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Lee SK, Kwon JH, Jang JW, Bae SH, Yoon SK, Jung ES, Choi JY. The Critical Role of Regulatory T Cells in Immune Tolerance and Rejection Following Liver Transplantation: Interactions With the Gut Microbiome. Transplantation 2024:00007890-990000000-00891. [PMID: 39375899 DOI: 10.1097/tp.0000000000005220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/09/2024]
Abstract
Liver transplantation (LT) is the ultimate treatment for patients with end-stage liver disease or early hepatocellular carcinoma. In the context of LT, because of the unique immunological characteristics of human liver allograft, 5%-20% of selected LT recipients can achieve operational tolerance. Nonetheless, there remains a risk of rejection in LT patients. Maintaining immune homeostasis is thus crucial for improving clinical outcomes in these patients. In mechanism, several immune cells, including dendritic cells, Kupffer cells, myeloid-derived suppressor cells, hepatic stellate cells, regulatory B cells, and CD4+ regulatory T cells (Treg), contribute to achieving tolerance following LT. In terms of Treg, it plays a role in successfully minimizing immunosuppression or achieving tolerance post-LT while also reducing the risk of rejection. Furthermore, the gut microbiome modulates systemic immune functions along the gut-liver axis. Recent studies have explored changes in the microbiome and its metabolites under various conditions, including post-LT, acute rejection, and tolerance. Certain functional microbiomes and metabolites exhibit immunomodulatory functions, such as the augmentation of Treg, influencing immune homeostasis. Therefore, understanding the mechanisms of tolerance in LT, the role of Treg in tolerance and rejection, as well as their interactions with gut microbiome, is vital for the management of LT patients.
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Affiliation(s)
- Soon Kyu Lee
- Division of Hepatology, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jung Hyun Kwon
- Division of Hepatology, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jeong Won Jang
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Si Hyun Bae
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Hepatology, Department of Internal Medicine, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seung Kew Yoon
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Eun Sun Jung
- Department of Pathology, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jong Young Choi
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of 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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3
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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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Odenwald MA, Roth HF, Reticker A, Segovia M, Pillai A. Evolving challenges with long-term care of liver transplant recipients. Clin Transplant 2023; 37:e15085. [PMID: 37545440 DOI: 10.1111/ctr.15085] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 07/17/2023] [Accepted: 07/23/2023] [Indexed: 08/08/2023]
Abstract
The number of liver transplants (LT) performed worldwide continues to rise, and LT recipients are living longer post-transplant. This has led to an increasing number of LT recipients requiring lifelong care. Optimal care post-LT requires careful attention to both the allograft and systemic issues that are more common after organ transplantation. Common causes of allograft dysfunction include rejection, biliary complications, and primary disease recurrence. While immunosuppression prevents rejection and reduces incidences of some primary disease recurrence, it has detrimental systemic effects. Most commonly, these include increased incidences of metabolic syndrome, various malignancies, and infections. Therefore, it is of utmost importance to optimize immunosuppression regimens to prevent allograft dysfunction while also decreasing the risk of systemic complications. Institutional protocols to screen for systemic disease and heightened clinical suspicion also play an important role in providing optimal long-term post-LT care. In this review, we discuss these common complications of LT as well as unique considerations when caring for LT recipients in the years after transplant.
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Affiliation(s)
- Matthew A Odenwald
- Department of Medicine, Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medicine, Chicago, USA
| | - Hannah F Roth
- Department of Medicine, Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medicine, Chicago, USA
| | - Anesia Reticker
- Department of Pharmacy, University of Chicago Medicine, Chicago, USA
| | - Maria Segovia
- Department of Medicine, Section of Gastroenterology, Duke University School of Medicine, Durham, USA
| | - Anjana Pillai
- Department of Medicine, Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medicine, Chicago, USA
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5
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Fuochi E, Anastasio L, Lynch EN, Campani C, Dragoni G, Milani S, Galli A, Innocenti T. Main factors influencing long-term outcomes of liver transplantation in 2022. World J Hepatol 2023; 15:321-352. [PMID: 37034235 PMCID: PMC10075010 DOI: 10.4254/wjh.v15.i3.321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/24/2022] [Accepted: 02/22/2023] [Indexed: 04/11/2023] Open
Abstract
Liver transplant (LT) outcomes have markedly improved in the recent decades, even if long-term morbidity and mortality are still considerable. Most of late deaths are independent from graft function and different comorbidities, including complications of metabolic syndrome and de novo neoplasms, seem to play a key role in determining long-term outcomes in LT recipients. This review discusses the main factors associated with late mortality and suggests possible strategies to improve long-term management and follow-up after liver transplantation. In particular, the reduction of drug toxicity, the use of tools to identify high-risk patients, and setting up a multidisciplinary team also for long-term management of LT recipients may further improve survival after liver transplantation.
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Affiliation(s)
- Elisa Fuochi
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Lorenzo Anastasio
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Erica Nicola Lynch
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Claudia Campani
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Gabriele Dragoni
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
- Department of Medical Biotechnologies, University of Siena, Siena 53100, Italy
| | - Stefano Milani
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Andrea Galli
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Tommaso Innocenti
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
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Ningappa M, Rahman SA, Higgs BW, Ashokkumar CS, Sahni N, Sindhi R, Das J. A network-based approach to identify expression modules underlying rejection in pediatric liver transplantation. Cell Rep Med 2022; 3:100605. [PMID: 35492246 PMCID: PMC9044102 DOI: 10.1016/j.xcrm.2022.100605] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 12/19/2021] [Accepted: 03/23/2022] [Indexed: 10/27/2022]
Abstract
Selecting the right immunosuppressant to ensure rejection-free outcomes poses unique challenges in pediatric liver transplant (LT) recipients. A molecular predictor can comprehensively address these challenges. Currently, there are no well-validated blood-based biomarkers for pediatric LT recipients before or after LT. Here, we discover and validate separate pre- and post-LT transcriptomic signatures of rejection. Using an integrative machine learning approach, we combine transcriptomics data with the reference high-quality human protein interactome to identify network module signatures, which underlie rejection. Unlike gene signatures, our approach is inherently multivariate and more robust to replication and captures the structure of the underlying network, encapsulating additive effects. We also identify, in an individual-specific manner, signatures that can be targeted by current anti-rejection drugs and other drugs that can be repurposed. Our approach can enable personalized adjustment of drug regimens for the dominant targetable pathways before and after LT in children.
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Affiliation(s)
- Mylarappa Ningappa
- Department of Surgery and Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA
| | - Syed A Rahman
- Center for Systems Immunology, Departments of Immunology and Computational & Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Brandon W Higgs
- Department of Surgery and Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA
| | - Chethan S Ashokkumar
- Department of Surgery and Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA
| | - Nidhi Sahni
- Department of Epigenetics, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA.,Department of Molecular Carcinogenesis and Bioinformatics, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA.,Department of Computational Biology, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA
| | - Rakesh Sindhi
- Department of Surgery and Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jishnu Das
- Center for Systems Immunology, Departments of Immunology and Computational & Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA
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8
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El Masri J, El Ayoubi LM, Zreika B, Adhami F, El Masri D, El Hage S, Abou-Jaoudé M. Current state of clinical trials regarding liver transplant rejection. Transpl Immunol 2021; 70:101522. [PMID: 34954324 DOI: 10.1016/j.trim.2021.101522] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 12/13/2021] [Accepted: 12/20/2021] [Indexed: 10/19/2022]
Abstract
BACKGROUND Liver transplant (LT) is the second most common transplant intervention. The rate of acute cellular rejection (ACR) is 15-25% after LT, while being higher in chronic rejection (CR). Clinical trials had a major role in getting more potent and selective immunosuppressive medications. Our study plays an important role by evaluating and tracking clinical trials related to liver transplant rejection, focusing on interventional therapeutic trials. METHODS On October 28, we searched Clinicaltrials.gov for interventional clinical trials related to liver transplant rejection. A total of 27 clinical trials included in this study. Characteristics on each trial were collected, and availability of linked publications was searched using Medline/PubMed and Embase/Scopus. Content of publications was reviewed and main findings were summarized. RESULTS Majority of trials were completed (15 out of 27). Eleven trials had between 11 and 50 participants, and 10 had above 100. The study duration was between 1 and 4 years for the majority of trials (16 trials), with an average of 3.77 years. Most of the trials were done in Europe/UK/Russia (n = 12). The results were provided in 9 trials but published in 4, showing the possible tolerogenic efficacy of MSC in liver transplantation, increased success of immunosuppression (IS) withdrawal after sirolimus addition, efficacy of Alemtuzumab, normal graft function and stability within 1 year of immunosuppression withdrawal. CONCLUSION This study revealed a low number of trials, lack of variety in location and low publishing rates. The focus of trials was mainly towards side effects and safety of immunosuppressants, and their withdrawal. These trials reached results that must be built on to reach definitive guidelines and treatment strategies. This highlights the need for better management of human and financial resources, in order to reach new and more effective therapeutic strategies, leading to the decrease in rate of LTR.
