|
1
|
Garcia J, Vianna R. B-Cell Induction Therapies in Intestinal Transplantation. Gastroenterol Clin North Am 2024; 53:343-357. [PMID: 39067999 DOI: 10.1016/j.gtc.2024.01.001] [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] [Indexed: 07/30/2024]
Abstract
Despite advancements in short-term outcomes since the inception of intestinal transplant, significant long-term graft failure persists. Early successes are attributed to the utilization of tacrolimus for maintenance therapy, coupled with T-cell modulating induction regimens, which effectively reduce the incidence of acute cellular rejection. However, the challenge of chronic allograft injury remains unresolved. There is increasing evidence indicating a correlation between donor-specific antibodies and the survival of visceral allografts. Strategies aimed at reducing the presence or load of these antibodies may potentially enhance long-term outcomes. Consequently, our focus is now turning toward B-cell induction therapies as a possible solution.
Collapse
Affiliation(s)
- Jennifer Garcia
- Adult and Pediatric Intestinal Transplant, Miami Transplant Institute, University of Miami-Jackson Memorial Hospital, 1801 Northwest 9th Avenue, MTI 7th Floor, Jackson Professional Building, Miami, FL 33136, USA.
| | - Rodrigo Vianna
- Adult and Pediatric Intestinal Transplant, Miami Transplant Institute, University of Miami-Jackson Memorial Hospital, 1801 Northwest 9th Avenue, MTI 7th Floor, Jackson Professional Building, Miami, FL 33136, USA
| |
Collapse
|
|
2
|
Cicalese L, Walton ZC, Du X, Kulkarni R, Qiu S, El Hag M, Stevenson HL. Antibody-Mediated Rejection in Liver Transplantation: Immuno-Pathological Characteristics and Long-Term Follow-Up. Transpl Int 2024; 37:13232. [PMID: 39267618 PMCID: PMC11391112 DOI: 10.3389/ti.2024.13232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 07/16/2024] [Indexed: 09/15/2024]
Abstract
The diagnosis of liver antibody-mediated rejection (AMR) is challenging and likely under-recognized. The association of AMR with donor-specific antibodies (DSA), and its clinical course in relation to pathologic findings and treatment are ill defined. We identified cases of liver AMR by following the criteria outlined by the 2016 Banff Working Group. Patient demographics, native liver disease, histopathologic findings, treatment type, clinical outcome, and transaminase levels during AMR diagnosis, treatment, and resolution were determined. Patients (n = 8) with AMR average age was 55.2 years (range: 19-68). Seven of eight cases met the Banff criteria for AMR. Personalized treatment regimens consisted of optimization of immunosuppression, intravenous pulse steroids, plasmapheresis, IVIG, rituximab, and bortezomib. Five patients experienced complete resolution of AMR, return of transaminases to baseline, and decreased DSA at long-term follow-up. One patient developed chronic AMR and two patients required re-transplantation. Follow-up after AMR diagnosis ranged from one to 11 years. Because AMR can present at any time, crossmatch, early biopsy, and routine monitoring of DSA levels should be implemented following transaminase elevation to recognize AMR. Furthermore, treatment should be immediately implemented to reverse AMR and prevent graft failure, chronic damage, re-transplantation, and possibly mortality.
Collapse
Affiliation(s)
- Luca Cicalese
- Division of Transplant Surgery, Department of Surgery, University of Texas Medical Branch, UTMB, Galveston, TX, United States
| | - Zachary C Walton
- John Sealy School of Medicine, University of Texas Medical Branch, UTMB, Galveston, TX, United States
| | - Xiaotang Du
- Department of Pathology, University of Texas Medical Branch, UTMB, Galveston, TX, United States
| | - Rupak Kulkarni
- Division of Transplant Surgery, Department of Surgery, University of Texas Medical Branch, UTMB, Galveston, TX, United States
| | - Suimin Qiu
- Department of Pathology, University of Texas Medical Branch, UTMB, Galveston, TX, United States
| | - Mohamed El Hag
- Department of Pathology, Cleveland Clinic, Cleveland, OH, United States
| | - Heather L Stevenson
- Department of Pathology, University of Texas Medical Branch, UTMB, Galveston, TX, United States
| |
Collapse
|
|
3
|
Han CZ, Wei Q, Yang MF, Zhuang L, Xu X. The critical role of therapeutic plasma exchange in ABO-incompatible liver transplantation. Hepatobiliary Pancreat Dis Int 2022; 21:538-542. [PMID: 35831217 DOI: 10.1016/j.hbpd.2022.06.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 05/17/2022] [Indexed: 02/05/2023]
Abstract
BACKGROUND The shortage of donor liver restricts liver transplantation (LT). Nowadays, donor liver with ABO blood group incompatibility between donor and recipient has become an option to expand the source of donor liver. Although it is now possible to perform ABO-incompatible (ABO-I) LT, antibody-mediated rejection (AMR) has been recognized as the primary cause of desperate outcomes after ABO-I LT. Anti-A/B antibody is the trigger of immune response to ABO-I LT graft injury. Therapeutic plasma exchange (TPE) can quickly reduce the titer of plasma antibodies and effectively inhibit humoral immunity. DATA SOURCES We searched PubMed and CNKI databases using search terms "therapeutic plasma exchange", "ABO-incompatible liver transplantation", "ABO-I LT", "liver transplantation", "LT", "antibody-mediated rejection", and "AMR". Additional publications were identified by a manual search of references from key articles. The relevant publications published before September 30, 2020 were included in this review. RESULTS Different centers have made different attempts on whether to use TPE, when to use TPE and how often to use TPE. However, the control standard of lectin revision level is always controversial, the target titer varies significantly from center to center, and the standard target titer has not yet been established. TPE has several schemes to reduce antibody titers, but there is a lack of clinical trials that provide standardized procedures. CONCLUSIONS TPE is essential for ABO-I LT. Hence, further research and clinical trials should be conducted to determine the best regimen for TPE to remove ABO antibodies and prevent AMR.
Collapse
Affiliation(s)
- Cheng-Zuo Han
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China; Institute of Organ Transplantation, Zhejiang University, Hangzhou 310003, China
| | - Qiang Wei
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China; Institute of Organ Transplantation, Zhejiang University, Hangzhou 310003, China; National Center for Healthcare Quality Management in Liver Transplant, Hangzhou 310003, China
| | - Meng-Fan Yang
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China; Institute of Organ Transplantation, Zhejiang University, Hangzhou 310003, China
| | - Li Zhuang
- Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou 310022, China
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China; Institute of Organ Transplantation, Zhejiang University, Hangzhou 310003, China; National Center for Healthcare Quality Management in Liver Transplant, Hangzhou 310003, China.
| |
Collapse
|
|
4
|
Acute Antibody-Mediated Rejection in Liver Transplantation: Impact and Applicability of the Banff Working Group on Liver Allograft Pathology 2016 Criteria. Hum Pathol 2022; 127:67-77. [PMID: 35728694 DOI: 10.1016/j.humpath.2022.06.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/14/2022] [Accepted: 06/14/2022] [Indexed: 11/22/2022]
Abstract
This study was aimed to examine the clinical utility and impact of the 2016 Banff criteria for acute antibody-mediated rejection (acute AMR) in patients with liver transplantation. Among adult patients with donor-specific antibody (DSA) assays performed between 2015 and 2020, cases with proved DSA (mean fluorescent index >2000) and matched liver biopsy available were reviewed. Among 55 patients identified, 28 (51%) had class I DSA, 45 (82%) had class II DSA and 18 (33%) had both. Mild, moderate and severe microvasculitis were observed in 11 (20%), 2 (4%) and 1 (2%) case, respectively. Diffuse immunoreactivity to C4d on portal microvascular endothelia was confirmed in 5 cases (9%), which met the criteria of definite (n=2) or suspicious for acute AMR (n=3). Cases of acute AMR more commonly had class I DSA (100% vs. 46%; p=0.027) or both class I and II DSA (80% vs. 28%; p=0.018) than cases of non-acute AMR. One case of pure acute AMR with veno-occlusion was successfully treated with plasma exchange. The remaining 4 cases had features of combined acute AMR/T cell-mediated rejection (TCMR), and two progressed to ductopenic rejection within 3 weeks. In conclusion, only 9% of DSA-positive patients met the Banff criteria for acute AMR, necessitating careful morphological and immunohistochemical assessments of the allograft biopsies according to the proposed standards. Combined acute AMR/TCMR was more common than isolated acute AMR, and additional AMR in TCMR cases may be associated with rapid progression to ductopenic rejection.
Collapse
|
|
5
|
Gambella A, Mastracci L, Caporalini C, Francalanci P, Mescoli C, Ferro J, Alaggio R, Grillo F. Not only a small liver - The pathologist's perspective in the pediatric liver transplant setting. Pathologica 2022; 114:89-103. [PMID: 35212319 PMCID: PMC9040542 DOI: 10.32074/1591-951x-753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 01/26/2022] [Indexed: 11/30/2022] Open
Abstract
Pediatric liver transplantation represents a safe and long-lasting treatment option for various disease types, requiring the pathologist's input. Indeed, an accurate and timely diagnosis is crucial in reporting and grading native liver diseases, evaluating donor liver eligibility and identifying signs of organ injury in the post-transplant follow-up. However, as the procedure is more frequently and widely performed, deceptive and unexplored histopathologic features have emerged with relevant consequences on patient management, particularly when dealing with long-term treatment and weaning of immunosuppression. In this complex and challenging scenario, this review aims to depict the most relevant histopathologic conditions which could be encountered in pediatric liver transplantation. We will tackle the conditions representing the main indications for transplantation in childhood as well as the complications burdening the post-transplant phases, either immunologically (i.e., rejection) or non-immunologically mediated. Lastly, we hope to provide concise, yet significant, suggestions related to innovative pathology techniques in pediatric liver transplantation.
Collapse
Affiliation(s)
| | - Luca Mastracci
- Department of Surgical and Diagnostic Sciences (DISC), University of Genoa, Genoa, Italy
- Pathology Unit, Ospedale Policlinico San Martino IRCCS, Genoa, Italy
| | - Chiara Caporalini
- Pathology Unit, Anna Meyer Children’s University Hospital, Florence, Italy
| | - Paola Francalanci
- Unit of Pathology, Children’s Hospital Bambino Gesù, IRCCS, Rome, Italy
| | - Claudia Mescoli
- Department of Pathology, Azienda Ospedale, Università Padova, Padova, Italy
| | - Jacopo Ferro
- Department of Surgical and Diagnostic Sciences (DISC), University of Genoa, Genoa, Italy
| | - Rita Alaggio
- Unit of Pathology, Children’s Hospital Bambino Gesù, IRCCS, Rome, Italy
| | - Federica Grillo
- Department of Surgical and Diagnostic Sciences (DISC), University of Genoa, Genoa, Italy
- Pathology Unit, Ospedale Policlinico San Martino IRCCS, Genoa, Italy
| |
Collapse
|
|
6
|
Chronic Antibody-Mediated Liver Rejection: More than Meets the Eye. TRANSPLANTOLOGY 2021. [DOI: 10.3390/transplantology2010001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Understanding the role of donor-specific antibodies (DSAs) in liver transplantation remains an investigative priority. Acute and chronic rejection associated with DSAs have been described. However, most transplant protocols did not consider the presence of DSAs at the moment of liver transplantation (LTx) or for the follow-up. A 65-year-old man received an ABO-compatible LTx for cirrhosis. Ten years after the LTx, he presented with a progressive elevation of liver enzymes and bilirubin. The single antigen Luminex bead assay showed the presence of DSAs against several DQ2, DQ7, and DQ8 alleles. The patient received several desensitization treatments regarding the persistence of DSAs. The anatomopathological study confirms chronic rejection. Although in this case the immunohistochemical deposits of C4d were negative, the data revealed morphological criteria of chronic graft injury and DSAs’ incompatibilities explained by structural analysis. These data support an antibody-mediated rejection (AMR). It could be reasonable to establish a protocol for human leukocyte antigen (HLA) typing of every LTx donor and recipient as well as a periodic follow-up to assess the presence of DSAs. This will make it possible to carry out studies of donor–recipient incompatibility and to confirm the existence of probable cases of AMR.
