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Altundaş N, Balkan E, Kizilkaya M, Aksungur N, Kara S, Demirci E, Korkut E, Öztürk G, Dursun H. Effects of de novo donor-specific Class I and II antibodies on graft outcomes after liver transplantation: A pilot cohort study. Open Life Sci 2025; 20:20251078. [PMID: 40129472 PMCID: PMC11931657 DOI: 10.1515/biol-2025-1078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 01/17/2025] [Accepted: 02/11/2025] [Indexed: 03/26/2025] Open
Abstract
This study investigates the role of donor-specific antibodies (DSAs) in liver transplantation outcomes, focusing on their effects on liver damage. Ninety-four patients who underwent liver transplantation between 2019 and 2024 at Atatürk University were included. DSA testing was performed using the Luminex QIAGEN LifeCodes method. Patient demographic data, laboratory results, clinical conditions, and biopsy findings were analyzed. Disease-specific analyses were conducted for Wilson's disease, autoimmune hepatitis, hepatocellular carcinoma (HCC), and hepatitis B virus (HBV). Due to the limited sample size, larger validation studies are needed, and the impact of the COVID-19 pandemic on the data collection process was considered. At the end of 1 year, persistent DSA had no significant effect on liver damage. However, early DSA positivity, particularly persistence and titration, requires further investigation. In Wilson's disease, two DSA-positive patients (mean fluorescence intensity [MFI] 1,000-1,500) showed no damage. Among autoimmune hepatitis patients, 5 of 19 were DSA positive (MFI 1,700-5,600), with no detected damage. Four HCC patients were DSA positive (MFI 1,300-2,200). Among HBV patients, 12 of 31 were DSA positive, and 5 experienced liver damage. Tacrolimus levels in the third month were statistically associated with bilirubin levels. Prospective studies are needed to further clarify the clinical significance of DSA.
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Affiliation(s)
- Necip Altundaş
- Department of General Surgery, Atatürk University, 25240, Erzurum, Turkey
| | - Eda Balkan
- Department of Medical Biology, Faculty of Medicine, Atatürk University, 21 Lalapaşa, 25240, Erzurum, Turkey
| | - Murat Kizilkaya
- Department of Medical Biology, Faculty of Medicine, Atatürk University, 21 Lalapaşa, 25240, Erzurum, Turkey
| | - Nurhak Aksungur
- Department of General Surgery, Atatürk University, 25240, Erzurum, Turkey
| | - Salih Kara
- Department of General Surgery, Atatürk University, 25240, Erzurum, Turkey
| | - Elif Demirci
- Department of Pathology, Atatürk University, 25240, Erzurum, Turkey
| | - Ercan Korkut
- Department of General Surgery, Atatürk University, 25240, Erzurum, Turkey
| | - Gürkan Öztürk
- Department of General Surgery, Atatürk University, 25240, Erzurum, Turkey
| | - Hakan Dursun
- Department of Internal Medicine, Atatürk University, 25240, Erzurum, Turkey
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Del Bello A, Vionnet J, Congy-Jolivet N, Kamar N. Simultaneous combined transplantation: Intricacies in immunosuppression management. Transplant Rev (Orlando) 2024; 38:100871. [PMID: 39096886 DOI: 10.1016/j.trre.2024.100871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 07/04/2024] [Accepted: 07/05/2024] [Indexed: 08/05/2024]
Abstract
Simultaneous combined transplantation (SCT), i.e. the transplantation of two solid organs within the same procedure, can be required when the patients develop more than one end-stage organ failure. The development of SCT over the last 20 years could only be possible thanks to progress in the surgical techniques and in the perioperative management of patients in an ageing population. Performing such major transplant surgeries from the same donor, in a short amount of time, and in critical pathophysiological conditions, is often considered to be counterbalanced by the immune benefits expected from these interventions. However, SCT includes a wide array of different transplant combinations, with each time a different immunological constellation. Recent research offers new insights into the immune mechanisms involved in these different settings. Progress in the understanding of these immunological intricacies help to address the optimal induction and maintenance immunosuppressive treatment strategies. In this review, we summarize the different immunological benefits according to the type of SCT performed. We also incorporate the main outcomes according to the immunological risk at transplantation, and the deleterious impact of preformed or de novo donor-specific antibodies (DSA) in the different types of SCT. Finally, we propose comprehensive and evidence-based induction and maintenance immunosuppression strategies guided by the type of SCT.
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Affiliation(s)
- Arnaud Del Bello
- Department of Nephrology and Organ Transplantation, CHU de Toulouse, Toulouse, France; Centre Hospitalier et Universitaire, Université Paul Sabatier Toulouse III, Toulouse, France; Department of Vascular Biology, Institute of Metabolic and Cardiovascular Diseases (I2MC), France.
| | - Julien Vionnet
- Transplantation Center and Service of Gastroenterology and Hepatology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Nicolas Congy-Jolivet
- Centre Hospitalier et Universitaire, Université Paul Sabatier Toulouse III, Toulouse, France; Laboratory of Immunology, Biology Department, Centre Hospitalier et Universitaire (CHU) de Toulouse, Toulouse, France; INSERM UMR 1037, DynAct team, CRCT, Université Paul Sabatier, Toulouse, France
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, CHU de Toulouse, Toulouse, France; Centre Hospitalier et Universitaire, Université Paul Sabatier Toulouse III, Toulouse, France; INSERM UMR 1037, DynAct team, CRCT, Université Paul Sabatier, Toulouse, France; Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1043-CNRS 5282, Toulouse, France
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Melere MU, Feier FH, Neumann J, Kalil AN, Montagner JDM, Nader LS, da Silva CS, Junior MAF, Coral GP, Bobsin GP, Ferreira CT. Human leukocyte antigen compatibility and incidence of donor-specific antibodies in pediatric liver transplant recipients. World J Gastroenterol 2024; 30:3837-3845. [PMID: 39351427 PMCID: PMC11438625 DOI: 10.3748/wjg.v30.i33.3837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 08/01/2024] [Accepted: 08/20/2024] [Indexed: 09/02/2024] Open
Abstract
BACKGROUND Antibody-mediated rejection following liver transplantation (LT) has been increasingly recognized, particularly with respect to the emergence of de novo donor-specific antibodies (DSAs) and their impact on graft longevity. While substantial evidence for adult populations exists, research focusing on pediatric LT outcomes remains limited. AIM To investigate the prevalence of human leukocyte antigen (HLA) mismatches and DSA and evaluate their association with rejection episodes after pediatric LT. METHODS A cohort of pediatric LT recipients underwent HLA testing at Santa Casa de Porto Alegre, Brazil, between December 2013 and December 2023. Only patients who survived for > 30 days after LT with at least one DSA analysis were included. DSA classes I and II and cross-matches were analyzed. The presence of de novo DSA (dnDSA) was evaluated at least 3 months after LT using the Luminex® single antigen bead method, with a positive reaction threshold set at 1000 MFI. Rejection episodes were confirmed by liver biopsy. RESULTS Overall, 67 transplanted children were analyzed; 61 received grafts from living donors, 85% of whom were related to recipients. Pre-transplant DSA (class I or II) was detected in 28.3% of patients, and dnDSA was detected in 48.4%. The median time to DSA detection after LT was 19.7 [interquartile range (IQR): 4.3-35.6] months. Biopsy-proven rejection occurred in 13 patients at follow-up, with C4d positivity observed in 5/13 Liver biopsies. The median time to rejection was 7.8 (IQR: 5.7-12.8) months. The presence of dnDSA was significantly associated with rejection (36% vs 3%, P < 0.001). The rejection-free survival rates at 12 and 24 months were 76% vs 100% and 58% vs 95% for patients with dnDSA anti-DQ vs those without, respectively. CONCLUSION Our findings highlight the importance of incorporating DSA assessment into pre- and post-transplantation protocols for pediatric LT recipients. Future implications may include immunosuppression minimization strategies based on this analysis in pediatric LT recipients.
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Affiliation(s)
- Melina U Melere
- Department of Hepatology and Liver Transplantation, Santa Casa de Porto Alegre, Porto Alegre 90050170, Rio Grande do Sul, Brazil
| | - Flavia H Feier
- Department of Hepato-biliary-pancreatic Surgery and Liver Transplantation, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020-090, Rio Grande do Sul, Brazil
- Postgraduation Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Rio Grande do Sul, Brazil
| | - Jorge Neumann
- Laboratory of Transplantation Immunology, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020-090, Rio Grande do Sul, Brazil
| | - Antônio N Kalil
- Department of Hepato-biliary-pancreatic Surgery and Liver Transplantation, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020-090, Rio Grande do Sul, Brazil
- Postgraduation Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Rio Grande do Sul, Brazil
| | - Juliana de M Montagner
- Laboratory of Transplantation Immunology, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020-090, Rio Grande do Sul, Brazil
| | - Luiza S Nader
- Department of Hepatology and Liver Transplantation, Santa Casa de Porto Alegre, Porto Alegre 90050170, Rio Grande do Sul, Brazil
| | - Carolina S da Silva
- Department of Hepatology and Liver Transplantation, Santa Casa de Porto Alegre, Porto Alegre 90050170, Rio Grande do Sul, Brazil
| | - Marco Aurélio F Junior
- Department of Hepatology and Liver Transplantation, Santa Casa de Porto Alegre, Porto Alegre 90050170, Rio Grande do Sul, Brazil
| | - Gabriela P Coral
- Department of Hepatology and Liver Transplantation, Santa Casa de Porto Alegre, Porto Alegre 90050170, Rio Grande do Sul, Brazil
- Postgraduation Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Rio Grande do Sul, Brazil
| | - Guilherme P Bobsin
- Department of Hepatology and Liver Transplantation, Santa Casa de Porto Alegre, Porto Alegre 90050170, Rio Grande do Sul, Brazil
| | - Cristina T Ferreira
- Department of Hepatology and Liver Transplantation, Santa Casa de Porto Alegre, Porto Alegre 90050170, Rio Grande do Sul, Brazil
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Kanamori H, Yamada Y, Ito Y, Shirosaki K, Yamagishi S, Maeda Y, Kudo Y, Umeyama T, Takahashi N, Kato M, Hasegawa Y, Matsubara K, Shinoda M, Obara H, Irie R, Tsujikawa H, Okita H, Nguyen PT, Saigo K, Mitsunaga S, Inoue I, Kitagawa Y, Kuroda T. Noninvasive graft monitoring using donor-derived cell-free DNA in Japanese liver transplantation. Hepatol Res 2024; 54:300-314. [PMID: 37850337 DOI: 10.1111/hepr.13978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 09/06/2023] [Accepted: 10/13/2023] [Indexed: 10/19/2023]
Abstract
AIM To evaluate the use of donor-derived cell-free DNA (dd-cfDNA) in diagnosing graft injuries in Japanese liver transplantation (LTx), including family-related living donors. METHODS A total of 321 samples from 10 newly operated LTx recipients were collected to monitor the early dynamics of dd-cfDNA levels after LTx. Fifty-five samples from 55 recipients were collected during protocol biopsies (PB), whereas 36 samples from 27 recipients were collected during event biopsies, consisting of 11 biopsy-proven acute rejection (AR), 20 acute dysfunctions without rejection (ADWR), and 5 chronic rejections. The levels of dd-cfDNA were quantified using a next-generation sequencer based on single nucleotide polymorphisms. RESULTS The dd-cfDNA levels were elevated significantly after LTx, followed by a rapid decline to the baseline in patients without graft injury within 30 days post-LTx. The dd-cfDNA levels were significantly higher in the 11 samples obtained during AR than those obtained during PB (p < 0.0001), which decreased promptly after treatment. The receiver operator characteristic curve analysis of diagnostic ability yielded areas under the curve of 0.975 and 0.897 for AR (rejection activity index [RAI] ≥3) versus PB and versus non-AR (ADWR + PB). The dd-cfDNA levels during AR were elevated earlier and correlated more strongly with the RAI (r = 0.740) than aspartate aminotransferase/alanine aminotransferase. The dd-cfDNA levels were neither associated with graft fibrosis based on histology nor the status of donor-specific antibodies in PB samples. CONCLUSIONS Donor-derived cell-free DNA serves as a sensitive biomarker for detecting graft injuries in LTx. Further large-scale cohort studies are warranted to optimize its use in differentiating various post-LTx etiologies.
