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1
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Kim J, Hong SK, Kim JY, Lee J, Choi HH, Kim M, Kim Y, Hong SY, Lee JM, Choi Y, Yi NJ, Lee KW, Suh KS. Impact of Preformed Donor-specific Antibodies in Comparison to ABO Incompatibility in Living Donor Liver Transplantation: A Propensity Score-Matched Analysis. Transplantation 2024; 108:e229-e238. [PMID: 38548705 DOI: 10.1097/tp.0000000000005019] [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: 08/22/2024]
Abstract
BACKGROUND Immunological factors play a pivotal role in the outcomes of solid organ transplantation. We aimed to elucidate the effects of donor-specific antibodies (DSAs) and ABO compatibility on living donor liver transplantation (LDLT) outcomes. METHODS A retrospective analysis was conducted on 584 LDLT recipients from 2015 to 2020. The recipients were stratified into 3 groups: ABO-compatible recipients without DSAs (group 1), ABO-compatible recipients with DSAs (group 2), and ABO-incompatible recipients without DSAs (group 3). Propensity score matching was used for balanced comparisons. RESULTS In the matched comparisons, group 2 exhibited a higher incidence of T cell-mediated rejection compared with group 1 (22.7% versus 4.5%, P = 0.030). Despite this, the 5-y survival rates were similar between groups 1 and 2 (81.6% versus 95.5%, P = 0.085). Group 3, in comparison with group 1, showed elevated rates of cytomegalovirus infection (23.2% versus 7.3%, P = 0.008), T cell-mediated rejection (28.0% versus 7.3%, P = 0.001), and antibody-mediated rejection (13.4% versus 0%, P = 0.001). However, the survival rates were comparable between group 3 and group 1 (82.0% versus 86.5%, P = 0.220, respectively). Comparisons between group 2 and group 3 did not reveal significant differences in postoperative outcomes or survival rates ( P > 0.05). CONCLUSIONS DSA positivity and ABO incompatibility contribute to distinct posttransplant complications in LDLT. The integrated consideration of both factors in pretransplant assessment may enhance risk stratification and inform tailored interventions. Further research is required to corroborate these findings and provide mechanistic insights.
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Affiliation(s)
- Jiyoung Kim
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
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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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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. SCIENCE ADVANCES 2024; 10:eadm8841. [PMID: 38608023 PMCID: PMC11014454 DOI: 10.1126/sciadv.adm8841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 03/12/2024] [Indexed: 04/14/2024]
Abstract
Allograft rejection is common following clinical organ transplantation, but defining specific immune subsets mediating alloimmunity has been elusive. Calcineurin inhibitor dose escalation, corticosteroids, and/or lymphocyte depleting antibodies have remained the primary options for treatment of clinical rejection episodes. Here, we developed a highly multiplexed imaging mass cytometry panel to study the immune response in archival biopsies from 79 liver transplant (LT) recipients with 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 (42 phenotypes) derived from 96 pathologist-selected regions of interest. Our analysis revealed that regulatory (HLADR+ Treg) and PD1+ T cell phenotypes (CD4+ and CD8+ subsets), combined with variations in M2 macrophage polarization, were a unique signature of active TCMR. These data provide insights into the alloimmune microenvironment in clinical LT, including identification of potential targets for focused immunotherapy during rejection episodes and suggestion of a substantial role for immune exhaustion in TCMR.
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Affiliation(s)
- Arianna Barbetta
- Division of Abdominal Organ Transplantation and Hepatobiliary Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Brittany Rocque
- Division of Abdominal Organ Transplantation and Hepatobiliary Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Sarah Bangerth
- Division of Abdominal Organ Transplantation and Hepatobiliary Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Kelly Street
- Division of Biostatistics, Department of Population and Public Health, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Carly Weaver
- Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital Los Angeles, Los Angeles, CA, USA
| | - Shefali Chopra
- Department of Pathology, University of Southern California, Los Angeles, CA, USA
| | - Janet Kim
- Division of Abdominal Organ Transplantation and Hepatobiliary Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Linda Sher
- Division of Abdominal Organ Transplantation and Hepatobiliary Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Brice Gaudilliere
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Omid Akbari
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Rohit Kohli
- Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital Los Angeles, Los Angeles, CA, USA
- Division of Abdominal Organ Transplantation, Children’s Hospital Los Angeles, Los Angeles, CA, USA
| | - Juliet Emamaullee
- Division of Abdominal Organ Transplantation and Hepatobiliary Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Division of Abdominal Organ Transplantation, Children’s Hospital Los Angeles, Los Angeles, CA, USA
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4
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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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5
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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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Merola J, Emond JC, Levitsky J. Novel Noninvasive Biomarkers in Liver Transplantation: A Tool on the Doorstep of Clinical Utilization. Transplantation 2023; 107:2120-2125. [PMID: 37019173 DOI: 10.1097/tp.0000000000004580] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/07/2023]
Abstract
Biomarkers have the potential to transform the detection, treatment, and outcomes of liver transplant complications, though their application is limited because of the lack of prospective validation. Although many genetic, proteomic, and immune markers correlating with allograft rejection and graft dysfunction have been described, evaluation of these markers in combination and validation among a broad liver transplant recipient population remain understudied. In this review, we present evidence supporting biomarker applications in 5 clinical liver transplant scenarios: (i) diagnosis of allograft rejection, (ii) prediction of allograft rejection, (iii) minimization of immunosuppression, (iv) detection of fibrosis and recurrent disease, and (v) prediction of renal recovery following liver transplantation. Current limitations for biomarker utilization and opportunities for further investigation are discussed. Accurate risk assessment, diagnosis, and evaluation of treatment responses using such noninvasive tools will pave the way for a more personalized and precise approach to management of the liver transplant patients that has profound potential to reduce morbidity and improve graft and patient longevity.
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Affiliation(s)
- Jonathan Merola
- Center for Liver Disease and Transplantation, Columbia University Medical Center, New York, NY
| | - Jean C Emond
- Center for Liver Disease and Transplantation, Columbia University Medical Center, New York, NY
| | - Josh Levitsky
- Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, IL
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7
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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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8
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Mugaanyi J, Tong J, Lu C, Mao S, Huang J, Lu C. Risk factors for acute rejection in liver transplantation and its impact on the outcomes of recipients. Transpl Immunol 2023; 76:101767. [PMID: 36470573 DOI: 10.1016/j.trim.2022.101767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 10/10/2022] [Accepted: 11/28/2022] [Indexed: 12/03/2022]
Abstract
OBJECTIVE To determine the risk factors for acute rejection in liver transplantation and its impact on the outcomes of the recipients. METHODS Clinicopathological data of 290 patients who underwent liver transplantation from January 2012 to December 2021 at our center were retrospectively evaluated. Patients were grouped into an acute rejection (AR) group and a normal (NM) group based on the confirmed histopathological diagnosis of acute rejection. Univariate and multivariate logistic regression were used to determine the risk factors for acute rejection. RESULTS 244 patients were included in the study. Acute rejection occurred in 27 (11.1%) of the patients. Warm ischemia time (P = 0.137), cold ischemia time (P = 0.064) and chronic liver failure (P = 0.001) were potential risk factors for acute rejection. Chronic liver failure (P < 0.001, OR = 8.22, 95% CI = 2.47-27.32) was the independent risk factor. There was no significant difference in overall survival between recipients with acute rejection and those without it (P = 0.985). The 1-, 3- and 5-year overall survival in the NM group was 98.1%, 85.7% and 78.6% respectively vs 88.9%, 82.5% and 82.5% respectively in the AR group. CONCLUSION Acute rejection does not appear to affect the long-term survival of the recipients. Only chronic liver failure was an independent risk factor for acute rejection. Our findings further illustrate that contradictions still exist on which factors influence acute rejection in liver transplant recipients. SUMMARY Clinicopathological data of 290 liver transplant recipients at our center between January 2012 and December 2021 were retrospectively evaluated to determine the risk factors for acute rejection and its impact on the outcomes of the recipients. 244 patients were included in the analysis. 27 of the 244 experienced acute rejection. Propensity score matching was performed to reduce the confounding effect. Patients were assigned to an acute rejection group (n = 27) and a normal group (n = 54). Chronic liver failure (P < 0.001, OR = 8.22, 95% CI = 2.47-27.32) was the determined to be independent risk factor for acute rejection. Acute rejection did not appear to affect the long-term survival of the recipients and there was no significant difference in overall survival between the patients with acute rejection and those without it.
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Affiliation(s)
- Joseph Mugaanyi
- Medical School of Ningbo University, Ningbo, Zhejiang, China; Department of Hepato-Pancreato-Biliary Surgery, Ningbo Medical Center Lihuili Hospital, The affiliated hospital of Ningbo University, Ningbo, Zhejiang, China.
| | - Jinshu Tong
- Department of Hepato-Pancreato-Biliary Surgery, Ningbo Medical Center Lihuili Hospital, The affiliated hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Changjiang Lu
- Department of Hepato-Pancreato-Biliary Surgery, Ningbo Medical Center Lihuili Hospital, The affiliated hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Shuqi Mao
- Department of Hepato-Pancreato-Biliary Surgery, Ningbo Medical Center Lihuili Hospital, The affiliated hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Jing Huang
- Department of Hepato-Pancreato-Biliary Surgery, Ningbo Medical Center Lihuili Hospital, The affiliated hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Caide Lu
- Department of Hepato-Pancreato-Biliary Surgery, Ningbo Medical Center Lihuili Hospital, The affiliated hospital of Ningbo University, Ningbo, Zhejiang, China.
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9
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Taner T, Bruner J, Emaumaullee J, Bonaccorsi-Riani E, Zarrinpar A. New Approaches to the Diagnosis of Rejection and Prediction of Tolerance in Liver Transplantation. Transplantation 2022; 106:1952-1962. [PMID: 35594482 PMCID: PMC9529763 DOI: 10.1097/tp.0000000000004160] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Immunosuppression after liver transplantation is essential for preventing allograft rejection. However, long-term drug toxicity and associated complications necessitate investigation of immunosuppression minimization and withdrawal protocols. Development of such protocols is hindered by reliance on current paradigms for monitoring allograft function and rejection status. The current standard of care for diagnosis of rejection is histopathologic assessment and grading of liver biopsies in accordance with the Banff Rejection Activity Index. However, this method is limited by cost, sampling variability, and interobserver variation. Moreover, the invasive nature of biopsy increases the risk of patient complications. Incorporating noninvasive techniques may supplement existing methods through improved understanding of rejection causes, hepatic spatial architecture, and the role of idiopathic fibroinflammatory regions. These techniques may also aid in quantification and help integrate emerging -omics analyses with current assessments. Alternatively, emerging noninvasive methods show potential to detect and distinguish between different types of rejection while minimizing risk of adverse advents. Although biomarkers have yet to replace biopsy, preliminary studies suggest that several classes of analytes may be used to detect rejection with greater sensitivity and in earlier stages than traditional methods, possibly when coupled with artificial intelligence. Here, we provide an overview of the latest efforts in optimizing the diagnosis of rejection in liver transplantation.