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Affiliation(s)
- Jad El Masri
- Faculty of Medicine, Lebanese University, Beirut, Lebanon; Faculty of Medicine, Neuroscience Research Center, Lebanese University, Beirut, Lebanon.
| | | | - Bachir Zreika
- Faculty of Medicine, Lebanese University, Beirut, Lebanon
| | - Fouad Adhami
- Faculty of Medicine, Lebanese University, Beirut, Lebanon
| | - Diala El Masri
- Faculty of Medicine, University of Balamand, Nord, Lebanon
| | - Said El Hage
- Faculty of Medicine, Lebanese University, Beirut, Lebanon; Faculty of Medicine, Neuroscience Research Center, Lebanese University, Beirut, Lebanon; INSPECT-LB (Institut National de Santé Publique, Epidémiologie Clinique et Toxicologie-Liban), Beirut, Lebanon
| | - Maroun Abou-Jaoudé
- Faculty of Medicine, Lebanese University, Beirut, Lebanon; Department of Surgery, Middle East Institute of Health, Bsalim, Lebanon; Department of Surgery, Saint-George Hospital-UMC, Beirut, Lebanon
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9
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Patel JA, Daoud D, Jain A. Review of Standardized Incidence Ratios (SIR) of non-lymphoid de novo malignancies after liver transplantation: Structured analysis of global differences. Transplant Rev (Orlando) 2021; 36:100670. [PMID: 34688986 DOI: 10.1016/j.trre.2021.100670] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 12/16/2022]
Abstract
INTRODUCTION De Novo malignancy after liver transplantation (LTx) is the second most common cause of death in adult LTx recipients. The current report identifies differences in Standardized Incidence Ratios (SIR) for various non-lymphoid de novo malignancies by comparing and analyzing post LTx SIR for non-lymphoid de novo malignancies. MATERIAL AND METHODS A thorough search of PubMed and Web of Science databases was conducted; 25 publications describing de novo malignancies post-LTx with SIR were identified. RESULTS Overall SIR varied from 1.4 to 11.6 (median 2.4). Oropharyngeal/larynx (OPL), lung, colo-rectal, and kidney malignancies were more prevalent with higher SIR (median = 4.4, 1.9, 2.67, 2.5, respectively). Breast and prostate malignancies were also more prevalent with lower SIR (median = 0.9, 1.0, respectively). Pancreatic, central nervous system (CNS), melanoma, rare cancers and Kaposi's sarcoma were less prevalent (except in Italy and Sweden) but had much higher SIR (median = 2.6, 2.4, 2.02, 22.5 and 53.6, respectively). The overall higher SIR values are related to the age of the recipient, length of follow-up, the grouping of different organ systems, inclusion or exclusion of epidermal non-malacotic skin cancers, lymphoid malignancy, and occurrence of rare malignancies including Kaposi's sarcoma. CONCLUSION OPL, lung, gastrointestinal, kidney, and bladder malignancies were more prevalent with higher SIR. Breast and prostate cancers were more prevalent with lower SIR. Pancreatic, CNS, melanoma, rare cancers and Kaposi's sarcoma were less prevalent with higher SIR. Age of the recipients, length of follow-up, and rare cancer types influence overall SIR values with some global differences.
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Affiliation(s)
- Jay A Patel
- Department of General Surgery, The Pennsylvania State University, College of Medicine, Hershey, PA, USA
| | - Deborah Daoud
- Division of Transplant Surgery, The Pennsylvania State University, College of Medicine, Hershey, PA, USA
| | - Ashokkumar Jain
- Department of General Surgery, The Pennsylvania State University, College of Medicine, Hershey, PA, USA; Division of Transplant Surgery, The Pennsylvania State University, College of Medicine, Hershey, PA, USA.
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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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Harrington CR, Yang GY, Levitsky J. Advances in Rejection Management: Prevention and Treatment. Clin Liver Dis 2021; 25:53-72. [PMID: 33978583 DOI: 10.1016/j.cld.2020.08.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Extended survival of liver transplant recipients has brought rejection management to the forefront of liver transplant research. This article discusses T-cell-mediated rejection, antibody-mediated rejection, and chronic rejection. We focus on the prevention and then discuss treatment options. Future directions of rejection management include biomarkers of rejection, which may allow for monitoring of patients who are considered high risk for rejection and detection of rejection before there is any clinical evidence to improve graft and patient survival. With improved graft life and survival of liver transplant recipients, the new frontier of rejection management focuses on immunosuppression minimization, withdrawal, and personalization.
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Affiliation(s)
- Claire R Harrington
- Department of Medicine, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street, Suite 2330, Chicago, IL 60611, USA
| | - Guang-Yu Yang
- Department of Pathology, Northwestern University Feinberg School of Medicine, 251 E Huron St. Chicago, IL 60611, USA
| | - Josh Levitsky
- Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street, Suite 1400, Chicago, IL 60611, USA; Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street, Suite 1900, Chicago, IL 60611, USA.
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Sousa JM, Barrera L, Gomez-Bravo MA, Nuñez-Roldan A, Aguilera I. Glutathione S-Transferase T1 Mismatch Is a Risk Factor for Chronic Ductopenic Rejection of Liver Allografts. Liver Transpl 2020; 26:1287-1297. [PMID: 32510757 DOI: 10.1002/lt.25815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 05/12/2020] [Accepted: 05/26/2020] [Indexed: 01/13/2023]
Abstract
The underlying causes of chronic rejection (CR) after liver transplantation (LT) are not completely known. The main aim of this study was to explore the involvement of the minor histocompatibility antigen glutathione S-transferase T1 (GSTT1) in CR. We retrospectively studied 611 patients who underwent LTs at University Hospital Virgen del Rocío between 2003 and 2016 with a median follow-up of 7.4 ± 4.2 years. The GSTT1 genotype was determined by polymerase chain reaction. We defined GSTT1 mismatch as a specific donor/recipient combination in which a recipient who was homozygous for the deletion allele received a transplant from a positive donor. The prevalence of CR in our whole cohort was 11.6% (71/611), and the prevalence in the GSTT1-mismatched group was 18.8% (16/85) versus 10.5% (55/526) in the GSTT1-matched group. In the cyclosporine A (CsA) group, the prevalence was 26.3% (26/99), much higher than the 8.8% (45/512) observed in the tacrolimus (Tac) group. For statistical analysis, the patients were distributed into 2 groups: group 1, regarded as GSTT1 mismatched, which included the donor (D)+/recipient (R)- allelic combination; and group 2, regarded as GSTT1 matched, which included the other allelic combinations of D+/R+, D-/R-, and D-/R+. All relevant clinical information was collected, and a diagnosis of CR was always confirmed by liver biopsy. GSTT1 mismatch (hazard ratio [HR], 1.99; 95% confidence interval [CI], 1.08-3.66; P = 0.03) and use of CsA/Tac (P < 0.001) were independent risk factors for CR. CR increased the risk of mortality (HR, 2; 95% CI, 1.2-3.6; P = 0.01). Out of the 71 CR patients, 12 (16.9%) needed retransplantation. In conclusion, the GSTT1 D+/R- allelic mismatch is an independent risk factor for CR. A long follow-up of LT patients is recommended because the incidence of CR in adults seems to be underestimated.
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Affiliation(s)
- Jose Manuel Sousa
- Digestive Diseases Service, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocio, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Sevilla, Spain
| | - Lydia Barrera
- Liver Transplant Unit, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocio, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Sevilla, Spain
| | - Miguel Angel Gomez-Bravo
- Liver Transplant Unit, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocio, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Sevilla, Spain
| | - Antonio Nuñez-Roldan
- Immunology Laboratory, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocio, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Sevilla, Spain
| | - Isabel Aguilera
- Immunology Laboratory, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocio, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Sevilla, Spain
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Abstract
INTRODUCTION Liver transplantation is a life-changing event for patients and survival following transplantation has improved significantly since the first transplantation in 1967. Following liver transplantation, patients face a unique set of healthcare management decisions including transplantation-specific complications, recurrence of primary liver disease, as well as metabolic and malignancy concerns related to immunosuppression. As more patients with liver disease receive transplantation and live longer, understanding and managing these patients will require not only transplant specialist but also local subspecialist and primary care physicians. AREAS COVERED This review covers common issues related to the management of patients following liver transplantation including immunosuppression, liver allograft dysfunction, metabolic complications, as well as routine health maintenance such as immunizations and cancer screening. EXPERT OPINION Optimizing medical care for patients following liver transplant will benefit from ensuring all providers, not just transplant specialist, have a basic understanding of the common issues encountered in the post-transplant patient. This review provides an overview of common healthcare concerns and management options for patients following liver transplantation.