Collapse
|
|
7
|
Enhancing the Value of Histopathological Assessment of Allograft Biopsy Monitoring. Transplantation 2020; 103:1306-1322. [PMID: 30768568 DOI: 10.1097/tp.0000000000002656] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Traditional histopathological allograft biopsy evaluation provides, within hours, diagnoses, prognostic information, and mechanistic insights into disease processes. However, proponents of an array of alternative monitoring platforms, broadly classified as "invasive" or "noninvasive" depending on whether allograft tissue is needed, question the value proposition of tissue histopathology. The authors explore the pros and cons of current analytical methods relative to the value of traditional and illustrate advancements of next-generation histopathological evaluation of tissue biopsies. We describe the continuing value of traditional histopathological tissue assessment and "next-generation pathology (NGP)," broadly defined as staining/labeling techniques coupled with digital imaging and automated image analysis. Noninvasive imaging and fluid (blood and urine) analyses promote low-risk, global organ assessment, and "molecular" data output, respectively; invasive alternatives promote objective, "mechanistic" insights by creating gene lists with variably increased/decreased expression compared with steady state/baseline. Proponents of alternative approaches contrast their preferred methods with traditional histopathology and: (1) fail to cite the main value of traditional and NGP-retention of spatial and inferred temporal context available for innumerable objective analyses and (2) belie an unfamiliarity with the impact of advances in imaging and software-guided analytics on emerging histopathology practices. Illustrative NGP examples demonstrate the value of multidimensional data that preserve tissue-based spatial and temporal contexts. We outline a path forward for clinical NGP implementation where "software-assisted sign-out" will enable pathologists to conduct objective analyses that can be incorporated into their final reports and improve patient care.
Collapse
|
|
8
|
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]
|
|
9
|
Gleißner M, Bornemann R, Stemerowicz R, Meißler M, Neuhaus P, Gerlach J. Immunoisolation of Hybrid Liver Support Systems by Semipermeable Membranes. Int J Artif Organs 2018. [DOI: 10.1177/039139889702001108] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Immunoisolation of hybrid liver support systems (LSS) utilizing suitable semipermeable membranes as an immune barrier enables neither immunocompetent cytotoxic factors to cause damage to the hepatocytes in the bioreactor nor xenogenic hepatocyte products to cause immunological side effects in patients. To determine the capability of membranes as an immune barrier, 6 flat membranes were investigated: Cuprophan (C-100), cut-off MW 1000, Cuprophan (C-240), cut-off MW 10,000, Polypropylen hydrophilic and hydrophobic (PPhi, PPho), cut-off MW 500,000-1,000,000, Polysulfon (PS), cut-off MW 1,000,000, Polyamid (PA), cut-off beyond MW 1,000,000. The permeability of the membranes to plasma factors and liver protein fractions (LP) was studied by routine biochemical methods and gel electrophoresis. In a second study, pigs (n=7) were immunised by LP after membrane passage. The results showed PA, PS, and PPhi to be completely permeable for plasma factors and LP, C-100 and C-240 for urophanic substances, and C-240 again for LP under MW 14.000. All 7 pig sera studied by Western blot discovered pre-formed xenoreactive natural IgG-antibodies (NAB) against human liver antigen (AG) with MW 26.000. AB de-novo-synthesis was demonstrated for AG with MW 45.000. No AB-synthesis was induced for epitopes under MW 26,000. These results suggest that limiting the cut-off of bioreactor outflow membranes to MW < 26,000 could avoid immunological side effects to patients.
Collapse
Affiliation(s)
- M. Gleißner
- Zentrum für Kinderheilkunde der Otto von Guericke Universität Magdeburg, Magdeburg
| | - R. Bornemann
- Virchow-Klinikum, Medizinische Fakultät der Humboldt-Universität zu Berlin Chirurgische Klinik, Berlin - Germany
| | - R. Stemerowicz
- Virchow-Klinikum, Medizinische Fakultät der Humboldt-Universität zu Berlin Chirurgische Klinik, Berlin - Germany
| | - M. Meißler
- Virchow-Klinikum, Medizinische Fakultät der Humboldt-Universität zu Berlin Chirurgische Klinik, Berlin - Germany
| | - P. Neuhaus
- Virchow-Klinikum, Medizinische Fakultät der Humboldt-Universität zu Berlin Chirurgische Klinik, Berlin - Germany
| | - J.C. Gerlach
- Virchow-Klinikum, Medizinische Fakultät der Humboldt-Universität zu Berlin Chirurgische Klinik, Berlin - Germany
| |
Collapse
|
|
10
|
Application and interpretation of histocompatibility data in liver transplantation. Curr Opin Organ Transplant 2018; 22:499-504. [PMID: 28708813 DOI: 10.1097/mot.0000000000000450] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW There has been a resurgence of interest in histocompatibility as it applies to liver transplantation. The association of persistent and de-novo donor specific antibody (DSA) and outcomes after liver transplantation continues to be investigated. RECENT FINDINGS Consensus continues to evolve regarding the existence of acute and chronic antibody-mediated rejection (AMR) and pathogenicity of DSA and associated pathologic findings after liver transplantation. The presence of persistent high level, complement fixing DSA or emergence of de novo, Class II DSA has been associated with rejection and worse long-term graft and patient survival. Significant adverse associations of DSA extend to patients after simultaneous liver kidney (SLK) transplant as well as in pediatric recipients of liver transplantation. A higher degree of HLA incompatibility has been recently associated with worse outcomes in living donor liver transplant. SUMMARY In summary, recent consensus guidelines describe and recognize the existence of acute and chronic AMR and provide a basis upon which to build further investigation. Important adverse outcomes including decreased survival, allograft failure and liver fibrosis have been linked to the presence of DSA. Routine donor and recipient HLA typing and DSA assessment will facilitate diagnosis and provide for baseline data, which may help guide future management. Future investigations may help to clarify the role of therapeutic interventions.
Collapse
|
|
11
|
Chronic AMR in Liver Transplant: Validation of the 1-Year cAMR Score's Ability to Determine Long-term Outcome. Transplantation 2017; 101:2062-2070. [PMID: 28452922 DOI: 10.1097/tp.0000000000001802] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND A proposed chronic antibody-mediated rejection (AMR) score has recently predicted 50%10-year death-censored allograft loss in patients with donor-specific alloantibodies (DSA) mean florescence intensity (MFI) greater than 10 000 and requires confirmation in patients with lower MFI (1000-10 000). METHODS All patients who underwent liver transplantation from January 2000 to April 2009, had DSA (MFI ≥1000) in serum 10 to 14 months postliver transplantation, and had a protocolized liver biopsy were evaluated (n = 230). The previously proposed chronic AMR (cAMR) score was used to risk-stratify putative chronic AMR in DSA+ patients with MFI from 1000 to 10 000. RESULTS The MFI distribution of DSA+ recipients were as follows: 66% had MFI 1000 to 4999, 14% had MFI 5000 to 10 000, and 20% had MFI greater than 10 000. The cAMR score distribution on 1-year protocol liver biopsy found that 41% had a score less than 13; 27% a score of 13 to 27.5, and 32% a score greater than 27.5. MFI correlated with 1-year cAMR category (<13, 46% vs 21% and >27.5, 29% vs 42% when MFI was 1000-10 000 vs MFI >10 000; P = 0.047). In patients with a cAMR score less than 13, 10-year death-censored allograft survival was 96% to 100% regardless of MFI (P = NS). The risk of allograft loss increased in patients with a cAMR score greater than 13 (P = 0.004) in DSA+ patients with MFI 1000 to 10 000. DSA MFI greater than 10 000 versus MFI 1000 to 10 000 at 1 year was also more likely to persist at 5 years (95% vs 68%; P < 0.0001). CONCLUSIONS Validation of the previously proposed cAMR score in a separate cohort predicts death-censored long-term allograft failure in DSA+ patients regardless of MFI, and higher MFI at 1 year predicts DSA persistence at 5 years.
Collapse
|
|
12
|
Non-HLA Antibodies Impact on C4d Staining, Stellate Cell Activation and Fibrosis in Liver Allografts. Transplantation 2017; 101:2399-2409. [DOI: 10.1097/tp.0000000000001853] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
|
|
13
|
Abstract
Antibody-mediated rejection (AMR) in liver transplants is a field in its infancy compared with its allograft cohorts of the kidney and lung. Acute AMR is diagnosed based on specific clinical and histopathologic criteria: serum donor specific antibodies, C4d staining, histopathologic findings on liver biopsy, and exclusion of other entities. In contrast, the histologic features of chronic AMR are not as specific and it is a more challenging diagnosis to make. Treatments of acute and chronic AMR include some combination of steroids, immune-modulating agents, intravenous immunoglobulin, plasmapheresis, and proteasome inhibitors.
Collapse
Affiliation(s)
- Michael Lee
- Department of Pathology and Cell Biology, Columbia University, 630 West 168th Street, VC14-238, New York, NY 10032, USA.
| |
Collapse
|
|
14
|
Del Bello A, Danjoux M, Congy-Jolivet N, Lavayssière L, Esposito L, Muscari F, Kamar N. Histological long-term outcomes from acute antibody-mediated rejection following ABO-compatible liver transplantation. J Gastroenterol Hepatol 2017; 32:887-893. [PMID: 27739606 DOI: 10.1111/jgh.13613] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/02/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM Acute antibody-mediated rejection (aAMR) is an unusual complication after orthotopic ABO-compatible liver transplantation. To date, the clinical and histological long-term outcomes after aAMR are not well known. METHOD Herein, we describe nine cases of aAMR that occurred in our liver-transplant center between 2008 and 2016, with an initial and reevaluation liver biopsy available for reexamination. RESULTS Two patients presented with aAMR at 10.5 (10, 11) days post-transplantation, caused by preformed donor-specific antibodies. Seven other recipients developed de novo donor-specific antibodies and aAMR at 11.2 (3-24) months post-transplantation. Eight of the nine patients received a B-cell targeting agent (rituximab, with or without plasma exchange), associated with polyclonal antibodies (three patients) or intravenous immunoglobulins (three patients). At the last follow up (i.e. 21 [4-90] months post-aAMR), seven patients were alive, including two patients with normal liver tests. Grafts' survival was 66%. A liver biopsy performed at 11.5 (5-48.5) months after the first biopsy showed no significant improvement in aAMR score (from 2 ± 1.3 to 1.6 ± 1.5, P = 0.6), a significant improvement in chronic AMR score (from 37 ± 9 to 25 ± 8, P = 0.003) and an increase in the Metavir score (1.2 ± 0.6 to 2.1 ± 0.9, P = 0.03). CONCLUSION In this study, a B-cell-depleting agent seemed to improve the prognosis of aAMR in selected cases, but several patients kept active lesions antibody-mediated rejection.