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Affiliation(s)
- Hiroki Kanamori
- Department of Pediatric Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yohei Yamada
- Department of Pediatric Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yoko Ito
- Department of Pediatric Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Koji Shirosaki
- Department of Pediatric Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Satoko Yamagishi
- Department of Pediatric Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yutaro Maeda
- Department of Pediatric Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yumi Kudo
- Department of Pediatric Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Tomoshige Umeyama
- Department of Pediatric Surgery, St Luke's International Hospital, Tokyo, Japan
| | - Nobuhiro Takahashi
- Department of Pediatric Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Mototoshi Kato
- Department of Pediatric Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yasushi Hasegawa
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Kentaro Matsubara
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Masahiro Shinoda
- Digestive Diseases Center, International University of Health and Welfare School of Medicine, Mita Hospital, Tokyo, Japan
| | - Hideaki Obara
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Rie Irie
- Department of Diagnostic Pathology, Nippon Koukan Hospital, Kawasaki, Japan
| | - Hanako Tsujikawa
- Division of Diagnostic Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Hajime Okita
- Division of Diagnostic Pathology, Keio University School of Medicine, Tokyo, Japan
| | | | - Kenichi Saigo
- Department of Transplantation Surgery, Japan Community Health Care Organization, Chiba Hospital, Chiba, Japan
| | - Shigeki Mitsunaga
- Human Genetics Laboratory, National Institute of Genetics, Mishima, Japan
| | - Ituro Inoue
- Human Genetics Laboratory, National Institute of Genetics, Mishima, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Tatsuo Kuroda
- Department of Pediatric Surgery, Keio University School of Medicine, Tokyo, Japan
- Kanagawa Children's Medical Center, Kanagawa, Japan
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5
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Gniewkiewicz M, Czerwinska K, Zielniok K, Durlik M. Impact of Resolved Preformed, Persistent Preformed, and De Novo Anti-HLA Donor-Specific Antibodies in Kidney Transplant Recipients on Long-Term Renal Graft Outcomes. J Clin Med 2023; 12:jcm12103361. [PMID: 37240467 DOI: 10.3390/jcm12103361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 04/28/2023] [Accepted: 05/08/2023] [Indexed: 05/28/2023] Open
Abstract
The post-transplant evolution of antihuman leukocyte antigen donor-specific antibodies (anti-HLA DSAs) includes three clinical patterns: resolved preformed DSAs, persistent preformed DSAs, and de novo DSAs. The aim of this retrospective study was to analyze the impact of resolved preformed, persistent preformed, and de novo anti-HLA-A, -B, and -DR DSAs in kidney transplant recipients on long-term renal allograft outcomes. This is a post hoc analysis of the study conducted in our transplant center. One hundred eight kidney transplant recipients were included in the study. Patients were followed for a minimum of 24 months after allograft biopsy, which was performed 3 to 24 months after kidney transplantation. The identification of persistent preformed DSAs at the time of biopsy was the most significant predictor of the combined endpoint of the study (>30% decline in estimated glomerular filtration rate or death-censored graft loss; HR = 5.96, 95% CI 2.041-17.431, p = 0.0011), followed by the occurrence of de novo DSAs (HR = 4.48, 95% CI 1.483-13.520, p = 0.0079). No increased risk was observed in patients with resolved preformed DSAs (HR = 1.10, 95% CI 0.139-8.676, p = 0.9305). Patients with resolved preformed DSAs have similar graft prognoses as patients without DSAs, therefore, the persistence of preformed DSAs and development of de novo DSAs are associated with inferior long-term allograft outcomes.
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Affiliation(s)
- Michal Gniewkiewicz
- Department of Transplantation Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland
| | - Katarzyna Czerwinska
- Department of Transplantation Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland
| | - Katarzyna Zielniok
- Department of Clinical Immunology, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland
| | - Magdalena Durlik
- Department of Transplantation Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland
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Narita S, Miuma S, Okudaira S, Koga Y, Fukushima M, Sasaki R, Haraguchi M, Soyama A, Hidaka M, Miyaaki H, Futakuchi M, Nagai K, Ichikawa T, Eguchi S, Nakao K. Regular protocol liver biopsy is useful to adjust immunosuppressant dose after adult liver transplantation. Clin Transplant 2023; 37:e14873. [PMID: 36443801 DOI: 10.1111/ctr.14873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 11/08/2022] [Accepted: 11/25/2022] [Indexed: 11/30/2022]
Abstract
INTRODUCTION Adjusting immunosuppression to minimal levels post-adult liver transplantation (LT) is critical; however, graft rejection has been reported in LT recipients with normal liver function evaluated by liver biopsy (LBx). Continual protocol liver biopsy (PLB) is performed regularly in LT recipients with normal liver function in some centers; however, its usefulness remains inadequately evaluated. This study aimed to assess retrospectively the usefulness of late PLB after adult LT. METHODS LBx evaluations of LT recipients with normal liver function and hepatitis B and C virus seronegativity were defined as PLB. The cases requiring immunosuppressive therapy for rejection findings based on Banff criteria were extracted from the PLBs, and pathological data collected before and after immunosuppressive dosage adjustment (based on modified histological activity index [HAI] score) were compared. RESULTS Among 548 LBx cases, 213 LBx in 110 recipients fulfilled the inclusion criteria for PLB. Immunosuppressive therapy after PLB was intensified in 14 LBx (6.6%) recipients (12.7%); of these, nine had late-onset acute rejection, three had isolated perivenular inflammation, one had plasma cell-rich rejection, and one had early chronic rejection. Follow-up LBx after immunosuppressive dose adjustment showed improvement in the modified HAI score grading in 10 of 14 cases (71.4%). No clinical background and blood examination data, including those from the post-LT period, immunosuppressant trough level, or examination for de novo DSA, predicted rejection in PLB. Complications of PLB were found in only three cases. CONCLUSION PLB is useful in the management of seemingly stable LT recipients, to discover subclinical rejection and allow for appropriate immunosuppressant dose adjustment.
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Affiliation(s)
- Shohei Narita
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Satoshi Miuma
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Sadayuki Okudaira
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Yoshito Koga
- Transfusion and Cell Therapy Unit, Nagasaki University Hospital, Nagasaki, Japan
| | - Masanori Fukushima
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Ryu Sasaki
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Masafumi Haraguchi
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Akihiko Soyama
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Masaaki Hidaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hisamitsu Miyaaki
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Mitsuru Futakuchi
- Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kazuhiro Nagai
- Transfusion and Cell Therapy Unit, Nagasaki University Hospital, Nagasaki, Japan
| | - Tatsuki Ichikawa
- Nagasaki Harbor Medical Center, Department of Gastroenterology, Nagasaki, Japan
| | - Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kazuhiko Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
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Liu W, Wang ZL, Kang ZY, Xiao YL, Liu C, Li DH. Liver graft injury caused by de novo donor-specific HLA antibodies in pediatric liver transplant recipients with low, moderate, and high immunologic risk. Am J Surg 2023; 225:275-281. [PMID: 36116972 DOI: 10.1016/j.amjsurg.2022.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 08/31/2022] [Accepted: 09/04/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND This study investigated the association between different risk levels of de novo donor-specific anti-human leukocyte antigen antibodies (dnDSAs) and liver graft injury after liver transplantation in pediatric patients. METHODS This retrospective cohort study enrolled 130 patients after liver transplantation. Subjects were divided into the following 4 groups according to the mean fluorescence intensity (MFI) of dnDSAs: high risk group(MFI ≥10,000), medium risk group(4000 ≤ MFI <10,000), low risk group(500 ≤ MFI <4000), and negative group(<500). Liver function indices were examined along with liver puncture biopsy，and the relationship between dnDSA risk level and liver injury after transplantation was assessed. RESULTS Pediatric liver transplant recipients showed significant differences in liver function (ALT, AST, GGT and Bilirubin) according to dnDSA risk level (P < 0.05), and no differences in cumulative incidences of rejection (P = 0.413) and liver fibrosis (P = 0.978) were observed among the number of dnDSAs group. There were differences in the cumulative incidences of antibody-mediated rejection (AMR) (P = 0.001) and T cell-mediated rejection （TCMR） (P = 0.003) across risk groups. The cumulative incidences of TCMR and liver fibrosis (P = 0.0001) were higher in the low-risk group than in the other 3 groups. There were no differences in graft survival rate (P = 0.846) across risk groups. CONCLUSION DnDSAs in pediatric liver transplant recipients are associated with liver transplant rejection and fibrosis. The level of dnDSAs in low risk group should not be disregarded. Routine detection of dnDSAs has clinical utility for noninvasive risk stratification in this population.
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Affiliation(s)
- Wei Liu
- Department of Blood Transfusion, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Zheng-Lu Wang
- Department of Pathology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Zhong-Yu Kang
- Department of Blood Transfusion, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Yan-Li Xiao
- Department of Blood Transfusion, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Chun Liu
- Department of Blood Transfusion, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Dai-Hong Li
- Department of Blood Transfusion, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China.
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8
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Clinical recommendations for posttransplant assessment of anti-HLA (Human Leukocyte Antigen) donor-specific antibodies: A Sensitization in Transplantation: Assessment of Risk consensus document. Am J Transplant 2023; 23:115-132. [PMID: 36695614 DOI: 10.1016/j.ajt.2022.11.013] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 10/29/2022] [Accepted: 11/04/2022] [Indexed: 01/13/2023]
Abstract
Although anti-HLA (Human Leukocyte Antigen) donor-specific antibodies (DSAs) are commonly measured in clinical practice and their relationship with transplant outcome is well established, clinical recommendations for anti-HLA antibody assessment are sparse. Supported by a careful and critical review of the current literature performed by the Sensitization in Transplantation: Assessment of Risk 2022 working group, this consensus report provides clinical practice recommendations in kidney, heart, lung, and liver transplantation based on expert assessment of quality and strength of evidence. The recommendations address 3 major clinical problems in transplantation and include guidance regarding posttransplant DSA assessment and application to diagnostics, prognostics, and therapeutics: (1) the clinical implications of positive posttransplant DSA detection according to DSA status (ie, preformed or de novo), (2) the relevance of posttransplant DSA assessment for precision diagnosis of antibody-mediated rejection and for treatment management, and (3) the relevance of posttransplant DSA for allograft prognosis and risk stratification. This consensus report also highlights gaps in current knowledge and provides directions for clinical investigations and trials in the future that will further refine the clinical utility of posttransplant DSA assessment, leading to improved transplant management and patient care.
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9
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Acute Antibody-Mediated Rejection in Liver Transplant Recipients with Autoimmune Liver Disease: A Clinical and Pathologic Study of 4 Cases. J Pers Med 2022; 13:jpm13010041. [PMID: 36675702 PMCID: PMC9865077 DOI: 10.3390/jpm13010041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 12/15/2022] [Accepted: 12/21/2022] [Indexed: 12/29/2022] Open
Abstract
Background: Acute antibody-mediated rejection (AMR) is an uncommon complication after ABO-compatible liver transplantation (LT). This case series investigated the clinicopathologic characteristics and outcomes of acute AMR in LT recipients with autoimmune liver disease (ALD). Patients and Methods: Among 809 patients who underwent LT from January 2014 to December 2020, four ALD patients developed AMR, which was confirmed based on clinical features, histopathology of liver biopsy, donor-specific antibodies (DSA) or panel reactive antibody (PRA) level. Therapies were individualized based on clinical manifestations. Results: The incidence of acute AMR was 0.49%, and the incidence of acute AMR with ALD and non-ALD recipients was 11.1% and 0%, respectively. Three patients had strongly positive HLA class II DSA, and one patient was with the PRA class I and II sensitivities, which were >80%; complement component 4d (C4d) staining was negative in all patients. The first patient underwent re-LT, and the other three patients had good prognoses with treatments. Conclusions: ALD patients are prone to acute AMR after LT, thus should be kept vigilant against the occurrence of acute AMR.
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10
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Vij M, Rammohan A, Rela M. Long-term liver allograft fibrosis: A review with emphasis on idiopathic post-transplant hepatitis and chronic antibody mediated rejection. World J Hepatol 2022; 14:1541-1549. [PMID: 36157865 PMCID: PMC9453462 DOI: 10.4254/wjh.v14.i8.1541] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 07/08/2022] [Accepted: 08/16/2022] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) is a life-saving surgical procedure and the current standard of care for most patients with end stage liver disease. With improvements in organ preservation techniques, perioperative care, and immunosuppression, there is better patient and graft survival following LT, and assessment of the liver allograft in long-term survivors is becoming increasingly important. Recurrent or de novo viral or autoimmune injury remains the most common causes of chronic hepatitis and fibrosis following liver transplantation in adults. However, no obvious cause can be identified in many adults with controlled recurrent disease and the majority of pediatric LT recipients, as they have been transplanted for non-recurrent liver diseases. Serial surveillance liver biopsies post LT have been evaluated in several adult and pediatric centers to identify long-term pathological changes. Pathological findings are frequently present in liver biopsies obtained after a year post LT. The significance of these findings is uncertain as many of these are seen in protocol liver biopsies from patients with clinically good allograft function and normal liver chemistry parameters. This narrative review summaries the factors predisposing to long-term liver allograft fibrosis, highlighting the putative role of idiopathic post-LT hepatitis and chronic antibody mediated rejection in its pathogenesis.
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Affiliation(s)
- Mukul Vij
- Department of Pathology, Dr. Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Ashwin Rammohan
- Institute of Liver disease and Transplantation, Dr. Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Mohamed Rela
- Institute of Liver disease and Transplantation, Dr. Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
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11
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The New Challenge in Pediatric Liver Transplantation: Chronic Antibody-Mediated Rejection. J Clin Med 2022; 11:jcm11164834. [PMID: 36013073 PMCID: PMC9409831 DOI: 10.3390/jcm11164834] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 08/07/2022] [Accepted: 08/16/2022] [Indexed: 12/21/2022] Open
Abstract
Antibody-mediated rejection (AMR) of liver allograft transplantation was considered as anecdotal for many decades. However recently, AMR has gained clinical awareness as a potential cause of chronic liver injury, leading to liver allograft fibrosis and eventual graft failure. (1) Methods: Literature on chronic AMR (cAMR) in pediatric post-liver transplant patients was reviewed for epidemiologic data, physiopathology, diagnosis, and treatment approaches. (2) Results: Accurate incidence of cAMR in pediatric liver transplantation remains unknown. Diagnostic criteria of cAMR were suggested by the Banff Working Group in 2016 and are based on standardized histopathological findings, C4d staining pattern, associated with the presence of donor-specific antibodies (DSA). Physio-pathological mechanisms are not clear for the technically difficult-to-obtain animal models reproducing cAMR. Treatment protocols are not established, being limited to case reports and case series, based on experience in ABO incompatible transplantation and kidney transplantation. Immunosuppression compliance with adequate dose adjustment may prevent cAMR. Conversion of Cyclosporine to Tacrolimus may improve pathological findings if treated in early phase. The association of steroids, Mycophenolate Mofetil (MMF) and mTOR inhibitors have shown some synergistic effects. Second-line treatments such as intravenous immunoglobulin (IVIG) and plasma exchange may decrease antibody titers based on ABO incompatible transplant protocols. The use of anti-CD20 (Rituximab) and proteasome inhibitors (Bortezomib) is controversial due to the lack of qualified studies. Therefore, multicenter randomized trials are needed to establish the best therapeutic strategy. In refractory cases, re-transplantation is the only treatment for allograft failure. (3) Conclusions: This literature review collects recent clinical, histopathological, and therapeutical advances of cAMR in liver allograft transplantation of pediatric patients. There are many physio-pathological aspects of cAMR to be clarified. Further efforts with multicenter prospective protocols to manage patients with cAMR are needed to improve its outcome.
