635, p < .001), mild congestion (HR 4.291, p = .009), and significant biopsy finding (HR 2.540, p = .02) predicted inferior death-censored graft survival. While the degree of elevation of LFTs was positively associated with significant biopsy findings, the discrimination was poor (AUC .572-.622). Combined LFTs and clinical risk factors remained suboptimal for discriminating significant biopsy findings (AUC .696). CONCLUSIONS Our findings support the use of protocol liver biopsies after liver transplantation since they frequently revealed changes associated with long-term outcomes, even when LFTs were normal.
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Affiliation(s)
- Ville H Liukkonen
- Gastroenterology, North Karelia Central Hospital, Joensuu, Finland
- Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Arno J Nordin
- Transplantation and liver surgery, Helsinki University Hospital, Helsinki, Finland
| | | | - Tuomas K Mirtti
- Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Pathology, Diagnostic Center, Helsinki University Hospital, Helsinki, Finland
| | - Johanna T Arola
- Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Pathology, Diagnostic Center, Helsinki University Hospital, Helsinki, Finland
| | - Fredrik O Åberg
- Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Transplantation and liver surgery, Helsinki University Hospital, Helsinki, Finland
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De Simone P, Bronzoni J, Martinelli C, Ducci J, Campani D, Gitto S, Marchetti P, Biancofiore G. Aging with a Liver Graft: Analysis of Very Long-Term Survivors after Liver Transplantation. J Clin Med 2024; 13:1087. [PMID: 38398400 PMCID: PMC10889074 DOI: 10.3390/jcm13041087] [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: 01/11/2024] [Revised: 01/31/2024] [Accepted: 02/09/2024] [Indexed: 02/25/2024] Open
Abstract
BACKGROUND In Italy, data on long-term survivors after liver transplantation are lacking. MATERIALS AND METHODS We conducted a hybrid design study on a cohort of 359 adult recipients who received transplants between 1996 and 2002 to identify predictors of survival and the prevalence of co-morbidities among long-term survivors. RESULTS The actuarial (95% CI) patient survival was 96% (94.6-98.3%), 69% (64.2-73.6%), 55% (49.8-59.9%), 42.8% (37.6-47.8%), and 34% (29.2-38.9%) at 1, 5, 10, 15, and 20 years, respectively. The leading causes of death were hepatitis C virus recurrence (24.6%), extrahepatic malignancies (16.9%), infection (14.4%), and hepatocellular carcinoma recurrence (14.4%). The factors associated with the survival probability were younger donor and recipient ages (p = 0.001 and 0.004, respectively), female recipient sex (p < 0.001), absence of HCV (p < 0.01), absence of HCC (p = 0.001), and absence of diabetes mellitus at one year (p < 0.01). At the latest follow-up, the leading comorbidities were hypertension (53.6%), obesity (18.7%), diabetes mellitus (17.1%), hyperlipidemia (14.7%), chronic kidney dysfunction (14.7%), and extrahepatic malignancies (13.8%), with 73.9% of patients having more than one complication. CONCLUSIONS Aging with a liver graft is associated with an increased risk of complications and requires ongoing care to reduce the long-term attrition rate resulting from chronic immunosuppression.
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Affiliation(s)
- Paolo De Simone
- Liver Transplant Program, University of Pisa Medical School Hospital, Via Paradisa 2, 56124 Pisa, Italy
- Department of Surgical, Medical, Biochemical Pathology and Intensive Care, University of Pisa, Via Savi 20, 56126 Pisa, Italy
| | - Jessica Bronzoni
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Via Paradisa 2, 56124 Pisa, Italy
| | - Caterina Martinelli
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Via Paradisa 2, 56124 Pisa, Italy
| | - Juri Ducci
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Via Paradisa 2, 56124 Pisa, Italy
| | - Daniela Campani
- Department of Surgical, Medical, Biochemical Pathology and Intensive Care, University of Pisa, Via Savi 20, 56126 Pisa, Italy
- Department of Pathology, University of Pisa Medical School Hospital, Via Paradisa 2, 56124 Pisa, Italy
| | - Stefano Gitto
- Internal Medicine and Liver Unit, University Hospital Careggi, Largo Brambilla 3, 50134 Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Piazza San Marco 4, 50121 Florence, Italy
| | - Piero Marchetti
- Diabetology Unit, University of Pisa Medical School Hospital, Via Paradisa 2, 56124 Pisa, Italy
| | - Giandomenico Biancofiore
- Department of Surgical, Medical, Biochemical Pathology and Intensive Care, University of Pisa, Via Savi 20, 56126 Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Savi 20, 56126 Pisa, Italy
- Intensive Care Unit, University of Pisa Medical School Hospital, Via Paradisa 2, 56124 Pisa, Italy
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Laue T, Junge N, Leiskau C, Mutschler F, Ohlendorf J, Baumann U. Diminished measles immunity after paediatric liver transplantation-A retrospective, single-centre, cross-sectional analysis. PLoS One 2024; 19:e0296653. [PMID: 38315673 PMCID: PMC10843477 DOI: 10.1371/journal.pone.0296653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 12/16/2023] [Indexed: 02/07/2024] Open
Abstract
Liver transplantation in childhood has an excellent long-term outcome, but is associated with a long-term risk of infection. Measles is a vaccine-preventable infection, with case series describing severe courses with graft rejection, mechanical ventilation and even death in liver transplant recipients. Since about 30% of liver transplanted children receive liver transplants in their first year of life, not all have reached the recommended age for live vaccinations. On the contrary, live vaccines are contraindicated after transplantation. In addition, vaccination response is poorer in individuals with liver disease compared to healthy children. This retrospective, single-centre, cross-sectional study examines measles immunity in paediatric liver transplant recipients before and after transplantation. Vaccination records of 239 patients, followed up at Hannover Medical School between January 2021 and December 2022 were analysed. Twenty eight children were excluded due to stem cell transplantation, regular immunoglobulin substitution or measles vaccination after transplantation. More than 55% of all 211 children analysed and 75% of all those vaccinated at least once are measles seropositive after transplantation-48% after one and 84% after two vaccinations-which is less than in healthy individuals. Interestingly, 26% of unvaccinated children also showed measles antibodies and about 5-15% of vaccinated patients who were seronegative at the time of transplantation were seropositive afterwards, both possibly through infection. In multivariable Cox proportional hazards regression, the number of vaccinations (HR 4.30 [95% CI 2.09-8.83], p<0.001), seropositivity before transplantation (HR 2.38 [95% CI 1.07-5.30], p = 0.034) and higher age at time of first vaccination (HR 11.5 [95% CI 6.92-19.1], p<0.001) are independently associated with measles immunity after transplantation. In contrast, older age at testing is inversely associated (HR 0.09 [95% CI 0.06-0.15], p<0.001), indicating a loss of immunity. Vaccination in the first year of life does not pose a risk of non-immunity. The underlying liver disease influences the level of measles titres of twice-vaccinated patients; those with acute liver failure being the lowest compared to children with metabolic disease. In summary, vaccine response is poorer in children with liver disease. Liver transplant candidates should be vaccinated before transplantation even if this is earlier in the first year of life. Checking measles IgG and re-vaccinating seronegative patients may help to achieve immunity after transplantation.
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Affiliation(s)
- Tobias Laue
- Division for Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver, and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Norman Junge
- Division for Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver, and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Christoph Leiskau
- Paediatric Gastroenterology, Department of Paediatrics and Adolescent Medicine, University Medical Centre Goettingen, Georg August University Goettingen, Goettingen, Germany
| | - Frauke Mutschler
- Division for Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver, and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Johanna Ohlendorf
- Division for Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver, and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Ulrich Baumann
- Division for Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver, and Metabolic Diseases, Hannover Medical School, Hannover, Germany
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27
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Dong SW, Blair BM, Alonso CD. Single-Center Outcomes of Epstein-Barr Virus DNAemia in Adult Solid Organ Transplant Recipients. J Transplant 2024; 2024:5598324. [PMID: 38283325 PMCID: PMC10810690 DOI: 10.1155/2024/5598324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 09/24/2023] [Accepted: 12/12/2023] [Indexed: 01/30/2024] Open
Abstract
Background Immunosuppression in solid organ transplantation (SOT) increases the risk of Epstein-Barr virus (EBV) DNAemia, which may herald development of posttransplant lymphoproliferative disease (PTLD). Few studies have characterized the incidence, risk factors, and clinical impact of EBV DNAemia in adult SOT recipients (SOTR). Methods A single-center, retrospective review of adult (≥18 years) SOTR between 01 January 2015 and 31 December 2019 was conducted. Patients were stratified by the primary study endpoint of development of EBV DNAemia (whole blood EBV DNA PCR > 200 copies/mL). Secondary endpoints included development of PTLD, reduction in immunosuppression (RIS), use of pre-emptive therapy, and all-cause mortality. Results Among 442 adult SOTR, the predominant transplant organs were the kidney (258, 58%) and liver (141, 31.9%). EBV serostatus in most subjects (430, 97%) was classified as intermediate risk (R+). Eight subjects (2%) were high risk (donor (D+/R-), and 4 (1%) were low risk (D-/R-). The overall incidence of EBV DNAemia was 4.1% (18/442) with a median time to detection of 14 months (range 3-60). The highest proportion of DNAemia was observed in D+/R- subjects (37.5%; p < 0.001). Development of PTLD was significantly associated with EBV DNAemia and occurred in 3/18 patients with DNAemia (16.7%) vs. 3/424 (0.7%) without DNAemia (p < 0.001). All patients with PTLD were managed with RIS and rituximab. Conclusion We observed that EBV D+/R- serostatus and development of sustained EBV DNAemia were high risk features associated with subsequent development of PTLD in our cohort of adult SOTR.