Collapse
Affiliation(s)
- Arnaud Del Bello
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Marie Danjoux
- Department of Pathology, Cancer University Institute of Toulouse Oncopole, CHU, Toulouse, France
| | - Nicolas Congy-Jolivet
- Molecular Immunogenetics Laboratory, EA 3034, Faculty of Medicine Purpan, IFR150 (INSERM), Toulouse, France.,Department of Immunology, Hospital Rangueil, CHU, Toulouse, France.,Paul Sabatier University, Toulouse, France
| | - Laurence Lavayssière
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Laure Esposito
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Fabrice Muscari
- Paul Sabatier University, Toulouse, France.,Department of Surgery and Liver Transplantation, Toulouse, France
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France.,Paul Sabatier University, Toulouse, France.,INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France
| |
Collapse
|
|
15
|
Lee KB. What Is Antibody-Mediated Rejection in Histologic Diagnosis in Liver Recipients? KOREAN JOURNAL OF TRANSPLANTATION 2017. [DOI: 10.4285/jkstn.2017.31.1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- Kyoung-Bun Lee
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| |
Collapse
|
|
16
|
Del Bello A, Congy-Jolivet N, Danjoux M, Muscari F, Lavayssière L, Esposito L, Cardeau-Desangles I, Guitard J, Dörr G, Milongo D, Suc B, Duffas JP, Alric L, Bureau C, Guilbeau-Frugier C, Rostaing L, Kamar N. De novo donor-specific anti-HLA antibodies mediated rejection in liver-transplant patients. Transpl Int 2016; 28:1371-82. [PMID: 26303035 DOI: 10.1111/tri.12654] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2015] [Revised: 05/19/2015] [Accepted: 07/23/2015] [Indexed: 12/13/2022]
Abstract
The incidence and consequences of de novo donor-specific anti-HLA antibodies (DSAs) after liver transplantation (LT) are not well known. We investigated the incidence, risk factors, and complications associated with de novo DSAs in this setting. A total of 152 de novo liver-transplant patients, without preformed anti-HLA DSAs, were tested for anti-HLA antibodies, with single-antigen bead technology, before, at transplantation, at 1, 3, 6 and 12 months after transplantation, and thereafter annually and at each time they presented with increased liver-enzyme levels until the last follow-up, that is, 34 (1.5-77) months. Twenty-one patients (14%) developed de novo DSAs. Of these, five patients had C1q-binding DSAs (24%). Younger age, low exposure to calcineurin inhibitors, and noncompliance were predictive factors for de novo DSA formation. Nine of the 21 patients (43%) with de novo DSAs experienced an acute antibody-mediated rejection (AMR). Positive C4d staining was more frequently observed in liver biopsies of patients with AMR (9/9 vs. 1/12, P < 0.0001). Eight patients received a B-cell targeting therapy, and one patient received polyclonal antibodies. Only one patient required retransplantation. Patient- and graft-survival rates did not differ between patients with and without DSAs. In conclusion, liver-transplant patients with liver abnormalities should be screened for DSAs and AMR.
Collapse
Affiliation(s)
- Arnaud Del Bello
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France.,Université Paul Sabatier, Toulouse, France
| | - Nicolas Congy-Jolivet
- Université Paul Sabatier, Toulouse, France.,Molecular Immunogenetics Laboratory, EA 3034, Faculté de Médecine Purpan, IFR150 (INSERM), Toulouse, France.,Department of Immunology, Hôpital de Rangueil, CHU de Toulouse, Toulouse, France
| | - Marie Danjoux
- Department of Pathology, CHU Purpan, Toulouse, France
| | - Fabrice Muscari
- Université Paul Sabatier, Toulouse, France.,Department of Surgery and Liver Transplantation, CHU Rangueil, Toulouse, France
| | - Laurence Lavayssière
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Laure Esposito
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | | | - Joëlle Guitard
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Gaëlle Dörr
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France.,Université Paul Sabatier, Toulouse, France
| | - David Milongo
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Bertrand Suc
- Université Paul Sabatier, Toulouse, France.,Department of Surgery and Liver Transplantation, CHU Rangueil, Toulouse, France
| | - Jean Pierre Duffas
- Department of Surgery and Liver Transplantation, CHU Rangueil, Toulouse, France
| | - Laurent Alric
- Université Paul Sabatier, Toulouse, France.,Internal Medecine-Digestive Department, UMR 152, IRD, CHU Purpan, Toulouse, France
| | - Christophe Bureau
- Université Paul Sabatier, Toulouse, France.,Department of Hepatology, Federation Digestive, CHU Purpan, Toulouse, France
| | - Céline Guilbeau-Frugier
- Université Paul Sabatier, Toulouse, France.,Department of Pathology, CHU Purpan, Toulouse, France
| | - Lionel Rostaing
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France.,Université Paul Sabatier, Toulouse, France.,INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France.,Université Paul Sabatier, Toulouse, France.,INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France
| |
Collapse
|
|
17
|
McCaughan JA, Robertson V, Falconer SJ, Cryer C, Turner DM, Oniscu GC. Preformed donor-specific HLA antibodies are associated with increased risk of early mortality after liver transplantation. Clin Transplant 2016; 30:1538-1544. [DOI: 10.1111/ctr.12851] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/18/2016] [Indexed: 01/15/2023]
Affiliation(s)
- Jennifer A. McCaughan
- Histocompatibility and Immunogenetics Laboratory; Royal Infirmary of Edinburgh; Edinburgh UK
| | - Victoria Robertson
- Histocompatibility and Immunogenetics Laboratory; Royal Infirmary of Edinburgh; Edinburgh UK
| | - Stuart J. Falconer
- Scottish Liver Transplant Unit; Royal Infirmary of Edinburgh; Edinburgh UK
| | - Claire Cryer
- Histocompatibility and Immunogenetics Laboratory; Royal Infirmary of Edinburgh; Edinburgh UK
| | - David M. Turner
- Histocompatibility and Immunogenetics Laboratory; Royal Infirmary of Edinburgh; Edinburgh UK
| | - Gabriel C. Oniscu
- Scottish Liver Transplant Unit; Royal Infirmary of Edinburgh; Edinburgh UK
| |
Collapse
|
|
18
|
Demetris AJ, Bellamy C, Hübscher SG, O'Leary J, Randhawa PS, Feng S, Neil D, Colvin RB, McCaughan G, Fung JJ, Del Bello A, Reinholt FP, Haga H, Adeyi O, Czaja AJ, Schiano T, Fiel MI, Smith ML, Sebagh M, Tanigawa RY, Yilmaz F, Alexander G, Baiocchi L, Balasubramanian M, Batal I, Bhan AK, Bucuvalas J, Cerski CTS, Charlotte F, de Vera ME, ElMonayeri M, Fontes P, Furth EE, Gouw ASH, Hafezi-Bakhtiari S, Hart J, Honsova E, Ismail W, Itoh T, Jhala NC, Khettry U, Klintmalm GB, Knechtle S, Koshiba T, Kozlowski T, Lassman CR, Lerut J, Levitsky J, Licini L, Liotta R, Mazariegos G, Minervini MI, Misdraji J, Mohanakumar T, Mölne J, Nasser I, Neuberger J, O'Neil M, Pappo O, Petrovic L, Ruiz P, Sağol Ö, Sanchez Fueyo A, Sasatomi E, Shaked A, Shiller M, Shimizu T, Sis B, Sonzogni A, Stevenson HL, Thung SN, Tisone G, Tsamandas AC, Wernerson A, Wu T, Zeevi A, Zen Y. 2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection. Am J Transplant 2016; 16:2816-2835. [PMID: 27273869 DOI: 10.1111/ajt.13909] [Citation(s) in RCA: 420] [Impact Index Per Article: 46.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 06/01/2016] [Accepted: 05/25/2016] [Indexed: 02/06/2023]
Abstract
The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.
Collapse
Affiliation(s)
- A J Demetris
- University of Pittsburgh Medical Center, Pittsburgh, PA
| | - C Bellamy
- The University of Edinburgh, Edinburgh, Scotland
| | | | - J O'Leary
- Baylor University Medical Center, Dallas, TX
| | - P S Randhawa
- University of Pittsburgh Medical Center, Pittsburgh, PA
| | - S Feng
- University of California San Francisco Medical Center, San Francisco, CA
| | - D Neil
- Queen Elizabeth Hospital Birmingham, Birmingham, UK
| | - R B Colvin
- Massachusetts General Hospital, Boston, MA
| | - G McCaughan
- Royal Prince Alfred Hospital, Sydney, Australia
| | | | | | - F P Reinholt
- Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - H Haga
- Kyoto University Hospital, Kyoto, Japan
| | - O Adeyi
- University Health Network and University of Toronto, Toronto, Canada
| | - A J Czaja
- Mayo Clinic College of Medicine, Rochester, MN
| | - T Schiano
- Mount Sinai Medical Center, New York, NY
| | - M I Fiel
- Icahn School of Medicine at Mount Sinai, New York, NY
| | - M L Smith
- Mayo Clinic Health System, Scottsdale, AZ
| | - M Sebagh
- AP-HP Hôpital Paul-Brousse, Paris, France
| | - R Y Tanigawa
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - F Yilmaz
- University of Ege, Faculty of Medicine, Izmir, Turkey
| | | | - L Baiocchi
- Policlinico Universitario Tor Vergata, Rome, Italy
| | | | - I Batal
- Columbia University College of Physicians and Surgeons, New York, NY
| | - A K Bhan
- Massachusetts General Hospital, Boston, MA
| | - J Bucuvalas
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - C T S Cerski
- Universidade Federal do Rio Grande do Sul, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
| | | | | | - M ElMonayeri
- Ain Shams University, Wady El-Neel Hospital, Cairo, Egypt
| | - P Fontes
- University of Pittsburgh Medical Center, Pittsburgh, PA
| | - E E Furth
- Hospital of the University of Pennsylvania, Philadelphia, PA
| | - A S H Gouw
- University Medical Center Groningen, Groningen, the Netherlands
| | | | - J Hart
- University of Chicago Hospitals, Chicago, IL
| | - E Honsova
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - W Ismail
- Beni-Suef University, Beni-Suef, Egypt
| | - T Itoh
- Kobe University Hospital, Kobe, Japan
| | | | - U Khettry
- Lahey Hospital and Medical Center, Burlington, MA
| | | | - S Knechtle
- Duke University Health System, Durham, NC
| | - T Koshiba
- Soma Central Hospital, Soma, Fukushima, Japan
| | - T Kozlowski
- University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - C R Lassman
- David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - J Lerut
- Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - J Levitsky
- Northwestern University Feinberg School of Medicine, Chicago, IL
| | - L Licini
- Pope John XXIII Hospital, Bergamo, Italy
| | - R Liotta
- Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione, University of Pittsburgh Medical Center, Palermo, Italy
| | - G Mazariegos
- Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA
| | - M I Minervini
- University of Pittsburgh Medical Center, Pittsburgh, PA
| | - J Misdraji
- Massachusetts General Hospital, Boston, MA
| | - T Mohanakumar
- St. Joseph's Hospital and Medical Center, Norton Thoracic Institute, Phoenix, AZ
| | - J Mölne
- University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - I Nasser
- Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA
| | - J Neuberger
- Queen Elizabeth Hospital Birmingham, Birmingham, UK
| | - M O'Neil
- University of Kansas Medical Center, Kansas City, KS
| | - O Pappo
- Hadassah Medical Center, Jerusalem, Israel
| | - L Petrovic
- University of Southern California, Los Angeles, CA
| | - P Ruiz
- University of Miami, Miami, FL
| | - Ö Sağol
- School of Medicine, Dokuz Eylul University, Izmir, Turkey
| | | | - E Sasatomi
- University of North Carolina School of Medicine, Chapel Hill, NC
| | - A Shaked
- University of Pennsylvania Health System, Philadelphia, PA
| | - M Shiller
- Baylor University Medical Center, Dallas, TX
| | - T Shimizu
- Toda Chuo General Hospital, Saitama, Japan
| | - B Sis
- University of Alberta Hospital, Edmonton, Canada
| | - A Sonzogni
- Pope John XXIII Hospital, Bergamo, Italy
| | | | - S N Thung
- Icahn School of Medicine at Mount Sinai, New York, NY
| | - G Tisone
- University of Rome-Tor Vergata, Rome, Italy
| | | | - A Wernerson
- Karolinska University Hospital, Stockholm, Sweden
| | - T Wu
- Tulane University School of Medicine, New Orleans, LA
| | - A Zeevi
- University of Pittsburgh, Pittsburgh, PA
| | - Y Zen
- Kobe University Hospital, Kobe, Japan
| |
Collapse
|
|
19
|
Prevention and treatment of liver allograft antibody-mediated rejection and the role of the 'two-hit hypothesis'. Curr Opin Organ Transplant 2016; 21:209-18. [PMID: 26918881 DOI: 10.1097/mot.0000000000000275] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW The review outlines the diagnosis, prevention strategies, and possible treatment options for acute and chronic antibody-mediated rejection (AMR). RECENT FINDINGS Although rare, severe acute AMR (aAMR) usually occurs in patients with high mean fluorescence intensity despite serial dilutions or high-titer preformed class I donor-specific alloantibodies (DSA). The diagnosis is suspected when allograft dysfunction occurs with DSA, diffuse C4d staining, and a microvascular injury, and may be aided by the aAMR score. However, the incidence of and treatment approach to combined T-cell-mediated rejection (TCMR) with DSA present and some but not all features of AMR is yet to be determined. Chronic liver allograft AMR is characterized by low-grade chronic inflammation and progressive fibrosis with DSA, the chronic AMR (cAMR) score may facilitate diagnosis. The 'two-hit' hypothesis, whereby a coexistent insult upregulates human leukocyte antigen class II target antigens on the microvascular endothelium, may explain why suboptimal donors with lower sensitization levels might suffer from acute AMR and those with chronic complications (e.g., recurrent original disease) might be more susceptible to chronic AMR. Although treatment algorithms are needed, prevention is preferable and at a minimum includes transfusion minimization, and medication adherence. SUMMARY Severe acute AMR is rare but diagnosable, and there is need to determine the incidence of and optimal therapy for less severe combined AMR and TCMR. Chronic AMR is likely more common and of significant relevance to long-term allograft survival improvement. The two-hit hypothesis may help to explain the rarity of both findings and shed insight onto future prevention and treatment strategies.