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12
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Shin S, Lee M, Dente E, Yazigi N, Khan KM, Kaufman SS, Ahn J, Timofeeva OA, Ekong UD. Mismatch epitope load predicts de novo-DSA-free survival in pediatric liver transplantation. Pediatr Transplant 2022; 26:e14251. [PMID: 35279919 DOI: 10.1111/petr.14251] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 01/28/2022] [Accepted: 02/03/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Our knowledge of de novo anti-HLA donor-specific antibodies (dnDSA) in liver transplantation continues to be defined. We hypothesized that differences of HLA-DR/DQ mismatches can improve precision in alloimmune risk categorization and be applied to tailor immunosuppression. METHODS A retrospective chart review of 244 pediatric patients consecutively transplanted at our center between 2003 and 2019 was performed to identify patients tested for dnDSA. Records were queried for: demographics, pre-transplant diagnosis, biopsy-proven T-cell-mediated rejection (TCMR), radiology proven biliary complications, tacrolimus trough levels, dnDSA characteristics, and HLA typing. The eplet mismatch analyses were performed using HLAMatchmaker™ 3.1. All statistical analyses were conducted using R software version 3.40. RESULTS There were 99 dnDSA-negative patients and 73 dnDSA-positive patients (n = 70 against class II and n = 3 against class I and II). ROC analysis identified optimal cutoff of eplet mismatch load for dnDSA and defined risk groups for an alloimmune outcome. Kaplan-Meier curves and log-rank tests showed high eplet mismatch load was associated with shorter dnDSA-free survival (log-rank p = .001). Multivariable Cox regression models showed that tacrolimus coefficient of variation and tacrolimus mean levels were significantly associated with dnDSA-free survival (p < .001 and p = .036). Fisher's exact test showed that dnDSA was associated with an increased likelihood of TCMR (OR 14.94; 95% CI 3.65 - 61.19; p < .001). Patients without TCMR were more likely to have dnDSA to HLA-DQ7 and less likely to have dnDSA to HLA-DQ2 (p = .03, p = .080). CONCLUSIONS Mismatched epitope load predicts dnDSA-free survival in pediatric liver transplant, while dnDSA specificity may determine alloimmune outcome.
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Affiliation(s)
- Stephanie Shin
- Georgetown University School of Medicine, Washington, District of Columbia, USA
| | - Margaret Lee
- Georgetown University School of Medicine, Washington, District of Columbia, USA
| | - Elizabeth Dente
- Georgetown University School of Medicine, Washington, District of Columbia, USA
| | - Nada Yazigi
- Georgetown University School of Medicine, Washington, District of Columbia, USA.,Medstar Georgetown Transplant Institute, Medstar Georgetown University Hospital, Washington, District of Columbia, USA
| | - Khalid M Khan
- Georgetown University School of Medicine, Washington, District of Columbia, USA.,Medstar Georgetown Transplant Institute, Medstar Georgetown University Hospital, Washington, District of Columbia, USA
| | - Stuart S Kaufman
- Georgetown University School of Medicine, Washington, District of Columbia, USA.,Medstar Georgetown Transplant Institute, Medstar Georgetown University Hospital, Washington, District of Columbia, USA
| | - Jaeil Ahn
- Department of Biostatistics, Bioinformatics, & Biomathematics, Georgetown University, Washington, District of Columbia, USA
| | - Olga A Timofeeva
- Georgetown University School of Medicine, Washington, District of Columbia, USA.,Histocompatibility Laboratory, Department of Pathology & Laboratory Medicine, Georgetown University, Washington, District of Columbia, USA
| | - Udeme D Ekong
- Georgetown University School of Medicine, Washington, District of Columbia, USA.,Medstar Georgetown Transplant Institute, Medstar Georgetown University Hospital, Washington, District of Columbia, USA
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13
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Meszaros M, Dubois V, Congy-Jolivet N, Hamada S, Thevenin C, Faure S, Boillot O, Kamar N, Pageaux GP, Del Bello A, Dumortier J. Impact of calcineurin inhibitor-free immunosuppression on de novo donor-specific antibody formation in liver transplant recipients. Liver Int 2022; 42:1132-1143. [PMID: 35184373 DOI: 10.1111/liv.15201] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 12/14/2021] [Accepted: 01/12/2022] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Low calcineurin inhibitor (CNI) levels expose liver transplant recipients to rejection episodes and potentially to antibody-mediated rejection. There are little data on the impact of CNI-free immunosuppression on de novo donor-specific HLA antibody (dnDSA) development. Here we evaluated the prevalence of dnDSA in liver transplant recipients on CNI-free maintenance regimens and their associations with histopathological abnormalities of allografts. METHODS Seven hundred and twenty-seven liver transplant recipients underwent a first liver transplant between 2000 and 2018 in three French transplant centres and had protocolized follow-up with dnDSA screening and allograft biopsy 1, 5 and 10 years after transplantation. RESULTS CNIs were withdrawn in 166 (22.8%) patients with or without conversion to mammalian target of rapamycin inhibitors and/or maintenance with mycophenolic acid. DSA were present after withdrawal in 30.1% (50/166) patients on CNI-free immunosuppression compared with 16% (90/561) on CNI maintenance therapy (p < 0.001). The cumulative incidence of dnDSA 10 years after transplant was 20% in the CNI group versus 28% in the CNI-free group (p < 0.01). dnDSAs were associated with histological graft abnormalities (significant allograft fibrosis or rejection) (HR 2.24, 95% CI 1.2-4.1; p = 0.01). In univariate Cox regression analysis, being on a CNI-free regimen did not impact graft histology. CONCLUSIONS Patients on a CNI-free IS regimen have a higher prevalence of dnDSA than patients on a standard IS regimen. dnDSAs but not CNI-free immunosuppression were associated with abnormal allograft histology.
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Affiliation(s)
- Magdalena Meszaros
- Département d'hépatologie et transplantation hépatique, CHU Saint Eloi, Montpellier, France
| | - Valérie Dubois
- Etablissement Français du Sang, Laboratoire d'Histocompatibilité, Lyon, France
| | | | - Sarah Hamada
- Etablissement Français du Sang, Laboratoire d'Histocompatibilité, Lyon, France
| | - Céline Thevenin
- Département d'Immunologie, CHU Montpellier, Montpellier, France
| | - Stephanie Faure
- Département d'hépatologie et transplantation hépatique, CHU Saint Eloi, Montpellier, France
| | - Olivier Boillot
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Unité de Transplantation hépatique, Lyon, France
| | - Nassim Kamar
- Département de Néphrologie et Transplantation d'Organes, CHU, Toulouse, France
| | | | - Arnaud Del Bello
- Département de Néphrologie et Transplantation d'Organes, CHU, Toulouse, France
| | - Jérôme Dumortier
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Unité de Transplantation hépatique, Lyon, France
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14
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Nakamura T, Shirouzu T. Antibody-Mediated Rejection and Recurrent Primary Disease: Two Main Obstacles in Abdominal Kidney, Liver, and Pancreas Transplants. J Clin Med 2021; 10:5417. [PMID: 34830699 PMCID: PMC8619797 DOI: 10.3390/jcm10225417] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 11/17/2021] [Accepted: 11/18/2021] [Indexed: 02/08/2023] Open
Abstract
The advances in acute phase care have firmly established the practice of organ transplantation in the last several decades. Then, the next issues that loom large in the field of transplantation include antibody-mediated rejection (ABMR) and recurrent primary disease. Acute ABMR is a daunting hurdle in the performance of organ transplantation. The recent progress in desensitization and preoperative monitoring of donor-specific antibodies enables us to increase positive outcomes. However, chronic active ABMR is one of the most significant problems we currently face. On the other hand, recurrent primary disease is problematic for many recipients. Notably, some recipients, unfortunately, lost their vital organs due to this recurrence. Although some progress has been achieved in these two areas, many other factors remain largely obscure. In this review, these two topics will be discussed in light of recent discoveries.
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Affiliation(s)
- Tsukasa Nakamura
- Department of Organ Transplantation and General Surgery, Kyoto Prefectural University of Medicine, Kajii-cho 465, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Takayuki Shirouzu
- Molecular Diagnositcs Division, Wakunaga Pharmaceutical Co., Ltd., 13-4 Arakicho, shinjyuku-ku, Tokyo 160-0007, Japan;
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15
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Baliellas C, Lladó L, Serrano T, Gonzalez-Vilatarsana E, Cachero A, Lopez-Dominguez J, Petit A, Fabregat J. Sinusoidal obstruction syndrome as a manifestation of acute antibody-mediated rejection after liver transplantation. Am J Transplant 2021; 21:3775-3779. [PMID: 34008326 DOI: 10.1111/ajt.16689] [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: 12/21/2020] [Revised: 05/10/2021] [Accepted: 05/10/2021] [Indexed: 01/25/2023]
Abstract
Antibody-mediated rejection (AMR) after liver transplantation is uncommon but, when present, manifests as graft dysfunction. We report the case of a 54-year-old woman who developed portal hypertension with pleural effusion and ascites secondary to sinusoidal obstruction syndrome (SOS) due to acute AMR following an ABO-matched liver transplantation for autoimmune cirrhosis and hepatocellular carcinoma. Initial immunosuppression comprised basiliximab, decreasing prednisone, tacrolimus, and mycophenolate mofetil. After 1 month, she presented with the massive pleural effusion, slight ascites, and normal liver tests. After excluding common causes of pleural effusion, we performed a liver biopsy that showed atypical rejection with the involvement of large centrilobular veins partially occluded by marked endotheliitis and lax fibrosis suggestive of SOS. Direct immunofluorescence study of C4d showed diffuse endothelial sinusoidal staining, and de novo donor-specific anti-human leukocyte antigen antibodies were detected in his blood. Thus, we diagnosed AMR focused on centrilobular veins and initiated treatment with defibrotide, steroid pulses, and diuretics. However, this was ineffective, and the pleural effusion only resolved when plasmapheresis and intravenous immunoglobulin were started. This case shows that AMR can cause SOS with portal hypertension and present with a pleural effusion, and as such, it should be suspected after excluding other more common causes of effusion.
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Affiliation(s)
- Carme Baliellas
- Liver Transplant Unit, Department of Gastroenterology, Bellvitge University Hospital, IDIBELL, University of Barcelona, Barcelona, Spain
| | - Laura Lladó
- Liver Transplant Unit, Department of Surgery, Bellvitge University Hospital, IDIBELL, University of Barcelona, Barcelona, Spain
| | - Teresa Serrano
- Liver Transplant Unit, Department of Pathology, Bellvitge University Hospital, University of Barcelona, Barcelona, Spain
| | | | - Alba Cachero
- Liver Transplant Unit, Department of Gastroenterology, Bellvitge University Hospital, Barcelona, Spain
| | | | - Anna Petit
- Liver Transplant Unit, Department of Pathology, Bellvitge University Hospital, University of Barcelona, Barcelona, Spain
| | - Joan Fabregat
- Liver Transplant Unit, Department of Surgery, Bellvitge University Hospital, IDIBELL, University of Barcelona, Barcelona, Spain
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16
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Lee BT, Fiel MI, Schiano TD. Antibody-mediated rejection of the liver allograft: An update and a clinico-pathological perspective. J Hepatol 2021; 75:1203-1216. [PMID: 34343613 DOI: 10.1016/j.jhep.2021.07.027] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 07/06/2021] [Accepted: 07/14/2021] [Indexed: 12/16/2022]
Abstract
Antibody-mediated rejection after liver transplantation is an under-recognised cause of allograft injury. While definitions of acute and chronic antibody-mediated rejection have increased clinical awareness, timely identification and management of antibody-mediated rejection remain difficult because of complexities in diagnosis and histopathology, lack of treatment protocols, and unclear long-term outcomes. While recent cohort studies assessing the importance of donor-specific antibodies have aided in its diagnosis, literature on the treatment of antibody-mediated rejection in liver transplantation remain limited to case reports and small series. Further increasing the awareness and timely recognition of antibody-mediated rejection post-liver transplantation is crucial in order to stimulate future research and the development of protocols for its diagnosis and treatment. This review will summarise recent advances in the clinical diagnosis and treatment of antibody-mediated rejection in liver transplantation, as well as some of the histopathologic features (on liver biopsy tissue) of acute and chronic antibody-mediated rejection.