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Affiliation(s)
- Timucin Taner
- Departments of Surgery & Immunology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Julia Bruner
- Department of Surgery, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Juliet Emaumaullee
- Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Eliano Bonaccorsi-Riani
- Abdominal Transplant Unit, Cliniques Universitaires Saint Luc, Université Catholique de Louvain, Brussels, Belgium
| | - Ali Zarrinpar
- Department of Surgery, College of Medicine, University of Florida, Gainesville, FL, USA
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10
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The Role of Immunosuppression for Recurrent Cholangiocellular Carcinoma after Liver Transplantation. Cancers (Basel) 2022; 14:cancers14122890. [PMID: 35740555 PMCID: PMC9221145 DOI: 10.3390/cancers14122890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 06/02/2022] [Accepted: 06/06/2022] [Indexed: 02/04/2023] Open
Abstract
Liver transplantation (LT) for cholangiocarcinoma (CCA), or biliary tract cancer (BTC), remains controversial regarding high recurrence rates and poor prognosis. Oncological follow-up may benefit from tumor-inhibiting properties of mTOR inhibitors (mTORI), shown with improved survival for recurrent hepatocellular carcinoma (HCC) patients after LT. The aim of this study was to investigate the recurrence and survival in relation to tumor type and type of immunosuppression (IS). LT patients with CCA or mixed HCC/CCA (mHCC/CCA) (n = 67) were retrospectively analyzed. Endpoints were the time from LT to recurrence (n = 44) and survival after recurrence. Statistically significant impairment in survival for recurrent CCA (rCCA) was shown in patients not eligible for surgical resection (HR 2.46 (CI: 1.2−5.1; p = 0.02). Histological proven grading >1 and N1 status at initial transplantation were associated with impaired survival (HR 0.13 (CI: 0.03−0.58); p < 0.01 and HR 3.4 (CI: 1.0−11.65); p = 0.05). Reduced IS after tumor recurrence improved survival (HR 4.2/CI: 1.3−13.6; p = 0.02). MTORI initiation before recurrence or after had no significant impact on survival. Our data thereby indicate, similar to findings in recurrent HCC after LT, that patients with rCCA after LT benefit from a reduction in IS upon recurrence.
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11
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Wu WK, Tumen A, Stokes JW, Ukita R, Hozain A, Pinezich M, O'Neill JD, Lee MJ, Reimer JA, Flynn CR, Talackine JR, Cardwell NL, Benson C, Vunjak-Novakovic G, Alexopoulos SP, Bacchetta M. Cross-Circulation for Extracorporeal Liver Support in a Swine Model. ASAIO J 2022; 68:561-570. [PMID: 34352819 PMCID: PMC9984766 DOI: 10.1097/mat.0000000000001543] [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] [Indexed: 11/26/2022] Open
Abstract
Although machine perfusion has gained momentum as an organ preservation technique in liver transplantation, persistent organ shortages and high waitlist mortality highlight unmet needs for improved organ salvage strategies. Beyond preservation, extracorporeal organ support platforms can also aid the development and evaluation of novel therapeutics. Here, we report the use of veno-arterial-venous (V-AV) cross-circulation (XC) with a swine host to provide normothermic support to extracorporeal livers. Functional, biochemical, and morphological analyses of the extracorporeal livers and swine hosts were performed over 12 hours of support. Extracorporeal livers maintained synthetic function through alkaline bile production and metabolic activity through lactate clearance and oxygen consumption. Beyond initial reperfusion, no biochemical evidence of hepatocellular injury was observed. Histopathologic injury scoring showed improvements in sinusoidal dilatation and composite acute injury scores after 12 hours. Swine hosts remained hemodynamically stable throughout XC support. Altogether, these outcomes demonstrate the feasibility of using a novel V-AV XC technique to provide support for extracorporeal livers in a swine model. V-AV XC has potential applications as a translational research platform and clinical biotechnology for donor organ salvage.
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Affiliation(s)
- Wei Kelly Wu
- From the Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Andrew Tumen
- From the Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - John W Stokes
- From the Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Rei Ukita
- From the Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Ahmed Hozain
- Department of Surgery, Columbia University Medical Center, New York, New York
- Department of Biomedical Engineering, Columbia University, New York, New York
| | - Meghan Pinezich
- Department of Biomedical Engineering, Columbia University, New York, New York
| | - John D O'Neill
- Department of Biomedical Engineering, Columbia University, New York, New York
- Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York City
| | - Michael J Lee
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York
| | - Jonathan A Reimer
- Department of Surgery, Columbia University Medical Center, New York, New York
- Department of Biomedical Engineering, Columbia University, New York, New York
| | - Charles R Flynn
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jennifer R Talackine
- From the Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Nancy L Cardwell
- From the Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Clayne Benson
- Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Gordana Vunjak-Novakovic
- Department of Biomedical Engineering, Columbia University, New York, New York
- Department of Medicine, Columbia University, New York, New York
| | - Sophoclis P Alexopoulos
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Matthew Bacchetta
- From the Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
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12
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Ung N, Goldbeck C, Man C, Hoeflich J, Sun R, Barbetta A, Matasci N, Katz J, Lee JSH, Chopra S, Asgharzadeh S, Warren M, Sher L, Kohli R, Akbari O, Genyk Y, Emamaullee J. Adaptation of Imaging Mass Cytometry to Explore the Single Cell Alloimmune Landscape of Liver Transplant Rejection. Front Immunol 2022; 13:831103. [PMID: 35432320 PMCID: PMC9009043 DOI: 10.3389/fimmu.2022.831103] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 03/08/2022] [Indexed: 12/14/2022] Open
Abstract
Rejection continues to be an important cause of graft loss in solid organ transplantation, but deep exploration of intragraft alloimmunity has been limited by the scarcity of clinical biopsy specimens. Emerging single cell immunoprofiling technologies have shown promise in discerning mechanisms of autoimmunity and cancer immunobiology. Within these applications, Imaging Mass Cytometry (IMC) has been shown to enable highly multiplexed, single cell analysis of immune phenotypes within fixed tissue specimens. In this study, an IMC panel of 10 validated markers was developed to explore the feasibility of IMC in characterizing the immune landscape of chronic rejection (CR) in clinical tissue samples obtained from liver transplant recipients. IMC staining was highly specific and comparable to traditional immunohistochemistry. A single cell segmentation analysis pipeline was developed that enabled detailed visualization and quantification of 109,245 discrete cells, including 30,646 immune cells. Dimensionality reduction identified 11 unique immune subpopulations in CR specimens. Most immune subpopulations were increased and spatially related in CR, including two populations of CD45+/CD3+/CD8+ cytotoxic T-cells and a discrete CD68+ macrophage population, which were not observed in liver with no rejection (NR). Modeling via principal component analysis and logistic regression revealed that single cell data can be utilized to construct statistical models with high consistency (Wilcoxon Rank Sum test, p=0.000036). This study highlights the power of IMC to investigate the alloimmune microenvironment at a single cell resolution during clinical rejection episodes. Further validation of IMC has the potential to detect new biomarkers, identify therapeutic targets, and generate patient-specific predictive models of clinical outcomes in solid organ transplantation.
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Affiliation(s)
- Nolan Ung
- Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, United States
| | - Cameron Goldbeck
- Division of Hepatobiliary and Abdominal Organ Transplant Surgery, Department of Surgery, University of Southern California, Los Angeles, CA, United States
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Cassandra Man
- Division of Hepatobiliary and Abdominal Organ Transplant Surgery, Department of Surgery, University of Southern California, Los Angeles, CA, United States
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Julianne Hoeflich
- Division of Hepatobiliary and Abdominal Organ Transplant Surgery, Department of Surgery, University of Southern California, Los Angeles, CA, United States
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Ren Sun
- Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, United States
| | - Arianna Barbetta
- Division of Hepatobiliary and Abdominal Organ Transplant Surgery, Department of Surgery, University of Southern California, Los Angeles, CA, United States
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Naim Matasci
- Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, United States
| | - Jonathan Katz
- Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, United States
| | - Jerry S. H. Lee
- Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, United States
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Chemical Engineering and Material Sciences, University of Southern California, Los Angeles, CA, United States
| | - Shefali Chopra
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Pathology, University of Southern California, Los Angeles, CA, United States
| | - Shahab Asgharzadeh
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Pediatrics, Children’s Hospital-Los Angeles, Los Angeles, CA, United States
| | - Mika Warren
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Pathology, Children’s Hospital-Los Angeles, Los Angeles, CA, United States
| | - Linda Sher
- Division of Hepatobiliary and Abdominal Organ Transplant Surgery, Department of Surgery, University of Southern California, Los Angeles, CA, United States
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Rohit Kohli
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Pediatrics, Children’s Hospital-Los Angeles, Los Angeles, CA, United States
| | - Omid Akbari
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, United States
| | - Yuri Genyk
- Division of Hepatobiliary and Abdominal Organ Transplant Surgery, Department of Surgery, University of Southern California, Los Angeles, CA, United States
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Juliet Emamaullee
- Division of Hepatobiliary and Abdominal Organ Transplant Surgery, Department of Surgery, University of Southern California, Los Angeles, CA, United States
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, United States
- *Correspondence: Juliet Emamaullee,
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13
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Vannas M, Arola J, Nordin A, Isoniemi H. Value of posttransplant protocol biopsies in 2 biliary autoimmune liver diseases: A step toward personalized immunosuppressive treatment. Medicine (Baltimore) 2022; 101:e28509. [PMID: 35029206 PMCID: PMC8758011 DOI: 10.1097/md.0000000000028509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 12/17/2021] [Indexed: 01/05/2023] Open
Abstract
The value of protocol liver graft biopsies with good liver function was evaluated in patients with primary sclerosing cholangitis (PSC) or primary biliary cholangitis (PBC).A total of 250 protocol liver biopsy reports from 182 PSC and PBC patients were compared. Overall histopathological findings and those leading to changes in immunosuppression therapy were retrospectively analyzed.The mean time to first protocol biopsy after transplantation was 5.5 (±4.5) years for PSC patients and 9.3 (±6.6) years for PBC patients. More than 1 abnormal histopathological parameter was found in 43% and 62% of PSC and PBC patients, respectively. However, the histology was interpreted as normal by the pathologist in 78% of PSC and 60% of PBC patients. Immunosuppression therapy was reduced in 10% and increased in 6% patients due to protocol biopsy findings. Biopsies leading to increased immunosuppression therapy had more portal (P = .004), endothelial (P = .008), interphase (P = .021), and lobular (P = .000) inflammation.Mild histopathological findings were frequently found in the protocol biopsies despite the normal biochemistry. PBC patients had more histological abnormalities than those transplanted due to PSC; however, PBC patients had longer follow-up times. Immunosuppression therapy could be safely increased or decreased according to protocol biopsy findings after multidisciplinary meeting discussions.