Collapse
|
|
20
|
Demetris AJ, Bellamy COC, Gandhi CR, Prost S, Nakanuma Y, Stolz DB. Functional Immune Anatomy of the Liver-As an Allograft. Am J Transplant 2016; 16:1653-80. [PMID: 26848550 DOI: 10.1111/ajt.13749] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 01/26/2016] [Accepted: 01/28/2016] [Indexed: 01/25/2023]
Abstract
The liver is an immunoregulatory organ in which a tolerogenic microenvironment mitigates the relative "strength" of local immune responses. Paradoxically, necro-inflammatory diseases create the need for most liver transplants. Treatment of hepatitis B virus, hepatitis C virus, and acute T cell-mediated rejection have redirected focus on long-term allograft structural integrity. Understanding of insults should enable decades of morbidity-free survival after liver replacement because of these tolerogenic properties. Studies of long-term survivors show low-grade chronic inflammatory, fibrotic, and microvascular lesions, likely related to some combination of environment insults (i.e. abnormal physiology), donor-specific antibodies, and T cell-mediated immunity. The resultant conundrum is familiar in transplantation: adequate immunosuppression produces chronic toxicities, while lightened immunosuppression leads to sensitization, immunological injury, and structural deterioration. The "balance" is more favorable for liver than other solid organ allografts. This occurs because of unique hepatic immune physiology and provides unintended benefits for allografts by modulating various afferent and efferent limbs of allogenic immune responses. This review is intended to provide a better understanding of liver immune microanatomy and physiology and thereby (a) the potential structural consequences of low-level, including allo-antibody-mediated injury; and (b) how liver allografts modulate immune reactions. Special attention is given to the microvasculature and hepatic mononuclear phagocytic system.
Collapse
Affiliation(s)
- A J Demetris
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - C O C Bellamy
- Department of Pathology, University of Edinburgh, Edinburgh, Scotland, UK
| | - C R Gandhi
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center and Department of Surgery, University of Cincinnati, Cincinnati, OH
| | - S Prost
- Department of Pathology, University of Edinburgh, Edinburgh, Scotland, UK
| | - Y Nakanuma
- Department of Diagnostic Pathology, Shizuoka Cancer Center, Shizuoka, Japan
| | - D B Stolz
- Center for Biologic Imaging, Cell Biology, University of Pittsburgh, Pittsburgh, PA
| |
Collapse
|
|
21
|
Del Bello A, Congy-Jolivet N, Danjoux M, Muscari F, Kamar N. Donor-specific antibodies and liver transplantation. Hum Immunol 2016; 77:1063-1070. [PMID: 26916836 DOI: 10.1016/j.humimm.2016.02.006] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Revised: 02/14/2016] [Accepted: 02/18/2016] [Indexed: 01/02/2023]
Abstract
In contrast to other types of organ transplantation, liver-transplant recipients used to be considered highly resistant to donor-specific antibodies (DSAs). Consequently, most transplant programs did not consider the presence of DSAs at transplantation or during the follow-up. However, since the early 1990s, antibody-mediated pathological lesions have been recognized in ABO-incompatible liver-transplant recipients. Recent data confirm the detrimental effect of preformed and de novo DSAs in ABO-compatible liver transplantation, with inferior clinical outcomes in patients presenting with circulating antibodies. Acute antibody-mediated rejection (AMR), plasma-cell hepatitis, biliary stricture, but also long-term complications, such as chronic rejection, liver ductopenia, and graft fibrosis, are now recognized to be associated with DSAs. Moreover, some non-HLA DSAs are suspected to induce graft dysfunction. Clinical, biological, and histological patterns within AMR need to be clarified. Treatment of these complications has yet to be defined. This article summarizes recent advances concerning the impact of preformed and de novo DSAs in liver transplantation, it defines the complications associated with DSAs, and discusses the potential strategies to manage patients with such complications.
Collapse
Affiliation(s)
- Arnaud Del Bello
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France; Université Paul Sabatier, Toulouse, France.
| | - Nicolas Congy-Jolivet
- Université Paul Sabatier, Toulouse, France; Molecular Immunogenetics Laboratory, EA 3034, Faculté de Médecine Purpan, IFR150 (INSERM), France; Department of Immunology, Hôpital de Rangueil, CHU de Toulouse, France
| | - Marie Danjoux
- Department of Pathology, CHU Purpan, Toulouse, France
| | - Fabrice Muscari
- Université Paul Sabatier, Toulouse, France; Department of Surgery and Liver Transplantation, Toulouse, France
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France; Université Paul Sabatier, Toulouse, France; INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France
| |
Collapse
|
|
22
|
O'Leary JG, Cai J, Freeman R, Banuelos N, Hart B, Johnson M, Jennings LW, Kaneku H, Terasaki PI, Klintmalm GB, Demetris AJ. Proposed Diagnostic Criteria for Chronic Antibody-Mediated Rejection in Liver Allografts. Am J Transplant 2016; 16:603-14. [PMID: 26469278 DOI: 10.1111/ajt.13476] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Revised: 06/11/2015] [Accepted: 07/19/2015] [Indexed: 01/25/2023]
Abstract
Donor-specific alloantibodies (DSA) can cause acute antibody-mediated rejection (AMR) in all solid organ allografts. However, long-term outcome in patients with posttransplant DSA needs further study. We retrospectively evaluated prospectively collected paired serum, tissue, and data on 45 matched DSA- positive [DSA+; mean florescence intensity (MFI) ≥10,000] and -negative (DSA-) recipients of a primary liver-only allograft from January 2000 to April 2009. Blinded histopathologic evaluation demonstrated that DSA+ versus DSA- patients were more likely to have subtle inflammation and unique patterns of fibrosis, despite normal or near-normal liver function tests. Stepwise multivariable modeling developed a score (putatively named the chronic AMR [cAMR] score) that included interface activity, lobular inflammation, portal tract collagenization, portal venopathy, sinusoidal fibrosis, and hepatitis C virus status. The score was developed (c = 0.811) and cross-validated (c = 0.704) to predict allograft failure. Two cutoffs were employed to optimize sensitivity and specificity (80% each); a value >27.5 predicted 50% 10-year allograft failure. We propose chronic AMR as a potential new entity defined by (1) a high cAMR score, (2) DSA, and (3) elimination of other potential causes of a similar injury pattern. In conclusion, cAMR score calculation identified liver allograft recipients with DSA at highest risk for allograft loss, although independent validation is needed.
Collapse
Affiliation(s)
- J G O'Leary
- Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX
| | - J Cai
- Terasaki Foundation Laboratory, Los Angeles, CA
| | - R Freeman
- Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX
| | - N Banuelos
- Terasaki Foundation Laboratory, Los Angeles, CA
| | - B Hart
- Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX
| | - M Johnson
- Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX
| | - L W Jennings
- Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX
| | - H Kaneku
- Terasaki Foundation Laboratory, Los Angeles, CA
| | | | - G B Klintmalm
- Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX
| | - A J Demetris
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA
| |
Collapse
|
|
23
|
Troxell ML, Lanciault C. Practical Applications in Immunohistochemistry: Evaluation of Rejection and Infection in Organ Transplantation. Arch Pathol Lab Med 2016; 140:910-25. [PMID: 26759930 DOI: 10.5858/arpa.2015-0275-cp] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT -Immunohistochemical analysis of tissue biopsy specimens is a crucial tool in diagnosis of both rejection and infection in patients with solid organ transplants. In the past 15 years, the concept of antibody-mediated rejection has been refined, and diagnostic criteria have been codified in renal, heart, pancreas, and lung allografts (with studies ongoing in liver, small intestine, and composite grafts), all of which include immunoanalysis for the complement split product C4d. OBJECTIVES -To review the general concepts of C4d biology and immunoanalysis, followed by organ-allograft-specific data, and interpretative nuances for kidney, pancreas, and heart, with discussion of early literature for lung and liver biopsies. Additionally, practical applications and limitations of immunostains for infectious organisms (Polyomavirus, Adenoviridae [adenovirus], and the herpes virus family, including Herpes simplex virus, Cytomegalovirus, Human herpes virus 8, and Epstein-Barr virus) are reviewed in the context of transplant recipients. DATA SOURCES -Our experience and published primary and review literature. CONCLUSIONS -Immunohistochemistry continues to have an important role in transplant pathology, most notably C4d staining in assessment of antibody-mediated rejection and assessment of viral pathogens in tissue. In all facets of transplant pathology, correlation of morphology with special studies and clinical data is critical, as is close communication with the transplant team.
