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Taner T, Biggins SW, Cummins N, Daly RC, Dietz AB, Emamaullee J, Gandhi MJ, Heimbach JK, Patel JK, Pereira NL, Rosenbaum A, Sanchez-Fueyo A, Shingina A, Stegall MD, Villavicencio Theoduloz MA, Wald JW, Kushwaha SS. Summary of a Consensus Conference on the Management of Highly Sensitized Multiorgan Transplant Candidates. Mayo Clin Proc 2025; 100:700-711. [PMID: 40057871 DOI: 10.1016/j.mayocp.2025.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 12/26/2024] [Accepted: 01/20/2025] [Indexed: 04/05/2025]
Abstract
The number of highly sensitized patients in need of a multiorgan transplant is increasing. Criteria informing their transplant candidacy, approaches to management on the waitlist, and protocols related to alloantibody monitoring vary widely. We convened a consensus conference to discuss these different practices in the United States and the United Kingdom and to review the contemporary outcomes of these challenging cases. A detailed analysis of the data regarding the liver allografts' immunoprotective effect on simultaneously transplanted other organs was also completed, and the prospect of the use of liver allografts primarily to facilitate transplantation of highly sensitized patients in need of other organs was discussed. The ethical and allocation-related issues about such prospect were debated with a goal to standardize the approach and provide an evidence-based pathway for pre-, peri-, and post-transplantation management for the highly sensitized multiorgan transplantation candidate.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Joyce W Wald
- University of Pennsylvania, Philadelphia, PA, USA
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Zhang IW, Lurje I, Lurje G, Knosalla C, Schoenrath F, Tacke F, Engelmann C. Combined Organ Transplantation in Patients with Advanced Liver Disease. Semin Liver Dis 2024; 44:369-382. [PMID: 39053507 PMCID: PMC11449526 DOI: 10.1055/s-0044-1788674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/27/2024]
Abstract
Transplantation of the liver in combination with other organs is an increasingly performed procedure. Over the years, continuous improvement in survival could be realized through careful patient selection and refined organ preservation techniques, in spite of the challenges posed by aging recipients and donors, as well as the increased use of steatotic liver grafts. Herein, we revisit the epidemiology, allocation policies in different transplant zones, indications, and outcomes with regard to simultaneous organ transplants involving the liver, that is combined heart-liver, liver-lung, liver-kidney, and multivisceral transplantation. We address challenges surrounding combined organ transplantation such as equity, utility, and logistics of dual organ implantation, but also advantages that come along with combined transplantation, thereby focusing on molecular mechanisms underlying immunoprotection provided by the liver to the other allografts. In addition, the current standing and knowledge of machine perfusion in combined organ transplantation, mostly based on center experience, will be reviewed. Notwithstanding all the technical advances, shortage of organs, and the lack of universal eligibility criteria for certain multi-organ combinations are hurdles that need to be tackled in the future.
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Affiliation(s)
- Ingrid Wei Zhang
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH) at Charité - Universitätsmedizin, Berlin, Germany
- European Foundation for the Study of Chronic Liver Failure (EF CLIF) and Grifols Chair, Barcelona, Spain
| | - Isabella Lurje
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Georg Lurje
- Department of Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Christoph Knosalla
- Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité, Berlin, Germany
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Felix Schoenrath
- Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité, Berlin, Germany
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Cornelius Engelmann
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH) at Charité - Universitätsmedizin, Berlin, Germany
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Chen G, Hu X, Huang Y, Xiang X, Pan S, Chen R, Xu X. Role of the immune system in liver transplantation and its implications for therapeutic interventions. MedComm (Beijing) 2023; 4:e444. [PMID: 38098611 PMCID: PMC10719430 DOI: 10.1002/mco2.444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 11/23/2023] [Accepted: 11/24/2023] [Indexed: 12/17/2023] Open
Abstract
Liver transplantation (LT) stands as the gold standard for treating end-stage liver disease and hepatocellular carcinoma, yet postoperative complications continue to impact survival rates. The liver's unique immune system, governed by a microenvironment of diverse immune cells, is disrupted during processes like ischemia-reperfusion injury posttransplantation, leading to immune imbalance, inflammation, and subsequent complications. In the posttransplantation period, immune cells within the liver collaboratively foster a tolerant environment, crucial for immune tolerance and liver regeneration. While clinical trials exploring cell therapy for LT complications exist, a comprehensive summary is lacking. This review provides an insight into the intricacies of the liver's immune microenvironment, with a specific focus on macrophages and T cells as primary immune players. Delving into the immunological dynamics at different stages of LT, we explore the disruptions after LT and subsequent immune responses. Focusing on immune cell targeting for treating liver transplant complications, we provide a comprehensive summary of ongoing clinical trials in this domain, especially cell therapies. Furthermore, we offer innovative treatment strategies that leverage the opportunities and prospects identified in the therapeutic landscape. This review seeks to advance our understanding of LT immunology and steer the development of precise therapies for postoperative complications.