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Affiliation(s)
- Marko Vannas
- Transplantation and Liver Surgery, Abdominal Centre, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Johanna Arola
- Department of Pathology, HUH Diagnostic Centre, Helsinki University Hospital and University of Helsinki, Finland
| | - Arno Nordin
- Transplantation and Liver Surgery, Abdominal Centre, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Helena Isoniemi
- Transplantation and Liver Surgery, Abdominal Centre, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
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14
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Gül-Klein S, Hegermann H, Röhle R, Schmelzle M, Tacke F, Schöning W, Öllinger R, Dziodzio T, Maier P, Plewe JM, Horst D, Sauer IM, Pratschke J, Lachmann N, Eurich D. Donor-Specific Antibodies Against Donor Human Leukocyte Antigen are Associated with Graft Inflammation but Not with Fibrosis Long-Term After Liver Transplantation: An Analysis of Protocol Biopsies. J Inflamm Res 2021; 14:2697-2712. [PMID: 34188517 PMCID: PMC8236257 DOI: 10.2147/jir.s307778] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 05/04/2021] [Indexed: 02/06/2023] Open
Abstract
Background Donor-specific antibodies (DSA) against donor human leukocyte antigen after liver transplantation, which are associated with histological changes, have been widely studied with respect to their sustained impact on transplant function. However, their long-term impact after liver transplantation remains unclear. Methods We performed a cross-sectional analysis from June 2016 to July 2017 that included all patients who presented themselves for scheduled follow-up after receiving a liver transplantation between September 1989 and December 2016. In addition to a liver protocol biopsy, patients were screened for human leukocyte antigen antibodies (HLAab) and donor-specific antibodies. Subsequently, the association between human leukocyte antigen antibodies, donor-specific antibodies, histologic and clinical features, and immunosuppression was analyzed. Results Analysis for human leukocyte antigen antibodies and donor-specific antibodies against donor human leukocyte antigen was performed for 291 and 271 patients. A significant association between higher inflammation grades and the presence of human leukocyte antigen antibodies and donor-specific antibodies was detected, while fibrosis stages remained unaffected. These results were confirmed by multivariate logistic regression for inflammation showing a significant increase for presence of human leukocyte antigen antibodies and donor-specific antibodies (OR: 4.43; 95% CI: 1.67–12.6; p=0.0035). Furthermore, the use of everolimus in combination with tacrolimus was significantly associated with the status of negative human leukocyte antigen antibodies and donor-specific antibodies. Viral etiology for liver disease, hepatocellular carcinoma (HCC) and higher steatosis grades of the graft were significantly associated with a lower rate of human leukocyte antigen antibodies. The impact of human leukocyte antigen antibodies and donor-specific antibodies against donor human leukocyte antigen was associated with higher levels of laboratory parameters, such as transaminases and bilirubin. Conclusion Donor-specific antibodies against donor human leukocyte antigen are associated with histological and biochemical graft inflammation after liver transplantation, while fibrosis seems to be unaffected. Future studies should validate these findings for longer observation periods and specific subgroups.
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Affiliation(s)
- Safak Gül-Klein
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Henriette Hegermann
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Robert Röhle
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Biometry and Clinical Epidemiology, Berlin, Germany.,Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Coordinating Center for Clinical Studies, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany
| | - Moritz Schmelzle
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Frank Tacke
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Hepatology & Gastroenterology, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Wenzel Schöning
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Robert Öllinger
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Tomasz Dziodzio
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Patrick Maier
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Julius M Plewe
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - David Horst
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Igor Maximilian Sauer
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Biometry and Clinical Epidemiology, Berlin, Germany
| | - Johann Pratschke
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Nils Lachmann
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, HLA Laboratory, Institute of Transfusion Medicine, Histocompatibility and Immunogenetics, Charité - Universitätsmedizin, Berlin, Germany
| | - Dennis Eurich
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
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15
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D’AMBROSIO D, TAVANO D, LATTANZI B, FRAMARINO DEI MALATESTA M, DE VILLE DE GOYET J, CORSI A, MITTERHOFER AP, GINANNI CORRADINI S, MENNINI G, ROSSI M, MERLI M. Acute rejection on immune-mediated chronic rejection after liver transplantation. GAZZETTA MEDICA ITALIANA ARCHIVIO PER LE SCIENZE MEDICHE 2021. [DOI: 10.23736/s0393-3660.19.04240-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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16
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DSA Are Associated With More Graft Injury, More Fibrosis, and Upregulation of Rejection-associated Transcripts in Subclinical Rejection. Transplantation 2020; 104:551-561. [PMID: 31651790 DOI: 10.1097/tp.0000000000003034] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND Subclinical T cell-mediated rejection (subTCMR) is commonly found after liver transplantation and has a good short-term prognosis, even when it is left untreated. Donor-specific antibodies (DSA) are putatively associated with a worse prognosis for recipient and graft after liver transplantation. METHODS To assess the immune regulation in subTCMR grafts, gene expression of 93 transcripts for graft injury, tolerance, and immune regulation was analyzed in 77 biopsies with "no histologic rejection" (NHR; n = 25), "clinical TCMR" (cTMCR; n = 16), and subTCMR (n = 36). In addition, all available subTCMR biopsies (n = 71) were tested for DSA with bead assays. RESULTS SubTCMR showed heterogeneous and intermediate expression profiles of transcripts that were upregulated in cTCMR. Graft gene expression suggested a lower activation of effector lymphocytes and a higher activation of regulatory T cells in grafts with subTCMR compared to cTCMR. DSA positivity in subTCMR was associated with histological evidence of more severe graft inflammation and fibrosis. This more severe DSA+ associated graft injury in subTCMR was converged with an upregulation of cTCMR-associated transcripts. In nonsupervised analysis, DSA positive subTCMR mostly clustered together with cTCMR, while DSA negative subTCMR clustered together with NHR. CONCLUSIONS T cell-mediated rejection seems to form a continuum of alloimmune activation. Although subTCMR exhibited less expression of TCMR-associated transcript, DSA positivity in subTCMR was associated with an upregulation of rejection-associated transcripts. The identification of DSA positive subclinical rejection might help to define patients with more inflammation in the graft and development of fibrosis.
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17
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Ronca V, Wootton G, Milani C, Cain O. The Immunological Basis of Liver Allograft Rejection. Front Immunol 2020; 11:2155. [PMID: 32983177 PMCID: PMC7492390 DOI: 10.3389/fimmu.2020.02155] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 08/07/2020] [Indexed: 12/15/2022] Open
Abstract
Liver allograft rejection remains a significant cause of morbidity and graft failure in liver transplant recipients. Rejection is caused by the recognition of non-self donor alloantigens by recipient T-cells. Antigen recognition results in proliferation and activation of T-cells in lymphoid tissue before migration to the allograft. Activated T-cells have a variety of effector mechanisms including direct T-cell mediated damage to bile ducts, endothelium and hepatocytes and indirect effects through cytokine production and recruitment of tissue-destructive inflammatory cells. These effects explain the histological appearances of typical acute T-cell mediated rejection. In addition, donor specific antibodies, most typically against HLA antigens, may give rise to antibody-mediated rejection causing damage to the allograft primarily through endothelial injury. However, as an immune-privileged site there are several mechanisms in the liver capable of overcoming rejection and promoting tolerance to the graft, particularly in the context of recruitment of regulatory T-cells and promotors of an immunosuppressive environment. Indeed, around 20% of transplant recipients can be successfully weaned from immunosuppression. Hence, the host immunological response to the liver allograft is best regarded as a balance between rejection-promoting and tolerance-promoting factors. Understanding this balance provides insight into potential mechanisms for novel anti-rejection therapies.
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Affiliation(s)
- Vincenzo Ronca
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy.,National Institute of Health Research Liver Biomedical Research Unit Birmingham, Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Grace Wootton
- National Institute of Health Research Liver Biomedical Research Unit Birmingham, Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Chiara Milani
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
| | - Owen Cain
- Department of Cellular Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
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18
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Goh SK, Do H, Testro A, Pavlovic J, Vago A, Lokan J, Jones RM, Christophi C, Dobrovic A, Muralidharan V. The Measurement of Donor-Specific Cell-Free DNA Identifies Recipients With Biopsy-Proven Acute Rejection Requiring Treatment After Liver Transplantation. Transplant Direct 2019; 5:e462. [PMID: 31334336 PMCID: PMC6616138 DOI: 10.1097/txd.0000000000000902] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 03/15/2019] [Accepted: 03/28/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Assessment of donor-specific cell-free DNA (dscfDNA) in the recipient is emerging as a noninvasive biomarker of organ rejection after transplantation. We previously developed a digital polymerase chain reaction (PCR)-based approach that readily measures dscfDNA within clinically relevant turnaround times. Using this approach, we characterized the dynamics and evaluated the clinical utility of dscfDNA after liver transplantation (LT). METHODS Deletion/insertion polymorphisms were used to distinguish donor-specific DNA from recipient-specific DNA. Posttransplant dscfDNA was measured in the plasma of the recipients. In the longitudinal cohort, dscfDNA was serially measured at days 3, 7, 14, 28, and 42 in 20 recipients. In the cross-sectional cohort, dscfDNA was measured in 4 clinically stable recipients (>1-y posttransplant) and 16 recipients (>1-mo posttransplant) who were undergoing liver biopsies. RESULTS Recipients who underwent LT without complications demonstrated an exponential decline in dscfDNA. Median levels at days 3, 7, 14, 28, and 42 were 1936, 1015, 247, 90, and 66 copies/mL, respectively. dscfDNA was higher in recipients with treated biopsy-proven acute rejection (tBPAR) when compared to those without. The area under the receiver operator characteristic curve of dscfDNA was higher than that of routine liver function tests for tBPAR (dscfDNA: 98.8% with 95% confidence interval, 95.8%-100%; alanine aminotransferase: 85.7%; alkaline phosphatase: 66.4%; gamma-glutamyl transferase: 80.1%; and bilirubin: 35.4%). CONCLUSIONS dscfDNA as measured by probe-free droplet digital PCR methodology was reflective of organ health after LT. Our findings demonstrate the potential utility of dscfDNA as a diagnostic tool of tBPAR.
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Affiliation(s)
- Su Kah Goh
- Department of Surgery, The University of Melbourne, Austin Health, Heidelberg, VIC, Australia
- Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia
| | - Hongdo Do
- Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia
- School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia
- Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, Australia
| | - Adam Testro
- Liver Transplant Unit, Austin Health, Heidelberg, VIC, Australia
- Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, VIC, Australia
| | - Julie Pavlovic
- Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, Australia
| | - Angela Vago
- Liver Transplant Unit, Austin Health, Heidelberg, VIC, Australia
| | - Julie Lokan
- Department of Anatomical Pathology, Austin Health, Heidelberg, VIC, Australia
| | - Robert M. Jones
- Department of Surgery, The University of Melbourne, Austin Health, Heidelberg, VIC, Australia
- Liver Transplant Unit, Austin Health, Heidelberg, VIC, Australia
- Hepato-Pancreato-Biliary & Transplant Surgery Unit, Austin Health, Heidelberg, VIC, Australia
| | - Christopher Christophi
- Department of Surgery, The University of Melbourne, Austin Health, Heidelberg, VIC, Australia
- Liver Transplant Unit, Austin Health, Heidelberg, VIC, Australia
- Hepato-Pancreato-Biliary & Transplant Surgery Unit, Austin Health, Heidelberg, VIC, Australia
| | - Alexander Dobrovic
- Department of Surgery, The University of Melbourne, Austin Health, Heidelberg, VIC, Australia
- Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia
- School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia
- Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, Australia
| | - Vijayaragavan Muralidharan
- Department of Surgery, The University of Melbourne, Austin Health, Heidelberg, VIC, Australia
- Liver Transplant Unit, Austin Health, Heidelberg, VIC, Australia
- Hepato-Pancreato-Biliary & Transplant Surgery Unit, Austin Health, Heidelberg, VIC, Australia
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19
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Jadlowiec CC, Morgan PE, Nehra AK, Hathcock MA, Kremers WK, Heimbach JK, Wiesner RH, Taner T. Not All Cellular Rejections Are the Same: Differences in Early and Late Hepatic Allograft Rejection. Liver Transpl 2019; 25:425-435. [PMID: 30615251 DOI: 10.1002/lt.25411] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 12/19/2018] [Indexed: 12/13/2022]
Abstract
T cell-mediated rejection (TCMR) is common after liver transplantation (LT), and it is often thought to have a minimum impact on outcomes. Because alloimmune response changes over time, we investigated the role of the timing of TCMR on patient and allograft survival and examined the risk factors for early and late TCMR. We reviewed protocol liver biopsies for 787 consecutive LT recipients with an 8.6-year follow-up. The incidence of early TCMR (≤6 weeks after LT) was 33.5% with nonalcoholic steatohepatitis patients having the lowest incidence. Younger recipient age (P < 0.01), number of human leukocyte antigen mismatches (P < 0.01), and use of deceased donor allografts (P = 0.01) were associated with increased risk of early TCMR, which had no impact on allograft (hazard ratio [HR], 1.02; 95% CI, 0.79-1.32; P = 0.89) or overall survival (HR, 1.03; 95% CI, 0.78-1.34; P = 0.86). Late TCMR (>6 weeks after LT) was less common (17.7%) and was associated with different risk factors. The majority of late TCMR (56.2%) episodes had no antecedent early TCMR, although moderate-to-severe early TCMR (HR, 2.85; 95% CI, 1.55-5.23; P < 0.01) and steroid resistance (HR, 3.62; 95% CI, 1.87-6.99; P < 0.01) were associated with late TCMR. Late TCMR increased risk of mortality (HR, 1.89; 95% CI, 1.35-2.65; P = 0.001) and graft loss (HR, 1.71; 95% CI, 1.23-2.37; P = 0.001). Thus, these data suggest that the timing and histologic grade of TCMR determine its impact on patient and allograft survival. Early mild TCMR episodes after LT do not adversely impact patient or allograft survival provided that they are adequately treated. The occurrence of late TCMR carries deleterious effects with increased longterm risk of graft loss and decreased survival. Patients with moderate-to-severe early TCMR are at an increased risk for late TCMR and warrant closer clinical follow-up.