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Affiliation(s)
- Nicholas Hoppmann
- Division of Gastroenterology and Hepatology, University of Alabama at Birmingham , Birmingham, Alabama, USA
| | - Omar Massoud
- Division of Gastroenterology and Hepatology, University of Alabama at Birmingham , Birmingham, Alabama, USA
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14
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Choudhary NS, Saha SK, Saigal S, Gautam D, Saraf N, Rastogi A, Bhangui P, Thiagrajan S, Soin AS. Do Recipients of Genetically Related Donors Have Better Outcomes After Living Donor Liver Transplantation? J Clin Exp Hepatol 2020; 10:334-338. [PMID: 32655237 PMCID: PMC7335709 DOI: 10.1016/j.jceh.2019.12.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 12/16/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND There are few data on genetic relation of the donor and outcomes in living donor liver transplantation (LDLT) recipients. We compared outcomes of LDLT between recipients of genetically related and unrelated donors in a large single-center series. METHODS The study included 1372 adult, ABO-compatible, primary LDLT recipients, who received a graft from either a first-degree relative (parent, sibling, son, or daughter; n = 756) or unrelated donor (spouse or relative of the spouse; n = 616). RESULTS The mean age of the recipients with a related donor was 50.2 ± 10.8 years compared with 47.3 ± 9.3 years for recipients with unrelated donors (P = 0.000). Chronic rejection was significantly more common in the genetically unrelated donor group than in the genetically related donor group (28 [4.5%] versus 9 [1.1%]; P = 0.000) at a mean follow-up of 37 months (15-95 months). There were no significant differences in other outcomes between the 2 groups. The 12-month and 36-month survival between the unrelated and related groups was 87.6% versus 90%, and 86.3% versus 89.7% respectively (P = 0.115). The multivariate analysis revealed genetically unrelated donors (odds ratio [OR]: 3.88, 95% confidence interval [CI]: 1.80-8.34, P = 0.001) and history of acute cellular rejection (OR: 3.39, 95% CI: 1.68-6.81, P = 0.001) as predictors of chronic rejection. CONCLUSION Although chronic rejection was found to be more common in genetically unrelated donors, the patient survival after LDLT was similar.
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Affiliation(s)
- Narendra S. Choudhary
- Institute of Liver Transplantation and Regenerative Medicine, Medanta, the Medicity, India
| | - Sujeet K. Saha
- Institute of Liver Transplantation and Regenerative Medicine, Medanta, the Medicity, India
| | - Sanjiv Saigal
- Institute of Liver Transplantation and Regenerative Medicine, Medanta, the Medicity, India,Address for correspondence: Dr. Sanjiv Saigal Director, Transplant Hepatology Institute of Liver Transplantation and Regenerative Medicine, Medanta The Medicity, Gurgaon, 122001, India.
| | - Dheeraj Gautam
- Department of Histopathology, Medanta, the Medicity, Gurgaon, India
| | - Neeraj Saraf
- Institute of Liver Transplantation and Regenerative Medicine, Medanta, the Medicity, India
| | - Amit Rastogi
- Institute of Liver Transplantation and Regenerative Medicine, Medanta, the Medicity, India
| | - Prashant Bhangui
- Institute of Liver Transplantation and Regenerative Medicine, Medanta, the Medicity, India
| | - Srinivasan Thiagrajan
- Institute of Liver Transplantation and Regenerative Medicine, Medanta, the Medicity, India
| | - Arvinder S. Soin
- Institute of Liver Transplantation and Regenerative Medicine, Medanta, the Medicity, India
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15
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Jain A, Riley TR, Krok KL, Schreibman I, Karamchandani DM, Liao X, Tian Y, Dohi T, Kadry Z. Incidence of Post-Liver Transplant Hepatic Dysfunction After Sustained Virologic Response Following Direct-Acting Anti-Hepatitis C Therapy. EXP CLIN TRANSPLANT 2018; 18:345-352. [PMID: 30295586 DOI: 10.6002/ect.2018.0127] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Newly developed, direct-acting antiviral therapy is effective in over 90% of cases to eradicate hepatitis C virus infection. Direct-acting antiviral therapy is also effective in liver transplant recipients with recurrent hepatitis C virus infection. However, hepatic function after sustained virologic response in transplant recipients is unknown. Here, we aimed to uncover the incidence of hepatic dysfunction in this patient group at our center. MATERIALS AND METHODS Our study included 40 consecutive (January 2014 to February 2016) and compliant posttransplant recipients who achieved sustained viral response from direct-acting antiviral therapy. Patients were investigated for incidence and causes of hepatic dysfunction. RESULTS In our patient group, 4 (10%) experienced hepatic dysfunction with stable baseline immunosuppression, with 2 having drastic increases in alanine aminotransferase at 15 and 32 weeks after direct-acting antiviral therapy. Biopsies showed hepatitis, and both patients were treated with hydrocortisone, which increased their baseline immunosuppression. The 3rd patient had an increase in bilirubin at 21 weeks posttherapy, with biopsy showing macrovascular steatosis. The 4th patient had a rapid increase in bilirubin at 7 weeks after direct-acting antiviral therapy, with biopsy showing significant duct loss. CONCLUSIONS During the study period, 10% of patients experienced hepatic dysfunction after sustained viral response. Presumed causative factors included partial immune reconstitution and nonalcoholic fatty liver disease.
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Affiliation(s)
- Ashokkumar Jain
- From the Department of Surgery, The Pennsylvania State University, College of Medicine, Hershey, Pennsylvania, USA
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16
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Dayoub JC, Cortese F, Anžič A, Grum T, de Magalhães JP. The effects of donor age on organ transplants: A review and implications for aging research. Exp Gerontol 2018; 110:230-240. [PMID: 29935294 PMCID: PMC6123500 DOI: 10.1016/j.exger.2018.06.019] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 06/15/2018] [Accepted: 06/18/2018] [Indexed: 12/21/2022]
Abstract
Despite the considerable amount of data available on the effect of donor age upon the outcomes of organ transplantation, these still represent an underutilized resource in aging research. In this review, we have compiled relevant studies that analyze the effect of donor age in graft and patient survival following liver, kidney, pancreas, heart, lung and cornea transplantation, with the aim of deriving insights into possible differential aging rates between the different organs. Overall, older donor age is associated with worse outcomes for all the organs studied. Nonetheless, the donor age from which the negative effects upon graft or patient survival starts to be significant varies between organs. In kidney transplantation, this age is within the third decade of life while the data for heart transplantation suggest a significant effect starting from donors over age 40. This threshold was less defined in liver transplantation where it ranges between 30 and 50 years. The results for the pancreas are also suggestive of a detrimental effect starting at a donor age of around 40, although these are mainly derived from simultaneous pancreas-kidney transplantation data. In lung transplantation, a clear effect was only seen for donors over 65, with negative effects of donor age upon transplantation outcomes likely beginning after age 50. Corneal transplants appear to be less affected by donor age as the majority of studies were unable to find any effect of donor age during the first few years posttransplantation. Overall, patterns of the effect of donor age in patient and graft survival were observed for several organ types and placed in the context of knowledge on aging.
Data on the effects of donor age upon the outcomes of organ transplantation are an underutilized resource in biogerontology We compiled data on the effect of donor age following liver, kidney, pancreas, heart, lung and cornea transplantation Older donor age is associated with worse outcomes for all the organs studied The donor age from which the negative effects upon survival starts to be significant varies between organs
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Affiliation(s)
- Jose Carlos Dayoub
- Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, William Henry Duncan Building, Room 281, 6 West Derby Street, Liverpool L7 8TX, United Kingdom
| | - Franco Cortese
- Biogerontology Research Foundation, Research Department, Oxford, United Kingdom
| | - Andreja Anžič
- Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, William Henry Duncan Building, Room 281, 6 West Derby Street, Liverpool L7 8TX, United Kingdom
| | - Tjaša Grum
- Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, William Henry Duncan Building, Room 281, 6 West Derby Street, Liverpool L7 8TX, United Kingdom
| | - João Pedro de Magalhães
- Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, William Henry Duncan Building, Room 281, 6 West Derby Street, Liverpool L7 8TX, United Kingdom; Biogerontology Research Foundation, Research Department, Oxford, United Kingdom.
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17
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Zhu A, Leto A, Shaked A, Keating B. Immunologic Monitoring to Personalize Immunosuppression After Liver Transplant. Gastroenterol Clin North Am 2018; 47:281-296. [PMID: 29735024 DOI: 10.1016/j.gtc.2018.01.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
Although immunosuppressive drugs have enhanced patient outcomes in transplantation, the liver transplant community has made significant research efforts into the discovery of more accurate and precise methods of posttransplant monitoring and diagnosing. Current research in biomarkers reveals many promising approaches.