Collapse
Affiliation(s)
| | - Christian Lanciault
- From the Department of Pathology, Oregon Health & Science University, Portland
| |
Collapse
|
|
24
|
Prospective Monitoring of Donor-specific Anti-HLA Antibodies After Intestine/Multivisceral Transplantation: Significance of De Novo Antibodies. Transplantation 2015; 99:e49-56. [PMID: 25769071 DOI: 10.1097/tp.0000000000000614] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Presence of circulating donor-specific antibodies (DSA) may be associated with worse clinical outcomes after intestine/multivisceral transplantation. METHODS In 79 intestine/multivisceral recipients, sera were prospectively screened for DSA by Luminex Single antigen test at 1, 3, 6, 9, 12, 18, 24, and 36 months after transplantation. Standard immunosuppression included thymoglobulin-rituximab induction and tacrolimus-prednisone maintenance. C4d staining was performed retrospectively on biopsies in patients that developed acute rejection (AR). RESULTS Twenty-two (28%) patients developed de novo DSA at a median posttransplant period of 3 (1-36) months. De novo DSA were observed in 10 of 40 liver-including and 12 of 39 liver-excluding transplants (P = 0.57). Occurrence of AR was slightly higher in patients with de novo DSA (45% vs 33%, respectively; P = 0.41). Similarly, chronic rejection (14% vs 5%; P = 0.21) and graft loss due to AR (18% vs 7%; P = 0.14) were numerically higher in patients with de novo DSA. Only 35% patients experiencing AR had circulating de novo DSA at the time of AR. Antibody-mediated rejection was diagnosed in 6 patients based on C4d staining, of these 2 patients had circulating de novo DSA at the time of biopsy. CONCLUSIONS De novo DSA formation, particularly early in the posttransplant course may be associated with trends toward worse outcomes. However, its significance in the pathophysiology of AR remains uncertain. Studies focusing mechanisms of DSA-related graft injury and intragraft DSA detection might provide further insight into this issue.
Collapse
|
|
25
|
Cuadrado A, San Segundo D, López-Hoyos M, Crespo J, Fábrega E. Clinical significance of donor-specific human leukocyte antigen antibodies in liver transplantation. World J Gastroenterol 2015; 21:11016-11026. [PMID: 26494958 PMCID: PMC4607901 DOI: 10.3748/wjg.v21.i39.11016] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2015] [Revised: 06/29/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
Antibody-mediated rejection (AMR) caused by donor-specific anti-human leukocyte antigen antibodies (DSA) is widely accepted to be a risk factor for decreased graft survival after kidney transplantation. This entity also plays a pathogenic role in other solid organ transplants as it appears to be an increasingly common cause of heart graft dysfunction and an emerging issue in lung transplantation. In contrast, the liver appears relatively resistant to DSA-mediated injury. This “immune-tolerance” liver property has been sustained by a low rate of liver graft loss in patients with preformed DSA and by the intrinsic liver characteristics that favor the absorption and elimination of DSA; however, alloantibody-mediated adverse consequences are increasingly being recognized, and several cases of acute AMR after ABO-compatible liver transplant (LT) have been reported. Furthermore, the availability of new solid-phase assays, allowing the detection of low titers of DSA and the refinement of objective diagnostic criteria for AMR in solid organ transplants and particularly in LT, have improved the recognition and management of this entity. A cost-effective strategy of DSA monitoring, avoidance of class II human leukocyte antigen mismatching, judicious immunosuppression attached to a higher level of clinical suspicion of AMR, particularly in cases unresponsive to conventional anti-rejection therapy, can allow a rational approach to this threat.
Collapse
|
|
26
|
Abstract
PURPOSE OF REVIEW Liver allograft antibody-mediated rejection (AMR) studies have lagged behind parallel efforts in kidney and heart because of a comparative inherent hepatic resistance to AMR. Three developments, however, have increased interest: first, solid phase antibody testing enabled more precise antibody characterization; second, increased expectations for long-term, morbidity-free survival; and third, immunosuppression minimization trials. RECENT FINDINGS Two overlapping liver allograft AMR phenotypic expressions are beginning to emerge: acute and chronic AMR. Acute AMR usually occurs within the several weeks after transplantation and characterized clinically by donor-specific antibodies (DSA) persistence, allograft dysfunction, thrombocytopenia, and hypocomplementemia. Acute AMR appears histopathologically similar to acute AMR in other organs: diffuse microvascular endothelial cell hypertrophy, C4d deposits, neutrophilic, eosinophilic, and macrophag-mediated microvasculitis/capillaritis, along with liver-specific ductular reaction, centrilobular hepatocyte swelling, and hepatocanalicular cholestasis often combined with T-cell-mediated rejection (TCMR). Chronic AMR is less well defined, but strongly linked to serum class II DSA and associated with late-onset acute TCMR, fibrosis, chronic rejection, and decreased survival. Unlike acute AMR, chronic AMR is a slowly evolving insult with a number of potential manifestations, but most commonly appears as low-grade lymphoplasmacytic portal and perivenular inflammation accompanied by unusual fibrosis patterns and variable microvascular C4d deposition; capillaritis can be more difficult to identify than in acute AMR. SUMMARY More precise DSA characterization, increasing expectations for long-term survival, and immunosuppression weaning precipitated a re-emergence of liver allograft AMR interest. Pathophysiological similarities exist between heart, kidney, and liver allografts, but liver-specific considerations may prove critical to our ultimate understanding of all solid organ AMR.
Collapse
|
|
27
|
Baron D, Giral M, Brouard S. Reconsidering the detection of tolerance to individualize immunosuppression minimization and to improve long-term kidney graft outcomes. Transpl Int 2015; 28:938-59. [DOI: 10.1111/tri.12578] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Revised: 02/03/2015] [Accepted: 04/02/2015] [Indexed: 01/03/2023]
Affiliation(s)
- Daniel Baron
- INSERM; UMR 1064; Nantes France
- CHU de Nantes; ITUN; Nantes France
- Faculté de Médecine; Université de Nantes; Nantes France
| | - Magali Giral
- INSERM; UMR 1064; Nantes France
- CHU de Nantes; ITUN; Nantes France
- Faculté de Médecine; Université de Nantes; Nantes France
| | - Sophie Brouard
- INSERM; UMR 1064; Nantes France
- CHU de Nantes; ITUN; Nantes France
- Faculté de Médecine; Université de Nantes; Nantes France
| |
Collapse
|
|
28
|
O'Leary JG, Shiller SM, Bellamy C, Nalesnik MA, Kaneku H, Terasaki PI, Klintmalm GB, Demetris AJ, Klintmalm GB, Demetris AJ. Acute liver allograft antibody-mediated rejection: an inter-institutional study of significant histopathological features. Liver Transpl 2014; 20:1244-55. [PMID: 25045154 PMCID: PMC4412307 DOI: 10.1002/lt.23948] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Accepted: 06/24/2014] [Indexed: 12/13/2022]
Abstract
Acute antibody-mediated rejection (AMR) occurs in a small minority of sensitized liver transplant recipients. Although histopathological characteristics have been described, specific features that could be used (1) to make a generalizable scoring system and (2) to trigger a more in-depth analysis are needed to screen for this rare but important finding. Toward this goal, we created training and validation cohorts of putative acute AMR and control cases from 3 high-volume liver transplant programs; these cases were evaluated blindly by 4 independent transplant pathologists. Evaluations of hematoxylin and eosin (H&E) sections were performed alone without knowledge of either serum donor-specific human leukocyte antigen alloantibody (DSA) results or complement component 4d (C4d) stains. Routine histopathological features that strongly correlated with severe acute AMR included portal eosinophilia, portal vein endothelial cell hypertrophy, eosinophilic central venulitis, central venulitis severity, and cholestasis. Acute AMR inversely correlated with lymphocytic venulitis and lymphocytic portal inflammation. These and other characteristics were incorporated into models created from the training cohort alone. The final acute antibody-mediated rejection score (aAMR score)--the sum of portal vein endothelial cell hypertrophy, portal eosinophilia, and eosinophilic venulitis divided by the sum of lymphocytic portal inflammation and lymphocytic venulitis--exhibited a strong correlation with severe acute AMR in the training cohort [odds ratio (OR) = 2.86, P < 0.001] and the validation cohort (OR = 2.49, P < 0.001). SPSS tree classification was used to select 2 cutoffs: one that optimized specificity at a score > 1.75 (sensitivity = 34%, specificity = 86%) and another that optimized sensitivity at a score > 1.0 (sensitivity = 81%, specificity = 71%). In conclusion, the routine histopathological features of the aAMR score can be used to screen patients for acute AMR via routine H&E staining of indication liver transplant biopsy samples; however, a definitive diagnosis requires substantiation by DSA testing, diffuse C4d staining, and the exclusion of other insults.
Collapse
Affiliation(s)
- Jacqueline G. O'Leary
- Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas TX
| | | | | | - Michael A. Nalesnik
- Department of Pathology, Division of Liver and Transplantation Pathology, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA 15213
| | - Hugo Kaneku
- University of California Los Angeles, Los Angeles, CA,Terasaki Foundation Laboratory, Los Angeles, CA
| | | | - Göran B. Klintmalm
- Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas TX
| | - Anthony J. Demetris
- Department of Pathology, Division of Liver and Transplantation Pathology, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA 15213
| | | | | |
Collapse
|
|
29
|
O'Leary JG, Kaneku H, Jennings L, Susskind BM, Terasaki PI, Klintmalm GB. Donor-specific alloantibodies are associated with fibrosis progression after liver transplantation in hepatitis C virus-infected patients. Liver Transpl 2014; 20:655-63. [PMID: 24678017 DOI: 10.1002/lt.23854] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Accepted: 02/09/2014] [Indexed: 12/24/2022]
Abstract
Hepatitis C virus (HCV) fibrosis progression after liver transplantation (LT) is accelerated in comparison with fibrosis progression before transplantation. The vast majority of the risk factors for fibrosis progression after LT are not modifiable. With the goal of identifying modifiable risk factors for fibrosis progression, we evaluated the impact of preformed and de novo donor-specific human leukocyte antigen alloantibodies (DSAs) on fibrosis progression after LT in HCV-viremic patients. After blinding, we analyzed all 507 HCV-viremic patients who underwent primary LT from January 2000 to May 2009 and had pretransplant and posttransplant samples available for analysis (86% of the total) for preformed and de novo class I and class II DSAs with a mean fluorescence intensity ≥ 5000 with single-antigen bead technology. Fibrosis was assessed on the basis of indication and protocol liver biopsies; compliance with protocol liver biopsies at 1, 2, and 5 years was ≥80%. Preformed class I DSAs [hazard ratio (HR) = 1.44, P = 0.04] and class II DSAs (HR = 1.86, P < 0.001) were independent predictors of progression to stage 2-4 fibrosis, and de novo DSAs (HR = 1.41, P = 0.07) had borderline significance. In addition, preformed class I DSAs (HR = 1.63, P = 0.03) and class II DSAs (HR = 1.72, P = 0.03) were statistically significantly associated with an increased risk of death. In conclusion, after we controlled for donor and recipient characteristics in multivariate modeling, DSAs were independently associated with fibrosis progression and death after LT in HCV-viremic patients.