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Affiliation(s)
| | - Paige E Morgan
- William J. von Liebig Center for Transplantation, Mayo Clinic, Rochester, MN
| | - Avinash K Nehra
- William J. von Liebig Center for Transplantation, Mayo Clinic, Rochester, MN
| | - Matthew A Hathcock
- William J. von Liebig Center for Transplantation, Mayo Clinic, Rochester, MN
| | - Walter K Kremers
- William J. von Liebig Center for Transplantation, Mayo Clinic, Rochester, MN
| | - Julie K Heimbach
- William J. von Liebig Center for Transplantation, Mayo Clinic, Rochester, MN
| | - Russell H Wiesner
- William J. von Liebig Center for Transplantation, Mayo Clinic, Rochester, MN
| | - Timucin Taner
- William J. von Liebig Center for Transplantation, Mayo Clinic, Rochester, MN
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20
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Jang JK, Kim KW, Choi SH, Jeong SY, Kim JH, Yu ES, Kwon JH, Song GW, Lee SG. CT of acute rejection after liver transplantation: a matched case-control study. Eur Radiol 2019; 29:3736-3745. [PMID: 30707276 DOI: 10.1007/s00330-018-5971-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 12/04/2018] [Accepted: 12/13/2018] [Indexed: 12/19/2022]
Abstract
PURPOSE This study was conducted in order to investigate computed tomography (CT) findings associated with acute cellular rejection (ACR) following liver transplantation (LT) and their relevance to clinical outcomes. MATERIALS AND METHODS We analyzed 120 patients with newly diagnosed ACR following LT for various liver diseases and 119 controls matched for age, sex, type of liver graft, and date of CT exam following LT. Two radiologists analyzed the images for morphological characteristics of the graft, morphological change in the major draining vein, graft enhancement in the portal venous phase, graft attenuation on noncontrast CT, and periportal halo. Univariate analysis was used to determine the association between radiological findings and ACR. Clinical outcomes, including treatment response and graft survival, were compared between patients with and without associated radiological findings. RESULTS Morphological characteristics of the graft (i.e., globular swelling), morphological change in the major draining vein (i.e., nonanastomotic luminal narrowing), and heterogeneous enhancement were significantly associated with ACR (all p < 0.001). On univariate analysis, the severity of morphological characteristics of the grafts (mild/severe: odds ratio [OR], 19.98/32.24) and morphological change in the major draining vein (without/with prestenotic dilatation: OR, 4.17/22.5) were significantly associated with the increased possibility of an ACR diagnosis. Clinical outcomes for treatment response and graft survival were not significantly different between patients with and without associated radiological findings. CONCLUSIONS Globular swelling, nonanastomotic stenosis with or without prestenotic dilatation of the major draining vein, and heterogeneous enhancement of the graft on portal venous-phase CT were significantly associated with ACR. KEY POINTS • Globular swelling of the graft, nonanastomotic narrowing in the major vein, and heterogeneous graft enhancement on CT were significantly associated with acute cellular rejection (ACR). • Associated CT findings were highly specific but not sensitive for differentiating ACRs from matched controls.
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Affiliation(s)
- Jong Keon Jang
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea
| | - Kyoung Won Kim
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea.
| | - Sang Hyun Choi
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea
| | - So Yeong Jeong
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea
| | - Ji Hun Kim
- Department of Diagnostic Pathology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea
| | - Eun Sil Yu
- Department of Diagnostic Pathology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea
| | - Jae Hyun Kwon
- Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea
| | - Gi Won Song
- Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea
| | - Sung Gyu Lee
- Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea
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21
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Abstract
Graft dysfunction of the liver allograft manifests across a spectrum in both timing posttransplantation and clinical presentation. This can range from mild transient abnormalities of liver tests to acute liver failure potentially leading to graft failure. The causes of graft dysfunction can be divided into those resulting in early and late graft dysfunction. Although nonspecific, liver biochemistry abnormalities are still the mainstay investigation used in monitoring for dysfunction. This article provides a summary of the main causes and management strategies for liver graft dysfunction in the early through late posttransplant stages.
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Affiliation(s)
- Beverley Kok
- Division of Gastroenterology (Liver Unit), Department of Critical Care Medicine, University of Alberta, 1-40 Zeidler Ledcor Building, Edmonton, Alberta T6G-2X8, Canada
| | - Victor Dong
- Division of Gastroenterology (Liver Unit), Department of Critical Care Medicine, University of Alberta, 1-40 Zeidler Ledcor Building, Edmonton, Alberta T6G-2X8, Canada
| | - Constantine J Karvellas
- Division of Gastroenterology (Liver Unit), Department of Critical Care Medicine, University of Alberta, 1-40 Zeidler Ledcor Building, Edmonton, Alberta T6G-2X8, Canada.
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22
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Angelico R, Gerlach UA, Gunson BK, Neil D, Mergental H, Isaac J, Muiesan P, Mirza D, Perera MTP. Severe Unresolved Cholestasis Due to Unknown Etiology Leading to Early Allograft Failure Within the First 3 Months of Liver Transplantation. Transplantation 2018; 102:1307-1315. [PMID: 29470351 DOI: 10.1097/tp.0000000000002139] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Causes of severe cholestasis after liver transplantation (LT) are multi-factorial. Although the etiology is predictable in some, others culminate in graft/patient loss without a definitive cause identified. Severe cholestasis is usually associated with overlapped histological findings of rejection and biliary features, and diagnostic interpretation may pose a challenge. METHODS This is 10-year retrospective analysis of patients with unexplained severe cholestasis resulting in death/graft loss within 90 days of LT. Of 1 583 LT during the study period, 90-day graft failure occurred in 129 (8%) cases; a total of 45 (3%) patients had unresolving severe cholestasis (bilirubin, >100 μmol/L; alkaline phosphatase, >400 UI/L after 15 days from LT), excluding those due to primary nonfunction/sepsis/vascular causes (n = 84). Demographics, allograft biopsies, radiological investigations, and clinical outcome were analyzed. RESULTS All patients had persistent abnormal liver biochemistry. Doppler ultrasound scan was normal in all cases. Thirty-five (78%) recipients had at least 1 allograft biopsy (2 [1-9]). On the first biopsy, 22 (63%) patients had acute rejection, 4 (18%) early-chronic rejection, 12 (34%) antibody-mediated rejection. In subsequent biopsies chronic rejection was evident in 5 (14%) cases. Donor-specific antibodies were detected in all patients tested. Biliary anatomy was studied in detail in 9 (20%) patients, all presenting biliary strictures. The majority (n = 39; 87%) died within 32 (10-91) days, only survivors were from retransplantation (n = 3;6.5%) and biliary intervention (n = 3;6.5%). CONCLUSIONS Unresolving severe cholestasis after LT is a key parameter predicting patient/allograft outcome. Histologically, rejection seems to overlap with biliary strictures; hence, allograft biopsy with signs of rejection should not be a reason to overlook biliary problems, in particular when biliary features are present. Only extensive radiological investigation/intervention or retransplantation prevents patient/allograft loss.
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Affiliation(s)
- Roberta Angelico
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
- Department of Abdominal Transplantation and Hepatobiliary and Pancreatic Surgery, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Undine A Gerlach
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
- Department of General, Visceral and Transplantation Surgery, Charité Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany
| | - Bridget K Gunson
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
- NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham and the University of Birmingham, Birmingham, United Kingdom
| | - Desley Neil
- Histopathology Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
| | - Hynek Mergental
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
- NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham and the University of Birmingham, Birmingham, United Kingdom
| | - John Isaac
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
| | - Paolo Muiesan
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
| | - Darius Mirza
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
- NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham and the University of Birmingham, Birmingham, United Kingdom
| | - M Thamara Pr Perera
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
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23
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Choudhary NS, Saigal S, Bansal RK, Saraf N, Gautam D, Soin AS. Acute and Chronic Rejection After Liver Transplantation: What A Clinician Needs to Know. J Clin Exp Hepatol 2017; 7:358-366. [PMID: 29234201 PMCID: PMC5715482 DOI: 10.1016/j.jceh.2017.10.003] [Citation(s) in RCA: 102] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 10/30/2017] [Indexed: 02/07/2023] Open
Abstract
While antibody mediated hyper-acute vasculitic rejection is rare in liver transplant recipients, acute and chronic rejection have clinical significance. The liver allograft behaves differently to other solid organ transplants as acute rejection generally does not impair graft survival and chronic rejection (CR) is uncommon. The incidence of acute and chronic rejection has declined in current era due to improved immunosuppressive regimens. Acute rejection generally improves with steroid boluses and steroid resistant rejection is uncommon. CR may improve with escalation of immunosuppression or may result in irreversible loss of graft function leading to retransplantation or death. The current review discusses diagnosis and management of acute and chronic liver allograft rejection.