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Affiliation(s)
- Sara W. Dong
- Division of Infectious Disease, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Division of Infectious Disease, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Barbra M. Blair
- Division of Infectious Disease, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Carolyn D. Alonso
- Division of Infectious Disease, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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Chen G, Hu X, Huang Y, Xiang X, Pan S, Chen R, Xu X. Role of the immune system in liver transplantation and its implications for therapeutic interventions. MedComm (Beijing) 2023; 4:e444. [PMID: 38098611 PMCID: PMC10719430 DOI: 10.1002/mco2.444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 11/23/2023] [Accepted: 11/24/2023] [Indexed: 12/17/2023] Open
Abstract
Liver transplantation (LT) stands as the gold standard for treating end-stage liver disease and hepatocellular carcinoma, yet postoperative complications continue to impact survival rates. The liver's unique immune system, governed by a microenvironment of diverse immune cells, is disrupted during processes like ischemia-reperfusion injury posttransplantation, leading to immune imbalance, inflammation, and subsequent complications. In the posttransplantation period, immune cells within the liver collaboratively foster a tolerant environment, crucial for immune tolerance and liver regeneration. While clinical trials exploring cell therapy for LT complications exist, a comprehensive summary is lacking. This review provides an insight into the intricacies of the liver's immune microenvironment, with a specific focus on macrophages and T cells as primary immune players. Delving into the immunological dynamics at different stages of LT, we explore the disruptions after LT and subsequent immune responses. Focusing on immune cell targeting for treating liver transplant complications, we provide a comprehensive summary of ongoing clinical trials in this domain, especially cell therapies. Furthermore, we offer innovative treatment strategies that leverage the opportunities and prospects identified in the therapeutic landscape. This review seeks to advance our understanding of LT immunology and steer the development of precise therapies for postoperative complications.
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Affiliation(s)
- Guanrong Chen
- The Fourth School of Clinical MedicineZhejiang Chinese Medical UniversityHangzhouChina
| | - Xin Hu
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
| | - Yingchen Huang
- The Fourth School of Clinical MedicineZhejiang Chinese Medical UniversityHangzhouChina
| | - Xiaonan Xiang
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
| | - Sheng Pan
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
| | - Ronggao Chen
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Xiao Xu
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
- Zhejiang Chinese Medical UniversityHangzhouChina
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29
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Bilbao I, Gómez Bravo MÁ, Otero A, Lladó L, Montero JL, González Dieguez L, Graus J, Pons Miñano JA. Effectiveness and safety of once-daily tacrolimus formulations in de novo liver transplant recipients: The PRETHI study. Clin Transplant 2023; 37:e15105. [PMID: 37615653 DOI: 10.1111/ctr.15105] [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: 04/24/2023] [Revised: 07/14/2023] [Accepted: 08/13/2023] [Indexed: 08/25/2023]
Abstract
Data comparing long-term effectiveness and safety of once-daily tacrolimus formulations in de novo liver transplantation are scarce. We compared the effectiveness, pharmacokinetic profile, and safety of LCPT (Envarsus) and PR-Tac (Advagraf) for up to 12 months post-transplant. Adult de novo liver transplant recipients who started IR-Tac (Prograf) and were converted to LCPT or PR-Tac 3-5 days post-transplant were included. Data from 163 patients were analyzed, 87 treated with LCPT and 76 with PR-Tac. The incidence of treatment failure was 30.5% in the LCPT group versus 23.0% in the PR-Tac group (p = .291). Biopsy-proven acute rejection (BPAR) was reported in 26.8% of patients in the LCPT group and 17.6% in the PR-Tac group (p = .166). Graft loss was experienced in one patient (1.2%) in the LCPT group and three patients (4.1%) in the PR-Tac group (p = .346). Death was registered in three patients (3.7%) in the LCPT group and three patients (4.1%) in the PR-Tac group (p > .999). Patients in the LCPT group showed 45.7% higher relative bioavailability (Cmin /total daily dose [TDD]; p < .01) with similar Cmin and 33.3% lower TDD versus PR-Tac (p < .01). The evolution of renal function, safety profile, and the incidence of post-transplant renal failure, dyslipidemia, obesity, hypertension, and diabetes mellitus were similar in patients treated with LCPT and PR-Tac. In de novo liver transplant patients, LCPT and PR-Tac showed comparable effectiveness with higher relative bioavailability, similar Cmin and lower TDD in the LCPT group. Renal function, safety, and post-transplant complications were comparable in LCPT and PR-Tac groups.
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Affiliation(s)
- Itxarone Bilbao
- Servicio de Cirugía Hepatobiliopancreática y Trasplantes Digestivos, Hospital Universitario Vall d'Hebron, VHIR, Universidad Autónoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | | | | | - Laura Lladó
- Hospital U Bellvitge, Hospitalet de Llobregat, Barcelona, Spain
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30
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Affiliation(s)
- Michael R Lucey
- From the Department of Medicine, Division of Gastroenterology and Hepatology (M.R.L.), the Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition (K.N.F.), and the Department of Surgery, Division of Transplantation (D.P.F.), University of Wisconsin, Madison
| | - Katryn N Furuya
- From the Department of Medicine, Division of Gastroenterology and Hepatology (M.R.L.), the Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition (K.N.F.), and the Department of Surgery, Division of Transplantation (D.P.F.), University of Wisconsin, Madison
| | - David P Foley
- From the Department of Medicine, Division of Gastroenterology and Hepatology (M.R.L.), the Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition (K.N.F.), and the Department of Surgery, Division of Transplantation (D.P.F.), University of Wisconsin, Madison
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31
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Wang H, Yang R, Wang Z, Cao L, Kong D, Sun Q, Yoshida S, Ren J, Chen T, Duan J, Lu J, Shen Z, Zheng H. Metronomic capecitabine with rapamycin exerts an immunosuppressive effect by inducing ferroptosis of CD4 + T cells after liver transplantation in rat. Int Immunopharmacol 2023; 124:110810. [PMID: 37625370 DOI: 10.1016/j.intimp.2023.110810] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 08/02/2023] [Accepted: 08/14/2023] [Indexed: 08/27/2023]
Abstract
Liver transplantation is one of the most effective treatments for hepatocellular carcinoma (HCC). The balance between inhibiting immune rejection and preventing tumor recurrence after liver transplantation is the key to determining the long-term prognosis of patients with HCC after liver transplantation. In our previous study, we found that capecitabine (CAP), an effective drug for the treatment of HCC, could exert an immunosuppressive effect after liver transplantation by inducing T cell ferroptosis. Recent studies have shown that ferroptosis is highly associated with autophagy. In this study, we confirmed that the autophagy inducer rapamycin (RAPA) combined with metronomic capecitabine (mCAP) inhibits glutathione peroxidase 4 (GPX4) and promotes ferroptosis in CD4+ T cells to exert immunosuppressive effects after rat liver transplantation. Compared with RAPA or mCAP alone, the combination of RAPA and mCAP could adequately reduce liver injury in rats with acute rejection after transplantation. The CD4+ T cell counts in peripheral blood, spleen, and transplanted liver of recipient rats significantly decreased, and the oxidative stress level and ferrous ion concentration of CD4+ T cells significantly increased in the combination group. In vitro, the combination of drugs significantly promoted autophagy, decreased GPX4 protein expression, and induced ferroptosis in CD4+ T cells. In conclusion, the autophagy inducer RAPA improved the mCAP-induced ferroptosis in CD4+ T cells. Our results support the concept of ferroptosis as an autophagy-dependent cell death and suggest that the combination of ferroptosis inducers and autophagy inducers is a new research direction for improving immunosuppressive regimens after liver transplantation.
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Affiliation(s)
- Hao Wang
- The First Central Clinical School, Tianjin Medical University, Tianjin, China
| | - Ruining Yang
- The First Central Clinical School, Tianjin Medical University, Tianjin, China
| | - Zhenglu Wang
- Organ Transplant Department, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China; Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Lei Cao
- Research Institute of Transplant Medicine, Nankai University, Tianjin, China; Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Dejun Kong
- School of Medicine, Nankai University, Tianjin, China
| | - Qian Sun
- The First Central Clinical School, Tianjin Medical University, Tianjin, China
| | - Sei Yoshida
- Research Institute of Transplant Medicine, Nankai University, Tianjin, China
| | - Jiashu Ren
- The First Central Clinical School, Tianjin Medical University, Tianjin, China
| | - Tao Chen
- School of Medicine, Nankai University, Tianjin, China
| | - Jinliang Duan
- School of Medicine, Nankai University, Tianjin, China
| | - Jianing Lu
- The First Central Clinical School, Tianjin Medical University, Tianjin, China
| | - Zhongyang Shen
- Organ Transplant Department, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China; Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, China; Research Institute of Transplant Medicine, Nankai University, Tianjin, China; Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China; National Health Commission's Key Laboratory for Critical Care Medicine, Tianjin, China
| | - Hong Zheng
- Organ Transplant Department, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China; Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, China; Research Institute of Transplant Medicine, Nankai University, Tianjin, China; Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China; National Health Commission's Key Laboratory for Critical Care Medicine, Tianjin, China.