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Affiliation(s)
- Brian T Lee
- Division of Gastroenterology and Transplant Institute, Loma Linda University Health, Loma Linda, CA, USA.
| | - M Isabel Fiel
- Department of Pathology, Molecular and Cell-Based Medicine, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Thomas D Schiano
- Division of Liver Diseases, Department of Medicine, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
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17
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Baradaran H, Dashti-Khavidaki S, Taher M, Talebian M, Nasiri-Toosi M, Jafarian A. Antibody-Mediated Rejection in Adult Liver Transplant Recipients: A Case Series and Literature Review. J Clin Pharmacol 2021; 62:254-271. [PMID: 34480762 DOI: 10.1002/jcph.1963] [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: 07/20/2021] [Accepted: 08/30/2021] [Indexed: 11/08/2022]
Abstract
Antibody-mediated rejection is a rare complication following liver transplantation and there is a lack of a comprehensive treatment strategy to provide detailed information about the dose and duration of antibody-mediated rejection treatment. This study describes eight adult liver transplantation recipients who developed antibody-mediated rejection between 2002 and 2021 in our center, as well as a review of the literature on the reported cases of antibody-mediated rejection in liver transplantation recipients. Our center's medical records were reviewed retrospectively to extract the necessary data on patients' characteristics, management, and outcomes. Then, a comprehensive search using Embase, PubMed, Web of Science, Cochrane library, and Google Scholar databases was conducted without time limitation until June, 2021. Finally, a stepwise protocol was developed for managing acute, chronic, and recurrent antibody-mediated rejection in liver transplantation patients, based on our own experience, reported cases in the literature, and data from kidney transplantation. By review of the literature, 24 case studies containing 64 patients were identified and their management strategies and outcomes were evaluated. Although, various combinations of corticosteroids, plasma exchange, intravenous immunoglobulin, and biological agents are used in the treatment of acute antibody-mediated rejection in liver transplantation, treatment strategies should be classified according to the type, severity, and the timing of its onset. Given the importance of early treatment, rituximab and/or bortezomib should be started as soon as possible if no improvement in liver enzymes/bilirubin is observed during the initial treatment strategy using corticosteroids, plasma exchange and intravenous immunoglobulin. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Hananeh Baradaran
- Resident of Clinical Pharmacy, Students Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Resident of Clinical Pharmacy, Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Simin Dashti-Khavidaki
- Professor of Clinical Pharmacy, Liver Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Taher
- Assistant Professor of Gastroenterology, Division of Gastroenterology and Hepatology, Tehran University of Medical Sciences, Imam Khomeini Hospital Complex, Tehran, Iran.,Assistant Professor of Gastroenterology, Liver Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Monavar Talebian
- General Physician, Liver Transplantation Physician, Liver Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohsen Nasiri-Toosi
- Associate Professor of Gastroenterology and Hepatology, Liver Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Jafarian
- Professor of General Surgery, Division of Hepatopancreatobiliary and Liver Transplantation, Liver Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
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18
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Sakamoto S, Akamatsu N, Hasegawa K, Ohdan H, Nakagawa K, Egawa H. The efficacy of rituximab treatment for antibody-mediated rejection in liver transplantation: A retrospective Japanese nationwide study. Hepatol Res 2021; 51:990-999. [PMID: 33818877 DOI: 10.1111/hepr.13643] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 02/17/2021] [Accepted: 03/27/2021] [Indexed: 12/17/2022]
Abstract
AIM Antibody-mediated rejection (AMR) has been consistently elucidated in liver transplantation (LT); however, the treatment for AMR, including rituximab, has not been indicated as a strongly recommended therapeutic protocol. METHODS This study was conducted as the Japanese multicenter retrospective study to accumulate data on the use of rituximab for AMR among patients undergoing LT between August 2001 and December 2016. Thirteen patients (five children and eight adults) were enrolled. RESULTS The types of AMR in the pediatric cases were chronic AMR in four cases and indeterminate AMR in one case. Among the pediatric cases, rituximab treatment only showed therapeutic efficacy in two patients with chronic AMR. Among the adult patients, five patients had chronic AMR, and three had acute AMR. Although two patients with chronic AMR died due to graft failure, liver function tests revealed improvement after rituximab treatment in the other patients. Two of the three patients with acute AMR died due to graft failure; rituximab treatment showed no therapeutic efficacy in these cases. Although bacterial infections occurred within 3 months after rituximab administration in three patients, rituximab treatment could be safely administered without any direct adverse effects. CONCLUSIONS The indication of rituximab therapy as an additional treatment for mild acute AMR and chronic AMR may be feasible; however, a prospective randomized control study is needed to evaluate the therapeutic efficacy of rituximab treatment for AMR.
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Affiliation(s)
- Seisuke Sakamoto
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Nobuhisa Akamatsu
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, Tokyo University Graduate School of Medicine, Tokyo, Japan
| | - Kiyoshi Hasegawa
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, Tokyo University Graduate School of Medicine, Tokyo, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Ken Nakagawa
- Department of Urology, Ichikawa General Hospital Tokyo Dental College, Chiba, Japan
| | - Hiroto Egawa
- Department of Gastroenterological Surgery, Institute of Gastroenterology, Tokyo Women's Medical University of Medicine, Tokyo, Japan
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19
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Zhou S, Mitsinikos T, Emamaullee J, Weaver C, Wang L, Shillingford N, Warren M, Bawab JH, Tiwari N, Genyk Y, Thomas D, Parham DM. Clinicopathologic Characteristics of Late Acute Antibody-mediated Rejection in Pediatric Liver Transplantation. Transplantation 2021; 105:2045-2053. [PMID: 33031223 DOI: 10.1097/tp.0000000000003469] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND An early and accurate diagnosis of liver antibody-mediated rejection (AMR) followed by timely intervention is important for clinical management but remains challenging. The aim of this study was to assess the clinicopathologic characteristics and outcomes of late acute AMR in pediatric liver transplantation recipients. METHODS We performed a retrospective review of 739 ABO-identical/compatible allograft liver biopsies from 199 pediatric transplantation recipients. RESULTS Based on Banff 2016 AMR criteria, 3 recipients fulfilled the criteria for definite for late acute AMR, 2 met the criteria for suspicious for AMR, and 2 were indeterminate for AMR. We further assessed the clinicopathologic characteristics of these 7 patients. All 7 patients had at least 1 biopsy with a histopathologic pattern compatible with acute AMR. Additionally, we observed accompanied moderately to markedly dilated portal/central veins and endothelialitis disproportionate to the degree of bile duct injury in all 7 patients; periportal/perivenular hepatocyte necrosis was seen in 6 of 7 patients; and arteritis was seen in 3 of 7 patients. In each case, microvascular C4d deposition was present in at least 1 biopsy. Posttransplant donor specific anti-HLA antibodies were detected in 5 patients. Two of 7 patients were retransplanted, and 2 died after developing refractory AMR. The remaining 5 patients were alive with stable graft function at a median follow-up of 4.1 years. CONCLUSIONS Our data suggest that acute AMR in pediatric liver grafts is rare, can develop late, and may be associated with graft loss or patient death. The recurrent histopathologic findings of moderately to markedly dilated portal/central veins and endothelialitis disproportionate to the degree of bile duct injury are features that appear unique to pediatric acute AMR of liver grafts.
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Affiliation(s)
- Shengmei Zhou
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA.,Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Tania Mitsinikos
- Keck School of Medicine, University of Southern California, Los Angeles, CA.,Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA
| | - Juliet Emamaullee
- Keck School of Medicine, University of Southern California, Los Angeles, CA.,Department of Surgery, Children's Hospital Los Angeles, Los Angeles, CA
| | - Carly Weaver
- Department of Surgery, Children's Hospital Los Angeles, Los Angeles, CA
| | - Larry Wang
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA.,Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Nick Shillingford
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA.,Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Mikako Warren
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA.,Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Julie Huss Bawab
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA
| | - Nishant Tiwari
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA
| | - Yuri Genyk
- Keck School of Medicine, University of Southern California, Los Angeles, CA.,Department of Surgery, Children's Hospital Los Angeles, Los Angeles, CA
| | - Danny Thomas
- Keck School of Medicine, University of Southern California, Los Angeles, CA.,Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA
| | - David M Parham
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA.,Keck School of Medicine, University of Southern California, Los Angeles, CA
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20
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Long-term, Prolonged-release Tacrolimus-based Immunosuppression in De Novo Liver Transplant Recipients: 5-year Prospective Follow-up of Patients in the DIAMOND Study. Transplant Direct 2021; 7:e722. [PMID: 34263020 PMCID: PMC8274734 DOI: 10.1097/txd.0000000000001166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 03/08/2021] [Accepted: 03/09/2021] [Indexed: 01/27/2023] Open
Abstract
Background Immunosuppression with calcineurin inhibitors (CNIs) is reportedly associated with risk of renal impairment in liver transplant recipients. It is believed that this can be mitigated by decreasing initial exposure to CNIs or delaying CNI introduction until 3-4 d posttransplantation. The ADVAGRAF studied in combination with mycophenolate mofetil and basiliximab in liver transplantation (DIAMOND) trial evaluated different administration strategies for prolonged-release tacrolimus (PR-T). Methods DIAMOND was a 24-wk, open-label, phase 3b trial in de novo liver transplant recipients randomized to: PR-T 0.2 mg/kg/d (Arm 1); PR-T 0.15-0.175 mg/kg/d plus basiliximab (Arm 2); or PR-T 0.2 mg/kg/d delayed until day 5 posttransplant plus basiliximab (Arm 3). In a 5-y follow-up, patients were maintained on an immunosuppressive regimen according to standard clinical practice (NCT02057484). Primary endpoint: graft survival (Kaplan-Meier analysis). Results Follow-up study included 856 patients. Overall graft survival was 84.6% and 73.5% at 1 and 5 y post transplant, respectively. Five-year rates for Arms 1, 2, and 3 were 74.7%, 71.5%, and 74.5%, respectively. At 5 y, death-censored graft survival in the entire cohort was 74.7%. Overall graft survival in patients remaining on PR-T for ≥30 d was 79.1%. Graft survival in patients who remained on PR-T at 5 y was 87.3%. Patient survival was 86.6% at 1 y and 76.3% at 5 y, with survival rates similar in the 3 treatment arms at 5 y. Estimated glomerular filtration rate at the end of the 24-wk initial study and 5 y posttransplant was 62.1 and 61.5 mL/min/1.73 m2, respectively, and was similar between the 3 treatment arms at 5 y. Overall, 18 (2.9%) patients had ≥1 adverse drug reaction, considered possibly related to PR-T in 6 patients. Conclusions In the DIAMOND study patient cohort, renal function, graft survival, and patient survival were similar between treatment arms at 5 y posttransplant.
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21
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Liu W, Wang K, Xiao YL, Liu C, Gao W, Li DH. Clinical relevance of donor-specific human leukocyte antigen antibodies after pediatric liver transplantation. Exp Ther Med 2021; 22:867. [PMID: 34194545 PMCID: PMC8237393 DOI: 10.3892/etm.2021.10299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 09/30/2020] [Indexed: 11/06/2022] Open
Abstract
Donor-specific human leukocyte antigen (HLA) antibodies (DSAs) have a significant role in graft survival after pediatric liver transplantation. To understand the significance of DSAs, a retrospective cohort study of 48 pediatric liver transplant recipients with posttransplant serum samples that were analyzed for DSAs was performed. According to their test results, the recipients were divided into a DSA-positive group and a DSA-negative group. Postoperative liver transplantation biopsies were performed in patients with abnormal liver function. The liver condition and prognosis of the recipients were recorded, and their association was analyzed. A total of 48 recipients were followed up for 2.7±0.8 years. DSA positivity was detected in 10 cases (20.8%). One case was positive for HLA class I and HLA class II antibodies, whereas 9 cases were positive for HLA class II antibodies, and the gene loci were HLA-DR and/or DQ. Antibody-mediated rejection (AMR) occurred in four of 10 patients in the DSA-positive group. Liver function was abnormal in 3 of 38 cases in the DSA-negative group. Multivariate analysis revealed that DSA positivity was an independent risk factor for liver insufficiency and long-term survival of recipients. In addition, Kaplan-Meier survival analysis demonstrated that there were significant differences in the survival of graft recipients between the DSA-positive group and the DSA-negative group (P<0.05). The positivity of DSAs after pediatric liver transplantation was closely related to the occurrence of AMR. These results suggested that DSAs should be routinely monitored post-operatively, and that DSA-positive recipients should be screened as soon as possible and given appropriate treatment.
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Affiliation(s)
- Wei Liu
- Department of Blood Transfusion, Tianjin First Central Hospital, Tianjin 300192, P.R. China
| | - Kai Wang
- Department of Transplantation Surgery, Tianjin First Central Hospital, Tianjin 300192, P.R. China
| | - Yan-Li Xiao
- Department of Blood Transfusion, Tianjin First Central Hospital, Tianjin 300192, P.R. China
| | - Chun Liu
- Department of Blood Transfusion, Tianjin First Central Hospital, Tianjin 300192, P.R. China
| | - Wei Gao
- Department of Transplantation Surgery, Tianjin First Central Hospital, Tianjin 300192, P.R. China
| | - Dai-Hong Li
- Department of Blood Transfusion, Tianjin First Central Hospital, Tianjin 300192, P.R. China
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22
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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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23
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Beyzaei Z, Geramizadeh B, Bagheri Z, Karimzadeh S, Shojazadeh A. De Novo Donor Specific Antibody and Long-Term Outcome After Liver Transplantation: A Systematic Review and Meta-Analysis. Front Immunol 2020; 11:613128. [PMID: 33424868 PMCID: PMC7786049 DOI: 10.3389/fimmu.2020.613128] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 11/13/2020] [Indexed: 12/23/2022] Open
Abstract
Background The impact of de novo anti-HLA donor-specific alloantibodies (DSA) which develop after long-term liver transplantation (LT) remains controversial and unclear. The aim of this study was to investigate the role of de novo DSAs on the outcome in LT. Methods We did a systematic review and meta-analysis of observational studies published until Dec 31, 2019, that reported de novo DSA outcome data (≥1 year of follow-up) after liver transplant. A literature search in the MEDLINE/PubMed, EMBASE, Cochrane Library, Scopus and Web of Science Core Collection databases was performed. Results Of 5,325 studies identified, 15 fulfilled our inclusion criteria. The studies which reported 2016 liver transplant recipients with de novo DSAs showed an increased complication risk, i.e. graft loss and chronic rejection (OR 3.61; 95% CI 1.94-6.71, P < 0.001; I2 58.19%), and allograft rejection alone (OR 6.43; 95% CI: 3.17-13.04; P < 0.001; I2 49.77%); they were compared to patients without de novo DSAs. The association between de novo DSAs and overall outcome failure was consistent across all subgroups and sensitivity analysis. Conclusions Our study suggested that de novo DSAs had a significant deleterious impact on the liver transplant risk of rejection. The routine detection of de novo DSAs may be beneficial as noninvasive biomarker-guided risk stratification.