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Affiliation(s)
- Narendra S. Choudhary
- Institute of Liver Transplantation and Regenerative Medicine, Medanta The Medicity, Gurugram, India
| | - Sanjiv Saigal
- Institute of Liver Transplantation and Regenerative Medicine, Medanta The Medicity, Gurugram, India,Address for correspondence: Sanjiv Saigal, Institute of Liver Transplantation and Regenerative Medicine, Medanta The Medicity, Sector 38, Gurgaon, Haryana 122001, India. Tel.: +91 9811552928.Sanjiv Saigal, Institute of Liver Transplantation and Regenerative Medicine, Medanta The MedicitySector 38GurgaonHaryana122001India
| | - Rinkesh K. Bansal
- Institute of Liver Transplantation and Regenerative Medicine, Medanta The Medicity, Gurugram, India
| | - Neeraj Saraf
- Institute of Liver Transplantation and Regenerative Medicine, Medanta The Medicity, Gurugram, India
| | - Dheeraj Gautam
- Department of Pathology, Medanta The Medicity, Gurugram, India
| | - Arvinder S. Soin
- Institute of Liver Transplantation and Regenerative Medicine, Medanta The Medicity, Gurugram, India
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24
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Rodríguez-Perálvarez M, De Luca L, Crespo G, Rubin Á, Marín S, Benlloch S, Colmenero J, Berenguer M, Navasa M, Tsochatzis E, De la Mata M. An objective definition for clinical suspicion of T-cell-mediated rejection after liver transplantation. Clin Transplant 2017; 31. [PMID: 28497582 DOI: 10.1111/ctr.13005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/07/2017] [Indexed: 04/21/2025]
Abstract
A uniform definition of clinical suspicion of T-cell-mediated rejection (TCMR) in liver transplantation (LT) is needed to homogenize clinical decisions, especially within randomized trials. This multicenter study included a total of 470 primary LT recipients. The derivation cohort consisted of 142 patients who had clinically driven liver biopsies at any time after LT. The external validation cohort included 328 patients who underwent protocol biopsies at day 7-10 after LT. The rates of moderate-severe histological TCMR were 33.8% in the derivation cohort and 43.6% in the validation cohort. Independent predictors (ie, risk factors) of moderate-severe TCMR in the derivation cohort were as follows: serum bilirubin >4 mg/dL (OR=5.83; P<.001), rising bilirubin within the 4 days prior to liver biopsy (OR=4.57; P=.003), and blood eosinophils count >0.1×109 /L (OR=3.81; P=.004). In the validation cohort, the number of risk factors was an independent predictor of moderate-severe TCMR (OR=1.74; P=.001), after controlling for hepatitis C status. The number of risk factors paralleled the rates of moderate-severe TCMR in the derivation and validation cohorts (P<.001 in both comparisons). In conclusion, increased serum bilirubin, rising bilirubin and eosinophilia are validated risk factors for moderate-severe histological TCMR and could be used as objective criteria to select candidates for liver biopsy.
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Affiliation(s)
- Manuel Rodríguez-Perálvarez
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain
| | - Laura De Luca
- UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital and UCL, London, UK
| | - Gonzalo Crespo
- Liver Transplant Unit, Hospital Clinic, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Ángel Rubin
- Hepatology and Liver Transplantation Unit, La Fe University Hospital, CIBERehd, Valencia, Spain
| | - Sandra Marín
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain
| | - Salvador Benlloch
- Hepatology and Liver Transplantation Unit, La Fe University Hospital, CIBERehd, Valencia, Spain
| | - Jordi Colmenero
- Liver Transplant Unit, Hospital Clinic, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Marina Berenguer
- Hepatology and Liver Transplantation Unit, La Fe University Hospital, CIBERehd, Valencia, Spain
| | - Miguel Navasa
- Liver Transplant Unit, Hospital Clinic, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Emmanuel Tsochatzis
- UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital and UCL, London, UK
| | - Manuel De la Mata
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain
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25
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Valenzuela NM, Reed EF. Antibody-mediated rejection across solid organ transplants: manifestations, mechanisms, and therapies. J Clin Invest 2017; 127:2492-2504. [PMID: 28604384 DOI: 10.1172/jci90597] [Citation(s) in RCA: 156] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Solid organ transplantation is a curative therapy for hundreds of thousands of patients with end-stage organ failure. However, long-term outcomes have not improved, and nearly half of transplant recipients will lose their allografts by 10 years after transplant. One of the major challenges facing clinical transplantation is antibody-mediated rejection (AMR) caused by anti-donor HLA antibodies. AMR is highly associated with graft loss, but unfortunately there are few efficacious therapies to prevent and reverse AMR. This Review describes the clinical and histological manifestations of AMR, and discusses the immunopathological mechanisms contributing to antibody-mediated allograft injury as well as current and emerging therapies.
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26
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Tang Y, Zhao J, Yu H, Wu H, Niu N. Acoustic Radiation Force Impulse and Doppler Ultrasonography: Comprehensive Evaluation of Acute Rejection After Liver Transplantation. JOURNAL OF ULTRASOUND IN MEDICINE : OFFICIAL JOURNAL OF THE AMERICAN INSTITUTE OF ULTRASOUND IN MEDICINE 2017; 36:1137-1145. [PMID: 28244127 DOI: 10.7863/ultra.16.05052] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Accepted: 08/25/2016] [Indexed: 06/06/2023]
Abstract
OBJECTIVES The aim of our study was to evaluate the clinical application of color Doppler flow imaging (CDFI) and acoustic radiation force impulse (ARFI) for the diagnosis of acute rejection after liver transplantation. METHODS B-Mode CDFI and ARFI assessments were performed in 76 patients who underwent biopsy after liver transplantation at our institution, between October 2011 and October 2014. The study group included 56 patients with acute rejection confirmed by biopsy, with 20 patients whose liver function recovered within 1 month of transplantation forming the control group. Anteroposterior diameter of the liver, hemodynamic index (consisting of the portal vein diameter, portal vein flow velocity, and hepatic vein flow waveform), and ARFI shear wave velocity (SWV) were measured. We used logistic regression modeling and receiver operating curve to evaluate between-group differences. RESULTS Compared with the control group, patients with acute rejection exhibited increased anteroposterior diameter (P = .035) and change in hemodynamic index (P = .021), including increased portal vein diameter, decreased portal vein flow, and loss of triphasic waveform of hepatic vein flow. Acoustic radiation force impulse SWV was markedly increased in the acute rejection group (P < .001). The correlation r-value of measured parameters to acute rejection diagnosis was 0.253 for anterioposterior diameters, 0.271 for change in hemodynamic index, and 0.721 for increased SWV. Shear wave velocity and change in the hemodynamic index had diagnostic value, with an area under the receiver operating curve of 0.933. CONCLUSIONS Combining CDFI with ARFI was useful for the diagnosis of acute rejection after liver transplantation.
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Affiliation(s)
- Ying Tang
- Department of Ultrasound, Tianjin First Center Hospital, Tianjin, China
| | - Jingwen Zhao
- Department of Ultrasound, Tianjin First Center Hospital, Tianjin, China
| | - Huimin Yu
- Department of Ultrasound, Tianjin First Center Hospital, Tianjin, China
| | - Hongtao Wu
- Department of Ultrasound, Tianjin First Center Hospital, Tianjin, China
| | - Ningning Niu
- Department of Ultrasound, Tianjin First Center Hospital, Tianjin, China
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27
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Baumann AK, Schlue J, Noyan F, Hardtke-Wolenski M, Lehner F, Barg-Hock H, Klempnauer J, Manns MP, Taubert R, Jaeckel E. Preferential accumulation of T helper cells but not cytotoxic T cells characterizes benign subclinical rejection of human liver allografts. Liver Transpl 2016; 22:943-55. [PMID: 26929119 DOI: 10.1002/lt.24427] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Revised: 02/12/2016] [Accepted: 02/16/2016] [Indexed: 12/11/2022]
Abstract
Subclinical rejection (SCR) is a common event in protocol biopsies after liver transplantation (LT). So far the interpretation of the underlying histological changes and clinical significance is limited. Previous studies were restricted to SCR manifestations within the first weeks after transplantation with limited follow-up. We analyzed clinical data from our prospective protocol biopsy program and found late SCR (at least 3 months after transplantation) to be a common event (41/94 patients). SCR manifested much later than acute cellular rejection (ACR). In the second year after transplantation, the SCR incidence in protocol biopsies reached a plateau of approximately 25% and remained at this level until the latest observed manifestations more than 5 years after transplantation. During a median follow-up of 32 months after SCR, no acute or chronic rejection, relevant graft fibrosis, graft loss, or liver-related death occurred even without specific therapy for SCR. Immunophenotyping of liver biopsies during SCR showed that similar to ACR, the composition of intrahepatic T cells depended on the severity of histological rejection. However, SCR showed a different pattern of infiltrating T cells with a stronger accumulation of CD4(+) cells, an increasing CD4(+) /CD8(+) ratio, and an increasing CD4(+) forkhead box P3 (FOXP3)(+) regulatory T cell (Treg)/CD8(+) ratio, which was not seen in ACR. These intrahepatic T cell patterns were not reflected in the peripheral blood. In conclusion, late SCR after LT has a good clinical prognosis, and it seems safe to leave it untreated. This benign clinical course compared to ACR is associated with intrahepatic T cell infiltration patterns showing less cytotoxic T cells and more CD4(+) FOXP3(+) Tregs. Liver Transplantation 22 943-955 2016 AASLD.
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Affiliation(s)
- Anna K Baumann
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Jerome Schlue
- Department of Pathology, Hannover Medical School, Hannover, Germany
| | - Fatih Noyan
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany
| | - Matthias Hardtke-Wolenski
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Frank Lehner
- Department of General, Abdominal, and Transplant Surgery, Hannover Medical School, Hannover, Germany.,Department of Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany
| | - Hannelore Barg-Hock
- Department of General, Abdominal, and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Juergen Klempnauer
- Department of General, Abdominal, and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany
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28
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Ascha MS, Ascha ML, Hanouneh IA. Management of immunosuppressant agents following liver transplantation: Less is more. World J Hepatol 2016; 8:148-161. [PMID: 26839639 PMCID: PMC4724578 DOI: 10.4254/wjh.v8.i3.148] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Revised: 09/12/2015] [Accepted: 01/07/2016] [Indexed: 02/06/2023] Open
Abstract
Immunosuppression in organ transplantation was revolutionary for its time, but technological and population changes cast new light on its use. First, metabolic syndrome (MS) is increasing as a public health issue, concomitantly increasing as an issue for post-orthotopic liver transplantation patients; yet the medications regularly used for immunosuppression contribute to dysfunctional metabolism. Current mainstay immunosuppression involves the use of calcineurin inhibitors; these are potent, but nonspecifically disrupt intracellular signaling in such a way as to exacerbate the impact of MS on the liver. Second, the impacts of acute cellular rejection and malignancy are reviewed in terms of their severity and possible interactions with immunosuppressive medications. Finally, immunosuppressive agents must be considered in terms of new developments in hepatitis C virus treatment, which undercut what used to be inevitable viral recurrence. Overall, while traditional immunosuppressive agents remain the most used, the specific side-effect profiles of all immunosuppressants must be weighed in light of the individual patient.