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Ruan W, Galvan NTN, Dike P, Koci M, Faraone M, Fuller K, Koomaraie S, Cerminara D, Fishman DS, Deray KV, Munoz F, Schackman J, Leung D, Akcan-Arikan A, Virk M, Lam FW, Chau A, Desai MS, Hernandez JA, Goss JA. The Multidisciplinary Pediatric Liver Transplant. Curr Probl Surg 2023; 60:101377. [PMID: 37993242 DOI: 10.1016/j.cpsurg.2023.101377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 08/29/2023] [Indexed: 11/24/2023]
Affiliation(s)
- Wenly Ruan
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX
| | - Nhu Thao N Galvan
- Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Department of Pediatric Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, TX.
| | - Peace Dike
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX
| | - Melissa Koci
- Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Department of Pediatric Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, TX
| | - Marielle Faraone
- Baylor College of Medicine, Texas Children's Hospital, Houston, TX
| | - Kelby Fuller
- Baylor College of Medicine, Texas Children's Hospital, Houston, TX
| | | | - Dana Cerminara
- Department of Pharmacy, Texas Children's Hospital, Houston, TX
| | - Douglas S Fishman
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX
| | - Kristen Valencia Deray
- Department of Pediatrics, Department of Pharmacy, Baylor College of Medicine, Texas Children's Hospital, Houston, TX
| | - Flor Munoz
- Department of Pediatrics, Department of Pharmacy, Baylor College of Medicine, Texas Children's Hospital, Houston, TX
| | - Julie Schackman
- Division of Anesthesiology, Perioperative, & Pain Medicine, Department of Anesthesiology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX
| | - Daniel Leung
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX
| | - Ayse Akcan-Arikan
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX
| | - Manpreet Virk
- Division of Critical Care, Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX
| | - Fong W Lam
- Division of Critical Care, Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX
| | - Alex Chau
- Division of Interventional Radiology, Department of Radiology, Edward B. Singleton Department of Radiology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX
| | - Moreshwar S Desai
- Division of Critical Care, Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX
| | - Jose A Hernandez
- Division of Interventional Radiology, Department of Radiology, Edward B. Singleton Department of Radiology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX
| | - John A Goss
- Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Department of Pediatric Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, TX
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Eurich D, Schlickeiser S, Ossami Saidy RR, Uluk D, Rossner F, Postel M, Schoening W, Oellinger R, Lurje G, Pratschke J, Reinke P, Gruen N. How to Estimate the Probability of Tolerance Long-Term in Liver Transplant Recipients. J Clin Med 2023; 12:6546. [PMID: 37892685 PMCID: PMC10607917 DOI: 10.3390/jcm12206546] [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: 09/03/2023] [Revised: 09/29/2023] [Accepted: 10/11/2023] [Indexed: 10/29/2023] Open
Abstract
BACKGROUND Operational tolerance as the ability to accept the liver transplant without pharmacological immunosuppression is a common phenomenon in the long-term course. However, it is currently underutilized due to a lack of simple diagnostic support and fear of rejection despite its recognized benefits. In the present work, we present a simple score based on clinical parameters to estimate the probability of tolerance. PATIENTS AND METHODS In order to estimate the probability of tolerance, clinical parameters from 82 patients after LT who underwent weaning from the IS for various reasons at our transplant center were extracted from a prospectively organized database and analyzed retrospectively. Univariate testing as well as multivariable logistic regression analysis were performed to assess the association of clinical variables with tolerance in the real-world setting. RESULTS The most important factors associated with tolerance after multivariable logistic regression were IS monotherapy, male sex, history of hepatocellular carcinoma pretransplant, time since LT, and lack of rejection. These five predictors were retained in an approximate model that could be presented as a simple scoring system to estimate the clinical probability of tolerance or IS dispensability with good predictive performance (AUC = 0.89). CONCLUSION In parallel with the existence of a tremendous need for further research on tolerance mechanisms, the presented score, after validation in a larger collective preferably in a multicenter setting, could be easily and safely applied in the real world and already now address all three levels of prevention in LT patients over the long-term course.
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Affiliation(s)
- Dennis Eurich
- Department of Surgery, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (R.R.O.S.); (D.U.); (M.P.); (W.S.); (R.O.); (G.L.); (J.P.)
| | - Stephan Schlickeiser
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.S.); (P.R.)
| | - Ramin Raul Ossami Saidy
- Department of Surgery, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (R.R.O.S.); (D.U.); (M.P.); (W.S.); (R.O.); (G.L.); (J.P.)
| | - Deniz Uluk
- Department of Surgery, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (R.R.O.S.); (D.U.); (M.P.); (W.S.); (R.O.); (G.L.); (J.P.)
| | - Florian Rossner
- Department of Pathology, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany;
- Max Delbrueck Center for Molecular Medicine, Helmholtz Association, 13125 Berlin, Germany
| | - Maximilian Postel
- Department of Surgery, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (R.R.O.S.); (D.U.); (M.P.); (W.S.); (R.O.); (G.L.); (J.P.)
| | - Wenzel Schoening
- Department of Surgery, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (R.R.O.S.); (D.U.); (M.P.); (W.S.); (R.O.); (G.L.); (J.P.)
| | - Robert Oellinger
- Department of Surgery, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (R.R.O.S.); (D.U.); (M.P.); (W.S.); (R.O.); (G.L.); (J.P.)
| | - Georg Lurje
- Department of Surgery, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (R.R.O.S.); (D.U.); (M.P.); (W.S.); (R.O.); (G.L.); (J.P.)
| | - Johann Pratschke
- Department of Surgery, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (R.R.O.S.); (D.U.); (M.P.); (W.S.); (R.O.); (G.L.); (J.P.)
| | - Petra Reinke
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.S.); (P.R.)
- Berlin Center for Advanced Therapies (BeCAT), Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité—Universitaetsmedizin Berlin, 13353 Berlin, Germany;
| | - Natalie Gruen
- Berlin Center for Advanced Therapies (BeCAT), Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité—Universitaetsmedizin Berlin, 13353 Berlin, Germany;
- Department of Nephrology and Internal Intensive Care Medicine, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
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Choi JY, Kim KW, Jang JK, Choi SH, Kwon HJ, Yoon YI, Song GW, Lee SG. Value of Doppler ultrasonography in predicting clinical outcomes for patients with acute cellular rejection after liver transplantation. Ultrasonography 2023; 42:572-579. [PMID: 37700431 PMCID: PMC10555689 DOI: 10.14366/usg.23112] [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: 06/08/2023] [Revised: 07/21/2023] [Accepted: 08/06/2023] [Indexed: 09/14/2023] Open
Abstract
PURPOSE This study investigated the value of Doppler ultrasonography in predicting clinical outcomes after antirejection treatment for patients with acute cellular rejection (ACR) following liver transplantation (LT). METHODS This retrospective study included 84 patients who were pathologically diagnosed with ACR and received antirejection treatment within 90 days following LT. Two radiologists searched for abnormal Doppler parameters at ACR diagnosis and within 7 days after antirejection treatment initiation, including portal blood velocity (PBV) <20 cm/s, hepatic artery resistive index <0.5, and a monophasic hepatic vein flow pattern. Interval PBV changes were also evaluated. The frequencies of abnormal Doppler parameters and PBV changes were compared by treatment outcome. RESULTS The frequency of abnormal PBV in the early post-treatment phase (PBVearly post-treatment) was significantly higher among poor responders (50.0% [10/20]) than among good responders (7.8% [5/64]) (P<0.001). The sensitivity, specificity, and accuracy of abnormal PBVearly post-treatment as a predictor of poor response to antirejection treatment were 50.0% (10/20), 92.2% (59/64), and 82.1% (69/84), respectively. A decrease (>10%) from the PBV at event (PBVevent) to PBVearly post-treatment was significantly more common among poor responders (50.0% [10/20]) than among good responders (20.3% [13/64]) (P=0.019). The sensitivity, specificity, and accuracy of this PBV decrease in predicting poor treatment response were 50.0% (10/20), 79.7% (51/64), and 72.6% (61/84), respectively. CONCLUSION Abnormal PBVearly post-treatment and a decrease between PBVevent and PBVearly post-treatment were significantly associated with poor treatment response in patients with ACR after LT. Consequently, Doppler ultrasonography may be useful for predicting clinical outcomes in these patients.