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Affiliation(s)
- Zahra Beyzaei
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Bita Geramizadeh
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pathology, Medical School of Shiraz University, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Bagheri
- Department of Biostatistics, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sara Karimzadeh
- Shiraz Medical School Library, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Alireza Shojazadeh
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
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24
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Ünlü S, Lachmann N, Jara M, Ritschl PV, Wiering L, Eurich D, Denecke C, Biebl M, Chopra S, Gül-Klein S, Schöning W, Schmelzle M, Reinke P, Tacke F, Pratschke J, Öllinger R, Dziodzio T. Treatment of Anti-HLA Donor-Specific Antibodies Results in Increased Infectious Complications and Impairs Survival after Liver Transplantation. J Clin Med 2020; 9:jcm9123986. [PMID: 33317012 PMCID: PMC7763868 DOI: 10.3390/jcm9123986] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 11/30/2020] [Accepted: 12/07/2020] [Indexed: 02/07/2023] Open
Abstract
Donor-specific anti-human leukocyte antigen antibodies (DSA) are controversially discussed in the context of liver transplantation (LT). We investigated the relationship between the presence of DSA and the outcome after LT. All the LTs performed at our center between 1 January 2008 and 31 December 2015 were examined. Recipients < 18 years, living donor-, combined, high-urgency-, and re-transplantations were excluded. Out of 510 LTs, 113 DSA-positive cases were propensity score-matched with DSA-negative cases based on the components of the Balance of Risk score. One-, three-, and five-year survival after LT were 74.3% in DSA-positive vs. 84.8% (p = 0.053) in DSA-negative recipients, 71.8% vs. 71.5% (p = 0.821), and 69.3% vs. 64.9% (p = 0.818), respectively. Rejection therapy was more often applied to DSA-positive recipients (n = 77 (68.1%) vs. 37 (32.7%) in the control group, p < 0.001). At one year after LT, 9.7% of DSA-positive patients died due to sepsis compared to 1.8% in the DSA-negative group (p = 0.046). The remaining causes of death were comparable in both groups (cardiovascular 6.2% vs. 8.0%; p = 0.692; hepatic 3.5% vs. 2.7%, p = 0.788; malignancy 3.5% vs. 2.7%, p = 0.788). DSA seem to have an indirect effect on the outcome of adult LTs, impacting decision-making in post-transplant immunosuppression and rejection therapies and ultimately increasing mortality due to infectious complications.
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Affiliation(s)
- Sinem Ünlü
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.Ü.); (M.J.); (P.V.R.); (L.W.); (D.E.); (C.D.); (M.B.); (S.C.); (S.G.-K.); (W.S.); (M.S.); (J.P.); (R.Ö.)
- Institute for Transfusion Medicine, H&I Laboratory, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany;
| | - Nils Lachmann
- Institute for Transfusion Medicine, H&I Laboratory, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany;
| | - Maximilian Jara
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.Ü.); (M.J.); (P.V.R.); (L.W.); (D.E.); (C.D.); (M.B.); (S.C.); (S.G.-K.); (W.S.); (M.S.); (J.P.); (R.Ö.)
| | - Paul Viktor Ritschl
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.Ü.); (M.J.); (P.V.R.); (L.W.); (D.E.); (C.D.); (M.B.); (S.C.); (S.G.-K.); (W.S.); (M.S.); (J.P.); (R.Ö.)
- BIH Charité Clinician Scientist Program, Berlin Institute of Health (BIH), 10178 Berlin, Germany
| | - Leke Wiering
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.Ü.); (M.J.); (P.V.R.); (L.W.); (D.E.); (C.D.); (M.B.); (S.C.); (S.G.-K.); (W.S.); (M.S.); (J.P.); (R.Ö.)
| | - Dennis Eurich
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.Ü.); (M.J.); (P.V.R.); (L.W.); (D.E.); (C.D.); (M.B.); (S.C.); (S.G.-K.); (W.S.); (M.S.); (J.P.); (R.Ö.)
| | - Christian Denecke
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.Ü.); (M.J.); (P.V.R.); (L.W.); (D.E.); (C.D.); (M.B.); (S.C.); (S.G.-K.); (W.S.); (M.S.); (J.P.); (R.Ö.)
| | - Matthias Biebl
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.Ü.); (M.J.); (P.V.R.); (L.W.); (D.E.); (C.D.); (M.B.); (S.C.); (S.G.-K.); (W.S.); (M.S.); (J.P.); (R.Ö.)
| | - Sascha Chopra
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.Ü.); (M.J.); (P.V.R.); (L.W.); (D.E.); (C.D.); (M.B.); (S.C.); (S.G.-K.); (W.S.); (M.S.); (J.P.); (R.Ö.)
| | - Safak Gül-Klein
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.Ü.); (M.J.); (P.V.R.); (L.W.); (D.E.); (C.D.); (M.B.); (S.C.); (S.G.-K.); (W.S.); (M.S.); (J.P.); (R.Ö.)
| | - Wenzel Schöning
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.Ü.); (M.J.); (P.V.R.); (L.W.); (D.E.); (C.D.); (M.B.); (S.C.); (S.G.-K.); (W.S.); (M.S.); (J.P.); (R.Ö.)
| | - Moritz Schmelzle
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.Ü.); (M.J.); (P.V.R.); (L.W.); (D.E.); (C.D.); (M.B.); (S.C.); (S.G.-K.); (W.S.); (M.S.); (J.P.); (R.Ö.)
| | - Petra Reinke
- Department of Nephrology and Internal Intensive Medicine, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany;
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany;
| | - Johann Pratschke
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.Ü.); (M.J.); (P.V.R.); (L.W.); (D.E.); (C.D.); (M.B.); (S.C.); (S.G.-K.); (W.S.); (M.S.); (J.P.); (R.Ö.)
| | - Robert Öllinger
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.Ü.); (M.J.); (P.V.R.); (L.W.); (D.E.); (C.D.); (M.B.); (S.C.); (S.G.-K.); (W.S.); (M.S.); (J.P.); (R.Ö.)
| | - Tomasz Dziodzio
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.Ü.); (M.J.); (P.V.R.); (L.W.); (D.E.); (C.D.); (M.B.); (S.C.); (S.G.-K.); (W.S.); (M.S.); (J.P.); (R.Ö.)
- Correspondence: ; Tel.: +48-(030)-450552001
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25
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Caballero Marcos A, Díaz Ruiz R, Romero Cristóbal M, Fernández Yunquera A, Díaz-Fontenla F, Pérez Carazo L, Peligros Gómez MI, Vicario Moreno JL, Salcedo Plaza M, Bañares Cañizares R. Long-term outcomes and clinical impact of anti-HLA donor-specific antibodies (DSA) after liver transplantation: a prospective study in a pilot cohort. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2020; 113:557-562. [PMID: 33244987 DOI: 10.17235/reed.2020.7337/2020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
INTRODUCTION the presence of donor-specific antibodies (DSA) is thought to affect survival of the allograft and patient after liver transplantation (LT). However, their significance is not well understood. PATIENTS AND METHODS a prospective study was performed of 32 adult patients who underwent LT in 2011 to analyze the existence of DSA, associated risk factors and medium-term impact. Immunological determinations were performed immediately before LT and at three, six, 12 months and five years after LT. RESULTS eight patients (24.2 %) presented pre-formed DSA. However, titers were negative in all patients five years after LT and there were no associated events. Eight out of 24 patients (33.3 %) developed de novo DSA. After five years, only two remained positive; both were class II with high mean fluorescence intensity (MFI) values at diagnosis (over 15,000). No association was found between the development of DSA and the risk of rejection, graft loss or death. However, an increase in liver stiffness values was observed in patients with persistent DSA, and focal sinusoidal deposition of C4d and moderate liver fibrosis were reported. CONCLUSION the incidence of DSA is high after LT. In addition, the persistence of de novo DSA could be associated with silent liver fibrosis with a potential impact on graft outcomes.
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Affiliation(s)
| | - Raquel Díaz Ruiz
- Digestive Diseases, Hospital General Universitario Gregorio Marañon, España
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26
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Kovandova B, Slavcev A, Honsova E, Erhartova D, Skibova J, Viklicky O, Trunecka P. De novo HLA Class II antibodies are associated with the development of chronic but not acute antibody-mediated rejection after liver transplantation - a retrospective study. Transpl Int 2020; 33:1799-1806. [PMID: 33020979 DOI: 10.1111/tri.13763] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 08/04/2020] [Accepted: 09/28/2020] [Indexed: 02/02/2023]
Abstract
Donor-specific antibodies (DSA) cause antibody-mediated rejection (AMR); however, their pathogenic role has not yet been adequately investigated after liver transplantation. The aim of our study was to analyse the clinical significance of DSA and complement-binding DSA for the prediction of AMR after liver transplantation. Our cohort included 120 liver recipients with assessed protocol biopsies one year post-transplant. All patients had defined HLA-specific and complement-binding (C1q + and C3d+) antibodies before and in regular intervals after transplantation. The incidence of DSA was evaluated in relation with clinical and histopathological data in the liver allografts. A higher occurrence of acute AMR was observed in recipients with preformed complement-binding DSA to HLA Class I antigens. Patients who developed chronic AMR had more frequently de novo-produced antibodies against HLA Class II antigens (P = 0.0002). A correlation was also found between de novo-formed C1q + and C3d+-binding antibodies to HLA Class II antigens and the development of chronic AMR (P = 0.043). Our study implies that preformed complement-binding DSA to HLA Class I antigens are related to increased risk of acute antibody-mediated rejection, while chronic AMR is more frequent in patients with de novo-produced antibodies to HLA Class II antigens after liver transplantation.
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Affiliation(s)
| | | | - Eva Honsova
- Department of Clinical & Transplantation Pathology, IKEM, Prague, Czech Republic
| | - Denisa Erhartova
- Department of Hepatogastroenterology, IKEM, Prague, Czech Republic
| | - Jelena Skibova
- Department of Medical Statistics, IKEM, Prague, Czech Republic
| | | | - Pavel Trunecka
- Department of Hepatogastroenterology, IKEM, Prague, Czech Republic
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27
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Donor-specific antibodies in liver transplantation: challenges in diagnosis and determining clinical impact. Curr Opin Organ Transplant 2020; 25:549-554. [PMID: 33105198 DOI: 10.1097/mot.0000000000000825] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW Our understanding of the clinical impact of donor-specific antibodies in liver transplant recipients has evolved in recent years as outcomes for liver allografts have improved and advances in diagnostic testing have made recognition of antibody mediated rejection in transplant patients more sensitive. RECENT FINDINGS Two main types of donor-specific antibodies - preformed and de novo - have been reported in the literature to have a negative impact on graft survival, and researchers have been able to further identify subclasses of class II donor-specific antibodies as being the most clinically impactful. Furthermore, there is evidence that donor-specific antibody formation can augment cellular rejection in liver grafts and lead to worsened clinical outcomes. Recent data have shown a higher prevalence of donor-specific antibody formation than previously reported. SUMMARY This review explores the most recent literature regarding the clinical impact of both preformed and de-novo donor-specific antibodies and potential management guidelines for patients undergoing liver transplantation. The best practice guidelines for undergoing monitoring for donor-specific antibody formation and protocol biopsies in sensitized patients will depend on further multiinstitutional studies.
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Kohut TJ, Barandiaran JF, Keating BJ. Genomics and Liver Transplantation: Genomic Biomarkers for the Diagnosis of Acute Cellular Rejection. Liver Transpl 2020; 26:1337-1350. [PMID: 32506790 DOI: 10.1002/lt.25812] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Revised: 04/26/2020] [Accepted: 05/18/2020] [Indexed: 02/07/2023]
Abstract
Acute cellular rejection (ACR) is a common complication in liver transplantation recipients (LTRs), especially within the first 12 months, and it is associated with increased morbidity and mortality. Although abnormalities in standard liver biochemistries may raise the clinical suspicion for ACR, it lacks specificity, and invasive liver biopsies, which are associated with numerous risks, are required for definitive diagnoses. Biomarker discovery for minimally invasive tools for diagnosis and prognostication of ACR after liver transplantation (LT) has become a rapidly evolving field of research with a recent shift in focus to omics-based biomarker discovery. Although none are yet ready to replace the standard of care, there are several promising minimally invasive, blood-derived biomarkers that are under intensive research for the diagnosis of ACR in LTRs. These omics-based biomarkers, encompassing DNA, RNA, proteins, and metabolites, hold tremendous potential. Some are likely to become integrated into ACR diagnostic algorithms to assist clinical decision making with a high degree of accuracy that is cost-effective and reduces or even obviates the need for an invasive liver biopsy.