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Affiliation(s)
- Guanrong Chen
- The Fourth School of Clinical MedicineZhejiang Chinese Medical UniversityHangzhouChina
| | - Xin Hu
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
| | - Yingchen Huang
- The Fourth School of Clinical MedicineZhejiang Chinese Medical UniversityHangzhouChina
| | - Xiaonan Xiang
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
| | - Sheng Pan
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
| | - Ronggao Chen
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Xiao Xu
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
- Zhejiang Chinese Medical UniversityHangzhouChina
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Taner T, Hilscher MB, Broda CR, Drenth JPH. Issues in multi-organ transplantation of the liver with kidney or heart in polycystic liver-kidney disease or congenital heart disease: Current practices and immunological aspects. J Hepatol 2023; 78:1157-1168. [PMID: 37208103 DOI: 10.1016/j.jhep.2023.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 02/08/2023] [Accepted: 02/09/2023] [Indexed: 05/21/2023]
Abstract
Solid organ transplantation has become an integral part of the management of patients with end-stage diseases of the kidney, liver, heart and lungs. Most procedures occur in isolation, but multi-organ transplantation of the liver with either the kidney or heart has become an option. As more patients with congenital heart disease and cardiac cirrhosis survive into adulthood, particularly after the Fontan procedure, liver transplant teams are expected to face questions regarding multi-organ (heart-liver) transplantation. Similarly, patients with polycystic kidneys and livers may be managed by multi-organ transplantation. Herein, we review the indications and outcomes of simultaneous liver-kidney transplantation for polycystic liver-kidney disease, and discuss the indications, timing and procedural aspects of combined heart-liver transplantation. We also summarise the evidence for, and potential mechanisms underlying, the immunoprotective impact of liver allografts on the simultaneously transplanted organs.
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Affiliation(s)
- Timucin Taner
- Departments of Surgery & Immunology, Mayo Clinic, Rochester, MN, USA.
| | - Moira B Hilscher
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Christopher R Broda
- Department of Pediatrics, Baylor College of Medicine/Texas Children's Hospital, Houston, TX, USA
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University, Nijmegen, the Netherlands
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Muro M, Legaz I. Importance of human leukocyte antigen antibodies and leukocyte antigen/killer-cell immunoglobulin-like receptor genes in liver transplantation. World J Gastroenterol 2023; 29:766-772. [PMID: 36816626 PMCID: PMC9932425 DOI: 10.3748/wjg.v29.i5.766] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/25/2022] [Accepted: 01/18/2023] [Indexed: 02/06/2023] Open
Abstract
Many mechanisms have been proposed to explain the hypothetical state of hepatic tolerance, which is described by eventual imbalances or deregulation in the balance of cytokines, mediators, effectors, and regulatory cells in the complex milieu of the liver. In this section, we will comment on the importance of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) as well as the compatibility and pairings of HLA and killer-cell immunoglobulin-like receptor (KIR) genotypes in the evolution of liver transplantation. Thus, HLA compatibility, viral infections, and HLA-C/KIR combinations have all been linked to liver transplant rejection and survival. There have been reports of increased risk of acute and chronic rejection with ductopenia, faster graft fibrosis, biliary problems, poorer survival, and even de novo autoimmune hepatitis when DSAs are present in the recipient. Higher mean fluorescence intensity (MFI) values of the DSAs and smaller graft size were associated with poorer patient outcomes, implying that high-risk patients with preformed DSAs should be considered for selecting the graft placed and desensitization methods, according to the investigators. Similarly, in a combined kidney-liver transplant, a pretransplant with a visible expression of several DSAs revealed that these antibodies were resistant to treatment. The renal graft was lost owing to antibody-mediated rejection (AMR). The HLA antigens expressed by the transplanted liver graft influenced antibody elimination. Pathologists are increasingly diagnosing AMR in liver transplants, and desensitization therapy has even been employed in situations of AMR, particularly in patients with DSAs in kidney-hepatic transplants and high-class II MFI due to Luminex. In conclusion, after revealing the negative impacts of DSAs with high MFI, pretransplant virtual crossmatch techniques may be appropriate to improve evolution; however, they may extend cold ischemia periods by requiring the donor to be typed.
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Affiliation(s)
- Manuel Muro
- Immunology Service, University Clinical Hospital Virgen de la Arrixaca-Biomedical Research Institute of Murcia (IMIB), Murcia 30120, Spain
| | - Isabel Legaz
- Department of Legal and Forensic Medicine, Biomedical Research Institute (IMIB), Regional Campus of International Excellence “Campus Mare Nostrum,” Faculty of Medicine, University of Murcia, Murcia 30120, Spain
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Me HM, Ravichandran R, Khamash HA, Nair SS, Hacke K, Ramon DS, Mohanakumar T, Heilman RL, Jaramillo A. Direct Correlation of Soluble HLA and HLA-Containing Exosomes and Inverse Correlation of Tolerance Marker-Containing Exosomes With Antibody-Mediated Rejection After Simultaneous Liver-Kidney Transplantation: A Case Study. Transplant Proc 2022; 54:2765-2768. [DOI: 10.1016/j.transproceed.2022.10.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 10/16/2022] [Indexed: 11/13/2022]
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