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Affiliation(s)
- Ji Young Choi
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyoung Won Kim
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jong Keon Jang
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sang Hyun Choi
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Heon-Ju Kwon
- Department of Radiology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young-In Yoon
- Department of Surgery, Division of Hepatobiliary and Liver Transplantation Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Gi-Won Song
- Department of Surgery, Division of Hepatobiliary and Liver Transplantation Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sung-Gyu Lee
- Department of Surgery, Division of Hepatobiliary and Liver Transplantation Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Kim JY, Chang S, Kim J, Choi HH, Lee J, Hong SY, Lee JM, Hong SK, Choi Y, Yi NJ, Lee KW, Suh KS. Evaluation of the efficacy and safety of conversion from the tacrolimus capsule to tablet in stable liver transplant recipients with maintenance therapy: a 24-week, open-label, single-center, phase IV exploratory clinical study. Ann Surg Treat Res 2023; 105:228-236. [PMID: 37908382 PMCID: PMC10613821 DOI: 10.4174/astr.2023.105.4.228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 07/19/2023] [Accepted: 08/17/2023] [Indexed: 11/02/2023] Open
Abstract
Purpose The tablet form of tacrolimus is more convenient for drug ingestion than the capsule form. We examined the efficacy and safety of tacrolimus tablets and a satisfaction survey after formula conversion in liver transplant (LT) recipients. Methods This study was an open-label, prospective clinical trial for tacrolimus formula 1:1 conversion from capsule to tablet in 41 adult LT recipients with tacrolimus maintenance therapy of more than 1 month. The primary endpoint was incidence of biopsy-proven acute rejection (BPAR) within 24 weeks. Surveys 1 week before and 4 weeks after formula conversion were conducted for total daily dose of medication, number, scale of discomfort and satisfaction. Results The overall incidence of BPAR was 0% and there was no graft loss or patient death. The incidence of adverse effects was 34.1% (n = 14) after formula conversion. The most common severe adverse effect was abnormal liver function test (n = 5): biliary complications (n = 4) and alcoholic recidivism (n = 1). Total daily dose and number of tacrolimus doses were significantly lower after formula conversion (P < 0.05) without changes in trough level. According to survey analysis, there was no significant difference in discomfort and satisfaction scales from capsule to tablet conversion (P < 0.05). Conclusion The present study suggests that the new tablet formula can be a useful treatment option to maintain a consistent level of tacrolimus with a lower total daily dose and number in adult LT recipients.
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Affiliation(s)
- Jae-Yoon Kim
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Sukyoung Chang
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Jiyoung Kim
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Hyun Hwa Choi
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Jaewon Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Su young Hong
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong-Moo Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Suk Kyun Hong
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - YoungRok Choi
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Nam-Joon Yi
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Kwang-Woong Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Kyung-Suk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
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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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Que W, Ueta H, Hu X, Morita-Nakagawa M, Fujino M, Ueda D, Tokuda N, Huang W, Guo WZ, Zhong L, Li XK. Temporal and spatial dynamics of immune cells in spontaneous liver transplant tolerance. iScience 2023; 26:107691. [PMID: 37694154 PMCID: PMC10485166 DOI: 10.1016/j.isci.2023.107691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 06/11/2023] [Accepted: 08/17/2023] [Indexed: 09/12/2023] Open
Abstract
The liver has long been deemed a tolerogenic organ. We employed high-dimensional mass cytometry and immunohistochemistry to depict the temporal and spatial dynamics of immune cells in the spleen and liver in a murine model of spontaneous liver allograft acceptance. We depicted the immune landscape of spontaneous liver tolerance throughout the rejection and acceptance stages after liver transplantation and highlighted several points of importance. Of note, the CD4+/CD8+ T cell ratio remained low, even in the tolerance phase. Furthermore, a PhenoGraph clustering analysis revealed that exhausted CD8+ T cells were the most dominant metacluster in graft-infiltrating lymphocytes (GILs), which highly expressed the costimulatory molecule CD86. The temporal and spatial dynamics of immune cells revealed by high-dimensional analyses enable a fine-grained analysis of GIL subsets, contribute to new insights for the discovery of immunological mechanisms of liver tolerance, and provide potential ways to achieve clinical operational tolerance after liver transplantation.
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Affiliation(s)
- Weitao Que
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Hisashi Ueta
- Department of Anatomy, Dokkyo Medical University, Tochigi 321-0293, Japan
| | - Xin Hu
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan
| | - Miwa Morita-Nakagawa
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan
- Oral Medicine Research Center, Fukuoka Dental College, Fukuoka 814-0175, Japan
| | - Masayuki Fujino
- Management Department of Biosafety, Laboratory Animal, and Pathogen Bank, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
| | - Daisuke Ueda
- Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto 606-8303, Japan
| | - Nobuko Tokuda
- Department of Anatomy, Dokkyo Medical University, Tochigi 321-0293, Japan
| | - Wenxin Huang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Wen-Zhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Lin Zhong
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Xiao-Kang Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan
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Maspero M, Ali K, Cazzaniga B, Yilmaz S, Raj R, Liu Q, Quintini C, Miller C, Hashimoto K, Fairchild RL, Schlegel A. Acute rejection after liver transplantation with machine perfusion versus static cold storage: A systematic review and meta-analysis. Hepatology 2023; 78:835-846. [PMID: 36988381 DOI: 10.1097/hep.0000000000000363] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 02/27/2023] [Indexed: 03/30/2023]
Abstract
BACKGROUND AND AIMS Acute cellular rejection (ACR) is a frequent complication after liver transplantation. By reducing ischemia and graft damage, dynamic preservation techniques may diminish ACR. We performed a systematic review to assess the effect of currently tested organ perfusion (OP) approaches versus static cold storage (SCS) on post-transplant ACR-rates. APPROACH AND RESULTS A systematic search of Medline, Embase, Cochrane Library, and Web of Science was conducted. Studies reporting ACR-rates between OP and SCS and comprising at least 10 liver transplants performed with either hypothermic oxygenated perfusion (HOPE), normothermic machine perfusion, or normothermic regional perfusion were included. Studies with mixed perfusion approaches were excluded. Eight studies were identified (226 patients in OP and 330 in SCS). Six studies were on HOPE, one on normothermic machine perfusion, and one on normothermic regional perfusion. At meta-analysis, OP was associated with a reduction in ACR compared with SCS [OR: 0.55 (95% CI, 0.33-0.91), p =0.02]. This effect remained significant when considering HOPE alone [OR: 0.54 (95% CI, 0.29-1), p =0.05], in a subgroup analysis of studies including only grafts from donation after cardiac death [OR: 0.43 (0.20-0.91) p =0.03], and in HOPE studies with only donation after cardiac death grafts [OR: 0.37 (0.14-1), p =0.05]. CONCLUSIONS Dynamic OP techniques are associated with a reduction in ACR after liver transplantation compared with SCS. PROSPERO registration: CRD42022348356.
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Affiliation(s)
- Marianna Maspero
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
- University of Milan, Università degli Studi di Milano, Milan, Italy
| | - Khaled Ali
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
| | - Beatrice Cazzaniga
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
| | - Sumeyye Yilmaz
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
| | - Roma Raj
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
| | - Qiang Liu
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
| | - Cristiano Quintini
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
- Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Charles Miller
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
| | - Koji Hashimoto
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
| | - Robert L Fairchild
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Andrea Schlegel
- Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Centre of Preclinical Research, Milan, Italy
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, Switzerland
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Khalil A, Quaglia A, Gélat P, Saffari N, Rashidi H, Davidson B. New Developments and Challenges in Liver Transplantation. J Clin Med 2023; 12:5586. [PMID: 37685652 PMCID: PMC10488676 DOI: 10.3390/jcm12175586] [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: 07/17/2023] [Revised: 08/15/2023] [Accepted: 08/26/2023] [Indexed: 09/10/2023] Open
Abstract
Liver disease is increasing in incidence and is the third most common cause of premature death in the United Kingdom and fourth in the United States. Liver disease accounts for 2 million deaths globally each year. Three-quarters of patients with liver disease are diagnosed at a late stage, with liver transplantation as the only definitive treatment. Thomas E. Starzl performed the first human liver transplant 60 years ago. It has since become an established treatment for end-stage liver disease, both acute and chronic, including metabolic diseases and primary and, at present piloting, secondary liver cancer. Advances in surgical and anaesthetic techniques, refined indications and contra-indications to transplantation, improved donor selection, immunosuppression and prognostic scoring have allowed the outcomes of liver transplantation to improve year on year. However, there are many limitations to liver transplantation. This review describes the milestones that have occurred in the development of liver transplantation, the current limitations and the ongoing research aimed at overcoming these challenges.