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Affiliation(s)
- Taisa J Kohut
- Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA.,The Children's Hospital of Philadelphia, Philadelphia, PA
| | - Jose F Barandiaran
- Department of General Surgery, Main Line Health System, Lankenau Medical Center, Wynnewood, PA
| | - Brendan J Keating
- Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA
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29
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Höfer A, Jonigk D, Hartleben B, Verboom M, Hallensleben M, Manns MP, Jaeckel E, Taubert R. Non-invasive screening for subclinical liver graft injury in adults via donor-specific anti-HLA antibodies. Sci Rep 2020; 10:14242. [PMID: 32859929 PMCID: PMC7455737 DOI: 10.1038/s41598-020-70938-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 07/02/2020] [Indexed: 02/06/2023] Open
Abstract
The majority of liver grafts exhibit abnormal histological findings late after transplantation, even when liver enzymes are normal. Such subclinical graft injuries were associated with rejection and fibrosis progression in recent studies. The identification of non-invasive biomarkers for subclinical graft injury might help to individualize immunosuppression. Therefore, graft injury was assessed in 133 liver biopsies with normal/near normal liver enzymes from a prospective liver biopsy program. Cytokeratin-18 cell death marker (M65) and donor specific anti-HLA antibodies (DSA) were measured as non-invasive markers in paired plasma samples in addition to routine parameters. M65 was associated with subclinical graft injury but this association was too weak for reasonable clinical application. DSA positivity was associated with more graft inflammation (OR = 5.4) and more fibrosis (OR = 4.2). Absence of DSA excluded fibrosis in 87–89%, while presence of DSA excluded histological criteria for immunosuppression minimization attempts in 92–97%. While CK18 cell death marker had no diagnostic value for the detection of subclinical liver graft injury, DSA testing can help to preselect patients for immunosuppression reduction in case of DSA negativity, while DSA positivity should prompt elastography or liver biopsy for the assessment of subclinical graft injury.
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Affiliation(s)
- Anne Höfer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany.,European Reference Network On Hepatological Diseases (ERN RARE-LIVER), Hannover, Germany
| | - Danny Jonigk
- Institute for Pathology, Hannover Medical School, Hannover, Germany
| | - Björn Hartleben
- Institute for Pathology, Hannover Medical School, Hannover, Germany
| | - Murielle Verboom
- Institute for Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
| | - Michael Hallensleben
- Institute for Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,European Reference Network On Hepatological Diseases (ERN RARE-LIVER), Hannover, Germany
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany.,European Reference Network On Hepatological Diseases (ERN RARE-LIVER), Hannover, Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. .,Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany. .,European Reference Network On Hepatological Diseases (ERN RARE-LIVER), Hannover, Germany.
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Willuweit K, Frey A, Bieniek L, Heinold A, Büchter M, Horn PA, Wedemeyer H, Herzer K. HLA class II donor specific antibodies are associated with graft cirrhosis after liver transplant independent of the mean fluorescence intensity level. BMC Gastroenterol 2020; 20:288. [PMID: 32854625 PMCID: PMC7457295 DOI: 10.1186/s12876-020-01427-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 08/16/2020] [Indexed: 11/18/2022] Open
Abstract
Background The importance of donor-specific antibodies (DSA) after liver transplantation (LT) for graft and patient survival is an ongoing controversy. So far it has not been elucidated when and in how far DSA are harmful for graft and patient survival. Therefore, we had the aim to investigate the association of DSA with complications after LT. Methods Data of 430 LT recipients were collected and statistically analyzed. Detection of HLA antibodies (Ab) was performed by Luminex assay. Results DSA were detected in 81 patients (18.8%). These were mainly HLA class II Ab (81.5%). HLA class II Ab show a higher MFI (median: 5.300) compared to HLA class I Ab (median: 2.300). There is no association between MFI levels and development of complications after LT. However, cirrhosis occurred significantly more often in DSA positive patients (18%) than in patients without detectable DSA (9%, P = 0.027). All DSA positive patients with cirrhosis of the graft showed HLA class II antibodies (OR: 3.028; 95% CI: 1.51–6.075; P = 0.002). Conclusion Occurrence of HLA class II DSA after LT is associated with graft cirrhosis and may indicate a higher risk to develop graft damage independent on MFI and requires an individualized risk management.
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Affiliation(s)
- Katharina Willuweit
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany.
| | - Alexandra Frey
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany
| | - Lisa Bieniek
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany
| | - Andreas Heinold
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Matthias Büchter
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany.,Department of Internal Medicine, St. Nikolaus Stiftshospital, Andernach Teaching Hospital, University of Bonn, Andernach, Germany
| | - Peter A Horn
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany
| | - Kerstin Herzer
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany
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Cousin VL, Rougemont AL, Rubbia-Brandt L, Wildhaber BE, Villard J, Ferrari-Lacraz S, McLin VA. Peripheral Donor-specific Antibodies Are Associated With Histology and Cellular Subtypes in Protocol Liver Biopsies of Pediatric Recipients. Transplantation 2020; 104:1633-1643. [PMID: 32732841 DOI: 10.1097/tp.0000000000003099] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND The cellular infiltrate in protocol liver biopsies (PB) following pediatric liver transplantation remains mostly uncharacterized, yet there is increasing concern about the role of inflammation and fibrosis in long-term liver allografts. We aimed to define cell types in PB and to analyze their relationship with donor-specific antibodies (DSA) and histological phenotype. METHODS PB were performed at least 1 year after transplantation. We identified 4 phenotypes: normal, fibrosis, inflammation, inflammation with fibrosis. Cell types were counted after immunostaining for CD3, CD4, CD8, CD68, CD20, MUM1, and FoxP3. RESULTS Forty-four patients underwent 1 PB between 2000 and 2015. Eleven percent (5/44) of PB displayed normal histology, 13.6% (6/44) fibrosis, 34.1% (15/44) inflammation, and 40.9% (18/44) inflammation and fibrosis. The main cell types in the portal tracts and lobules were CD3+ and CD68+ cells. Frequency of de novo DSA was 63% (27/44). The presence of CD8+ cells in the lobules was associated with fibrosis. Inflammation and fibrosis in PB were associated with the presence of circulating de novo DSA, number of de novo DSA, and C1q binding activity when compared to other phenotypes. CONCLUSIONS T cells (CD3+) and macrophages (CD68+) were the most prevalent cell-types in PB. In the presence of inflammation, portal tracts were enriched in CD3+, CD20+ but displayed fewer CD68+. This coincided with the presence and number of de novo DSA. How these cellular and humoral actors interact is unclear, but peripheral DSA may be a marker of immune cellular activity in the seemingly quiescent allograft.
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Affiliation(s)
- Vladimir L Cousin
- Swiss Pediatric Liver Center, Geneva University Hospitals, Department of Pediatrics, Gynecology, and Obstetrics, University of Geneva, Geneva, Switzerland
| | - Anne-Laure Rougemont
- Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Laura Rubbia-Brandt
- Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Barbara E Wildhaber
- Swiss Pediatric Liver Center, Geneva University Hospitals, Department of Pediatrics, Gynecology, and Obstetrics, University of Geneva, Geneva, Switzerland
- Department of Pediatrics, Gynecology, and Obstetrics, University of Geneva, Geneva, Switzerland
| | - Jean Villard
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
- Transplantation Immunology Unit and National Reference Laboratory for Histocompatibility, Geneva University Hospital and Medical School, Geneva, Switzerland
| | - Sylvie Ferrari-Lacraz
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
- Transplantation Immunology Unit and National Reference Laboratory for Histocompatibility, Geneva University Hospital and Medical School, Geneva, Switzerland
| | - Valérie A McLin
- Swiss Pediatric Liver Center, Geneva University Hospitals, Department of Pediatrics, Gynecology, and Obstetrics, University of Geneva, Geneva, Switzerland
- Department of Pediatrics, Gynecology, and Obstetrics, University of Geneva, Geneva, Switzerland
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Hann A, Osei-Bordom DC, Neil DAH, Ronca V, Warner S, Perera MTPR. The Human Immune Response to Cadaveric and Living Donor Liver Allografts. Front Immunol 2020; 11:1227. [PMID: 32655558 PMCID: PMC7323572 DOI: 10.3389/fimmu.2020.01227] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 05/15/2020] [Indexed: 12/13/2022] Open
Abstract
The liver is an important contributor to the human immune system and it plays a pivotal role in the creation of both immunoreactive and tolerogenic conditions. Liver transplantation provides the best chance of survival for both children and adults with liver failure or cancer. With current demand exceeding the number of transplantable livers from donors following brain death, improved knowledge, technical advances and the desire to prevent avoidable deaths has led to the transplantation of organs from living, ABO incompatible (ABOi), cardiac death donors and machine based organ preservation with acceptable results. The liver graft is the most well-tolerated, from an immunological perspective, of all solid organ transplants. Evidence suggests successful cessation of immunosuppression is possible in ~20–40% of liver transplant recipients without immune mediated graft injury, a state known as “operational tolerance.” An immunosuppression free future following liver transplantation is an ambitious but perhaps not unachievable goal. The initial immune response following transplantation is a sterile inflammatory process mediated by the innate system and the mechanisms relate to the preservation-reperfusion process. The severity of this injury is influenced by graft factors and can have significant consequences. There are minimal experimental studies that delineate the differences in the adaptive immune response to the various forms of liver allograft. Apart from ABOi transplants, antibody mediated hyperacute rejection is rare following liver transplant. T-cell mediated rejection is common following liver transplantation and its incidence does not differ between living or deceased donor grafts. Transplantation in the first year of life results in a higher rate of operational tolerance, possibly due to a bias toward Th2 cytokines (IL4, IL10) during this period. This review further describes the current understanding of the immunological response toward liver allografts and highlight the areas of this topic yet to be fully understood.
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Affiliation(s)
- Angus Hann
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.,Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | | | - Desley A H Neil
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Department of Cellular Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Vincenzo Ronca
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Suz Warner
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,The Liver Unit, Birmingham Children's Hospital, Birmingham, United Kingdom
| | - M Thamara P R Perera
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.,The Liver Unit, Birmingham Children's Hospital, Birmingham, United Kingdom
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Influence of Preformed Antibodies in Liver Transplantation. J Clin Med 2020; 9:jcm9030708. [PMID: 32151032 PMCID: PMC7141359 DOI: 10.3390/jcm9030708] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 03/02/2020] [Indexed: 12/12/2022] Open
Abstract
The significance of human leukocyte antigen (HLA) matching and preformed donor-specific antibodies (DSAs) in liver transplantation remains unclear. The aim of this study was to analyze the presence of DSAs in a large cohort of 810 liver recipients undergoing liver transplant to determine the influence on acute (AR) or chronic liver rejection (CR), graft loss and allograft survival. DSAs were identified using complement dependent cytotoxicity crossmatch (CDC-CM) and multiplexed solid-phase-based flow cytometry assay (Luminex). CDC-CM showed that a 3.2% of liver transplants were positive (+CDC-CM) with an AR frequency of 19.2% which was not different from that observed in negative patients (-CDC-CM, 22.3%). Only two patients transplanted with +CDC-CM (7.6%) developed CR and suffered re-transplant. +CDC-CM patients showed a significantly lower survival rate compared to -CDC-CM patients (23.1% vs. 59.1%, p = 0.0003), developing allograft failure within the first three months (p < 0.00001). In conclusion, we have demonstrated a relationship between the presence of preformed DSAs and the low graft liver survival, indicating the important role and the potential interest of performing this analysis before liver transplantation. Our results could help to detect patients with an increased risk of graft loss, a better choice of liver receptors as well as the establishment of individualized immunosuppressive regimens.
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Meszaros M, Niemann M, Ursic-Bedoya J, Faure S, Meunier L, Rivière B, Costes-Martineau V, Thevenin C, Pageaux GP. Exploring predicted indirectly recognizable HLA epitopes (PIRCHE-II) in liver transplant recipients on calcineurin inhibitor-free maintenance immunosuppression. A retrospective single center study. Transpl Immunol 2020; 59:101272. [PMID: 32061667 DOI: 10.1016/j.trim.2020.101272] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 02/09/2020] [Accepted: 02/11/2020] [Indexed: 12/12/2022]
Abstract
The PIRCHE (Predicted Indirectly ReCognizable HLA Epitopes) score is an HLA epitope matching algorithm. PIRCHE algorithm estimates the level of presence of T-cell epitopes in mismatched HLA. The PIRCHE-II numbers associate with de novo donor-specific antibody (dnDSA) formation following liver transplantation and kidney allograft survival following renal transplantation. The aim of our study was to assess the PIRCHE-II score in calcineurin inhibitor (CNI)-free maintenance immunosuppression recipients. This was a retrospective study of forty-one liver transplant recipients on CNI-free immunosuppression and with available liver allograft biopsies. Donors and recipients were HLA typed. The HLA-derived mismatched peptide epitopes that could be presented by the recipient's HLA-DRB1 molecules were calculated using PIRCHE-II algorithm. The associations between PIRCHE-II scores and graft immune-mediated events were assessed using receiver operating characteristics curves and subsequent univariate and multivariate analyses. CNI-free patients with cellular rejection, humoral rejection, or severe portal inflammation had higher mean PIRCHE-II scores compared to patients with normal liver allografts. PIRCHE-II score and donor age were independent risk factors for liver graft survival in CNI-free patients (HR: 8.0, 95% CI: 1.3-49, p = .02; and HR: 0.88, 95% CI: 0.00-0.96, p = .007, respectively). PIRCHE-II scores could be predictive of liver allograft survival in CNI-free patients following liver transplantation. Larger studies are needed to confirm these results.