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29
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Raschzok N, Reutzel-Selke A, Schmuck RB, Morgul MH, Gauger U, Prabowo KA, Tannus LM, Leder A, Struecker B, Boas-Knoop S, Bartels M, Jonas S, Lojewski C, Puhl G, Seehofer D, Bahra M, Pascher A, Pratschke J, Sauer IM. CD44 and CXCL9 serum protein levels predict the risk of clinically significant allograft rejection after liver transplantation. Liver Transpl 2015; 21:1195-207. [PMID: 25950774 DOI: 10.1002/lt.24164] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 04/20/2015] [Indexed: 02/07/2023]
Abstract
The diagnosis of acute cellular rejection (ACR) after liver transplantation is based on histological analysis of biopsies because noninvasive biomarkers for allograft rejection are not yet established for clinical routines. CD31, CD44, and chemokine (C-X-C motif) ligand (CXCL) 9 have previously been described as biomarkers for cross-organ allograft rejection. Here, we assessed the predictive and diagnostic value of these proteins as serum biomarkers for clinically significant ACR in the first 6 months after liver transplantation in a prospective study. The protein levels were measured in 94 patients immediately before transplantation, at postoperative days (PODs) 1, 3, 7, and 14 and when biopsies were performed during episodes of biochemical graft dysfunction. The CD44 serum protein levels were significantly lower at POD 1 in patients who experienced histologically proven ACR in the follow-up compared with patients without ACR (P < 0.001). CXCL9 was significantly higher before transplantation (P = 0.049) and at POD 1 (P < 0.001) in these patients. Low CD44 values (cutoff, <200.5 ng/mL) or high CXCL9 values (cutoff, >2.7 ng/mL) at POD 1 differentiated between rejection and no rejection with a sensitivity of 88% or 60% and a specificity of 61% or 79%, respectively. The combination of both biomarker cutoffs at POD 1 had a positive predictive value of 91% and a negative predictive value of 67% for clinically significant ACR. Moreover, CD44 was significantly lower at the time of ACR (P < 0.001) and differentiated the rejection group from patients with graft dysfunction due to other reasons. Our results suggest that CD44 and CXCL9 may serve as predictive biomarkers to identify liver allograft recipients at risk for clinically significant ACR.
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Affiliation(s)
- Nathanael Raschzok
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Anja Reutzel-Selke
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Rosa Bianca Schmuck
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Mehmet Haluk Morgul
- Visceral, Transplantation, Thoracic, and Vascular Surgery, University of Leipzig, Leipzig, Germany
| | | | - Kukuh Aji Prabowo
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Laura-Marie Tannus
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Annekatrin Leder
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Benjamin Struecker
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Sabine Boas-Knoop
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Michael Bartels
- Visceral, Transplantation, Thoracic, and Vascular Surgery, University of Leipzig, Leipzig, Germany
| | - Sven Jonas
- Centre Hépato-Biliaire, Hôpital Paul Brousse, Université Paris Sud, Villejuif, France
| | - Christian Lojewski
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Gero Puhl
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Daniel Seehofer
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Marcus Bahra
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Andreas Pascher
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Johann Pratschke
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Igor Maximilian Sauer
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
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Rodríguez-Perálvarez M, García-Caparrós C, Tsochatzis E, Germani G, Hogan B, Poyato-González A, O'Beirne J, Senzolo M, Guerrero-Misas M, Montero-Álvarez JL, Patch D, Barrera P, Briceño J, Dhillon AP, Burra P, Burroughs AK, De la Mata M. Lack of agreement for defining 'clinical suspicion of rejection' in liver transplantation: a model to select candidates for liver biopsy. Transpl Int 2015; 28:455-464. [PMID: 25557691 DOI: 10.1111/tri.12514] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Revised: 10/17/2014] [Accepted: 12/30/2014] [Indexed: 12/14/2022]
Abstract
The gold standard to diagnose acute cellular rejection (ACR) after liver transplantation (LT) is histological evaluation, but there is no consensus to select patients for liver biopsy. We aimed to evaluate the agreement among clinicians to select candidates for liver biopsy early after LT. From a protocol biopsy population (n = 690), we randomly selected 100 LT patients in whom the biopsy was taken 7-10 days after LT. The clinical information between LT and protocol biopsy was given to nine clinicians from three transplant centres who decided whether a liver biopsy was needed. The agreement among clinicians to select candidates for liver biopsy was poor: κ = 0.06-0.62, being κ < 0.40 in 76% of comparisons. The concordance between indication for liver biopsy and moderate-severe ACR in the protocol biopsy was κ < 0.30 in all cases. A multivariate model based on the product age-by-MELD (OR = 0.81; P = 0.013), delta eosinophils (OR = 1.5; P = 0.002) and mean tacrolimus trough concentrations <6 ng/ml within the prior 4 days (OR = 11.4; P = 0.047) had an AUROC = 0.84 to diagnose moderate-severe histological ACR. In conclusion, the agreement among clinicians to select patients for liver biopsy is very poor. If further validated the proposed model would provide an objective method to select candidates for liver biopsy after LT.
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Affiliation(s)
- Manuel Rodríguez-Perálvarez
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain
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31
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Loupy A, Vernerey D, Tinel C, Aubert O, Duong van Huyen JP, Rabant M, Verine J, Nochy D, Empana JP, Martinez F, Glotz D, Jouven X, Legendre C, Lefaucheur C. Subclinical Rejection Phenotypes at 1 Year Post-Transplant and Outcome of Kidney Allografts. J Am Soc Nephrol 2015; 26:1721-31. [PMID: 25556173 DOI: 10.1681/asn.2014040399] [Citation(s) in RCA: 245] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Accepted: 10/03/2014] [Indexed: 12/12/2022] Open
Abstract
Kidney allograft rejection can occur in clinically stable patients, but long-term significance is unknown. We determined whether early recognition of subclinical rejection has long-term consequences for kidney allograft survival in an observational prospective cohort study of 1307 consecutive nonselected patients who underwent ABO-compatible, complement-dependent cytotoxicity-negative crossmatch kidney transplantation in Paris (2000-2010). Participants underwent prospective screening biopsies at 1 year post-transplant, with concurrent evaluations of graft complement deposition and circulating anti-HLA antibodies. The main analysis included 1001 patients. Three distinct groups of patients were identified at the 1-year screening: 727 (73%) patients without rejection, 132 (13%) patients with subclinical T cell-mediated rejection (TCMR), and 142 (14%) patients with subclinical antibody-mediated rejection (ABMR). Patients with subclinical ABMR had the poorest graft survival at 8 years post-transplant (56%) compared with subclinical TCMR (88%) and nonrejection (90%) groups (P<0.001). In a multivariate Cox model, subclinical ABMR at 1 year was independently associated with a 3.5-fold increase in graft loss (95% confidence interval, 2.1 to 5.7) along with eGFR and proteinuria (P<0.001). Subclinical ABMR was associated with more rapid progression to transplant glomerulopathy. Of patients with subclinical TCMR at 1 year, only those who further developed de novo donor-specific antibodies and transplant glomerulopathy showed higher risk of graft loss compared with patients without rejection. Our findings suggest that subclinical TCMR and subclinical ABMR have distinct effects on long-term graft loss. Subclinical ABMR detected at the 1-year screening biopsy carries a prognostic value independent of initial donor-specific antibody status, previous immunologic events, current eGFR, and proteinuria.
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Affiliation(s)
- Alexandre Loupy
- Paris Translational Research Center for Organ Transplantation, National Institute of Health and Medical Research, UMR-S970, Paris, France; Paris Descartes University and Hôpital Necker,
| | - Dewi Vernerey
- Paris Translational Research Center for Organ Transplantation, National Institute of Health and Medical Research, UMR-S970, Paris, France; Methodology Unit (EA 3181), CHRU de Besançon, France
| | | | - Olivier Aubert
- Paris Translational Research Center for Organ Transplantation, National Institute of Health and Medical Research, UMR-S970, Paris, France
| | - Jean-Paul Duong van Huyen
- Paris Translational Research Center for Organ Transplantation, National Institute of Health and Medical Research, UMR-S970, Paris, France; Department of Pathology, Necker Hospital, Paris, France; and
| | - Marion Rabant
- Department of Pathology, Necker Hospital, Paris, France; and
| | - Jérôme Verine
- Department of Pathology, Saint Louis Hospital, Paris, France
| | | | - Jean-Philippe Empana
- Paris Translational Research Center for Organ Transplantation, National Institute of Health and Medical Research, UMR-S970, Paris, France
| | | | - Denis Glotz
- Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Xavier Jouven
- Paris Translational Research Center for Organ Transplantation, National Institute of Health and Medical Research, UMR-S970, Paris, France
| | - Christophe Legendre
- Paris Translational Research Center for Organ Transplantation, National Institute of Health and Medical Research, UMR-S970, Paris, France; Paris Descartes University and Hôpital Necker
| | - Carmen Lefaucheur
- Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, Paris, France
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32
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Musat AI, Pigott CM, Ellis TM, Agni RM, Leverson GE, Powell AJ, Richards KR, D'Alessandro AM, Lucey MR. Pretransplant donor-specific anti-HLA antibodies as predictors of early allograft rejection in ABO-compatible liver transplantation. Liver Transpl 2013; 19:1132-41. [PMID: 23873778 DOI: 10.1002/lt.23707] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2013] [Accepted: 06/30/2013] [Indexed: 02/07/2023]
Abstract
The significance of preexisting donor-specific HLA antibodies (HLA-DSAs) for liver allograft function is unclear. Our previous studies have shown that humoral alloreactivity frequently accompanies acute cellular rejection (ACR). In the present study, we set out to determine whether pretransplant HLA-DSAs correlate with clinically significant ACR in the first 90 days after transplantation and, if so, to determine their predictive values. Class I HLA-DSAs and class II HLA-DSAs were determined by single-antigen bead flow cytometry for 113 consecutive adult transplants. A statistical analysis was performed for data from 109 consecutive patients with graft survival greater than or equal to 90 days. All patients who developed biochemical graft dysfunction underwent liver biopsy for hematoxylin-eosin and complement component 4d staining. Cox proportional hazards models and associated hazard ratios revealed a significant association of pretransplant HLA-DSAs with clinically significant ACR: this association started with a mean fluorescence intensity (MFI) as low as 300 for both class I (hazard ratio = 2.7, P < 0.01) and class II (hazard ratio = 6.0, P < 0.01). Pretransplant HLA-DSAs were associated with an increased risk of ACR: P < 0.01 for class I (42% versus 18%), P < 0.001 for class II (37% versus 7%), and P < 0.001 for either class I or II (36% versus 3%). Class I or II HLA-DSAs with an MFI ≥ 1000 had the best positive predictive value for clinically significant ACR at 46%, whereas class I or II HLA-DSAs with an MFI ≥ 300 had the best negative predictive value at 97.1%. Although our study was based on consecutive patients, it was limited by the relatively low number of single-center subjects. In conclusion, the present study indicates that pretransplant HLA-DSAs, even at low levels of allosensitization, correlate with the risk of clinically significant ACR. Our findings suggest that anti-human leukocyte antigen antibodies could serve as donor-specific markers of immunoreactivity to the liver graft.
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Affiliation(s)
- Alexandru I Musat
- Departments of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
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33
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Perrakis A, Förtsch T, Niebling N, Croner RS, Nissler V, Yedibela S, Lohmüller C, Zopf S, Kammerer F, Hohenberger W, Müller V. The Diagnostic Value of Systolic Acceleration Time and Resistive Index as Noninvasive Modality for Detection of Graft Rejection After Orthotopic Liver Transplantation. Transplant Proc 2013; 45:1961-5. [DOI: 10.1016/j.transproceed.2013.01.058] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Revised: 11/30/2012] [Accepted: 01/15/2013] [Indexed: 11/30/2022]
Affiliation(s)
- A Perrakis
- Department of Surgery, University of Erlangen-Nuremberg, Erlangen, Germany.