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Affiliation(s)
- Andrew Zhu
- Division of Transplantation, Department of Surgery, Penn Transplant Institute, The University of Pennsylvania, 3400 Spruce Street, Two Dulles Pavilion, Philadelphia, PA 19104, USA
| | - Alexandra Leto
- Division of Transplantation, Department of Surgery, Penn Transplant Institute, The University of Pennsylvania, 3400 Spruce Street, Two Dulles Pavilion, Philadelphia, PA 19104, USA
| | - Abraham Shaked
- Division of Transplantation, Department of Surgery, Penn Transplant Institute, The University of Pennsylvania, 3400 Spruce Street, Two Dulles Pavilion, Philadelphia, PA 19104, USA.
| | - Brendan Keating
- Division of Transplantation, Department of Surgery, Penn Transplant Institute, The University of Pennsylvania, 3400 Spruce Street, Two Dulles Pavilion, Philadelphia, PA 19104, USA
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18
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Neves Souza L, de Martino RB, Sanchez-Fueyo A, Rela M, Dhawan A, O'Grady J, Heaton N, Quaglia A. Histopathology of 460 liver allografts removed at retransplantation: A shift in disease patterns over 27 years. Clin Transplant 2018; 32:e13227. [DOI: 10.1111/ctr.13227] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/19/2018] [Indexed: 12/25/2022]
Affiliation(s)
| | - Rodrigo Bronze de Martino
- Institute of Liver Studies; King's College Hospital; London UK
- Faculdade de Medicina; Departamento de Gastroenterologia; Hospital das Clínicas; Universidade de São Paulo; São Paulo Brazil
| | | | - Mohamed Rela
- Institute of Liver Studies; King's College Hospital; London UK
- Institute of Liver Disease and Transplantation; Global Health City; Chennai India
| | - Anil Dhawan
- Paediatric Liver Centre; King's College Hospital; London UK
| | - John O'Grady
- Institute of Liver Studies; King's College Hospital; London UK
| | - Nigel Heaton
- Institute of Liver Studies; King's College Hospital; London UK
| | - Alberto Quaglia
- Institute of Liver Studies; King's College Hospital; London UK
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19
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Choudhary NS, Saraf N, Saigal S, Gautam D, Rastogi A, Goja S, Bhangui P, Srinivasan T, Yadav SK, Soin A. Revisiting chronic rejection following living donor liver transplantation in the tacrolimus era: A single center experience. Clin Transplant 2018; 32. [DOI: 10.1111/ctr.13161] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/12/2017] [Indexed: 01/02/2023]
Affiliation(s)
- Narendra Singh Choudhary
- Institute of Liver Transplantation and Regenerative Medicine; Medanta, The Medicity; Gurgaon India
| | - Neeraj Saraf
- Institute of Liver Transplantation and Regenerative Medicine; Medanta, The Medicity; Gurgaon India
| | - Sanjiv Saigal
- Institute of Liver Transplantation and Regenerative Medicine; Medanta, The Medicity; Gurgaon India
| | - Dheeraj Gautam
- Department of Histopathology; Medanta, The Medicity; Gurgaon India
| | - Amit Rastogi
- Institute of Liver Transplantation and Regenerative Medicine; Medanta, The Medicity; Gurgaon India
| | - Sanjay Goja
- Institute of Liver Transplantation and Regenerative Medicine; Medanta, The Medicity; Gurgaon India
| | - Prashant Bhangui
- Institute of Liver Transplantation and Regenerative Medicine; Medanta, The Medicity; Gurgaon India
| | - Thiagrajan Srinivasan
- Institute of Liver Transplantation and Regenerative Medicine; Medanta, The Medicity; Gurgaon India
| | - Sanjay Kumar Yadav
- Institute of Liver Transplantation and Regenerative Medicine; Medanta, The Medicity; Gurgaon India
| | - Arvinder Soin
- Institute of Liver Transplantation and Regenerative Medicine; Medanta, The Medicity; Gurgaon India
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20
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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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21
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Cheung A, Levitsky J. Follow-up of the Post-Liver Transplantation Patient: A Primer for the Practicing Gastroenterologist. Clin Liver Dis 2017; 21:793-813. [PMID: 28987263 DOI: 10.1016/j.cld.2017.06.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The focus in liver transplantation in the next 10 years will likely change from preventing viral disease recurrence to minimizing the toll of rejection and fatty liver disease, minimizing the complications from immunosuppression with withdrawal strategies, and more optimal management of long-term risks, such as malignancy, cardiovascular disease, and renal failure. In addition, now that short-term results (<1 year) have improved significantly, there will be a shift toward improving long-term patient and graft survival, as well as a focus on primary care preventive strategies.
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Affiliation(s)
- Amanda Cheung
- Division of Gastroenterology and Hepatology, Northwestern University, 676 North Saint Clair, Suite 1400, Chicago, IL 60611, USA
| | - Josh Levitsky
- Division of Gastroenterology and Hepatology, Northwestern University, 676 North Saint Clair, Suite 1400, Chicago, IL 60611, USA.
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22
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Filipec Kanizaj T, Mijic M. Inflammatory bowel disease in liver transplanted patients. World J Gastroenterol 2017; 23:3214-3227. [PMID: 28566881 PMCID: PMC5434427 DOI: 10.3748/wjg.v23.i18.3214] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 04/13/2017] [Accepted: 04/21/2017] [Indexed: 02/06/2023] Open
Abstract
Most common hepatobiliary manifestation of inflammatory bowel disease (IBD) are primary sclerosing cholangitis (PSC) and autoimmune hepatitis, ranking them as the main cause of liver transplantation (LT) in IBD setting. Course of pre-existing IBD after LT differs depending on many transplant related factors. Potential risk factors related to IBD deterioration after LT are tacrolimus-based immunosuppressive regimens, active IBD and cessation of 5-aminosalicylates at the time of LT. About 30% patients experience improvement of IBD after LT, while approximately the same percentage of patients worsens. Occurrence of de novo IBD may develop in 14%-30% of patients with PSC. Recommended IBD therapy after LT is equivalent to recommendations to overall IBD patients. Anti-tumor necrosis factor alpha appears to be efficient for refractory IBD. Due to potential side effects it needs to be applied with caution. In average 9% of patients require proctocolectomy due to medically refractory IBD or colorectal carcinoma. The most frequent complication in patients who undergo proctocolectomy with ileal-pouch anal anastomosis is pouchitis. It is still undeterminable if LT adds to risk of developing pouchitis in PSC patients. Annual colonoscopies are recommended as surveillance and precaution of colonic malignancies.
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23
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The Role of Humoral Alloreactivity in Liver Transplantation: Lessons Learned and New Perspectives. J Immunol Res 2017; 2017:3234906. [PMID: 28164136 PMCID: PMC5253491 DOI: 10.1155/2017/3234906] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 12/19/2016] [Indexed: 12/13/2022] Open
Abstract
More than ten years after the initial description of the humoral theory of transplantation by Dr. Paul I. Terasaki, the significance of humoral alloimmunity in liver transplantation has yet to be clearly defined. The liver allograft has an inherent tolerogenic capacity which confers its resistance to cell-mediated as well as antibody-mediated rejection. Nevertheless, the protection against alloimmunity is not complete, and antibody-mediated tissue injury can occur in the liver graft under specific circumstances. In this article the evidence on the clinicopathologic effects of donor-specific alloantibodies in liver transplantation will be examined and interpreted in parallel with lessons learned from renal transplantation. The unique anatomic and immunologic features of the liver will be reviewed to gain new insights into the complex interactions between humoral immune system and the liver allograft.
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24
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Tannuri ACA, Lima F, de Mello ES, Tanigawa RY, Tannuri U. Prognostic factors for the evolution and reversibility of chronic rejection in pediatric liver transplantation. Clinics (Sao Paulo) 2016; 71:216-20. [PMID: 27166772 PMCID: PMC4825201 DOI: 10.6061/clinics/2016(04)07] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 02/01/2016] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Chronic rejection remains a major cause of graft failure with indication for re-transplantation. The incidence of chronic rejection remains high in the pediatric population. Although several risk factors have been implicated in adults, the prognostic factors for the evolution and reversibility of chronic rejection in pediatric liver transplantation are not known. Hence, the current study aimed to determine the factors involved in the progression or reversibility of pediatric chronic rejection by evaluating a series of chronic rejection cases following liver transplantation. METHODS Chronic rejection cases were identified by performing liver biopsies on patients based on clinical suspicion. Treatment included maintaining high levels of tacrolimus and the introduction of mofetil mycophenolate. The children were divided into 2 groups: those with favorable outcomes and those with adverse outcomes. Multivariate analysis was performed to identify potential risk factors in these groups. RESULTS Among 537 children subjected to liver transplantation, chronic rejection occurred in 29 patients (5.4%). In 10 patients (10/29, 34.5%), remission of chronic rejection was achieved with immunosuppression (favorable outcomes group). In the remaining 19 patients (19/29, 65.5%), rejection could not be controlled (adverse outcomes group) and resulted in re-transplantation (7 patients, 24.1%) or death (12 patients, 41.4%). Statistical analysis showed that the presence of ductopenia was associated with worse outcomes (risk ratio=2.08, p=0.01). CONCLUSION The presence of ductopenia is associated with poor prognosis in pediatric patients with chronic graft rejection.