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Affiliation(s)
- Magdalena Meszaros
- CHU Saint Eloi, Hepatology and Liver transplantation unit, Montpellier, France.
| | | | - José Ursic-Bedoya
- CHU Saint Eloi, Hepatology and Liver transplantation unit, Montpellier, France
| | - Stéphanie Faure
- CHU Saint Eloi, Hepatology and Liver transplantation unit, Montpellier, France
| | - Lucy Meunier
- CHU Saint Eloi, Hepatology and Liver transplantation unit, Montpellier, France
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Del Bello A, Neau-Cransac M, Lavayssiere L, Dubois V, Congy-Jolivet N, Visentin J, Danjoux M, Le Bail B, Hervieu V, Boillot O, Antonini T, Kamar N, Dumortier J. Outcome of Liver Transplant Patients With Preformed Donor-Specific Anti-Human Leukocyte Antigen Antibodies. Liver Transpl 2020; 26:256-267. [PMID: 31612580 DOI: 10.1002/lt.25663] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 09/22/2019] [Indexed: 02/07/2023]
Abstract
After liver transplantation (LT), the role of preformed donor-specific anti-human leukocyte antigen antibodies (pDSAs) remains incompletely understood. We conducted a retrospective, case-control analysis to determine the impact of pDSAs after LT in 3 French transplant centers (Bordeaux, Lyon, and Toulouse). Among the 1788 LTs performed during the study period, 142 (7.9%) had at least 1 pDSA. The patient survival rate was not different between patients who received an LT with pDSAs and the matched-control group. A liver biopsy was performed 1 year after transplantation in 87 recipients. The metavir fibrosis score did not differ between both groups (1 ± 0.8 versus 0 ± 0.8; P = 0.80). However, undergoing a retransplantation (hazard ratio [HR] = 2.6, 95% confidence interval [CI], 1.02-6.77; P = 0.05) and receiving induction therapy with polyclonal antibodies (HR = 2.5; 95% CI, 1.33-4.74; P = 0.01) were associated with a higher risk of mortality. Nonetheless, high mean fluorescence intensity (MFI) donor-specific antibodies (ie, >10,000 with One Lambda assay or >5000 with Immucor assay) were associated with an increased risk of acute rejection (HR = 2.0; 95% CI, 1.12-3.49; P = 0.02). Acute antibody-mediated rejection was diagnosed in 10 patients: 8 recipients were alive 34 (1-125) months after rejection. The use of polyclonal antibodies or rituximab as an induction therapy did not reduce the risk of acute rejection, but it increased the risk of infectious complications. In conclusion, high MFI pDSAs increase the risk of graft rejection after LT, but they do not reduce medium-term and longterm patient survival. The use of a T or B cell-depleting agent did not reduce the risk of acute rejection.
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Affiliation(s)
- Arnaud Del Bello
- Department of Nephrology and Organ Transplantation, Centre Hospitalier Universitaire Toulouse-Rangueil, Toulouse, France.,Université Paul Sabatier, Toulouse, France
| | - Martine Neau-Cransac
- Department of Nephrology and Kidney Transplantation, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
| | - Laurence Lavayssiere
- Department of Nephrology and Organ Transplantation, Centre Hospitalier Universitaire Toulouse-Rangueil, Toulouse, France
| | - Valérie Dubois
- Etablissement Français du Sang Auvergne Rhône Alpes site de Lyon, Lyon, France
| | - Nicolas Congy-Jolivet
- Laboratoire d'Immunogénétique Moléculaire, Laboratoire d'Immunologie, Centre Hospitalier Universitaire Rangueil, Toulouse, France
| | - Jonathan Visentin
- Laboratoire d'Immunologie et Immunogénétique, Hôpital Pellegrin, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.,Immuno Concept, Unités Mixtes de Recherche Centre National de la Recherche Scientifique 5164, Bordeaux, France.,Université de Bordeaux, Bordeaux, France
| | - Marie Danjoux
- Département d'Anatomie et de Cytologie Pathologiques, IUCT Oncopole, Toulouse, France
| | - Brigitte Le Bail
- Département d'Anatomie et de Cytologie pathologiques, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
| | - Valérie Hervieu
- Groupement Hospitalier est Département d'Anatomie et de Cytologie Pathologiques, Hospices Civils de Lyon, Bron, France.,Université Claude Bernard Lyon 1, Villeurbanne, France
| | - Olivier Boillot
- Université Claude Bernard Lyon 1, Villeurbanne, France.,Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Teresa Antonini
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, Centre Hospitalier Universitaire Toulouse-Rangueil, Toulouse, France.,Université Paul Sabatier, Toulouse, France
| | - Jérôme Dumortier
- Université Claude Bernard Lyon 1, Villeurbanne, France.,Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
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Vionnet J, Sempoux C, Pascual M, Sánchez-Fueyo A, Colmenero J. Donor-specific antibodies in liver transplantation. GASTROENTEROLOGIA Y HEPATOLOGIA 2020; 43:34-45. [DOI: 10.1016/j.gastrohep.2019.09.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 09/18/2019] [Accepted: 09/30/2019] [Indexed: 12/22/2022]
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Wang J, Wang P, Wang S, Tan J. Donor-specific HLA Antibodies in Solid Organ Transplantation: Clinical Relevance and Debates. EXPLORATORY RESEARCH AND HYPOTHESIS IN MEDICINE 2019; 000:1-11. [DOI: 10.14218/erhm.2019.00012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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Exploring pre-surgery donor-specific antibodies in the context of organ shortage in liver transplant. Langenbecks Arch Surg 2019; 404:865-874. [PMID: 31748871 DOI: 10.1007/s00423-019-01831-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 10/09/2019] [Indexed: 10/25/2022]
Abstract
BACKGROUND There is a growing disparity between the number of liver transplant (LT) candidates and availability of suitable liver allografts. Antibody-mediated rejection (AMR), secondary to positive donor-specific antibodies (DSA), remains a concern in liver transplantation. This study aimed to correlate expression of DSA on pre-transplant screening and outcomes of LT, specifically development of AMR in liver allografts and liver function profile in the post-operative period. METHODS Data of consecutive patients undergoing orthotopic LT (OLT) at the South Australian Liver Transplant Unit was analysed. All patients underwent DSA testing pre-transplant. RESULTS Within a cohort of 96 patients, over a post-OLT median follow-up of 849 days, only 2 patients (2%) developed AMR. While both patients had a positive DSA test preoperatively, overall DSA positivity was noted in 31% patients, with a specificity for prediction of AMR of 0.708. No significant association was noted between AMR (p = 0.092), T cell-mediated rejection/TCMR (p = 0.797) or late hepatic artery thrombosis/LHAT (p = 0.521). There was no significant interaction effect between DSA positivity and serum bilirubin or transaminases over a period of 100 days. CONCLUSION AMR following LT is uncommon. A positive DSA pre-transplant does not imply a definite risk of AMR. Also, there does not exist a significant interaction in time between DSA expression and serum bilirubin or transaminase levels. Until there emerges evidence to the contrary, it appears reasonable to consider DSA-positive donors within the broad context of marginal donors in the context of a worldwide shortage of LT donor allografts.
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Tamura K, Tohyama T, Watanabe J, Nakamura T, Ueno Y, Inoue H, Honjo M, Sakamoto K, Takai A, Ogawa K, Takada Y. Preformed donor-specific antibodies are associated with 90-day mortality in living-donor liver transplantation. Hepatol Res 2019; 49:929-941. [PMID: 30991451 DOI: 10.1111/hepr.13352] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 03/27/2019] [Accepted: 04/07/2019] [Indexed: 12/19/2022]
Abstract
AIM The impact of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) on living donor liver transplantation (LDLT) is unclear. The aim of this study was to investigate the association between DSAs and short-term outcomes in LDLT recipients, and to clarify the clinical impact of DSAs. METHOD Anti-HLA antibodies were screened in preoperative serum samples taken from 40 liver transplant recipients at Ehime University (Toon, Japan) between August 2001 and July 2015. Screening was carried out using the Flow-PRA method, and DSAs were detected in anti-HLA antibody-positive recipients using the Luminex single-antigen identification test. A mean fluorescence intensity of 1000 was used as the cut-off for positivity. We retrospectively reviewed the clinical courses of patients who were DSA-positive to elucidate early clinical manifestations in LDLT recipients. RESULTS Fifteen (12 female and 3 male) patients (38%) had anti-HLA antibodies. Eight of the 15 anti-HLA antibody-positive patients were positive for DSAs, and all were women. The 90-day survival rate of DSA-positive patients (50%) was significantly lower than that of DSA-negative patients (84.4%) (0.0112; Wilcoxon test). On univariate analysis, the DSA-positive rate was significantly higher in the 90-day mortality group. Postoperatively, the incidence of acute cellular rejection was higher in DSA-positive than DSA-negative patients. Thrombotic microangiopathy developed only in DSA-positive patients. We found no relationship between DSA status and bile duct stricture. CONCLUSION Preformed DSAs could be associated with elevated 90-day mortality in LDLT recipients. Further large-scale studies are required to verify the risk associated with DSAs in LDLT.
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Affiliation(s)
- Kei Tamura
- Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, Toon, Japan
| | - Taiji Tohyama
- Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, Toon, Japan
| | - Jota Watanabe
- Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, Toon, Japan
| | - Taro Nakamura
- Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, Toon, Japan
| | - Yoshitomo Ueno
- Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, Toon, Japan
| | - Hitoshi Inoue
- Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, Toon, Japan
| | - Masahiko Honjo
- Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, Toon, Japan
| | - Katsunori Sakamoto
- Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, Toon, Japan
| | - Akihiro Takai
- Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, Toon, Japan
| | - Kohei Ogawa
- Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, Toon, Japan
| | - Yasutsugu Takada
- Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, Toon, Japan
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Wozniak LJ, Venick RS. Donor-specific antibodies following liver and intestinal transplantation: Clinical significance, pathogenesis and recommendations. Int Rev Immunol 2019; 38:106-117. [DOI: 10.1080/08830185.2019.1630404] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Laura J. Wozniak
- Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Robert S. Venick
- Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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Dumortier J, Dedic T, Erard-Poinsot D, Rivet C, Guillaud O, Chambon-Augoyard C, Bosch A, Lachaux A, Couchonnal E, Thaunat O, Boillot O, Dubois V. Pregnancy and donor-specific HLA-antibody-mediated rejection after liver transplantation: “Liaisons dangereuses”? Transpl Immunol 2019; 54:47-51. [DOI: 10.1016/j.trim.2019.02.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 02/06/2019] [Accepted: 02/07/2019] [Indexed: 01/13/2023]
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Prevalence and Impact of Reformed and De Novo Anti-HLA Donor-Specific Antibodies in Liver Transplantation. Transplant Proc 2019; 51:424-428. [PMID: 30879557 DOI: 10.1016/j.transproceed.2019.01.074] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
INTRODUCTION The prevalence and impact of pre-existing and de novo anti-HLA donor-specific antibodies (DSAs) after orthotopic liver transplantation (OLT) is still controversial. We investigated the prevalence of DSAs and their implication in the development of allograft dysfunction after OLT. PATIENTS AND METHODS A total of 65 liver transplant patients were tested for anti-HLA antibodies, with single antigen bead technology, before, 1, 3, 6, and 12 months after transplantation, and thereafter annually, along with other risk factors. Sixteen out of 65 patients (24.6%) had circulating pre-existing anti-HLA antibodies, and 4 of them (25%) had DSAs. All patients positive for anti-HLA antibodies (100%) presented allograft dysfunction. Fourteen out of 65 patients (21.5%) had circulating de novo DSAs, and 12 out of 14 (85.7%) presented allograft dysfunction. The investigated risk factors for allograft dysfunction were: recipient and donor age, time on the waiting list, cold ischemia time, cytomegalovirus infection, immunosuppression regimen, de novo DSAs, Model for End-Stage Liver Disease, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase (GGT), direct bilirubin and total bilirubin peak post-transplant, and alkaline phosphatase. The multivariate analysis showed that de novo DSAs and time on the waiting list were independent risk factors for allograft dysfunction. CONCLUSION Our results show that de novo DSAs are an independent risk factor for allograft dysfunction, along with time on the waiting list.