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Affiliation(s)
- Amjad Khalil
- Liver Unit, Wellington Hospital, London NW8 9TA, UK
- Centre for Surgical Innovation, Organ Regeneration and Transplantation, University College London, London NW3 2PS, UK
- Clinical Service of HPB Surgery and Liver Transplantation, Royal Free Hospital, London NW3 2QG, UK
| | - Alberto Quaglia
- Cancer Institute, University College London, London WC1E 6DD, UK
| | - Pierre Gélat
- Division of Surgery and Interventional Science, University College London, London NW3 2PS, UK
| | - Nader Saffari
- Department of Mechanical Engineering, University College London, London WC1E 7JE, UK
| | - Hassan Rashidi
- Institute of Child Health, University College London, London WC1N 1EH, UK;
| | - Brian Davidson
- Liver Unit, Wellington Hospital, London NW8 9TA, UK
- Centre for Surgical Innovation, Organ Regeneration and Transplantation, University College London, London NW3 2PS, UK
- Clinical Service of HPB Surgery and Liver Transplantation, Royal Free Hospital, London NW3 2QG, UK
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Chen Q, Yang Z, Lin H, Lai J, Hu D, Yan M, Wu Z, Liu W, Li Z, He Y, Sun Z, Shuai L, Peng Z, Wang Y, Li S, Cui Y, Zhang H, Zhang L, Bai L. Comparative effects of hepatocyte growth factor and tacrolimus on acute liver allograft early tolerance. Front Immunol 2023; 14:1162439. [PMID: 37614233 PMCID: PMC10444199 DOI: 10.3389/fimmu.2023.1162439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 06/27/2023] [Indexed: 08/25/2023] Open
Abstract
Allostimulated CD8+ T cells (aCD8+ T cells), as the main mediators of acute liver rejection (ARJ), are hyposensitive to apoptosis due to the inactivation of death receptor FAS-mediated pathways and fail to allow tolerance induction, eventually leading to acute graft rejection. Although tacrolimus (FK506), the most commonly used immunosuppressant (IS) in the clinic, allows tolerance induction, its use is limited because its target immune cells are unknown and it is associated with increased incidences of malignancy, infection, and nephrotoxicity, which substantially impact long-term liver transplantation (LTx) outcomes. The dark agouti (DA)-to-Lewis rat LTx model is a well-known ARJ model and was hence chosen for the present study. We show that both hepatocyte growth factor (HGF) (cHGF, containing the main form of promoting HGF production) and recombinant HGF (h-rHGF) exert immunoregulatory effects mainly on allogeneic aCD8+ T cell suppression through FAS-mediated apoptotic pathways by inhibiting cMet to FAS antagonism and Fas trimerization, leading to acute tolerance induction. We also showed that such inhibition can be abrogated by treatment with neutralizing antibodies against cMet (HGF-only receptor). In contrast, we did not observe these effects in rats treated with FK506. However, we observed that the effect of anti-rejection by FK506 was mainly on allostimulated CD4+ T cell (aCD4+ T cell) suppression and regulatory T cell (Treg) promotion, in contrast to the mechanism of HGF. In addition, the protective mechanism of HGF in FK506-mediated nephrotoxicity was addressed. Therefore, HGF as a tolerance inducer, whether used in combination with FK506 or as monotherapy, may have good clinical value. Additional roles of these T-cell subpopulations in other biological systems and studies in these fields will also be meaningful.
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Affiliation(s)
- Quanyu Chen
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, Chongqing, China
- Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Laboratory of Molecular Developmental Biology, School of Life Sciences, Southwest University, Chongqing, China
| | - Zhiqing Yang
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, Chongqing, China
| | - Heng Lin
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, Chongqing, China
| | - Jiejuan Lai
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, Chongqing, China
| | - Deyu Hu
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, Chongqing, China
- Bioengineering College, Chongqing University, Chongqing, China
| | - Min Yan
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, Chongqing, China
- Department of Special Medicine, Shanxi Medical University, Taiyuan, China
| | - Zhifang Wu
- Department of Special Medicine, Shanxi Medical University, Taiyuan, China
| | - Wei Liu
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, Chongqing, China
| | - Zhehai Li
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
| | - Yu He
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, Chongqing, China
| | - Zhe Sun
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
| | - Ling Shuai
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, Chongqing, China
| | - Zhiping Peng
- Department of Radiological Medicine, Chongqing Medical University, Chongqing, China
| | - Yangyang Wang
- Bioengineering College, Chongqing University, Chongqing, China
| | - Sijin Li
- Department of Special Medicine, Shanxi Medical University, Taiyuan, China
| | - Youhong Cui
- Department of Pathology, Southwest Hospital, Army Medical University, Chongqing, China
| | - Hongyu Zhang
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, Chongqing, China
| | - Leida Zhang
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, Chongqing, China
| | - Lianhua Bai
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, Chongqing, China
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Song S, Zhi Y, Tian G, Sun X, Chen Y, Qiu W, Jiao W, Huang H, Yu Y, Li M, Lv G. Immature and activated phenotype of blood NK cells is associated with acute rejection in adult liver transplant. Liver Transpl 2023; 29:836-848. [PMID: 37002601 DOI: 10.1097/lvt.0000000000000139] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 03/08/2023] [Indexed: 05/10/2023]
Abstract
Natural killer (NK) cells contribute to liver transplant (LTx) rejection. However, the blood-circulating NK-cell dynamics of patients who experience acute rejection (AR) are unclear. Herein, we longitudinally profiled the total NK cells and their subsets, along with the expression of activating and inhibitory receptors in sequential peripheral blood mononuclear cell samples, spanning from before LTx to the first year after LTx of 32 patients with AR and 30 patients under a steady immune status. Before transplantation, patients with AR (rejectors) contained a significantly higher proportion of the immature CD56 bright CD16 - subset and a lower cytolytic CD56 dim CD16 + in the total blood-circulating NK cells than patients with steady immunity. Both subsets contained a high NKp30-positive population, and CD56 dim CD16 + additionally exhibited a high NKp46-positive ratio. The NKp30-positive ratio in CD56 dim CD16 + subset showed the most prominent AR predictive ability before LTx and was an independent risk factor of LTx AR. After transplantation, the blood-circulating NK cells in rejectors maintained a higher CD56 bright CD16 - and lower CD56 dim CD16 + composition than the controls throughout the first year after LTx. Moreover, both subsets maintained a high NKp30-positive ratio, and CD56 dim CD16 + retained a high NKp46-positive ratio. The blood-circulating NK cell subset composition was consistent during AR, while the expressions of NKp30 and NKp46 were augmented. Collectively, a more immature CD56 bright CD16 - subset composition and an activated phenotype of high NKp30 expression were the general properties of blood-circulating NK cells in rejected LTx recipients, and the NKp30-positive ratio in CD56 dim CD16 + NK subset before LTx possessed AR predictive potential.
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Affiliation(s)
- Shifei Song
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
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Wang H, Li C, Xiong Z, Li T. Luteolin attenuates acute liver allograft rejection in rats by inhibiting T cell proliferation and regulating T cell subsets. Int Immunopharmacol 2023; 121:110407. [PMID: 37290328 DOI: 10.1016/j.intimp.2023.110407] [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: 01/26/2023] [Revised: 05/28/2023] [Accepted: 05/28/2023] [Indexed: 06/10/2023]
Abstract
Allograft rejection continues to be a significant cause of morbidity and graft failure for liver transplant recipients. Existing immunosuppressive regimens have many drawbacks, thus safe and effective long-term immunosuppressive regimens are still required. Luteolin (LUT), a natural component found in many plants, has a variety of biological and pharmacological effects and shows good anti-inflammatory activity in inflammatory and autoimmune diseases. Nevertheless, it remains unclear how it affects acute organ rejection after allogeneic transplantation. In this study, a rat liver transplantation model was constructed to investigate the effect of LUT on acute rejection of organ allografts. We found that LUT significantly protected the structure and function of liver grafts, prolonged recipient rat survival, ameliorated T cell infiltration, and downregulated proinflammatory cytokines. Moreover, LUT inhibited the proliferation of CD4+ T cells and Th cell differentiation but increased the proportion of Tregs, which is the key to its immunosuppressive effect. In vitro, LUT also significantly inhibited CD4+ T cell proliferation and Th1 differentiation. There may be important implications for improving immunosuppressive regimens for organ transplantation as a result of this discovery.
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Affiliation(s)
- Hao Wang
- Department of Liver Transplantation, The Second Xiang-ya Hospital, Central South University, Changsha, Hunan 410011, China; The First Central Clinical School, Tianjin Medical University, Tianjin 300190, China
| | - Chenxuan Li
- Department of Liver Transplantation, The Second Xiang-ya Hospital, Central South University, Changsha, Hunan 410011, China; Transplant Medical Research Center, The Second Xiang-ya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Zhiwei Xiong
- Department of Liver Transplantation, The Second Xiang-ya Hospital, Central South University, Changsha, Hunan 410011, China; Transplant Medical Research Center, The Second Xiang-ya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Ting Li
- Department of Liver Transplantation, The Second Xiang-ya Hospital, Central South University, Changsha, Hunan 410011, China; Transplant Medical Research Center, The Second Xiang-ya Hospital, Central South University, Changsha, Hunan 410011, China.
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43
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Thomson M, Lake JR. CAQ Corner: Immune-mediated complications. Liver Transpl 2023; 29:885-893. [PMID: 35748497 PMCID: PMC10344430 DOI: 10.1002/lt.26535] [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: 02/19/2022] [Revised: 06/04/2022] [Accepted: 06/14/2022] [Indexed: 01/12/2023]
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Engel B, Görzer I, Campos-Murguia A, Hartleben B, Puchhammer-Stöckl E, Jaeckel E, Taubert R. Association of torque teno virus viremia with liver fibrosis in the first year after liver transplantation. Front Immunol 2023; 14:1215868. [PMID: 37533865 PMCID: PMC10392936 DOI: 10.3389/fimmu.2023.1215868] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 06/29/2023] [Indexed: 08/04/2023] Open
Abstract
Introduction Torque teno virus (TTV) replication is controlled by immune status, mirroring a degree of immunosuppression after solid organ transplantation. TTV viraemia (TTVv) was associated with acute cellular rejection and infection within the first year after liver transplantation (LT). Long-term data on TTV after LT and correlation with graft injury from protocol biopsies are limited. Methods One hundred plasma samples paired with graft biopsies from a prospective single-center biorepository were analyzed. Results The median time post-LT was 23 months (range, 2-298). TTVv was detectable in 97%. TTVv decreased over time after LT and showed a significant decline from year 1 to later time points. Hence, TTVv correlated negatively with histologic liver fibrosis (liver allograft fibrosis and Ishak scores) and positively with the overall immunosuppression degree quantified by an immunosuppression score in the first year after LT. There was no association with dosages or trough levels of single immunosuppressants. The pharmacodynamic marker TTVv did not correlate with pharmacokinetic assessments of immunosuppression degree [calcineurin inhibitor (CNI) trough levels or immunosuppressant dosages]-our clinical gold standards to guide immunosuppressive therapy. TTVv was independently associated with histologically proven liver fibrosis after LT in the first year after LT in multivariate analysis. Discussion The independent association of histological graft fibrosis with lower TTVv in year 1 underscores that a pharmacodynamic marker would be preferable to individualize immunosuppression after LT. However, a high variability of TTVv at the low immunosuppression doses given after the first year precludes TTV as a clinically useful marker after LT in the long-term liver transplant recipients.