Collapse
Affiliation(s)
- Jacqueline G O'Leary
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX
| | | | | | | | | | | |
Collapse
|
|
30
|
O’Leary JG, Demetris AJ, Friedman LS, Gebel HM, Halloran PF, Kirk AD, Knechtle SJ, McDiarmid SV, Shaked A, Terasaki PI, Tinckam KJ, Tomlanovich SJ, Wood KJ, Woodle ES, Zachary AA, Klintmalm GB. The role of donor-specific HLA alloantibodies in liver transplantation. Am J Transplant 2014; 14:779-87. [PMID: 24580828 PMCID: PMC4412601 DOI: 10.1111/ajt.12667] [Citation(s) in RCA: 156] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Revised: 12/23/2013] [Accepted: 01/13/2014] [Indexed: 01/25/2023]
Abstract
The impact of donor-specific HLA alloantibodies (DSA) on short- and long-term liver transplant outcome is not clearly defined. While it is clear that not all levels of allosensitization produce overt clinical injury, and that liver allografts possess some degree of alloantibody resistance, alloantibody-mediated adverse consequences are increasingly being recognized. To better define the current state of this topic, we assembled experts to provide insights, explore controversies and develop recommendations for future research on the consequences of DSA in liver transplantation. This article summarizes the proceedings of this inaugural meeting. Several insights emerged. Acute antibody-mediated rejection (AMR), although rarely diagnosed, is increasingly understood to overlap with T cell-mediated rejection. Isolated liver allograft recipients are at increased risk of early allograft immunologic injury when preformed DSA are high titer and persist posttransplantation. Persons who undergo simultaneous liver-kidney transplantation are at risk of renal AMR when Class II DSA persist posttransplantation. Other under-appreciated DSA associations include ductopenia and fibrosis, plasma cell hepatitis, biliary strictures and accelerated fibrosis associated with recurrent liver disease. Standardized DSA testing and diagnostic criteria for both acute and chronic AMR are needed to distil existing associations into etiological processes in order to develop responsive therapeutic strategies.
Collapse
Affiliation(s)
- J. G. O’Leary
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX,Corresponding author: Jacqueline G. O’Leary,
| | - A. J. Demetris
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA
| | - L. S. Friedman
- Department of Medicine, Newton-Wellesley Hospital, Newton, MA
| | - H. M. Gebel
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA
| | - P. F. Halloran
- Transplant Applied Genomics Centre, University of Alberta, Edmonton, AB, Canada
| | - A. D. Kirk
- Department of Surgery, Emory University, Atlanta, GA
| | | | - S. V. McDiarmid
- Pediatric Transplantation, University of California, Los Angeles, Los Angeles, CA
| | - A. Shaked
- Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | | | - K. J. Tinckam
- Histocompatibility Laboratory, University Health Network, Toronto, ON, Canada
| | - S. J. Tomlanovich
- Pancreas Transplant Services, University of California, San Francisco, San Francisco, CA
| | - K. J. Wood
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - E. S. Woodle
- Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH
| | - A. A. Zachary
- Immunogenetics Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD
| | - G. B. Klintmalm
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX
| |
Collapse
|
|
31
|
O’Leary JG, Kaneku H, Demetris AJ, Marr JD, Shiller SM, Susskind BM, Tillery GW, Terasaki PI, Klintmalm GB. Antibody-mediated rejection as a contributor to previously unexplained early liver allograft loss. Liver Transpl 2014; 20:218-27. [PMID: 24382837 PMCID: PMC4623588 DOI: 10.1002/lt.23788] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Revised: 10/12/2013] [Accepted: 10/21/2013] [Indexed: 12/23/2022]
Abstract
We analyzed 60 patients with idiopathic early allograft loss (defined as death or retransplantation at <90 days) to determine the relative contribution of preformed donor-specific human leukocyte antigen alloantibodies (DSAs) to this endpoint, and we defined strict criteria for the diagnosis of antibody-mediated rejection (AMR) in liver allografts. The inclusion criteria encompassed the availability of a pretransplant serum sample and both postreperfusion and follow-up tissue specimens for a blinded, retrospective re-review of histology and complement component 4d (C4d) staining. AMR was diagnosed on the basis of the presence of all 4 of the following strict criteria: (1) DSAs in serum, (2) histopathological evidence of diffuse microvascular injury/microvasculitis consistent with antibody-mediated injury, (3) diffuse C4d staining in the portal microvasculature with or without staining in the sinusoids or central veins in at least 1 sample, and (4) the exclusion of other causes of a similar type of injury. Patients thought to be experiencing definite AMR on the basis of routine histopathology alone showed the highest levels of DSA sensitization. Forty percent of patients with pretransplant DSAs with a pattern of bead saturation after serial dilutions developed AMR. Another multiparous female developed what appeared to be a strong recall response, which resulted in combined AMR and acute cellular rejection (ACR) causing graft failure. A contribution of DSAs to allograft failure could not be excluded for 3 additional patients who received marginal grafts. In conclusion, liver allograft recipients with preformed DSAs with a high mean fluorescence intensity despite dilution seem to be at risk for clinically significant allograft injury and possibly for loss from AMR, often in combination with ACR.
Collapse
Affiliation(s)
- Jacqueline G. O’Leary
- Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas TX
| | - Hugo Kaneku
- University of California Los Angeles, Los Angeles, CA,Terasaki Foundation Laboratory, Los Angeles, CA
| | | | - John D. Marr
- Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas TX
| | | | - Brian M. Susskind
- Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas TX
| | - Glenn W. Tillery
- Department of Pathology, Baylor University Medical Center, Dallas, TX
| | - Paul I. Terasaki
- University of California Los Angeles, Los Angeles, CA,Terasaki Foundation Laboratory, Los Angeles, CA
| | - Göran B. Klintmalm
- Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas TX
| |
Collapse
|
|
32
|
O'Leary JG, Kaneku H, Jennings LW, Bañuelos N, Susskind BM, Terasaki PI, Klintmalm GB. Preformed class II donor-specific antibodies are associated with an increased risk of early rejection after liver transplantation. Liver Transpl 2013; 19:973-80. [PMID: 23780820 DOI: 10.1002/lt.23687] [Citation(s) in RCA: 104] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2013] [Accepted: 05/26/2013] [Indexed: 12/12/2022]
Abstract
Preformed donor-specific human leukocyte antigen antibodies (DSAs) are considered a contraindication to the transplantation of most solid organs other than the liver. Conflicting data currently exist on the importance of preformed DSAs in rejection and patient survival after liver transplantation (LT). To evaluate preformed DSAs in LT, we retrospectively analyzed prospectively collected samples from all adult recipients of primary LT without another organ from January 1, 2000 to May 31, 2009 with a pre-LT sample available (95.8% of the patients). Fourteen percent of the patients had preformed class I and/or II DSAs with a mean fluorescence intensity (MFI) ≥ 5000. Preformed class I DSAs with an MFI ≥ 5000 remained persistent in only 5% of patients and were not associated with rejection. Preformed class II DSAs with an MFI of 5000 to 10,000 remained persistent in 23% of patients, and this rate increased to 33% for patients whose MFI was ≥10,000 (P < 0.001). Preformed class II DSAs in multivariable Cox proportional hazards modeling were associated with an increased risk of early rejection [hazard ratio (HR) = 1.58; p = 0.004]. In addition, multivariate modeling showed that in comparison with no DSAs (MFI < 1000), preformed class I and/or II DSAs with an MFI ≥ 5000 were independently correlated with the risk of death (HR = 1.51; p = 0.02).
Collapse
Affiliation(s)
- Jacqueline G O'Leary
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX
| | | | | | | | | | | | | |
Collapse
|
|
33
|
Tissue biopsy monitoring of operational tolerance in liver allograft recipients. Curr Opin Organ Transplant 2013; 18:345-53. [PMID: 23619515 DOI: 10.1097/mot.0b013e3283615d48] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW Highly selected, long-surviving, liver allograft recipients with normal/near normal liver injury tests can be weaned from immunosuppression. Baseline biopsies document changes before weaning and can help stratify risk of rejection or dysfunction after weaning; biopsies after weaning are used to study mechanisms of operational tolerance and to monitor for subclinical events. RECENT FINDINGS Clinicopathological features associated with successful weaning include a lack of sensitization [negative donor-specific antibodies (DSA) and lack of tissue C4d deposits]; 'inexperienced' recipient immune system with limited potential for cross-reactivity (less immunological memory; infant recipients); noninflamed allograft in those with nonviral, nonimmunological original diseases; upregulation of liver genes associated with iron metabolism; allograft colonization with 'immunosuppressive' cells (Treg and γδ-1>γδ-2); and longer time on immunosuppression, which might signal slow clonal deletion or silencing. The differential diagnosis of histopathological findings detected before and after weaning includes emerging infections, typical and atypical cellular rejection, indolent antibody-mediated rejection, 'autoimmunity', and other causes of progressive fibrosis. SUMMARY Operationally tolerant liver allograft recipients can be successfully managed with very low, and sometimes no immunosuppression, but challenges exist. Newer approaches to tissue pathology and tissue, serum, and cross-platform analytics are needed to predict successful weaning and to monitor for subclinical events.
Collapse
|
|
34
|
Abstract
PURPOSE OF REVIEW There is increasing evidence to suggest that antibody-mediated mechanisms play a role in the pathogenesis of liver allograft rejection. This article will review the pathology of antibody-mediated rejection (AMR) focusing on recent studies which have improved our understanding of the clinicopathological features and diagnostic approaches. RECENT FINDINGS Recent studies have investigated the patterns of immunohistochemical staining for C4d as a tissue marker of AMR in posttransplant biopsies, and have correlated these findings with other histopathological changes and with the presence of donor-specific antibodies (DSAs). These studies have highlighted the diagnostic applications and limitations of C4d immunostaining. They have also emphasized the importance of using strict criteria for defining 'pure' AMR in the liver allograft - that is, graft dysfunction associated with compatible histological findings (typically resembling biliary obstruction), the presence of DSAs and diffusely positive staining for C4d. SUMMARY Pure AMR is relatively uncommon in ABO-compatible grafts - it should be diagnosed on the basis of strict criteria and requires treatment with antibody-depleting immunosuppression. C4d immunostaining in isolation has limited diagnostic value. However, the presence of diffuse C4d immunostaining (involving endothelium or stroma in >50% of portal tracts or sinusoids) suggests a significant component of antibody-mediated graft damage. In a person with suggestive histological features, this finding should prompt testing for DSAs. Even in the absence of typical histological features of AMR, the combined presence of DSAs and diffuse C4d positivity is associated with more frequent or severe acute and chronic rejection, which may also warrant treatment with antibody-depleting immunosuppression.
Collapse
|
|
35
|
Kim YK, Kim SH, Moon IS, Han SS, Cho SY, You T, Park SJ. The effect of a positive T-lymphocytotoxic crossmatch on clinical outcomes in adult-to-adult living donor liver transplantation. JOURNAL OF THE KOREAN SURGICAL SOCIETY 2013; 84:245-51. [PMID: 23577320 PMCID: PMC3616279 DOI: 10.4174/jkss.2013.84.4.245] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Revised: 12/26/2012] [Accepted: 01/13/2013] [Indexed: 11/30/2022]
Abstract
Purpose There is controversy concerning the effect of a positive T-lymphocytotoxic crossmatch (TLC) on clinical outcomes in adult living donor liver transplantation (LDLT). The aim of this study was to investigate the effect of TLC on clinical outcomes in LDLT and to determine how long a pretransplant positive TLC continues after liver transplantation (LT). Methods Between January 2005 and June 2010, 219 patients underwent adult LDLT at National Cancer Center. The TLC test was routinely performed before LDLT. TLC test results were positive in 8 patients (3.7%). Patients were divided into 2 groups according to the result of TLC: positive TLC (n = 8) and negative TLC (n = 211) groups. All patients with a pretransplant positive TLC (n = 6) underwent a TLC test every week until negative conversion of TLC, except 2 patients who refused to receive the TLC test. Results Acute cellular rejection, surgical complications and patient or graft survival were not significantly different between both groups. All patients with a positive TLC (n = 6) had a posttransplant negative TLC. The median time to negative conversion of TLC was 1.5 weeks (range, 1 to 3 weeks). Conclusion A pretransplant positive TLC does not affect clinical outcomes in adult LDLT. Moreover, T-lymphocytotoxic cross-reactivity disappeared within 3 weeks (range, 1 to 3 weeks) after LT.