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Abstract
PURPOSE OF REVIEW Liver allograft antibody-mediated rejection (AMR) studies have lagged behind parallel efforts in kidney and heart because of a comparative inherent hepatic resistance to AMR. Three developments, however, have increased interest: first, solid phase antibody testing enabled more precise antibody characterization; second, increased expectations for long-term, morbidity-free survival; and third, immunosuppression minimization trials. RECENT FINDINGS Two overlapping liver allograft AMR phenotypic expressions are beginning to emerge: acute and chronic AMR. Acute AMR usually occurs within the several weeks after transplantation and characterized clinically by donor-specific antibodies (DSA) persistence, allograft dysfunction, thrombocytopenia, and hypocomplementemia. Acute AMR appears histopathologically similar to acute AMR in other organs: diffuse microvascular endothelial cell hypertrophy, C4d deposits, neutrophilic, eosinophilic, and macrophag-mediated microvasculitis/capillaritis, along with liver-specific ductular reaction, centrilobular hepatocyte swelling, and hepatocanalicular cholestasis often combined with T-cell-mediated rejection (TCMR). Chronic AMR is less well defined, but strongly linked to serum class II DSA and associated with late-onset acute TCMR, fibrosis, chronic rejection, and decreased survival. Unlike acute AMR, chronic AMR is a slowly evolving insult with a number of potential manifestations, but most commonly appears as low-grade lymphoplasmacytic portal and perivenular inflammation accompanied by unusual fibrosis patterns and variable microvascular C4d deposition; capillaritis can be more difficult to identify than in acute AMR. SUMMARY More precise DSA characterization, increasing expectations for long-term survival, and immunosuppression weaning precipitated a re-emergence of liver allograft AMR interest. Pathophysiological similarities exist between heart, kidney, and liver allografts, but liver-specific considerations may prove critical to our ultimate understanding of all solid organ AMR.
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Abstract
Advances in pharmacologic immunosuppression are responsible for the excellent outcomes experienced by recipients of liver transplants. However, long-term follow-up of these patients reveals an increasing burden of morbidity and mortality that is attributable to these drugs. The authors summarize the agents used in contemporary liver transplantation immunosuppression protocols and discuss the emerging trend within the community to minimize or eliminate these agents from use. The authors present recently published data that may provide the foundation for immunosuppression minimization or tolerance induction in the future and review studies that have focused on the utility of biomarkers in guiding immunosuppression management.
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One thousand consecutive primary liver transplants under tacrolimus immunosuppression: a 17- to 20-year longitudinal follow-up. Transplantation 2011; 91:1025-30. [PMID: 21378604 DOI: 10.1097/tp.0b013e3182129215] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Tacrolimus has proven to be a potent immunosuppressive agent in orthotopic liver transplantation (OLT). The aim of this study is to examine its long-term efficacy and safety. METHODS AND RESULTS One thousand consecutive primary OLTs performed between August 1989 and December 1992 and maintained under tacrolimus-based immunosuppression were followed up until January 2009. Patient and graft survivals with corresponding causes of death and retransplantation, maintenance immunosuppression, and adverse effects were examined. The study population includes 600 males and 400 females comprising 166 children, 630 adults, and 204 seniors. The mean follow-up was 17.83 (range, 16.1-19.50) years. The overall 20-year actuarial patient and graft survivals were 35.8% and 32.6%, respectively. At the last follow-up, 442 patients were alive; 133 (77.1%) children, 265 (34.5%) adults, and 44 (16.1%) seniors (P=0.0001). After the first post-OLT year, cardiopulmonary events, recurrence of primary disease, and malignancy were the main causes of death. Overall, 183 recipients underwent retransplants; mainly for primary nonfunction, hepatic artery thrombosis, and recurrent primary disease, 180 required dialysis, and 45 underwent kidney transplant. A total of 97.7% of the survivors were on tacrolimus and 26.2% were also receiving adjunctive immunosuppressants at the last follow-up. CONCLUSIONS The overall 20-year actuarial patient and graft survivals were 35.8% and 32.6%, respectively, with significantly better survival among children. Age-related complications, recurrence of primary disease, and malignancy were the major causes of late graft loss. Graft loss related to immunologic reasons was rare. The prevention of recurrent disease and newer immunosuppressive regimen will further improve these results.
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28
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Bellizzi AM, LeGallo RD, Boyd JC, Iezzoni JC. Hepatocyte cytokeratin 7 expression in chronic allograft rejection. Am J Clin Pathol 2011; 135:238-44. [PMID: 21228364 DOI: 10.1309/ajcpnrxcap92knoj] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
We examined hepatocyte cytokeratin 7 (CK7) expression in chronic allograft rejection (CR), a ductopenic condition in which this has not been systematically evaluated, in 20 patients with the clinicopathologic diagnosis of CR and age-, sex-, and native-disease-matched control subjects. We also studied baseline biopsy specimens from both groups. Three pathologists independently reviewed H&E- and CK7-stained sections, counting interlobular bile ducts (BDs) and portal tracts (PTs), noting the morphologic pattern of injury and scoring hepatocyte CK7 expression (0, none; 1+, rare; 2+, multifocal, predominantly periportal; 3+, extension into the lobule; 4+, diffuse). Mean BD/PT ratios and CK7 scores were calculated. The mean BD/PT ratio (0.58) and CK7 score (1.01) for the "CR, diagnostic" group were significantly different from all other group means (P < .05); no other comparisons were significant (P > .05). A CK7 score of 1 or more was observed in 9 (56%) of 16 CR specimens and in 3 (7%) of 41 remaining specimens. Hepatocyte CK7 expression is frequently noted in CR, and it would appear to reflect ductopenia. CK7 staining may be a useful diagnostic adjunct in evaluation of transplant liver biopsy specimens.
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Affiliation(s)
- Andrew M. Bellizzi
- Departments of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | | | - James C. Boyd
- University of Virginia Health System, Charlottesville
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29
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Abstract
Liver transplantation is currently the definitive treatment of end-stage liver disease. This article reviews the complex multidisciplinary care of the liver transplant recipient beginning immediately after transplantation but extending into the long term. The presentation, evaluation and treatment of common post-transplant complications are outlined. Importantly, immunosuppression strategies along with the issues of acute and chronic rejection are discussed in detail with an emphasis on how practice has evolved over time. The spectrum of infectious problems is systematically presented, based on the time since transplantation and the institution of immunosuppression. Finally, the substantial challenges of recurrent disease and long-term medical comorbidities are addressed as these are clearly the primary issues that threaten the longevity and wellbeing of the liver transplant recipient.
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Affiliation(s)
- Bruce Gelb
- Division of Transplantation, Department of Surgery, UCSF Medical Center, San Francisco, CA, USA
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30
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Rouyer O, Talha S, Di Marco P, Ellero B, Doutreleau S, Diemunsch P, Piquard F, Geny B. Lack of endothelial dysfunction in patients under tacrolimus after orthotopic liver transplantation. Clin Transplant 2009; 23:897-903. [DOI: 10.1111/j.1399-0012.2009.01013.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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31
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Abstract
Liver transplantation has become a lifesaving procedure for patients who have chronic end-stage liver disease and acute liver failure. The satisfactory outcome of liver transplantation has led to insufficient supplies of deceased donor organs, particularly in East Asia. Hence, East Asian surgeons are concentrating on developing and performing living-donor liver transplantation (LDLT). This review article describes an update on the present status of liver transplantation, mainly in adults, and highlights some recent developments on indications for transplantation, patient selection, donor and recipient operation between LDLT and deceased-donor liver transplantation (DDLT), immunosuppression, and long-term management of liver transplant recipients. Currently, the same indication criteria that exist for DDLT are applied to LDLT, with technical refinements for LDLT. In highly experienced centers, LDLT for high-scoring (>30 points) Model of End-Stage Liver Disease (MELD) patients and acute-on-chronic liver-failure patients yields comparably good outcomes to DDLT, because timely liver transplantation with good-quality grafting is possible. With increasing numbers of liver transplantations and long-term survivors, specialized attention should be paid to complications that develop in the long term, such as chronic renal failure, hypertension, diabetes mellitus, dyslipidemia, obesity, bone or neurological complications, and development of de novo tumors, which are highly related to the immunosuppressive treatment.