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Affiliation(s)
- Bastian Engel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Irene Görzer
- Center for Virology, Medical University of Vienna, Vienna, Austria
| | - 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
| | | | - 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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Sirgi Y, Stanojevic M, Ahn J, Yazigi N, Kaufman S, Khan K, Vitola B, Matsumoto C, Kroemer A, Fishbein T, Ekong UD. COVID-19 Disease in Pediatric Solid Organ Transplantation from Alpha to Omicron: A High Monocyte Count in the Preceding Three Months Portends a Risk for Severe Disease. Viruses 2023; 15:1559. [PMID: 37515245 PMCID: PMC10383409 DOI: 10.3390/v15071559] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/12/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023] Open
Abstract
IMPORTANCE Planning for future resurgences in SARS-CoV-2 infection is necessary for providers who care for immunocompromised patients. OBJECTIVE to determine factors associated with COVID-19 disease severity in immunosuppressed children. DESIGN a case series of children with solid organ transplants diagnosed with SARS-CoV-2 infection between 15 March 2020 and 31 March 2023. SETTING a single pediatric transplant center. PARTICIPANTS all children with a composite transplant (liver, pancreas, intestine), isolated intestine transplant (IT), isolated liver transplant LT), or simultaneous liver kidney transplant (SLK) with a positive PCR for SARS-CoV-2. EXPOSURE SARS-CoV-2 infection. MAIN OUTCOME AND MEASURES We hypothesized that children on the most immunosuppression, defined by the number of immunosuppressive medications and usage of steroids, would have the most severe disease course and that differential white blood cell count in the months preceding infection would be associated with likelihood of having severe disease. The hypothesis being tested was formulated during data collection. The primary study outcome measurement was disease severity defined using WHO criteria. RESULTS 77 children (50 LT, 24 intestine, 3 SLK) were infected with SARS-CoV-2, 57.4 months from transplant (IQR 19.7-87.2). 17% were ≤1 year post transplant at infection. 55% were male, 58% were symptomatic and ~29% had severe disease. A high absolute lymphocyte count at diagnosis decreased the odds of having severe COVID-19 disease (OR 0.29; CI 0.11-0.60; p = 0.004). Conversely, patients with a high absolute monocyte count in the three months preceding infection had increased odds of having severe disease (OR 30.49; CI 1.68-1027.77; p = 0.033). Steroid use, higher tacrolimus level, and number of immunosuppressive medications at infection did not increase the odds of having severe disease. CONCLUSIONS AND RELEVANCE The significance of a high monocyte count as predictor of severe disease potentially confirms the importance of monocytic inflammasome-driven inflammation in COVID-19 pathogenesis. Our data do not support reducing immunosuppression in the setting of infection. Our observations may have important ramifications in resource management as vaccine- and infection-induced immunity wanes.
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Affiliation(s)
- Yasmina Sirgi
- Department of Surgery, Georgetown University Medical School, Washington, DC 20007, USA
| | - Maja Stanojevic
- Department of Pediatrics, MedStar Georgetown University Hospital, Washington, DC 20007, USA
| | - Jaeil Ahn
- Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University, Washington, DC 20007, USA
| | - Nada Yazigi
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, DC 20007, USA
| | - Stuart Kaufman
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, DC 20007, USA
| | - Khalid Khan
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, DC 20007, USA
| | - Bernadette Vitola
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, DC 20007, USA
| | - Cal Matsumoto
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, DC 20007, USA
| | - Alexander Kroemer
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, DC 20007, USA
| | - Thomas Fishbein
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, DC 20007, USA
| | - Udeme D Ekong
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, DC 20007, USA
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Barbetta A, Rocque B, Bangerth S, Street K, Weaver C, Chopra S, Kim J, Sher L, Gaudilliere B, Akbari O, Kohli R, Emamaullee J. Spatially resolved immune exhaustion within the alloreactive microenvironment predicts liver transplant rejection. RESEARCH SQUARE 2023:rs.3.rs-3044385. [PMID: 37461437 PMCID: PMC10350170 DOI: 10.21203/rs.3.rs-3044385/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/23/2023]
Abstract
Allograft rejection is a frequent complication following solid organ transplantation, but defining specific immune subsets mediating alloimmunity has been elusive due to the scarcity of tissue in clinical biopsy specimens. Single cell techniques have emerged as valuable tools for studying mechanisms of disease in complex tissue microenvironments. Here, we developed a highly multiplexed imaging mass cytometry panel, single cell analysis pipeline, and semi-supervised immune cell clustering algorithm to study archival biopsy specimens from 79 liver transplant (LT) recipients with histopathological diagnoses of either no rejection (NR), acute T-cell mediated rejection (TCMR), or chronic rejection (CR). This approach generated a spatially resolved proteomic atlas of 461,816 cells derived from 98 pathologist-selected regions of interest relevant to clinical diagnosis of rejection. We identified 41 distinct cell populations (32 immune and 9 parenchymal cell phenotypes) that defined key elements of the alloimmune microenvironment (AME), identified significant cell-cell interactions, and established higher order cellular neighborhoods. Our analysis revealed that both regulatory (HLA-DR+ Treg) and exhausted T-cell phenotypes (PD1+CD4+ and PD1+CD8+ T-cells), combined with variations in M2 macrophage polarization, were a unique signature of TCMR. TCMR was further characterized by alterations in cell-to-cell interactions among both exhausted immune subsets and inflammatory populations, with expansion of a CD8 enriched cellular neighborhood comprised of Treg, exhausted T-cell subsets, proliferating CD8+ T-cells, and cytotoxic T-cells. These data enabled creation of a predictive model of clinical outcomes using a subset of cell types to differentiate TCMR from NR (AUC = 0.96 ± 0.04) and TCMR from CR (AUC = 0.96 ± 0.06) with high sensitivity and specificity. Collectively, these data provide mechanistic insights into the AME in clinical LT, including a substantial role for immune exhaustion in TCMR with identification of novel targets for more focused immunotherapy in allograft rejection. Our study also offers a conceptual framework for applying spatial proteomics to study immunological diseases in archival clinical specimens.
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Affiliation(s)
| | | | | | | | | | | | | | - Linda Sher
- University of Southern California Keck School of Mdicine
| | | | - Omid Akbari
- University of Southern California, Keck School of Medicine
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Magaz M, Giudicelli-Lett H, Nicoară-Farcău O, Rajoriya N, Goel A, Raymenants K, Hillaire S, Crespo G, Téllez L, Elkrief L, Fondevila C, Orts L, Nery F, Shukla A, Larrue H, Fundora Y, Degroote H, Aguilera V, LLop E, Turco L, Indulti F, Gioia S, Tosetti G, Bitto N, Becchetti C, Alvarado E, Roig C, Diaz R, Praktiknjo M, Konicek AL, Soy G, Olivas P, Fortea JI, Masnou H, Puente Á, Ardèvol A, Álvarez-Navascués C, Romero M, Scheiner B, Semmler G, Mandorfer M, Damião F, Baiges A, Turon F, Simón-Talero M, González-Alayón C, Díaz A, García-Criado Á, de Gottardi A, Reverter E, Blasi A, Genescà J, Roux O, Francoz C, Noronha Ferreira C, Reiberger T, Rodríguez M, Morillas RM, Crespo J, Trebicka J, Bañares R, Villanueva C, Berzigotti A, Primignani M, La Mura V, Riggio O, Schepis F, Procopet B, Verhelst X, Calleja JL, Bureau C, Albillos A, Nevens F, Hernández-Gea V, Tripathi D, Rautou PE, Durand F, García-Pagán JC. Liver Transplantation for Porto-sinusoidal Vascular Liver Disorder: Long-term Outcome. Transplantation 2023; 107:1330-1340. [PMID: 36479977 DOI: 10.1097/tp.0000000000004444] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Porto-sinusoidal vascular liver disorder (PSVD) is a rare disease that occasionally requires liver transplantation (LT), despite usually presenting preserved liver function. There remains a paucity of data pertaining to LT in PSVD. The aim was to identify features associated with post-LT outcomes in PSVD. METHODS Retrospective multicentre study of 79 patients who received LT for PSVD. RESULTS Median post-LT follow-up was 37 (range 1-261) mo. Refractory ascites 24 (30%), hepatic encephalopathy 16 (20%), and hepatopulmonary syndrome 13 (16.3%) were the most frequent indications for LT. Hepatocellular carcinoma was the indication in only 2 patients. Twenty-four patients died, 7 due to liver and 17 to non-liver related causes. Post-LT survival was 82.2%, 80.7%, and 68.6% at 1, 2, and 5 y, respectively. Post-LT survival was significantly better in patients without (n = 58) than in those with a persistent severe PSVD-associated condition (n = 21). Pre-LT hyperbilirubinemia levels and creatinine >100 µmol/L were also independently associated with poor survival. Six patients (7.6%) required a second LT. Recurrence of PSVD was confirmed by liver biopsy in only 1 patient and in 3 further patients it was likely. CONCLUSIONS LT in PSVD is associated with an acceptable outcome in the absence of associated severe conditions. However, persistence of a severe associated condition, pre-LT high bilirubin levels, or creatinine >100 µmol/L impact outcome, and these are features that should be considered when evaluating PSVD patients for LT. PSVD recurrence is possible after LT and needs to be explored, at least, in cases of posttransplant portal hypertension.