Collapse
Affiliation(s)
- Young-Kyu Kim
- Center for Liver Cancer, National Cancer Center, Goyang, Korea
| | | | | | | | | | | | | |
Collapse
|
|
36
|
Abu-Elmagd KM, Wu G, Costa G, Lunz J, Martin L, Koritsky DA, Murase N, Irish W, Zeevi A. Preformed and de novo donor specific antibodies in visceral transplantation: long-term outcome with special reference to the liver. Am J Transplant 2012; 12:3047-60. [PMID: 22947059 DOI: 10.1111/j.1600-6143.2012.04237.x] [Citation(s) in RCA: 149] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Despite improvement in early outcome, rejection particularly chronic allograft enteropathy continues to be a major barrier to long-term visceral engraftment. The potential role of donor specific antibodies (DSA) was examined in 194 primary adult recipients. All underwent complement-dependent lymphocytotoxic crossmatch (CDC-XM) with pre- and posttransplant solid phase HLA-DSA assay in 156 (80%). Grafts were ABO-identical with random HLA-match. Liver was included in 71 (37%) allografts. Immunosuppression was tacrolimus-based with antilymphocyte recipient pretreatment in 150 (77%). CDC-XM was positive in 55 (28%). HLA-DSA was detectable before transplant in 49 (31%) recipients with 19 continuing to have circulating antibodies. Another 19 (18%) developed de novo DSA. Ninety percent of patients with preformed DSA harbored HLA Class-I whereas 74% of recipients with de novo antibodies had Class-II. Gender, age, ABO blood-type, cold ischemia, splenectomy and allograft type were significant DSA predictors. Preformed DSA significantly (p < 0.05) increased risk of acute rejection. Persistent and de novo HLA-DSA significantly (p < 0.001) increased risk of chronic rejection and associated graft loss. Inclusion of the liver was a significant predictor of better outcome (p = 0.004, HR = 0.347) with significant clearance of preformed antibodies (p = 0.04, OR = 56) and lower induction of de novo DSA (p = 0.07, OR = 24). Innovative multifaceted anti-DSA strategies are required to further improve long-term survival particularly of liver-free allografts.
Collapse
Affiliation(s)
- K M Abu-Elmagd
- Department of Surgery Department of Pathology, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
37
|
Importance of liver biopsy findings in immunosuppression management: biopsy monitoring and working criteria for patients with operational tolerance. Liver Transpl 2012; 18:1154-70. [PMID: 22645090 DOI: 10.1002/lt.23481] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Obstacles to morbidity-free long-term survival after liver transplantation (LT) include complications of immunosuppression (IS), recurrence of the original disease and malignancies, and unexplained chronic hepatitis and graft fibrosis. Many programs attempt to minimize chronic exposure to IS by reducing dosages and stopping steroids. A few programs have successfully weaned a highly select group of recipients from all IS without apparent adverse consequences, but long-term follow-up is limited. Patients subjected to adjustments in IS are usually followed by serial liver chemistry tests, which are relatively insensitive methods for detecting allograft damage. Protocol biopsy has largely been abandoned for hepatitis C virus-negative recipients, at least in part because of the inability to integrate routine histopathological findings into a rational clinical management algorithm. Recognizing a need to more precisely categorize and determine the clinical significance of findings in long-term biopsy samples, the Banff Working Group on Liver Allograft Pathology has reviewed the literature, pooled the experience of its members, and proposed working definitions for biopsy changes that (1) are conducive to lowering IS and are compatible with operational tolerance (OT) and (2) raise concern for closer follow-up and perhaps increased IS during or after IS weaning. The establishment of guidelines should help us to standardize analyses of the effects of various treatments and/or weaning protocols and more rigorously categorize patients who are assumed to show OT. Long-term follow-up using standardized criteria will help us to determine the consequences of lowering IS and to define and determine the incidence and robustness of OT in liver allografts.
Collapse
Affiliation(s)
-
- University of Pittsburgh Medical Center, 3459 5th Avenue, UPMC Montefiore E741, Pittsburgh, PA 15213, USA
| |
Collapse
|
|
38
|
Taner T, Gandhi MJ, Sanderson SO, Poterucha CR, De Goey SR, Stegall MD, Heimbach JK. Prevalence, course and impact of HLA donor-specific antibodies in liver transplantation in the first year. Am J Transplant 2012; 12:1504-10. [PMID: 22420671 DOI: 10.1111/j.1600-6143.2012.03995.x] [Citation(s) in RCA: 124] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The presence of preformed donor-specific HLA antibodies (DSA) in liver transplant recipients is increasingly recognized; however, the prevalence of DSA and their impact on early allograft function remains unknown. We prospectively followed serum DSA levels of 90 consecutive liver transplant recipients from baseline to 4 months. Twenty recipients (22.2%) had preformed DSA. No antibody-targeting treatments were undertaken. Seven days after transplantation, DSA levels decreased markedly in all but three patients. Day 7 protocol biopsies showed diffuse C4d deposition along the portal stroma, central vein, subendothelial and stromal space in the patients with persistent high DSA levels. The rate of acute cellular rejection was not significantly different in patients with DSA. The transaminase and bilirubin levels remained comparable during the first year despite the presence of DSA. The three patients with persistently high DSA levels continue to have normal allograft function. We conclude that in most cases, DSA disappear after liver transplant, however in rare instances where they persist, there is evidence of complement activation in the liver allograft, without significant clinical impact in the first year.
Collapse
Affiliation(s)
- T Taner
- Division of Transplant Surgery, Mayo Clinic, Rochester, MN, USA
| | | | | | | | | | | | | |
Collapse
|
|
39
|
Kozlowski T, Andreoni K, Schmitz J, Hayashi PH, Nickeleit V. Sinusoidal C4d deposits in liver allografts indicate an antibody-mediated response: diagnostic considerations in the evaluation of liver allografts. Liver Transpl 2012; 18:641-58. [PMID: 22298469 DOI: 10.1002/lt.23403] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
There is a paucity of data concerning the correlation of complement component 4d (C4d) staining in liver allografts and antibody-mediated rejection. Data about the location and character of C4d deposits in native and allograft liver tissues are inconsistent. We performed C4d immunofluorescence (IF) on 141 fresh-frozen liver allograft biopsy samples and native livers, documented the pattern of C4d IF staining, and correlated the findings with the presence of donor-specific alloantibodies (DSAs). A linear/granular sinusoidal pattern of C4d IF was noted in 18 of 28 biopsy samples obtained after transplantation from patients with positive crossmatch and detectable donor-specific alloantibody (pos-XM/DSA) findings. None of the 59 tested biopsy samples from patients with negative crossmatch and detectable donor-specific alloantibody (neg-XM/DSA) findings were C4d-positive (P < 0.001). No significant association was found between pos-XM/DSA and C4d IF staining in other nonsinusoidal liver compartments. To compare the results of sinusoidal C4d staining with IF and 2 immunohistochemistry (IHC) techniques, C4d IHC was performed on 19 liver allograft biopsy samples in which a sinusoidal pattern of C4d IF had been noted. Sinusoidal C4d IHC findings were negative for 17 of the 19 biopsy samples; 2 showed weak and focal staining, and both patients had pos-XM/DSA findings. Portal vein endothelium staining was present in only 1 IF-stained biopsy sample (pos-XM/DSA) but in 11 IHC-stained biopsy samples (2 of the 11 samples had neg-XM/DSA findings). We conclude that sinusoidal C4d deposits detected by IF in frozen tissue samples from liver allograft recipients correlate with the presence of DSAs and an antibody-mediated alloresponse. These observations are similar to findings reported for other solid organ transplants and can provide relevant information for patient management. Further validation of IHC techniques for C4d detection in liver allograft tissue is required.
Collapse
Affiliation(s)
- Tomasz Kozlowski
- Departments of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | | | | | | | | |
Collapse
|
|
40
|
Kwon GY. The Diagnosis of Acute Antibody-Mediated Rejection in ABO-Incompatible Liver Transplants. KOREAN JOURNAL OF TRANSPLANTATION 2012. [DOI: 10.4285/jkstn.2012.26.1.6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- Ghee Young Kwon
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| |
Collapse
|
|
41
|
Lunz J, Ruppert KM, Cajaiba MM, Isse K, Bentlejewski CA, Minervini M, Nalesnik MA, Randhawa P, Rubin E, Sasatomi E, de Vera ME, Fontes P, Humar A, Zeevi A, Demetris AJ. Re-examination of the lymphocytotoxic crossmatch in liver transplantation: can C4d stains help in monitoring? Am J Transplant 2012; 12:171-82. [PMID: 21992553 DOI: 10.1111/j.1600-6143.2011.03786.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
C4d-assisted recognition of antibody-mediated rejection (AMR) in formalin-fixed paraffin-embedded tissues (FFPE) from donor-specific antibody-positive (DSA+) renal allograft recipients prompted study of DSA+ liver allograft recipients as measured by lymphocytotoxic crossmatch (XM) and/or Luminex. XM results did not influence patient or allograft survival, or cellular rejection rates, but XM+ recipients received significantly more prophylactic steroids. Endothelial C4d staining strongly correlates with XM+ (<3 weeks posttransplantation) and DSA+ status and cellular rejection, but not with worse Banff grading or treatment response. Diffuse C4d staining, XM+, DSA+ and ABO- incompatibility status, histopathology and clinical-serologic profile helped establish an isolated AMR diagnosis in 5 of 100 (5%) XM+ and one ABO-incompatible, recipients. C4d staining later after transplantation was associated with rejection and nonrejection-related causes of allograft dysfunction in DSA- and DSA+ recipients, some of whom had good outcomes without additional therapy. Liver allograft FFPE C4d staining: (a) can help classify liver allograft dysfunction; (b) substantiates antibody contribution to rejection; (c) probably represents nonalloantibody insults and/or complete absorption in DSA- recipients and (d) alone, is an imperfect AMR marker needing correlation with routine histopathology, clinical and serologic profiles. Further study in late biopsies and other tissue markers of liver AMR with simultaneous DSA measurements are needed.