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Affiliation(s)
- Deok-Bog Moon
- Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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33
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Lladó L, Fabregat J, Castellote J, Ramos E, Torras J, Serrano T, Figueras J, Rafecas A. Sirolimus-based rescue therapy after rejection in liver transplantation. Clin Transplant 2009; 23:89-95. [PMID: 19200220 DOI: 10.1111/j.1399-0012.2008.00906.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Steroid-resistant acute rejection (SR-AR) and ductopenic rejection (DR) after liver transplantation are infrequent, but difficult to manage. We performed a retrospective review of patients with SR-AR or DR treated with sirolimus-based therapy. Since 2002, we have treated five patients with SR-AR and eight patients with DR. All patients had associated renal insufficiency. Six patients showed no response, of whom five died and one was retransplanted. In six cases, rejection was resolved after changing, while one improved. Therefore, the total response rate was 54%. Ten of 13 patients (77%) suffered some type of adverse event. Ten of these (77%) suffered a hematologic event. Four patients (31%) had infection. Only two patients had to discontinue treatment. Univariate analysis showed that pre-conversion bilirubin was lower in responders (Bilirubin: R: 210 +/- 205 vs. NoR: 554 +/- 159 micromol/L; p = 0.07 and Creatinine clearance higher: R: 37 +/- 11 vs. NoR: 25 +/- 11 mL/min; p = 0.09). Sirolimus trough levels one month after switching were higher in responders (R: 11 +/- 1.8 vs. NoR: 7.5 +/- 3.3 ng/mL; p = 0.03). We conclude that a dual therapy regimen of tacrolimus and sirolimus can achieve a high response rate as a rescue therapy for SR-AR and DR, provided it is begun as soon as possible.
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Affiliation(s)
- Laura Lladó
- Department of Surgery, Liver Transplant Unit Hospital, Universitari de Bellvitge, Barcelona, Spain.
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Jain A, Patil VP, Fung J. Incidence of de novo cancer and lymphoproliferative disorders after liver transplantation in relation to age and duration of follow-up. Liver Transpl 2008; 14:1406-11. [PMID: 18825680 DOI: 10.1002/lt.21609] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Shi XL, Ding YT, Wu YF, Wu XY, Qiu YD, Zhou JX, Jiang CP, Zhang WW. Etiological diagnosis and management of chronic graft dysfunction after liver transptantation: an analysis of 18 cases. Shijie Huaren Xiaohua Zazhi 2008; 16:2669-2672. [DOI: 10.11569/wcjd.v16.i23.2669] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze the etiology, diagnosis and management of chronic graft dysfunction after liver transplantation.
METHODS: A total of 291cases underwent orthotopic liver transplantation in our hospital from Janunary 1996 to December 2006. The clinical data of 18 cases with chronic graft dysfunction after liver transplantation were analyzed retrospectively.
RESULTS: Of 18 patients with chronic graft dysfunction after liver transplantation, 2 were found with recurrent biliary inflammation, 2 with biliary sludge, 1 with anastomotic biliary stricture, 4 with nonanastomotic biliary stricture, 3 with reccurent hepatitis B, 1 with recurrent hepatitis C, 1 with recurrent primary biliary cirrhosis, 1with hepatic artery stricture, 1 with cytomegalovirus (CMV) infection and 2 with chronic rejection. After different medical support treatment, intervention or liver re-transplantation, 11 patients were improved, and 4 cases were found with recurrent diseases. The rest 3 cases died.
CONCLUSION: Different therapeutic approaches may be taken in accordance with different causes of chronic graft dysfunction after liver transplantation. For irreversible hepatic allograft failure, liver re-transplantation should be carried out.
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Pharmacokinetics of Tacrolimus in Living Donor Liver Transplant and Deceased Donor Liver Transplant Recipients. Transplantation 2008; 85:554-60. [PMID: 18347534 DOI: 10.1097/tp.0b013e3181642c95] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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Gaynor JJ, Moon JI, Kato T, Nishida S, Selvaggi G, Levi DM, Island ER, Pyrsopoulos N, Weppler D, Ganz S, Ruiz P, Tzakis AG. A cause-specific hazard rate analysis of prognostic factors among 877 adults who received primary orthotopic liver transplantation. Transplantation 2007; 84:155-65. [PMID: 17667806 DOI: 10.1097/01.tp.0000269090.90068.0f] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND In orthotopic liver transplantation (OLT) distinct causes of graft failure (GF) and death with a functioning graft (DFG) exist. Prognostic factors for one failure type may be distinctly different from those predictive of other types, and an accurate portrayal of these relationships may more clearly explain each factor's importance. METHODS A multivariable cause-specific hazard (CSH) rate analysis using Cox stepwise regression was performed among 877 adults who received primary OLT during 1996-2004 with tacrolimus+steroids as immunosuppression. RESULTS Older donor age (P=0.004) implied greater primary dysfunction GF, while primary sclerosing cholangitis (PSC; P=0.0002) implied greater vascular thrombosis GF. Recurrent nonmalignant liver disease GF was higher among hepatitis C virus patients (P<0.00001), and younger recipient age (P=0.005) implied greater death from recurrent (metastatic) hepatocellular carcinoma. African-American race (P<0.00001), PSC (P=0.003), and younger recipient age (P=0.005) were independently associated with greater GF due to chronic rejection. Older donor age (P=0.003) implied greater infection DFG, while older recipient age (P=0.003) and pretransplant diabetes (P=0.03) were independently associated with greater cardiovascular/cerebrovascular DFG. Finally, most of these cause-specific predictors were not significant in an overall Cox model for graft survival. CONCLUSIONS The CSH approach should be more widely used in investigations of prognostic factors. The result of older donor age implying greater primary dysfunction GF and infection DFG but having no association with other failure types demonstrates that its impact is specific to the graft's early posttransplant functional status. In addition, while recipient age was an important prognosticator, its direction of association reverses depending upon the outcome being analyzed.
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Affiliation(s)
- Jeffrey J Gaynor
- Department of Surgery, University of Miami School of Medicine, Miami, FL, 33101, USA.
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Jain A, Ryan C, Mohanka R, Orloff M, Abt P, Romano J, Bryan L, Batzold P, Mantry P, Bozorgzadeh A. Characterization of CD4, CD8, CD56 positive lymphocytes and C4d deposits to distinguish acute cellular rejection from recurrent hepatitis C in post-liver transplant biopsies. Clin Transplant 2007; 20:624-33. [PMID: 16968489 DOI: 10.1111/j.1399-0012.2006.00528.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Hepatitis C viral (HCV) infection is the most common cause for liver transplantation (LTx) in USA. Hepatitis C viral recurrence in liver allograft is almost universal, which is often difficult to distinguish from acute cellular rejection (ACR). AIM Aim of the present study is to examine the differences between distribution of CD4, CD8, CD56 positive lymphocytes, and C4d deposits in patients with ACR and recurrent HCV. PATIENTS AND METHODS As a pilot project, a group of five post-LTx HCV RNA negative patients, strongly suspicious for ACR based on clinical findings and history of medication non-compliance and another group of five post-LTx HCV positive, medication compliant patients with abnormal liver function were retrospectively selected. Liver biopsies of these patients were stained with monoclonal CD4, CD8, CD56, and polyclonal C4d antibodies and compared. RESULTS Mean CD4, CD8, and CD56 counts in ACR group were 156.7 +/- 17.6, 35.4 +/- 8.8, and 1.0 +/- 1.8/HPF, respectively and were 89.7 +/- 41.3, 20.3 +/- 23.2, and 0.6 +/- 0.9/HPF, respectively in HCV recurrence group. Biopsies of four of five patients with ACR demonstrated moderate to strong C4d staining, whereas all patients with recurrent HCV had none to mild C4d staining. CONCLUSION Mean CD4, CD8, and CD56 were similar for acute rejection and recurrent HCV infection. However, 80% of patients with ACR showed moderate to strong staining for C4d and all recurrent HCV patients showed none to mild C4d staining.
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Affiliation(s)
- Ashok Jain
- Department of Surgery, Division of Transplantation, University of Rochester Medical Center, Rochester, NY 14642, USA.
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Verdonk RC, Dijkstra G, Haagsma EB, Shostrom VK, Van den Berg AP, Kleibeuker JH, Langnas AN, Sudan DL. Inflammatory bowel disease after liver transplantation: risk factors for recurrence and de novo disease. Am J Transplant 2006; 6:1422-9. [PMID: 16686766 DOI: 10.1111/j.1600-6143.2006.01333.x] [Citation(s) in RCA: 116] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Inflammatory bowel disease (IBD) is associated with primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) and can recur or develop de novo after orthotopic liver transplantation (OLT). The aim of this study was to investigate the incidence and severity of IBD after liver transplantation and to perform a multivariate analysis for possible risk factors. In this retrospective study, 91 patients transplanted for PSC or AIH, without prior colectomy, were included. Sixty patients were transplanted for PSC, 31 for AIH. IBD activity before and after OLT and other possible risk factors were analysed in a multivariate model. Forty-nine patients (54%) had IBD before OLT. Forty patients (44%) had active IBD after transplantation: recurrence in 32 and de novo in 8. Cumulative risk for IBD after OLT was 15, 39 and 54% after 1, 5 and 10 years, respectively. In 59% of patients with IBD prior to OLT the disease was more active after transplantation. Risk factors for recurrent disease were: symptoms at time of OLT, short interval of IBD before OLT and use of tacrolimus. 5-aminosalicylates were protective. A cytomegalovirus positive donor/negative recipient combination increased the risk for de novo IBD.