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Affiliation(s)
- Marta Magaz
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain
- CIBEREHD (Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas)
- Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver)
| | - Heloïse Giudicelli-Lett
- Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver)
- Service d'Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, DHU Unity, Pôle des Maladies de l'Appareil Digestif, Hôpital Beaujon, AP-HP, Clichy, France
| | - Oana Nicoară-Farcău
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain
- CIBEREHD (Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas)
- Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver)
- Regional Institute of Gastroenterology and Hepatology "Octavian Fodor," Hepatology Department and "Iuliu Hatieganu" University of Medicine and Pharmacy, 3rd Medical Clinic, Cluj-Napoca, Romania
| | - Neil Rajoriya
- The Liver Unit, University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Ashish Goel
- The Liver Unit, University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Karlien Raymenants
- Department of Gastroenterology and Hepatology, University Hospital KU Leuven, Leuven, Belgium
| | - Sophie Hillaire
- Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver)
- Service d'Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, DHU Unity, Pôle des Maladies de l'Appareil Digestif, Hôpital Beaujon, AP-HP, Clichy, France
| | - Gonzalo Crespo
- Liver Transplantation Unit, Hospital Clínic, Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Luis Téllez
- Department of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, IRYCIS, CIBERehd, Universidad de Alcalá, Madrid, Spain
| | - Laure Elkrief
- Service d'Hépato-Gastroentérologie, Hôpitaux Universitaires de Genève, Geneva, Switzerland. Service d'Hépato-Gastroentérologie, CHU de Tours, France
- Université de Paris, Centre de recherche sur l'inflammation, Inserm, U1149, CNRS, ERL8252, Paris, France
| | - Constantino Fondevila
- Department of Surgery, Division of Hepatobiliary and General Surgery, Institut de Malalties Digestives I Metabòliques (IMDiM), Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Lara Orts
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain
- CIBEREHD (Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas)
- Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver)
| | - Filipe Nery
- Liver Unit, Centro Hospitalar do Porto, Hospital Sto Antonio, Porto, Portugal
| | - Akash Shukla
- Department of Gastroenterology, Lokmanya Tilak Municipal General Hospital and Lokmanya Tilak Municipal Medical College, Sion, Mumbai, India
| | - Hélène Larrue
- Department of Hepatology, Rangueil Hospital, CHU Toulouse, University Paul Sabatier of Toulouse, Toulouse, France
| | - Yiliam Fundora
- Department of Surgery, Division of Hepatobiliary and General Surgery, Institut de Malalties Digestives I Metabòliques (IMDiM), Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Helena Degroote
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| | - Victoria Aguilera
- Liver Transplantation and Hepatology Unit, Hospital Universitari i Politécnic La Fe, Valencia, Spain
- CIBERehd (Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Valencia Spain), Instituto de Salud Carlos III
| | - Elba LLop
- Liver Unit, Hospital U, Puerta de Hierro, Universidad Autònoma de Madrid, CIBERehd, Madrid, Spain
| | - Laura Turco
- Department of Gastroenterology and Hepatology, University of Modena & Reggio Emilia and Azienda Ospedaliero-Universitaria di Modena, Modena, Italy
| | - Federica Indulti
- Department of Gastroenterology and Hepatology, University of Modena & Reggio Emilia and Azienda Ospedaliero-Universitaria di Modena, Modena, Italy
| | - Stefania Gioia
- Department of Gastroenterology and Hepatology, Centre for the Diagnosis and Treatment of Portal Hypertension, "Sapienza" University of Rome, Rome, Italy
| | - Giulia Tosetti
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M.and A.Miglaivacca" Center for Liver Disease, Milan, Italy
| | - Niccolò Bitto
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M.and A.Miglaivacca" Center for Liver Disease, Milan, Italy
| | - Chiara Becchetti
- Hepatology Group, Swiss Liver Center, University Clinic for Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland
| | - Edilmar Alvarado
- Liver Unit, Department of Gastroenterology Hospital Sant Pau, Barcelona, Autonomous University, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Cristina Roig
- Liver Unit, Department of Gastroenterology Hospital Sant Pau, Barcelona, Autonomous University, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Raquel Diaz
- Department of Gastroenterology and Hepatology, University Gregorio Marañón Hospital, liSGM, CIBERehd, Barcelona, Spain
| | - Michael Praktiknjo
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany
| | - Anna-Lena Konicek
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany
| | - Guillem Soy
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain
- CIBEREHD (Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas)
- Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver)
| | - Pol Olivas
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain
- CIBEREHD (Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas)
- Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver)
| | - José Ignacio Fortea
- Liver Unit, Digestive Disease Department, Marqués de Valdecilla University Hospital, Santander, Cantabria University, Cantabria, Spain
| | - Helena Masnou
- Liver Unit, University Hospital Germans Trias i Pujol, Badalona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd)
| | - Ángela Puente
- Liver Unit, Digestive Disease Department, Marqués de Valdecilla University Hospital, Santander, Cantabria University, Cantabria, Spain
| | - Alba Ardèvol
- Liver Unit, University Hospital Germans Trias i Pujol, Badalona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd)
| | - Carmen Álvarez-Navascués
- Liver Unit, Department of Gastroenterology and Hepatology, Hospital Universitario Central de Asturias, University of Oviedo, Oviedo, Spain
| | - Marta Romero
- Liver Unit, Department of Gastroenterology, Hospital Virgen de la Salud, Toledo, Spain
| | - Bernhard Scheiner
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - Georg Semmler
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - Mattias Mandorfer
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - Filipe Damião
- Department of Gastroenterology and Hepatology, Hospital de Santa Maria - Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
| | - Anna Baiges
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain
- CIBEREHD (Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas)
- Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver)
| | - Fanny Turon
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain
- CIBEREHD (Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas)
- Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver)
| | - Macarena Simón-Talero
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebrón, Vall d'Hebron Research Institute (VHIR), Vall d'Hebron Barcelona Hospital Campus, CIBERehd, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Carlos González-Alayón
- Liver Unit, Department of Gastroenterology and Hepatology, Hospital Universitario de Canarias, Tenerife, Spain
| | - Alba Díaz
- Department of Histopathology, Hospital Clínic, Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Ángeles García-Criado
- Department of Radiology, Hospital Clínic, Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Andrea de Gottardi
- Servizio di Gastroenterología e Epatologia, Ente Ospedaliero Cantonale, Università della Svizzera Italiana, Lugano, Switzerland
| | - Enric Reverter
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
- Liver ICU, Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomèdiques August-Pi-Sunyer (IDIBAPS), Barcelona, Spain
| | - Annabel Blasi
- Anesthesiology Department, Hospital Clinic-IDIBAPS, Barcelona, Spain
| | - Joan Genescà
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebrón, Vall d'Hebron Research Institute (VHIR), Vall d'Hebron Barcelona Hospital Campus, CIBERehd, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Olivier Roux
- Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver)
- Service d'Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, DHU Unity, Pôle des Maladies de l'Appareil Digestif, Hôpital Beaujon, AP-HP, Clichy, France
| | - Claire Francoz
- Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver)
- Service d'Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, DHU Unity, Pôle des Maladies de l'Appareil Digestif, Hôpital Beaujon, AP-HP, Clichy, France
| | - Carlos Noronha Ferreira
- Department of Gastroenterology and Hepatology, Hospital de Santa Maria - Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
| | - Thomas Reiberger
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - Manuel Rodríguez
- Liver Unit, Department of Gastroenterology and Hepatology, Hospital Universitario Central de Asturias, University of Oviedo, Oviedo, Spain
| | - Rosa María Morillas
- Liver Unit, University Hospital Germans Trias i Pujol, Badalona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd)
| | - Javier Crespo
- Liver Unit, Digestive Disease Department, Marqués de Valdecilla University Hospital, Santander, Cantabria University, Cantabria, Spain
| | - Jonel Trebicka
- Translational Hepatology, Department of Internal Medicine I, Goethe University Frankfurt, Frankfurt, Germany
- European Foundation for Study of Chronic Liver Failure, Barcelona, Spain
| | - Rafael Bañares
- Department of Gastroenterology and Hepatology, University Gregorio Marañón Hospital, liSGM, CIBERehd, Barcelona, Spain
| | - Càndid Villanueva
- Liver Unit, Department of Gastroenterology Hospital Sant Pau, Barcelona, Autonomous University, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Annalisa Berzigotti
- Hepatology Group, Swiss Liver Center, University Clinic for Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland
| | - Massimo Primignani
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M.and A.Miglaivacca" Center for Liver Disease, Milan, Italy
| | - Vincenzo La Mura
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M.and A.Miglaivacca" Center for Liver Disease, Milan, Italy
| | - Oliviero Riggio
- Department of Gastroenterology and Hepatology, Centre for the Diagnosis and Treatment of Portal Hypertension, "Sapienza" University of Rome, Rome, Italy
| | - Filippo Schepis
- Department of Gastroenterology and Hepatology, University of Modena & Reggio Emilia and Azienda Ospedaliero-Universitaria di Modena, Modena, Italy