Collapse
Affiliation(s)
- J Lunz
- Department of Pathology, Division of Transplantation, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Andreoni KA, Kozlowski T. Complement component 4d immunohistochemistry in the assessment of liver allograft biopsy samples: applications and pitfalls. Liver Transpl 2011; 17:1366-7; author reply 1368. [PMID: 21837736 DOI: 10.1002/lt.22399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
|
|
43
|
Ali S, Ormsby A, Shah V, Segovia MC, Kantz KL, Skorupski S, Eisenbrey AB, Mahan M, Huang MAY. Significance of complement split product C4d in ABO-compatible liver allograft: diagnosing utility in acute antibody mediated rejection. Transpl Immunol 2011; 26:62-9. [PMID: 21907804 DOI: 10.1016/j.trim.2011.08.005] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2011] [Revised: 08/10/2011] [Accepted: 08/21/2011] [Indexed: 12/11/2022]
Abstract
Diagnosis of liver allograft antibody-mediated rejection (AMR) is difficult and requires a constellation of clinical, laboratory and histologic features that support the disease and exclude other causes. Histologic features of AMR may intermix with those of biliary obstruction, preservation/reperfusion injury, and graft ischemia. Tissue examination for complement degradation product 4d (C4d) has been proved to support this diagnosis in other allografts. For this reason, we conducted a retrospective review of all ABO compatible/identical re-transplanted liver patients with primary focus on identifying AMR as a possible cause of graft failure and to investigate the utility of C4d in liver allograft specimens. We reviewed 193 liver samples obtained from 53 consecutive ABO-compatible re-transplant patients. 142 specimens were stained with C4d. Anti-donor antibody screening and identification was determined by Luminex100 flow cytometry. For the study analysis, patients were stratified into 3 groups according to time to graft failure: group A, patients with graft failure within 0-7 days (n=7), group B within 8-90 days (n=13) and C >90 days (n=33). Two patients (3.7%) met the diagnostic criteria of acute AMR. Both patients experienced rapid decline of graft function with presence of donor specific antibodies (DSA), morphologic evidence of humoral rejection and C4d deposition in liver specimens. C4d-positive staining was identified in different medical liver conditions i.e., acute cellular rejection (52%), chronic ductopenic rejection (50%), recurrent liver disease (48%), preservation injury (18%), and hepatic necrosis (54%). Univariate analysis showed no significant difference of C4d-positive staining among the 3 patients groups, or patients with DSA (P>.05). In conclusion, AMR after ABO-compatible liver transplantation is an uncommon cause of graft failure. Unlike other solid organ allografts, C4d-positive staining is not a rugged indicator of humoral rejection, thus, interpretation should be done with caution to avoid diagnostic dilemmas.
Collapse
|
|
44
|
Kozlowski T, Rubinas T, Nickeleit V, Woosley J, Schmitz J, Collins D, Hayashi P, Passannante A, Andreoni K. Liver allograft antibody-mediated rejection with demonstration of sinusoidal C4d staining and circulating donor-specific antibodies. Liver Transpl 2011; 17:357-68. [PMID: 21445918 DOI: 10.1002/lt.22233] [Citation(s) in RCA: 116] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The importance of antibody-mediated rejection (AMR) in ABO-compatible liver transplantation is controversial. Here we report a prospective series of liver recipients with a preoperative positive crossmatch. To establish the diagnosis of AMR in liver recipients, the criteria described for kidney allografts were adopted. In approximately 10% of 197 liver transplants, we observed a positive T and B cell flow crossmatch before transplantation. Fifteen of 19 patients converted to negative crossmatches early after transplantation and displayed normal liver function while they were on routine immunosuppression. Four patients maintained positive crossmatches. Three of the 4 met the criteria for AMR and showed evidence of graft dysfunction, the presence of donor-specific antibodies (DSAs), morphological tissue destruction with positive C4d linear staining on the graft sinusoidal endothelium, and improved function with attempts to eliminate DSAs. A persistently positive crossmatch after liver transplantation may lead to early, severe AMR and liver failure. C4d staining in the liver sinusoidal endothelium should alert one to the possibility of AMR. In our experience, patients with a positive crossmatch should have it repeated at 2 weeks and, if it is positive, again at 3 to 5 weeks. Recipients with an unknown preoperative crossmatch who develop early cholestasis of unclear etiology should be crossmatched or tested for the presence of DSAs to evaluate for AMR.
Collapse
Affiliation(s)
- Tomasz Kozlowski
- Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7211, USA.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Chan KM, Lee CS, Wu TJ, Lee CF, Chen TC, Lee WC. Clinical perspective of acute humoral rejection after blood type-compatible liver transplantation. Transplantation 2011; 91:e29-e30. [PMID: 21336085 DOI: 10.1097/tp.0b013e318208138c] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
|
|
46
|
Musat A, Agni R, Wai P, Pirsch J, Lorentzen D, Powell A, Leverson G, Bellingham J, Fernandez L, Foley D, Mezrich J, D'Alessandro A, Lucey M. The significance of donor-specific HLA antibodies in rejection and ductopenia development in ABO compatible liver transplantation. Am J Transplant 2011; 11:500-10. [PMID: 21342448 PMCID: PMC3357120 DOI: 10.1111/j.1600-6143.2010.03414.x] [Citation(s) in RCA: 142] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The role of humoral alloreactivity in ABO-compatible liver transplantation remains unclear. To understand the significance of donor-specific HLA alloantibodies (DSA) in liver rejection, we applied the currently used strategy for detection of antibody-mediated rejection of other solid allografts. For this purpose we reviewed the data on 43 recipients of ABO identical/compatible donor livers who had indication liver biopsy stained for complement element C4d and contemporaneous circulating DSA determination. Seventeen (40%) patients had significant circulating DSA in association with diffuse portal C4d deposition (DSA+/diffuse C4d+). These DSA+/diffuse C4d+ subjects had higher frequency of acute cellular rejection (ACR) 15/17 versus 13/26 (88% vs. 50%), p = 0.02, and steroid resistant rejection 7/17 versus 5/26 (41% vs. 19%), p = 0.03. Based on detection of the combination DSA+/diffuse C4d+, 53.6% of cases of ACR had evidence of concurrent humoral alloreactivity. Six of the 10 patients with ductopenic rejection had circulating DSA and diffuse portal C4d, three of whom (2 early and 1 late posttransplantation) developed unrelenting cholestasis, necessitating specific antibody-depleting therapy to salvage the allografts. Thus, in ABO-compatible liver transplantation humoral alloreactivity mediated by antibodies against donor HLA molecules appears to be frequently intertwined with cellular mechanisms of rejection, and to play a role in ductopenia development.
Collapse
Affiliation(s)
- A.I. Musat
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI,Corresponding author: Alexandru I. Musat,
| | - R.M. Agni
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - P.Y. Wai
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - J.D. Pirsch
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - D.F. Lorentzen
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - A. Powell
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - G.E. Leverson
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - J.M. Bellingham
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - L.A. Fernandez
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - D.P. Foley
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - J.D. Mezrich
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - A.M. D'Alessandro
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - M.R. Lucey
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| |
Collapse
|
|
47
|
Demetris AJ, Lunz JG, Randhawa P, Wu T, Nalesnik M, Thomson AW. Monitoring of human liver and kidney allograft tolerance: a tissue/histopathology perspective. Transpl Int 2008; 22:120-41. [PMID: 18980624 DOI: 10.1111/j.1432-2277.2008.00765.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Several factors acting together have recently enabled clinicians to seriously consider whether chronic immunosuppression is needed in all solid organ allograft recipients. This has prompted a dozen or so centers throughout the world to prospectively wean immunosuppression from conventionally treated liver allograft recipients. The goal is to lessen the impact of chronic immunosuppression and empirically identify occasional recipients who show operational tolerance, defined as gross phenotype of tolerance in the presence of an immune response and/or immune deficit that has little or no significant clinical impact. Rare operationally tolerant kidney allograft recipients have also been identified, usually by single case reports, but only a couple of prospective weaning trials in conventionally treated kidney allograft recipients have been attempted and reported. Pre- and postweaning allograft biopsy monitoring of recipients adds a critical dimension to these trials, not only for patient safety but also for determining whether events in the allografts can contribute to a mechanistic understanding of allograft acceptance. The following is based on a literature review and personal experience regarding the practical and scientific aspects of biopsy monitoring of potential or actual operationally tolerant human liver and kidney allograft recipients where the goal, intended or attained, was complete withdrawal of immunosuppression.
Collapse
Affiliation(s)
- Anthony J Demetris
- Thomas E Starzl Transplantation Institute, University of Pittsburgh Medical Center, PA 15213, USA.
| | | | | | | | | | | |
Collapse
|
|
48
|
Abstract
1. Recurrent primary sclerosing cholangitis (PSC) is extremely difficult, if not impossible, to distinguish from other causes of biliary strictures or sclerosing cholangitis in allografts using needle biopsy evaluation alone. Technical problems with biliary reconstruction, long cold ischemic times, non-heart beating donors, ABO blood group incompatibility, antibody-mediated rejection, and small-for-size syndrome in reduced-size or living donor livers can also cause similar manifestations in a peripheral core biopsy. 2. Some difficulties in distinguishing between sclerosing cholangitis and chronic rejection (CR) arise because: a) at risk populations are similar; b) both can cause "cholestatic" elevation of liver injury tests; and c) both can lead to intrahepatic cholestasis and small bile duct loss. 3. Etiopathogenesis and pathology of CR and sclerosing cholangitis have some overlapping features, but show distinct differences that result in significantly different and discriminating pathologic manifestations. 4. Clues in the clinical history, evaluation of serial biopsies, and histopathology can be used to distinguish with confidence between sclerosing cholangitis and CR. 5. Potential discriminating features include liver size and gross appearance, and histopathology findings in the arterial tree, hilar lymph nodes, large and small bile ducts, interface zone, lobular, and perivenular regions.
Collapse
Affiliation(s)
- Anthony Jake Demetris
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA.
| |
Collapse
|
|
49
|
Demetris AJ, Fontes P, Lunz JG, Specht S, Murase N, Marcos A. Wound healing in the biliary tree of liver allografts. Cell Transplant 2006; 15 Suppl 1:S57-65. [PMID: 16826796 DOI: 10.3727/000000006783982386] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
An increasing need for liver transplantation requires evaluation and triage of organs harvested from "extended criteria" donors. Although there is currently no widely accepted definition, most would agree that "extended criteria" includes organs donated by individuals that are old (>65 years), obese, infected with HBV or HCV, non-heart beating (NHBD), or had an unstable blood pressure before harvesting or the organ experienced a long cold ischemic time. These organs carry a statistical risk of dysfunction early after transplantation, but in the majority of recipients, hepatic parenchymal function recovers. Later, however, a small but significant percentage of extended criteria donors develop biliary strictures within several months after transplantation. The strictures occur primarily because of preservation injury that leads to "ischemic cholangitis" or deep wounding of the bile duct wall. Subsequent partial wound healing and wound contraction, but failed restitution of the biliary epithelial cell (BEC) lining, result in biliary tract strictures that cause progressive biliary fibrosis, increased morbidity, and decreased organ half-life. Better understanding of the pathophysiologic mechanisms that lead to biliary strictures in extended criteria donors provides an ideal proving ground for regenerative medicine; it also can provide insights into other diseases, such as extrahepatic biliary atresia and primary sclerosing cholangitis, that likely share certain pathogenic mechanisms. Possible points of therapeutic intervention include limiting cold and warm ischemic times, donor and/or donor organ treatment, ex vivo, to minimize the ischemic/preservation injury, maximize blood flow after transplantation, promote BEC wound healing, and limit myofibroblasts activation and proliferation in the bile duct wall. The pathobiology of biliary wound healing and therapeutic potential of interleukin-6 (IL-6) are highlighted.
Collapse
Affiliation(s)
- A J Demetris
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
| | | | | | | | | | | |
Collapse
|
|
50
|
Rostron A, Carter V, Mutunga M, Cavanagh G, O'Suilleabhain C, Burt A, Jaques B, Talbot D, Manas D. A case of acute humoral rejection in liver transplantation: successful treatment with plasmapheresis and mycophenolate mofetil. Transpl Int 2005; 18:1298-301. [PMID: 16221162 DOI: 10.1111/j.1432-2277.2005.00200.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
We present a case of a 23-year-old female who underwent orthotopic liver transplantation (OLTx) for biliary atresia, 22 years after a failed Kasai operation. Unusually, her postoperative course was complicated by severe acute humoral rejection. In this case report, we discuss her management as well as the role of plasmapheresis in treating allograft dysfunction secondary to acute humoral rejection in liver transplant patients.
Collapse
|