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Affiliation(s)
- R C Verdonk
- Department of Surgery, Section of Transplant Surgery, University of Nebraska Medical Center, Omaha, Nebraska, USA.
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Jain A, Costa G, Marsh W, Fontes P, Devera M, Mazariegos G, Reyes J, Patel K, Mohanka R, Gadomski M, Fung J, Marcos A. Thrombotic and nonthrombotic hepatic artery complications in adults and children following primary liver transplantation with long-term follow-up in 1000 consecutive patients*. Transpl Int 2006; 19:27-37. [PMID: 16359374 DOI: 10.1111/j.1432-2277.2005.00224.x] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Arterial complications have a major impact on survival after liver transplantation (LTx). The aim of this study was to examine arterial complications in adults and children after LTx. A total of 1000 consecutive primary LTx patients [mean age 40.5 years: 600 males, 400 females, 834 adults; 166 children (age <18 years)] were studied. Forty-two patients (4.2%; 31 adults, 11 children) developed hepatic artery thrombosis (HAT). Thrombosis in children occurred significantly early (mean 5.4 days) compared with adults (mean 418.7 days, P = 0.0001). Nonthrombotic complications occurred in 30 patients (29 adults, one child). Overall, 13-year patient survival after HAT was 43.2% (72.7% children, 32.9% adults). For nonthrombotic complications, 54.3% of adults died and 69.4% grafts were lost. An overall incidence of 4.2% thrombotic and 3.2% nonthrombotic complications was observed. Rate of HAT was higher in children, but survival was better compared with adults.
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Affiliation(s)
- Ashokkumar Jain
- Department of Surgery, Division of Transplantation, University of Rochester Medical Centre, Rochester, NY 14642, USA.
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Jain A, Vekatramanan R, Eghtesad B, Gadomski M, Mohanka R, Marcos A, Fung J. Long-term outcome of adding mycophenolate mofetil to tacrolimus for nephrotoxicity following liver transplantation. Transplantation 2005; 80:859-64. [PMID: 16210976 DOI: 10.1097/01.tp.0000173994.63299.63] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Mycophenolate mofetil (MMF) has no known nephrotoxicity. This report examines the outcome in patients who received MMF for renal impairment on tacrolimus-based immunosuppression. From 1995 to 1996, twelve liver transplantation (LTx) patients (mean age 54.6 years) with serum creatinine >1.8 mg/dl were included in the study. MMF was introduced and tacrolimus dose was reduced by 30-50%. Each patient was followed for 6 years. Renal function showed improvement in seven patients, deterioration in four, and no change in one patient. Overall mean serum creatinine decreased from 2.5 to 1.9 mg/dl at 6 months but increased to 2.2 mg/dl at 18 to 24 months. After that, renal function remained stable for 72 months. Iothalamate clearance showed 18.5% improvement at 1 year. Three patients developed renal failure. Six patients died in the follow-up period. Addition of MMF with reduced tacrolimus dose resulted in sustained improvement in renal function in 58% of patients.
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Affiliation(s)
- Ashokkumar Jain
- Department of Surgery, Transplant Division, Strong Memorial Hospital, University of Rochester, Rochester, NY 14642, USA.
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Aydogdu S, Arikan C, Kilic M, Ozgenc F, Akman S, Unal F, Yagci RV, Tokat Y. Outcome of pediatric liver transplant recipients in Turkey: single center experience. Pediatr Transplant 2005; 9:723-8. [PMID: 16269042 DOI: 10.1111/j.1399-3046.2005.00366.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
To summarize the evolution of the pediatric liver transplant program in a developing country. Between April 1997, and September 2003, 32 cadaveric (CD) and 35 living donor (LD) liver transplantations were performed on 61 children (median age 3.8 yr, range 0.5-16) at Ege University Organ Transplantation and Research Center. The patient's charts were reviewed retrospectively. The outcome of patient and graft survival was analyzed and the incidence of graft loss, complications and rejections was calculated. Indications for liver transplantation were metabolic liver disease (n = 17), biliary atresia (n = 14), viral hepatitis (n = 4), autoimmune hepatitis (n = 6), cryptogenic cirrhosis (n = 11), fulminant liver failure (n = 5) and others (n = 5). Seven of 61 children with chronic liver disease had hepatocellular carcinoma concomitantly. Median pediatric end-stage liver disease score was 23 (range 1-54). Seven children (11.4%) were UNOS status I, 44 (72%) were UNOS status II and 10 (16.6%) were UNOS status III. The median follow-up of the study population was 3.6 yr (range 0.5-6). Actuarial patient survival rates at 1, 2, 3 and 4 yr were 86, 86, 71.3 and 65% in the CD group vs. 80, 76, 67 and 67% in the LR group, respectively (p = NS). Patients listed as UNOS status 1 had lower survival rates than patients listed as UNOS status 2 and 3 (p < 0.05). The mortality rate was 26.2%. Graft survival rates were 81, 81, 75 and 64% at 1, 2, 3 and 4-yr respectively. Six patients (9%) underwent retransplantation. The main complications were infections (64.7%) and surgical complications (43.2%) (including biliary complication, vascular problems, postoperative bleeding, small for size and large for size). The incidence of acute cellular rejection was 39.3%, whereas chronic rejection was 7.4%. The result of liver transplantation in Turkish children was slightly inferior to those reported for North American and European children. However, an important characteristic of these patients that distinguishes them from Europe and North America is that most were UNOS status IIa and UNOS status I (44%). Despite technical and medical progress, infectious and biliary problems have continued to be an important cause of mortality in these patients.
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Affiliation(s)
- S Aydogdu
- Department of Pediatrics, Division of Gastroenterology, Ege University School of Medicine, Izmir, Turkey
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Affiliation(s)
- Lois E Krahn
- Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Scottsdale, AZ 85259, USA.
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Jain A, Orloff M, Abt P, Kashyap R, Mohanka R, Lansing K, Bozorgzadeh A. Transplantation of Liver Grafts From Older Donors: Impact on Recipients With Hepatitis C Virus Infection. Transplant Proc 2005; 37:3162-4. [PMID: 16213337 DOI: 10.1016/j.transproceed.2005.07.050] [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: 01/22/2023]
Abstract
INTRODUCTION Older donor allografts are being accepted for liver transplantation (LTx) due to shortage of organs. Hepatitis C virus (HCV) infection-related disease is presently the most common indication of LT in the United States. We studied the impact of donor age on patient and graft survivals in patients with HCV infection. PATIENTS AND METHODS One hundred fifty four consecutive HCV(+) LTx recipients (117 men, 37 women) were studied. The mean follow-up period was 41.0 +/- 30.2 months. The population was divided into four groups according to donor age: group I (< or =20 years); group II (21 to 40 years); group III (41 to 60 years); group IV (>60 years). RESULTS Thirty-two (20.8%) patients died during follow-up and 16 patients (10.4%) required retransplantation. The actuarial 7-year patient survivals for groups I, II, III, and IV were 87.1%, 73.7%, 69.3%, and 68.5%, respectively (P = .4). Patient survivals for donor age groups III + IV (n = 95) and groups I + II (n = 59) were 68.9% and 77.2%, respectively (P = .19). The 7-year graft survivals for groups I, II, III, and IV were 82.7%, 71.8%, 65.8%, and 62.5%, respectively (P = .17). Graft survivals for groups III + IV and groups I + II were 58.4% and 76.2%, respectively (P = .03). CONCLUSION Patient and graft survivals for HCV-positive liver transplant recipients in this study decreased progressively as the donor age increased. Patient and graft survivals were best for group I recipients. There were significant differences in graft survivals when recipients were grouped with a cutoff donor age of 40 years.
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Affiliation(s)
- A Jain
- Department of Surgery, Division of Transplantation, University of Rochester Medical Centre, Rochester, New York 14642, USA.
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Jain A, Marcos A, Reyes J, Mazariagos G, Kashyap R, Eghtesad B, Marsh W, Fontas P, De Vera M, Costa G, Patel K, Gadomski M, Starzl T, Fung J. Tacrolimus for Primary Liver Transplantation: 12 to 15 Years Actual Follow-Up With Safety Profile. Transplant Proc 2005; 37:1207-10. [PMID: 15848671 DOI: 10.1016/j.transproceed.2004.12.077] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
BACKGROUND Tacrolimus has been increasingly used for liver transplantation during the last decade. The drug has immunological advantages in short- to medium-term follow-up. However, data on longitudinal follow-up are lacking. AIM The aim of the present report was to examine the impact of tacrolimus in primary adult and pediatric liver transplantation (LTx) patients. MATERIAL AND METHOD One thousand consecutive primary LTx patients were performed under tacrolimus between August 1989 and December 1992 were followed up until August 2004. Mean follow-up was 13.4 +/- 0.92 (range, 11.7-15) years. There were 600 males and 400 females with a mean age of 42.6 +/- 20.2 years. There were 166 children (age 18 years or younger) and 834 adults, of whom 204 were older than 60 years (seniors). RESULTS Four hundred ninety-seven (49.7%) patients died in the follow-up period. The overall 15-year actuarial patient survival rate was 51.4%. The survival rate for children was significantly better (81.3%) compared with adults (47.5%) and seniors (36.4%) (P = .0001). One hundred fifty-one patients received a second LTx, 22 patients received a third LTx, and 4 patients received a fourth LTx. Over all 15 years the actuarial graft survival rate was 46.1%. At last follow-up, 69.1% of patients were off steroids. The majority of late deaths were due to age-related complications, recurrence of disease, and De novo cancers. CONCLUSION The data on longitudinal follow-up have shown actuarial survival for children to be significantly better than in adults and seniors. Graft loss from immunological causes are rare even with long-term follow-up.