| | - Bogdan Procopet
- Regional Institute of Gastroenterology and Hepatology "Octavian Fodor," Hepatology Department and "Iuliu Hatieganu" University of Medicine and Pharmacy, 3rd Medical Clinic, Cluj-Napoca, Romania
| | - Xavier Verhelst
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| | - José Luis Calleja
- Liver Unit, Hospital U, Puerta de Hierro, Universidad Autònoma de Madrid, CIBERehd, Madrid, Spain
| | - Christophe Bureau
- Department of Hepatology, Rangueil Hospital, CHU Toulouse, University Paul Sabatier of Toulouse, Toulouse, France
| | - Agustín Albillos
- Department of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, IRYCIS, CIBERehd, Universidad de Alcalá, Madrid, Spain
| | - Frederik Nevens
- Department of Gastroenterology and Hepatology, University Hospital KU Leuven, Leuven, Belgium
| | - Virginia Hernández-Gea
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain
- CIBEREHD (Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas)
- Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver)
| | - Dhiraj Tripathi
- The Liver Unit, University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Pierre-Emmanuel Rautou
- Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver)
- Service d'Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, DHU Unity, Pôle des Maladies de l'Appareil Digestif, Hôpital Beaujon, AP-HP, Clichy, France
| | - François Durand
- Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver)
- Service d'Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, DHU Unity, Pôle des Maladies de l'Appareil Digestif, Hôpital Beaujon, AP-HP, Clichy, France
| | - Juan Carlos García-Pagán
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain
- CIBEREHD (Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas)
- Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver)
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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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49
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Wang H, Wang ZL, Zhang S, Kong DJ, Yang RN, Cao L, Wang JX, Yoshida S, Song ZL, Liu T, Fan SL, Ren JS, Li JH, Shen ZY, Zheng H. Metronomic capecitabine inhibits liver transplant rejection in rats by triggering recipients’ T cell ferroptosis. World J Gastroenterol 2023; 29:3084-3102. [PMID: 37346150 PMCID: PMC10280797 DOI: 10.3748/wjg.v29.i20.3084] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Revised: 02/19/2023] [Accepted: 04/28/2023] [Indexed: 05/26/2023] Open
Abstract
BACKGROUND Capecitabine (CAP) is a classic antimetabolic drug and has shown potential antirejection effects after liver transplantation (LT) in clinical studies. Our previous study showed that metronomic CAP can cause the programmed death of T cells by inducing oxidative stress in healthy mice. Ferroptosis, a newly defined non-apoptotic cell death that occurs in response to iron overload and lethal levels of lipid peroxidation, is an important mechanism by which CAP induces cell death. Therefore, ferroptosis may also play an important role in CAP-induced T cell death and play an immunosuppressive role in acute rejection after trans-plantation.
AIM To investigate the functions and underlying mechanisms of antirejection effects of metronomic CAP.
METHODS A rat LT model of acute rejection was established, and the effect of metronomic CAP on splenic hematopoietic function and acute graft rejection was evaluated 7 d after LT. In vitro, primary CD3+ T cells were sorted from rat spleens and human peripheral blood, and co-cultured with or without 5-fluorouracil (5-FU) (active agent of CAP). The levels of ferroptosis-related proteins, ferrous ion concentration, and oxidative stress-related indicators were observed. The changes in mito-chondrial structure were observed using electron microscopy.
RESULTS With no significant myelotoxicity, metronomic CAP alleviated graft injury (Banff score 9 vs 7.333, P < 0.001), prolonged the survival time of the recipient rats (11.5 d vs 16 d, P < 0.01), and reduced the infiltration rate of CD3+ T cells in peripheral blood (6.859 vs 3.735, P < 0.001), liver graft (7.459 vs 3.432, P < 0.001), and spleen (26.92 vs 12.9, P < 0.001), thereby inhibiting acute rejection after LT. In vitro, 5-FU, an end product of CAP metabolism, induced the degradation of the ferritin heavy chain by upregulating nuclear receptor coactivator 4, which caused the accumulation of ferrous ions. It also inhibited nuclear erythroid 2 p45-related factor 2, heme oxygenase-1, and glutathione peroxidase 4, eventually leading to oxidative damage and ferroptosis of T cells.
CONCLUSION Metronomic CAP can suppress acute allograft rejection in rats by triggering CD3+ T cell ferroptosis, which makes it an effective immunosuppressive agent after LT.
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Affiliation(s)
- Hao Wang
- The First Central Clinical School, Tianjin Medical University, Tianjin 300190, China
| | - Zheng-Lu Wang
- Department of Organ Transplant, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300190, China
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300190, China
| | - Sai Zhang
- School of Medicine, Nankai University, Tianjin 300190, China
| | - De-Jun Kong
- School of Medicine, Nankai University, Tianjin 300190, China
| | - Rui-Ning Yang
- The First Central Clinical School, Tianjin Medical University, Tianjin 300190, China
| | - Lei Cao
- Research Institute of Transplant Medicine, Nankai University, Tianjin 300071, China
- Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300071, China
| | - Jian-Xi Wang
- Research Institute of Transplant Medicine, Nankai University, Tianjin 300071, China
- Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300071, China
| | - Sei Yoshida
- Research Institute of Transplant Medicine, Nankai University, Tianjin 300071, China
| | - Zhuo-Lun Song
- Department of Organ Transplant, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300190, China
| | - Tao Liu
- National Health Commission’s Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300071, China
| | - Shun-Li Fan
- Department of Organ Transplant, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300190, China
| | - Jia-Shu Ren
- The First Central Clinical School, Tianjin Medical University, Tianjin 300190, China
| | - Jiang-Hong Li
- The First Central Clinical School, Tianjin Medical University, Tianjin 300190, China
| | - Zhong-Yang Shen
- Department of Organ Transplant, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300190, China
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300190, China
- Research Institute of Transplant Medicine, Nankai University, Tianjin 300071, China
- Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300071, China
- National Health Commission’s Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300071, China
| | - Hong Zheng
- Department of Organ Transplant, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300190, China
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300190, China
- Research Institute of Transplant Medicine, Nankai University, Tianjin 300071, China
- Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300071, China
- National Health Commission’s Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300071, China
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50
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Leonard NB, Hale GL, Boylan KE, Ou Z, Zhang C, Kim R, Chandna S, Dong ZM, Evason KJ. Histologic features of allograft livers in patients treated for rejection before biopsy. Hum Pathol 2023; 135:11-21. [PMID: 36804507 PMCID: PMC10121875 DOI: 10.1016/j.humpath.2023.02.005] [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: 12/23/2022] [Revised: 02/04/2023] [Accepted: 02/13/2023] [Indexed: 02/19/2023]
Abstract
Liver biopsy is essential for management in liver transplant patients with clinical features suspicious for acute cellular rejection (ACR). As more patients are transplanted for noninfectious indications, it has become increasingly common for them to receive treatment for presumed ACR before biopsy. The effect of pretreatment on the classic histologic triad of ACR's mixed portal inflammation, endothelialitis, and bile duct damage is not well described. Here we report a retrospective study of 70 liver transplant biopsies performed on 53 patients for suspected ACR between 2018 and 2021. Thirty-seven biopsies had a clinical diagnosis of ACR after biopsy. Pretreatment with steroids, antithymocyte globulin, or other increased immunosuppression was given before biopsy in 17 of 37 cases; 20 not-pretreated cases acted as controls. A representative hematoxylin and eosin-stained slide from each biopsy was reviewed independently in a blinded fashion by 3 hepatic pathologists, graded according to the Banff system, assigned a Rejection Activity Index (RAI), and assessed for other histologic features. We found that pretreated biopsies had significantly less portal inflammation (P < .001), less endothelialitis (P < .001), lower RAI (P < .001), and less prominent eosinophils (P = .048) compared to not-pretreated biopsies. There was no significant difference for the other examined variables, including bile duct inflammation/damage (P = .32). Our findings suggest that portal inflammation and endothelialitis become less prominent with pretreatment, whereas bile duct inflammation/damage may take longer to resolve. When evaluating biopsies for suspected ACR, the finding of bile duct inflammation/damage should raise the possibility of partially treated ACR, even in the absence of endothelialitis and portal inflammation.
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Affiliation(s)
- Nicole B Leonard
- Department of Pathology, University of Utah, Salt Lake City, UT, 84112, USA
| | - Gillian L Hale
- Department of Pathology, University of Utah, Salt Lake City, UT, 84112, USA
| | - Katherine E Boylan
- Department of Pathology, University of Utah, Salt Lake City, UT, 84112, USA
| | - Zhining Ou
- Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, UT, 84132, USA
| | - Chong Zhang
- Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, UT, 84132, USA
| | - Robin Kim
- Department of Surgery, University of Utah, Salt Lake City, UT, 84132, USA
| | - Shaun Chandna
- Department of Internal Medicine, Division of Gastroenterology, Hepatology, And Nutrition, University of Utah, Salt Lake City, UT, 84132, USA
| | - Zachary M Dong
- Department of Pathology, University of Utah, Salt Lake City, UT, 84112, USA
| | - Kimberley J Evason
- Department of Pathology, University of Utah, Salt Lake City, UT, 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA.
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