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Advancing Transplantation: New Questions, New Possibilities in Kidney and Liver Transplantation. Transplantation 2018; 101 Suppl 2S:S1-S41. [PMID: 28125449 DOI: 10.1097/tp.0000000000001563] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Vandevoorde K, Ducreux S, Bosch A, Guillaud O, Hervieu V, Chambon-Augoyard C, Poinsot D, André P, Scoazec JY, Robinson P, Boillot O, Dubois V, Dumortier J. Prevalence, Risk Factors, and Impact of Donor-Specific Alloantibodies After Adult Liver Transplantation. Liver Transpl 2018; 24:1091-1100. [PMID: 29665189 DOI: 10.1002/lt.25177] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 03/19/2018] [Accepted: 03/31/2018] [Indexed: 02/06/2023]
Abstract
The incidence and impact of anti-human leukocyte antigen donor-specific alloantibodies (DSAs) developing after liver transplantation (LT) remains controversial and not extensively studied. The aim of the present study was to assess the incidence of DSAs, to identify risk factors for the development of DSAs, and to understand the impact of DSAs in a large population of adult LT recipients. This single-center retrospective study included all adult patients who underwent a first LT between 2000 and 2010 in our center. The study population mainly consisted of male patients, the mean age was 52.4 years, and the main indication was alcoholic cirrhosis (54.1%). From the 297 patients included in the cross-sectional study, 14 (4.7%) had preformed DSAs, and 59 (19.9%) presented de novo DSAs (12.2% at 1 year, 13.4% at 5 years, and 19.5% at 10 years). Multivariate analysis found that female donor sex (hazard ratio [HR], 1.50; 95% confidence interval [CI], 1.12-2.01; P = 0.01) and delay between LT and DSA screening (HR, 1.10; 95% CI, 1.01-1.20; P = 0.03) were associated with occurrence of de novo DSAs. From the 190 patients included in the subgroup longitudinal analysis, exposure to tacrolimus (mean trough level during the periods 0-2 years and 0-3 years) was significantly lower for patients having DSAs at 5 years. Concerning histology, only acute rejection (P = 0.04) and portal fibrosis ≥2 (P = 0.02) were more frequent at 1 year for patients with DSAs. Patient survival and graft survival were not significantly different according to the presence or not of DSAs at 1 year. Among the 44 patients who had de novo or persistent preformed DSAs, the diagnosis of antibody-mediated rejection was made in 4 (9.1%) patients after 1, 47, 61, and 74 months following LT. In conclusion, the results of the present study suggest that DSAs are observed in a minority of LT adult patients, with limited overall impact on graft and patient outcome.
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Affiliation(s)
- Katia Vandevoorde
- Unité de Transplantation Hépatique, Hospices Civils de Lyon, Lyon, France
| | - Stéphanie Ducreux
- Etablissement Français du Sang, Laboratoire d'Histocompatibilité, Lyon, France
| | - Alexie Bosch
- Unité de Transplantation Hépatique, Hospices Civils de Lyon, Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France
| | - Olivier Guillaud
- Unité de Transplantation Hépatique, Hospices Civils de Lyon, Lyon, France
| | - Valérie Hervieu
- Service d'Anatomie Pathologique, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France
| | | | - Domitille Poinsot
- Unité de Transplantation Hépatique, Hospices Civils de Lyon, Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France
| | - Patrice André
- Laboratoire de Virologie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France
| | - Jean-Yves Scoazec
- Service d'Anatomie Pathologique, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France
| | - Philip Robinson
- Direction de la Recherche Clinique et de l'Innovation, Hospices Civils de Lyon, Lyon, France
| | - Olivier Boillot
- Unité de Transplantation Hépatique, Hospices Civils de Lyon, Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France
| | - Valérie Dubois
- Etablissement Français du Sang, Laboratoire d'Histocompatibilité, Lyon, France
| | - Jérôme Dumortier
- Unité de Transplantation Hépatique, Hospices Civils de Lyon, Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France
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45
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Aday AW, O'Leary JG. Donor-Specific Antibodies' Meaningful Impact on Liver Transplantation. Liver Transpl 2018; 24:999-1000. [PMID: 30028076 DOI: 10.1002/lt.25299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 06/25/2018] [Indexed: 01/13/2023]
Affiliation(s)
| | - Jacqueline G O'Leary
- University of Texas Southwestern, Dallas, TX.,Dallas VA Medical Center, Dallas, TX
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46
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Cillo U, Bechstein WO, Berlakovich G, Dutkowski P, Lehner F, Nadalin S, Saliba F, Schlitt HJ, Pratschke J. Identifying risk profiles in liver transplant candidates and implications for induction immunosuppression. Transplant Rev (Orlando) 2018; 32:142-150. [DOI: 10.1016/j.trre.2018.04.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 04/03/2018] [Accepted: 04/05/2018] [Indexed: 12/16/2022]
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47
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Dao M, Habès D, Taupin JL, Mussini C, Redon MJ, Suberbielle C, Jacquemin E, Gonzales E, Guettier C. Morphological characterization of chronic antibody-mediated rejection in ABO-identical or ABO-compatible pediatric liver graft recipients. Liver Transpl 2018; 24:897-907. [PMID: 29704327 DOI: 10.1002/lt.25187] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 03/24/2018] [Accepted: 04/15/2018] [Indexed: 12/17/2022]
Abstract
This study aims to define the morphological profile associated with the presence of donor-specific antibodies (DSAs) and/or C4d immunostaining in ABO-identical or compatible pediatric liver grafts. Ten-year protocol liver graft biopsies performed at 131.3 ± 15.3 months after transplantation in 53 pediatric liver graft recipients were reviewed. Immunostaining for C4d was systematically performed and semiquantitatively analyzed. DSAs were concurrently quantified, and results were available for 44 patients. All biopsies demonstrated fibrotic changes with a mean liver allograft fibrosis score (LAFSc) of 5.1 ± 2.2. A total of 31 (58%) biopsies exhibited C4d positivity. DSAs were detected in 20 (45%) patients, and mean maximal mean fluorescence intensity was 12,977 ± 6731. LAFSc (6.3 ± 1.3 versus 3.9 ± 2.2; P = 0.008), perivenular fibrosis (2.7 ± 0.5 versus 1.3 ± 1.0; P < 0.001), and portal inflammation (1.4 ± 0.8 versus 0.3 ± 0.5; P = 0.009) were significantly higher in the double-DSA and C4d-positive group versus the double-negative group. We defined a histological scoring system from these results, which was integrated with the 2016 Banff definition and allowed reclassifying patients for the diagnosis of chronic active antibody-mediated rejection (cAMR; 11/53 versus 13/53). Diagnoses of probable cAMR according to Banff 2016 (n = 4) were unchanged, but 2 among the 9 patients classified as possible cAMR according to the 2016 Banff definition were excluded for this diagnostic when using our histological score. In conclusion, our results confirmed that perivenular fibrosis and portal inflammation in late pediatric liver graft biopsies are features of cAMR. Our histological score could improve the accuracy of the 2016 Banff definition for the diagnosis of cAMR. Liver Transplantation 24 897-907 2018 AASLD.
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Affiliation(s)
- Myriam Dao
- Pathology Department, Centre Hospitalier Universitaire Bicêtre, Le Kremlin-Bicêtre, France
- Université Paris Sud, Le Kremlin-Bicêtre, France
| | - Dalila Habès
- Pediatric Hepatology and Pediatric Liver Transplantation Unit, Centre Hospitalier Universitaire Bicêtre, Le Kremlin-Bicêtre, France
| | - Jean-Luc Taupin
- Immunology and Histocompatibility Department, Saint Louis Hospital, Paris, France
| | - Charlotte Mussini
- Pathology Department, Centre Hospitalier Universitaire Bicêtre, Le Kremlin-Bicêtre, France
| | - Marie-José Redon
- Pathology Department, Centre Hospitalier Universitaire Bicêtre, Le Kremlin-Bicêtre, France
| | - Caroline Suberbielle
- Immunology and Histocompatibility Department, Saint Louis Hospital, Paris, France
| | - Emmanuel Jacquemin
- Pediatric Hepatology and Pediatric Liver Transplantation Unit, Centre Hospitalier Universitaire Bicêtre, Le Kremlin-Bicêtre, France
- Université Paris Sud, Le Kremlin-Bicêtre, France
- INSERM, Unité Mixte de Recherche en Santé 1174, Université Paris Sud 11, Orsay, France
- Département Hospitalo-Universitaire Hepatinov, Villejuif, France
| | - Emmanuel Gonzales
- Pediatric Hepatology and Pediatric Liver Transplantation Unit, Centre Hospitalier Universitaire Bicêtre, Le Kremlin-Bicêtre, France
- Université Paris Sud, Le Kremlin-Bicêtre, France
- INSERM, Unité Mixte de Recherche en Santé 1174, Université Paris Sud 11, Orsay, France
- Département Hospitalo-Universitaire Hepatinov, Villejuif, France
| | - Catherine Guettier
- Pathology Department, Centre Hospitalier Universitaire Bicêtre, Le Kremlin-Bicêtre, France
- Université Paris Sud, Le Kremlin-Bicêtre, France
- Département Hospitalo-Universitaire Hepatinov, Villejuif, France
- INSERM, Unité 1193, Villejuif, France
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48
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Grimbert P, Thaunat O. mTOR inhibitors and risk of chronic antibody-mediated rejection after kidney transplantation: where are we now? Transpl Int 2018; 30:647-657. [PMID: 28445619 DOI: 10.1111/tri.12975] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 02/13/2017] [Accepted: 04/21/2017] [Indexed: 12/28/2022]
Abstract
Antibody-mediated rejection (AMR) usually starts with generation of donor-specific anti-HLA antibodies (DSAs), arising from a B-cell response to antigen recognition. In vitro and preclinical data demonstrate that mammalian target of rapamycin (mTOR) inhibition attenuates the mTOR-mediated intracellular signaling pathway involved in AMR-related kidney damage. The limited available data from immunological studies in kidney transplant patients, however, have not shown such effects in vivo. In terms of clinical immunosuppression, the overriding influence on rates of de novo DSA (dnDSA) or AMR-regardless of the type of regimen-is patient adherence. To date, limited data from patients given mTOR inhibitor therapy with adequate concurrent immunosuppression, such as reduced-exposure calcineurin inhibitor (CNI) therapy, have not shown an adverse effect on the risk of dnDSA or AMR. Early switch to an mTOR inhibitor (<6-12 months post-transplant) in a CNI-free regimen, in contrast, can increase the risk of dnDSA, especially if adjunctive therapy is inadequate. Late conversion to CNI-free therapy with mTOR inhibition does not appear to affect the risk of dnDSA. More data, from prospective studies, are required to fully understand that association between use of mTOR inhibitors with different types of concomitant therapy and risk of dnDSA and AMR.
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Affiliation(s)
- Philippe Grimbert
- Unité INSERM 955 CHU Henri Mondor, Service de Néphrologie et Transplantation, Pôle Cancérologie-Immunité-Transplantation-Infectiologie (CITI), Université Paris-Est (UPEC), Paris, France.,Service de Transplantation, Néphrologie et Immunologie Clinique, INSERM U1111, Hospices Civils de Lyon, Hôpital Edouard Herriot, Université Lyon-I, Lyon, France
| | - Olivier Thaunat
- Unité INSERM 955 CHU Henri Mondor, Service de Néphrologie et Transplantation, Pôle Cancérologie-Immunité-Transplantation-Infectiologie (CITI), Université Paris-Est (UPEC), Paris, France.,Service de Transplantation, Néphrologie et Immunologie Clinique, INSERM U1111, Hospices Civils de Lyon, Hôpital Edouard Herriot, Université Lyon-I, Lyon, France
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49
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Koo J, Wang HL. Acute, Chronic, and Humoral Rejection: Pathologic Features Under Current Immunosuppressive Regimes. Surg Pathol Clin 2018; 11:431-452. [PMID: 29751884 DOI: 10.1016/j.path.2018.02.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Under current immunosuppressive regimes, T-cell-mediated acute and chronic rejection remain common and important posttransplant complications. The definition of humoral (antibody-mediated) rejection has been greatly expanded in recent years. The histopathologic assessment of allograft biopsies continues to serve an important role in the diagnosis of rejection and to facilitate patient management. The diagnosis of both acute and chronic antibody-mediated rejection requires integration of the results of donor-specific antibody testing and C4d immunostaining, as well as exclusion of other potential etiologies of allograft dysfunction. Chronic antibody-mediated rejection should also be included in the differential diagnosis for unexplained allograft fibrosis.
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Affiliation(s)
- Jamie Koo
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room 8707, Los Angeles, CA 90048, USA
| | - Hanlin L Wang
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 27-061-C8 CHS, Los Angeles, CA 90095, USA.
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50
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Kim H, Yi NJ, Song EY, Lee K, Lee KW, Lee HW, Ahn HY, Yoon KC, Hong SK, Suh KS. Preformed donor-specific antibodies do not affect the 1-year allograft survival in living donor liver transplantation. Clin Transplant 2018; 32:e13244. [DOI: 10.1111/ctr.13244] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/17/2018] [Indexed: 12/16/2022]
Affiliation(s)
- Hyeyoung Kim
- Department of Surgery; Seoul National University College of Medicine; Seoul Korea
- Department of Surgery; Seoul Metropolitan Government - Seoul National University Boramae Medical Center; Seoul Korea
| | - Nam-Joon Yi
- Department of Surgery; Seoul National University College of Medicine; Seoul Korea
| | - Eun Young Song
- Department of Laboratory Medicine; Seoul National University College of Medicine; Seoul Korea
| | - Kyoungbun Lee
- Department of Pathology; Seoul National University College of Medicine; Seoul Korea
| | - Kwang-Woong Lee
- Department of Surgery; Seoul National University College of Medicine; Seoul Korea
| | - Hae Won Lee
- Department of Surgery; Seoul National University College of Medicine; Seoul Korea
- Department of Surgery; Seoul Metropolitan Government - Seoul National University Boramae Medical Center; Seoul Korea
| | - Hye Young Ahn
- Department of Surgery; Seoul National University College of Medicine; Seoul Korea
| | - Kyung Chul Yoon
- Department of Surgery; Seoul National University College of Medicine; Seoul Korea
| | - Suk Kyun Hong
- Department of Surgery; Seoul National University College of Medicine; Seoul Korea
| | - Kyung-Suk Suh
- Department of Surgery; Seoul National University College of Medicine; Seoul Korea
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