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Basiliximab en el tratamiento del rechazo celular agudo resistente a los corticoides postrasplante hepático. GASTROENTEROLOGIA Y HEPATOLOGIA 2012; 35:649-51. [DOI: 10.1016/j.gastrohep.2012.03.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2012] [Revised: 03/24/2012] [Accepted: 03/28/2012] [Indexed: 11/19/2022]
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Rodríguez-Perálvarez M, Germani G, Darius T, Lerut J, Tsochatzis E, Burroughs AK. Tacrolimus trough levels, rejection and renal impairment in liver transplantation: a systematic review and meta-analysis. Am J Transplant 2012; 12:2797-2814. [PMID: 22703529 DOI: 10.1111/j.1600-6143.2012.04140.x] [Citation(s) in RCA: 133] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
We hypothesized that current trough concentrations of tacrolimus after liver transplantation are set too high, considering that clinical consequences of rejection are not severe while side effects are increased.We systematically reviewed 64 studies (32 randomized controlled trials and 32 observational studies) to determine how lower tacrolimus trough concentrations than currently recommended affect acute rejection rates and renal impairment. Among randomized trials the mean of tacrolimus trough concentration during the first month was positively correlated with renal impairment within 1 year (r = 0.73; p = 0.003), but not with acute rejection, either defined using protocol biopsies (r = -0.37; p = 0.32) or not (r = 0.11; p = 0.49). A meta-analysis of randomized trials directly comparing tacrolimus trough concentrations (five trials for acute rejection [n = 957] and two trials for renal impairment [n = 712]) showed that "reduced tacrolimus" trough concentrations (<10 ng/mL) within the first month after liver transplantation were associated with less renal impairment at 1 year (RR = 0.51 [0.38-0.69]), with no significant influence on acute rejection (RR = 0.92 [0.65-1.31]) compared to "conventional tacrolimus" trough levels (>10 ng/mL). Lower trough concentrations of tacrolimus (6-10 ng/mL during the first month) would be more appropriate after liver transplantation. Regulatory authorities and the pharmaceutical industry should allow changes of regulatory drug information.
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Affiliation(s)
- M Rodríguez-Perálvarez
- The Royal Free Sheila Sherlock Liver Centre and University Department of Surgery, UCL, and Royal Free Hospital, Pond Street, London, UK
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36
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Rodríguez-Perálvarez M, Germani G, Tsochatzis E, Rolando N, Luong TV, Dhillon AP, Thorburn D, O'Beirne J, Patch D, Burroughs AK. Predicting severity and clinical course of acute rejection after liver transplantation using blood eosinophil count. Transpl Int 2012; 25:555-563. [PMID: 22420754 DOI: 10.1111/j.1432-2277.2012.01457.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Acute cellular rejection remains an important source of morbidity after liver transplantation, particularly if rejection is moderate or severe, as this usually is treated. Currently liver biopsies are seldom performed, so diagnostic noninvasive markers would be useful. We evaluated 690 consecutive first liver transplant patients to assess whether peripheral eosinophilia could predict moderate-severe rejection and its course. A protocol biopsy was performed 6 ± 2.5 days after transplant. A second biopsy was taken 6.1 ± 2 days after the first in 487 patients to assess histological improvement. Liver function tests, peripheral eosinophil count and changes between first and second biopsy, were evaluated using logistic regression. Histological rejection was present in 532 patients (77.1%), with moderate (30.6%) and severe rejection (3.9%). Peripheral eosinophil count was strongly associated with moderate-severe rejection (OR = 2.15; P = 0.007), although the area under ROC curve (AUROC) was 0.58. On second biopsy, rejection improved in 119 (24.4%) patients. The delta in eosinophil count between the first and second biopsies was the only independent predictor of histological improvement (OR = 3.12; P = 0.001), irrespective of whether bolus steroids were used (OR = 2.77; P = 0.004); AUROC was 0.72. Peripheral eosinophilia is not sufficiently predictive of moderate-severe histological rejection. However the changes in eosinophil count over time can accurately predict the histological resolution of rejection.
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Affiliation(s)
- Manuel Rodríguez-Perálvarez
- The Royal Free Sheila Sherlock Liver Centre and University Department of Surgery, Royal Free Hospital London, UK
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37
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Weng MZ, Xu YG, Zhang Y, Zhang JY, Quan ZW, Xu JM, Peng Z. Indoleamine 2,3-Dioxygenase as a Predictor of Acute Rejection After Orthotopic Liver Transplantation in Rat Model. Transplant Proc 2011; 43:3969-72. [DOI: 10.1016/j.transproceed.2011.09.061] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2011] [Revised: 09/04/2011] [Accepted: 09/13/2011] [Indexed: 10/14/2022]
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38
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Recurrent hepatitis C and acute allograft rejection: clinicopathologic features with emphasis on the differential diagnosis between these entities. Adv Anat Pathol 2011; 18:393-405. [PMID: 21841407 DOI: 10.1097/pap.0b013e31822a5a10] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Chronic hepatitis C virus infection is the leading etiology for liver transplantation in the United States. Recurrent hepatitis C occurs nearly universally in these patients and represents a serious posttransplantation complication. Despite the detailed characterization of the histologic features of both recurrent hepatitis C and acute cellular rejection (ACR) over the last decades, the pathologic distinction between these 2 conditions remains one of the greatest diagnostic challenges in liver pathology. An accurate diagnosis, nevertheless, plays an essential role in patient management, as different therapeutic strategies are used for these conditions. In this review, the clinicopathologic features of posttransplantation recurrent hepatitis C and ACR are discussed, with emphasis on distinguishing histopathologic features, morphologic variants, ancillary techniques, and diagnostic pitfalls.
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39
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Ruiz P, Takahashi H, Delacruz V, Island E, Selvaggi G, Nishida S, Moon J, Smith L, Asaoka T, Levi D, Tekin A, Tzakis A. International Grading Scheme for Acute Cellular Rejection in Small-Bowel Transplantation: Single-Center Experience. Transplant Proc 2010; 42:47-53. [DOI: 10.1016/j.transproceed.2009.12.026] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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40
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Sugimoto H, Kato K, Hirota M, Takeda S, Kamei H, Nakamura T, Kiuchi T, Nakao A. Serial measurement of Doppler hepatic hemodynamic parameters for the diagnosis of acute rejection after live donor liver transplantation. Liver Transpl 2009; 15:1119-25. [PMID: 19718629 DOI: 10.1002/lt.21777] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
To elucidate the role of Doppler hepatic hemodynamic parameters as surrogate markers of acute rejection (AR) after live donor liver transplantation (LDLT), serial Doppler measurements were prospectively performed during the first 2 weeks after LDLT to compare the longitudinal hepatic hemodynamic changes between patients with histologically proven AR and patients without histologically proven AR. Forty-six patients that had undergone adult-to-adult LDLT using a right lobe graft were enrolled in this study. The portal venous maximum velocity (PVV; cm/second), portal venous flow volume, hepatic arterial peak systolic velocity, hepatic arterial pulsatility index, hepatic venous maximum velocity, hepatic venous pulsatility index, and splenic arterial pulsatility index were measured. Fourteen patients were diagnosed by biopsy to have clinically relevant AR. Markedly increased PVV was seen soon after surgery and gradually decreased in both patients with clinically relevant AR and patients without clinically relevant AR. This serial change of decreasing PVV was significantly greater in patients with clinically relevant AR (P < 0.0001). After postoperative day 6, the PVV in patients with clinically relevant AR was significantly lower than that in patients without clinically relevant AR (PVV on postoperative day 6: 35.6 +/- 21.3 versus 58.3 +/- 27.1 cm/second, respectively, P = 0.0080). A PVV cutoff value of 20.2 cm/second demonstrated the best accuracy for predicting clinically relevant AR. The sensitivity and specificity for predicting clinically relevant AR were 92.9% and 87.1%, respectively. The area under the curve was 0.94. In conclusion, serial Doppler measurement of hepatic parameters in LDLT is useful for the diagnosis of clinically relevant AR. Clinically relevant AR should therefore be suspected when a marked unexpected decrease in the PVV is observed.
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Affiliation(s)
- Hiroyuki Sugimoto
- Department of Surgery II, Nagoya University Graduate School of Medicine, Nagoya, Japan.
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41
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Hama N, Yanagisawa Y, Dono K, Kobayashi S, Marubashi S, Nagano H, Umeshita K, Watanabe S, Uchiyama Y, Monden M. Gene expression profiling of acute cellular rejection in rat liver transplantation using DNA microarrays. Liver Transpl 2009; 15:509-21. [PMID: 19399741 DOI: 10.1002/lt.21708] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Acute cellular rejection (ACR) is still a major problem in organ transplantation, and its genetic and molecular mechanisms remain poorly understood. We used DNA microarrays to investigate the gene expression profiles in ACR. We hypothesized that changes of gene expression in grafts could also be detected in peripheral blood leukocytes. We first compared the gene expression profiles in liver isografts (Lewis to Lewis) and allografts (Dark Agouti to Lewis) harvested from rats at days 1, 3, 5, and 7 after transplantation. Hierarchical clustering analysis indicated that gene expression started to change on day 3, and 89 differentially expressed genes were extracted from allografts in comparison with isografts at day 3. Most of the up-regulated genes were associated with graft-infiltrating leukocytes. We then confirmed the similarity of gene expression changes in peripheral leukocytes by quantitative real-time polymerase chain reaction. We also investigated the gene expression changes in other inflammatory and liver dysfunction models. Two interferon-gamma inducible genes, interferon regulatory factor 1 and guanylate nucleotide binding protein 2, were overexpressed in both the peripheral leukocytes and liver graft during ACR. Although further studies are necessary, these 2 genes in peripheral leukocytes could be potentially useful markers for rejection or immunosuppression.
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Affiliation(s)
- Naoki Hama
- Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
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42
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Metabonomic Profile of Rats with Acute Liver Rejection. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2009; 13:81-91. [DOI: 10.1089/omi.2008.0061] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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43
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Killackey MT, Gondolesi GE, Liu LU, Paramesh AS, Thung SN, Suriawinata A, Nguyen E, Roayaie S, Schwartz ME, Emre S, Schiano TD. Effect of ischemia-reperfusion on the incidence of acute cellular rejection and timing of histologic hepatitis C virus recurrence after liver transplantation. Transplant Proc 2008; 40:1504-10. [PMID: 18589139 DOI: 10.1016/j.transproceed.2008.03.101] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2008] [Accepted: 03/11/2008] [Indexed: 02/08/2023]
Abstract
BACKGROUND Because of a critical shortage of deceased donor (DD) livers, more extended criteria allografts are being utilized; these allografts are at increased risk for ischemia-reperfusion injury (IRI). We assessed whether, in a large cohort of patients transplanted for hepatitis C virus (HCV) either via a DD or live donor (LD), there was a relationship between the degree of IRI and the frequency and timing of acute cellular rejection (ACR) and histologic HCV recurrence. METHODS During an 8-year study, patients were separated into four groups based on peak alanine aminotransferase (ALT) levels and three groups based on severity of IRI on postreperfusion liver biopsy. RESULTS The mean follow-up time of 433 DD and 44 LD recipients was 1212 days. We noted a strong correlation in DD between peak ALT and the histologic degree of IRI (P = .01). There was no difference in the incidence or grade of ACR among the four groups. There was no correlation between the severity of IRI and the incidence or time to histologic recurrence of HCV. CONCLUSIONS The magnitude of peak ALT correlated with the severity of IRI on postreperfusion liver biopsy. Among this large HCV cohort, there was no correlation between the severity of IRI and the incidence or timing of histologic HCV recurrence or incidence of ACR.