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Affiliation(s)
- A Jain
- Strong Memorial Hospital, Department of Surgery, Transplant Division, University of Rochester, Rochester, NY 14642, USA.
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Abstract
Once regarded as a last-resort therapy for patients with end-stage liver disease, liver transplantation has become a viable therapeutic option because of sweeping improvements in surgical techniques and the development of more powerful immunosuppressive agents. The addition of tacrolimus to the immunosuppression regimen represents a highly potent therapy and a powerful defense against acute rejection. In the decade since tacrolimus was approved for use in the United States, it has become a widely used immunosuppressant in the field of liver transplantation.
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Affiliation(s)
- Ronald W Busuttil
- Division of Liver and Pancreas Transplant, Department of Surgery, UCLA School of Medicine, Los Angeles, CA, USA
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Strong C. Should we be putting a good face on facial transplantation? THE AMERICAN JOURNAL OF BIOETHICS : AJOB 2004; 4:13-4; discussion W23-31. [PMID: 16192124 DOI: 10.1080/15265160490496985] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
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Abstract
There are two critical issues on opposite ends of the timeline for patients who are eligible for liver transplantation. On the one hand, the crisis in the cadaveric organ supply makes surviving to transplant ever more risky. On the other hand, patients who receive successful transplants face the consequences of long-term immunosuppression and its potentially life-threatening complications. The donor shortage is forcing difficult decisions that affect all patients who await liver transplantation. It is important to scrutinize carefully the results of all policies that govern allocation and the ethics of the solutions we advocate to ensure that no patient subgroup is being at a disadvantage. Current immunosuppression practices are being challenged by an increasing understanding of the immunologic events triggered by the allograft and the goal to free patients from consequences of a lifetime of immunosuppression. Clinicians can expect, and perhaps require, that new immunosuppressive protocols will address how the planned intervention might be expected to advance the understanding of tolerance mechanisms. As knowledge increases, clinicians can anticipate innovative new immunosuppressive proposals. Calcineurin and steroid-free induction, the use of donor-derived bone marrow infusion, recipient pretreatment, costimulatory blockade, and new antibody induction approaches are all being proposed--often in combination--for clinical trials. Researchers face additional challenges in defining endpoints if the goal is not just the short-term reduction in rejection but the minimization, and eventual discontinuation, of immunosuppressive drugs while maintaining excellent long-term graft function. How much "failure" will be accepted and how will it be defined? How will clinicians interpret liver biopsies if they begin to accept that some lymphocytic infiltrates may be beneficial mediators of the ongoing immune activation necessary for the maintenance of tolerance? How will they adjust immunosuppression practices to the dynamic processes in the immune response that maintain tolerance? Remarkable short-term successes in providing transplants for thousands of children with liver failure have brought these challenges into sharp focus. Clinicians must seek to move the life-giving science of transplantation toward a new goal: providing long lifetimes of excellent graft function with minimal toxicity from immunosuppressive drugs and the hope of freedom from immunosuppression altogether. Pediatric liver recipients, whose grafts have inherent tolerogenic potential and for whom we can anticipate decades of life after transplant, may prove to be an ideal study population to further these goals.
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Affiliation(s)
- S V McDiarmid
- Division of Gastroenterology, Hepatology, and Nutrition, David Geffen School of Medicine, University of California, Los Angeles, Medical Center, 10833 Le Conte Avenue, Los Angeles, CA 90095-1752, USA.
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Scott LJ, McKeage K, Keam SJ, Plosker GL. Tacrolimus: a further update of its use in the management of organ transplantation. Drugs 2003; 63:1247-97. [PMID: 12790696 DOI: 10.2165/00003495-200363120-00006] [Citation(s) in RCA: 310] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
UNLABELLED Extensive clinical use has confirmed that tacrolimus (Prograf) is a key option for immunosuppression after transplantation. In large, prospective, randomised, multicentre trials in adults and children receiving solid organ transplants, tacrolimus was at least as effective or provided better efficacy than cyclosporin microemulsion in terms of patient and graft survival, treatment failure rates and the incidence of biopsy-proven acute and corticosteroid-resistant rejection episodes. Notably, the lower incidence of rejection episodes after renal transplantation in tacrolimus recipients was reflected in improved cost effectiveness. In bone marrow transplant (BMT) recipients, the incidence of tacrolimus grade II-IV graft-versus-host disease was significantly lower with tacrolimus than cyclosporin treatment. Efficacy was maintained in renal and liver transplant recipients after total withdrawal of corticosteroid therapy from tacrolimus-based immunosuppression, with the incidence of acute rejection episodes at up to 2 years' follow-up being similar with or without corticosteroids. Tacrolimus provided effective rescue therapy in transplant recipients with persistent acute or chronic allograft rejection or drug-related toxicity associated with cyclosporin treatment. Typically, conversion to tacrolimus reversed rejection episodes and/or improved the tolerability profile, particularly in terms of reduced hyperlipidaemia. In lung transplant recipients with obliterative bronchiolitis, conversion to tacrolimus reduced the decline in and/or improved lung function in terms of forced expiratory volume in 1 second. Tolerability issues may be a factor when choosing a calcineurin inhibitor. Cyclosporin tends to be associated with a higher incidence of significant hypertension, hyperlipidaemia, hirsutism, gingivitis and gum hyperplasia, whereas the incidence of some types of neurotoxicity, disturbances in glucose metabolism, diarrhoea, pruritus and alopecia may be higher with tacrolimus treatment. Renal function, as assessed by serum creatinine levels and glomerular filtration rates, was better in tacrolimus than cyclosporin recipients at up to 5 years' follow-up. CONCLUSION Recent well designed trials have consolidated the place of tacrolimus as an important choice for primary immunosuppression in solid organ transplantation and in BMT. Notably, in adults and children receiving transplants, tacrolimus-based primary immunosuppression was at least as effective or provided better efficacy than cyclosporin microemulsion treatment in terms of patient and graft survival, treatment failure and the incidence of acute and corticosteroid-resistant rejection episodes. The reduced incidence of rejection episodes in renal transplant recipients receiving tacrolimus translated into a better cost effectiveness relative to cyclosporin microemulsion treatment. The optimal immunosuppression regimen is ultimately dependent on balancing such factors as the efficacy of the individual drugs, their tolerability, potential for drug interactions and pharmacoeconomic issues.
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Ziolkowski J, Paczek L, Niewczas M, Senatorski G, Oldakowska-Jedynak U, Wyzgal J, Foroncewicz B, Mucha K, Zegarska J, Nyckowski P, Zieniewicz K, Patkowski W, Krawczyk M, Ziarkiewicz-Wroblewska B, Gornicka B. Effect of immunosuppressive regimen on acute rejection and liver graft function. Transplant Proc 2003; 35:2281-3. [PMID: 14529915 DOI: 10.1016/s0041-1345(03)00794-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Despite the use of modern immunosuppressive drugs, acute liver rejection (AR) continues to affect up to 70% of transplant recipients. The aim of this retrospective study was to assess the incidence of acute rejection episodes in patients treated with different immunosuppressive protocols. In our series, 37.3% of patients developed a clinical episode of AR. Analysis of immunosuppression has shown that the most effective immunosuppressive protocols, with regard to prevention of AR, include: antibody anti-IL-2R (anti-IL-2R) + tacrolimus (Tac) + mycophenolate mofetil (MMF) + prednisolone (Pred); anti-IL-2R + tacrolimus (Tac) + Pred; or Tac + Pred (25% vs 28.6% vs 30.4%, respectively). The highest rate of AR (66.6%) was observed among patients with anti-IL-2R and Tac but no steroid treatment, mostly (77.7%) in the initial period after liver transplantation. There were no statistical differences in liver function tests between the group treated with a CsA-based versus a Tac-based therapy. Strong immunosuppression contributed to a relatively low incidence of clinical AR in our series. The lowest rate of AR was observed among patients treated with anti-IL-2R antibody. Tac, and Pred. Deprivation of steroids in the early phase after liver transplantation substantially increased the risk of acute rejection episodes despite the use of anti-CD25. There were no statistically significant differences in liver function tests among those treated with Tac versus CsA in the short-term follow-up.
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Affiliation(s)
- J Ziolkowski
- Department of Immunology, Transplant Medicine, and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
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