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Affiliation(s)
- M T Killackey
- Recanati/Miller Transplantation Institute, The Mount Sinai Medical Center, New York, USA
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Histologic abnormalities are common in protocol liver allograft biopsies from patients with normal liver function tests. Am J Surg Pathol 2008; 32:965-73. [PMID: 18460980 DOI: 10.1097/pas.0b013e3181622490] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The utility of protocol liver allograft biopsies remains controversial, particularly in patients with normal liver function tests (LFTs). However, histologic evaluation of these biopsies provides an opportunity to examine the types and severity of liver diseases that can occur in livers with normal clinical and biochemical function. We studied 165 protocol allograft biopsies taken from 100 liver transplant patients at the time of normal LFTs and normal clinical function at 3 to 8 months (n=36), 1 year (n=52), 2 to 3 years (n=54), and 4 to 5 years (n=23). Biopsies were classified as normal, minimal changes (eg, nonaggressive portal or lobular mononuclear inflammation, steatosis <10%), fatty liver disease, recurrent primary liver disease, and transplant-related disease (portal-based rejection or central venulitis, an inflammatory pattern that encompasses perivenular hepatocyte dropout, mononuclear inflammation, pigment-laden macrophages, and variable zone 3 fibrosis). Among these 100 patients, a total of 394 protocol biopsies were performed, and 165 (42%) were taken at the time of normal LFTs and normal clinical function. One hundred twenty-one (73%) were normal or showed minimal/nonspecific changes. Forty-four (27%) showed histologic abnormalities that included fatty liver disease (n=19, nonalcoholic in 18 cases; 13 with mild steatosis, 6 with moderate steatosis, 7 with grade 1/3 steatohepatitic activity, and 2 with stage 1/4 steatohepatitic fibrosis), recurrent primary biliary cirrhosis (n=9; all stage 1/4), recurrent hepatitis C infection (n=6; grade 0/4 in 1, grade 1/4 in 5, stage 0/4 in 4, stage 1/4 in 1, and stage 2/4 in 1), recurrent sarcoidosis (n=1), Ito cell hyperplasia (n=4; marked in 2 and mild in 2), central venulitis (n=10; 5 with mild zone 3 fibrosis or central vein obliteration and 1 with central-portal bridging fibrosis), and mild acute portal rejection (n=2). We judged the histologic changes to be of clinical significance in 19 (11.5%) cases. These results indicate that even at the time of normal clinical and laboratory function, a significant fraction of protocol allograft biopsies harbor histologic (27%) and clinically significant (11.5%) abnormalities. These most commonly include fatty liver disease, low-grade/low-stage recurrent hepatitis C and primary biliary cirrhosis, and central venulitis (including some cases with subsequent fibrosis progression). The data support performance of protocol biopsies to assess allograft status, and provide insight into the types and severity of liver diseases that can smolder in transplanted (and by extension, probably also in native) livers with apparent normal function.
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45
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Takahashi H, Kato T, Selvaggi G, Nishida S, Gaynor JJ, Delacruz V, Moon JI, Levi DM, Tzakis AG, Ruiz P. Subclinical Rejection in the Initial Postoperative Period in Small Intestinal Transplantation: A Negative Influence on Graft Survival. Transplantation 2007; 84:689-96. [PMID: 17893601 DOI: 10.1097/01.tp.0000280541.83994.93] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Subclinical rejection (SCR) is a known entity in various solid organ transplants but not in intestinal transplantation. METHODS The purpose of this study is to characterize the presence and effect of SCR in small intestinal transplantation (Itx). A total of 151 patients who underwent Itx and maintained a functioning graft for at least 3 months after Itx were investigated. The clinicopathological characteristics associated with a SCR episode within 3 months after Itx were analyzed. Cox regression with the landmark method (the landmark time being 3 months after Itx) was used for the analyses of overall graft survival and cause-specific hazard rate of SCR. RESULTS A total of 2744 small intestinal transplant biopsies within 3 months after Itx were available for retrospective evaluation; 171 cases (6.2%) were determined as SCR and 78 patients (51.7%) experienced SCR episode within 3 months after Itx. Adult patients were associated with a significantly higher occurrence of a SCR episode (P=0.001). Overall graft survival at 5 years posttransplant for patients experiencing SCR within 3 months posttransplant and for patients without SCR was 37.2% and 60.2%, respectively (P=0.009). Cause-specific hazard rate analysis showed that a SCR episode was associated with a significantly higher hazard rate of death due to infection (P=0.005). CONCLUSIONS A SCR episode in the initial postoperative period of Itx is a significant factor for unfavorable graft prognosis, likely representing alloimmune injury ultimately resulting in patient morbidity due to infection.
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Affiliation(s)
- Hidenori Takahashi
- Department of Surgery, Division of Liver/Gastrointestinal Transplant, University of Miami School of Medicine, Miami, FL 33136, USA
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46
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47
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Cho JY, Suh KS, Lee HW, Cho EH, Yang SH, Cho YB, Yi NJ, Kim MA, Jang JJ, Lee KU. The clinical significance of early histological rejection with or without biochemical abnormality in adult living donor liver transplantation for hepatitis B virus related end stage liver disease. Transpl Int 2007; 20:37-44. [PMID: 17181651 DOI: 10.1111/j.1432-2277.2006.00384.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
There is no agreement regarding the treatment of early allograft rejection (EAR) in adult living donor liver transplantation (LDLT). A protocol biopsy was performed in 62 adult LDLT recipients. Twenty-one patients (33.9%) had histological evidence of EAR. Of these, 14 patients had biochemical abnormalities and seven patients had no associated biochemical abnormalities. None of the seven patients with subclinical EAR (11.3% of the entire study population) were treated, and no subsequent rejection was observed. Gender mismatch (female-to-male) was the single independent risk factor for histological EAR [odds ratio (OR) = 13.458; 95% confidence interval (CI), 1.836-98.649] and the cumulative probability for a subsequent rejection was higher in patients with EAR (OR = 11.085; 95% CI, 1.221-100.654). However, the actuarial 1 year patient and graft survival rate in patients with EAR (81.0% and 85.5%) were similar to those without EAR (92.7% and 97.25%; P = 0.127 and 0.302, respectively). The presence of an initial biochemical abnormality was an independent risk factor for both a decreased patient survival (OR = 5.827; 95% CI, 1.095-31.017; P = 0.039) and graft loss (OR = 20.646; 95% CI, 2.044-208.524; P = 0.010). Subsequent rejection developed more frequently in patients with EAR. However, the survival is not determined by the presence of EAR but by the presence of a biochemical abnormality.
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Affiliation(s)
- Jai Young Cho
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
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Vivarelli M, Vetrone G, Zanello M, La Barba G, Cucchetti A, Lauro A, Grazi GL, Pinna AD. Sirolimus as the main immunosuppressant in the early postoperative period following liver transplantation: a report of six cases and review of the literature. Transpl Int 2006; 19:1022-1025. [PMID: 17081233 DOI: 10.1111/j.1432-2277.2006.00381.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The use of sirolimus as the main immunosuppressant in a calcineurin inhibitor-free regimen in the early postoperative period of liver transplantation (LT), when the incidence of rejection is the highest, has seldom been reported. We report six patients who received sirolimus in association with steroids only, at a median time of 10 days after LT (range 3-23). Tacrolimus, initially given as the standard immunosuppressant, was discontinued because of nephrotoxicity in three of these patients and neurotoxicity in the other three. Resolution of the neurological symptoms was observed in all cases and a marked improvement of the renal function in two of three patients. Two patients died, one of sepsis and the other of recurrent hepatitis C virus hepatitis, after 47 and 143 days respectively. Three patients developed acute rejection which responded to intravenous steroids. In this cohort of patients, the use of sirolimus appeared safe and provided an adequate prophylaxis against rejection, even though the drug was administered in the immediate postoperative period after LT.
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Affiliation(s)
- Marco Vivarelli
- Department of Surgery and Transplantation, University of Bologna, S. Orsola Hospital, Bologna, Italy.
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Höroldt BS, Burattin M, Gunson BK, Bramhall SR, Nightingale P, Hübscher SG, Neuberger JM. Does the Banff rejection activity index predict outcome in patients with early acute cellular rejection following liver transplantation? Liver Transpl 2006; 12:1144-1151. [PMID: 16799959 DOI: 10.1002/lt.20779] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The Banff schema incorporates a semiquantitative scoring system for grading of acute cellular rejection (ACR) of the liver allograft. The Banff rejection activity index (RAI) comprises 3 components scored from 0 to 3: venous endothelial inflammation (E); bile duct damage (B); and portal inflammation (P); the scores are combined to an overall score (the RAI). The purpose of this research was to determine the prognostic value of the Banff RAI score in predicting the response to increased immunosuppression and the long-term outcome of the graft. A retrospective study was done of patients undergoing primary liver transplantation between January 2000 and October 2004 with tacrolimus-based immunosuppression; 495 patients were included, 231 had histologically-confirmed ACR, 193 responded to 1 cycle of high-dose steroids. There was no correlation between the total RAI score and response to steroids, resistant rejection, development of chronic rejection, or graft survival. The E score was related to patient survival, a lower score being associated with a worse outcome (P = 0.048). In multivariable analysis, serum bilirubin, serum aspartate aminotransferase, and E score were significant predictors of death (P = 0.012). In univariable analysis, B score and bilirubin were significantly related to "resistant rejection" (P = 0.018 and 0.002, respectively), but only bilirubin was significant in multivariable analysis (logistic regression). In conclusion, although the Banff RAI score is a useful marker of the severity of rejection, neither the total RAI score nor any of the individual components correlated with response to steroids or graft survival.
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Górnicka B, Ziarkiewicz-Wróblewska B, Bogdańska M, Ołdakowska-Jedynak U, Wróblewski T, Morton M, Ziółkowski J, Paczek L, Krawczyk M, Wasiutyński A. Pathomorphological Features of Acute Rejection in Patients After Orthotopic Liver Transplantation: Own Experience. Transplant Proc 2006; 38:221-5. [PMID: 16504708 DOI: 10.1016/j.transproceed.2006.01.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
INTRODUCTION Acute hepatic allograft rejection remains an important problem following liver transplantation. Liver biopsy specimens show a combination of characteristic changes, first observed by Snover as a diagnostic triad: portal inflammation, bile duct damage, and central or portal vein endothelial inflammation (endothelitis or endothelialitis). The aim of this study was to describe our histopathological assessment of liver transplants. MATERIALS AND METHODS In the period between September 2000 and June 2004, we evaluated 150 liver biopsy specimens from 105 liver recipients. RESULTS Acute rejection was diagnosed in 26.6% of liver biopsies taken from 31.4% patients who demonstrated clinical symptoms of liver damage. In 90% of cases the rejection was described as minimal or mild, and in 10% as moderate. There was no episode of severe acute rejection. Only four biopsies (10%) showed nothing but Snover triad changes. In 9 (22.5%) cases only acute rejection was diagnosed; the remaining showed in addition to acute rejection the possibility of other concomitant pathologies: viral infection in 15 cases (37.5%), biliary flow obstruction in 11 cases (28.5%), functional cholestasis in two cases (5%), and ischemic complications in three cases (7.5%). CONCLUSIONS Histologically confirmed acute rejection episodes were diagnosed in 14.9% liver recipients. Liver biopsy specimens, aside from Snover triad features, often showed other unspecific morphological changes. Differentiation of acute rejection from other accompanying diseases is sometimes difficult, requiring precise clinical data and pathologist experience.
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Affiliation(s)
- B Górnicka
- Department of Pathology, Warsaw Medical University, ul. Pawińskiego 7, 02-106 Warsaw, Poland.
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