Morphological characterization of chronic antibody‐mediated rejection in ABO‐identical or ABO‐compatible pediatric liver graft recipients (original) (raw)
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The New Challenge in Pediatric Liver Transplantation: Chronic Antibody-Mediated Rejection
Journal of Clinical Medicine
Antibody-mediated rejection (AMR) of liver allograft transplantation was considered as anecdotal for many decades. However recently, AMR has gained clinical awareness as a potential cause of chronic liver injury, leading to liver allograft fibrosis and eventual graft failure. (1) Methods: Literature on chronic AMR (cAMR) in pediatric post-liver transplant patients was reviewed for epidemiologic data, physiopathology, diagnosis, and treatment approaches. (2) Results: Accurate incidence of cAMR in pediatric liver transplantation remains unknown. Diagnostic criteria of cAMR were suggested by the Banff Working Group in 2016 and are based on standardized histopathological findings, C4d staining pattern, associated with the presence of donor-specific antibodies (DSA). Physio-pathological mechanisms are not clear for the technically difficult-to-obtain animal models reproducing cAMR. Treatment protocols are not established, being limited to case reports and case series, based on experience...
International Congress Series, 2006
In ABO blood type-incompatible liver transplantation (ABO-I LT), acute humoral rejection triggered by antibodies against donor-type isoagglutinins is the most serious form of rejection and often associated with graft loss. Typical histology of humoral rejection is recognized by biopsies taken at the onset of elevation of alloantibody titers; such biopsies reveal marked portal edema with or without hemorrhagic necrosis. Edema disappears several days after the onset of humoral rejection, and follow-up biopsies reveal relatively nonspecific findings such as hepatocyte necrosis or cholangitis-like portal fibrosis. In our series enrolled between 1995 and 2004, hemorrhagic portal edema was recognized in 17 of 114 (15%) patients who underwent primary ABO-I LT. All 17 patients showed elevation of anti-donor A/B IgM antibody titers (1:64 or higher), and 6-month graft survival was 59%. Deposition of C4d in portal stroma was demonstrated in 11 of 12 (92%) patients with hemorrhagic portal edema and some patients with other histology showing high postoperative alloantibody titers. Although more study is needed, these results suggest that C4d immunostaining can be a useful marker to demonstrate humoral rejection in ABO-I LT. D 2006 Published by Elsevier B.V.
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2016
The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding liver allograft antibody-mediated at the 11(th) (Paris, France, June 5 to 10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013) and 13(th) (Vancouver, British Columbia Dates: 05 - 10 Oct, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued on line. 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 C4d 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. This article is protected by copyright. All rights reserved.
Journal of Pediatric Gastroenterology & Nutrition, 2020
Objectives: Autoantibodies (AAb) and donor-specific HLA antibodies (DSA) are frequently present in pediatric liver transplant (LT) recipients. Their clinical significance remains incompletely understood. We aimed to investigate the prevalence of serum AAb and DSA in pediatric LT recipients and its correlation with patient characteristics and histological and biochemical parameters. Methods: We retrospectively reviewed the data from 62 pediatric LT patients in follow-up at Ghent University Hospital between January 2007 and February 2018. Blood samples with AAb measurement were taken systematically, liver biopsies (LB) were performed on clinical indication. Results: AAb were detected in 27 (43,3%) patients, with antinuclear antibodies (ANA) being the most frequently (24%) encountered AAb. There was an association between AAb positivity and female gender (p=0,032) and deceased donor LT (p=0,006). Patients with positive AAb underwent a higher number of LB during their follow-up (p<0,001), and an association was found with the presence of non-specific histologic alterations (p=0,032) in the absence of de novo autoimmune hepatitis. Positive AAb were also associated with higher alkaline phosphatase (p<0,001), ALT (p<0,001), AST (p<0,001), γ-GT (p=0,001), IgG (p=0,011) and lower albumin (p=0,029). Fourteen out of 50 (28%) patients were DSA positive, mostly anti-HLA class II. DSA positivity was associated with T cell-mediated rejection (p=0,019), higher total (p=0,033) and direct (p=0,012) bilirubin and γ-GT (p<0,001). Conclusions: The presence of AAb and DSA is associated with histological and biochemical parameters of graft dysfunction. Larger prospective studies are warranted to investigate the
Hepatology, 2000
In contrast with other vascularized allografts, chronic liver allograft rejection is uncommon. Over the last two decades, the incidence at 5 years after transplantation has decreased from 15% to 20% in the 1980s to an expected incidence of 3% to 5% in current liver allograft recipients. 1 This is likely attributable to the unique immunologic properties of a liver allograft, better recognition and control of acute and the early phases of chronic rejection (CR), and the remarkable regenerative capabilities of the liver. 2-11 Nevertheless, CR is still an important cause of late liver allograft dysfunction and failure. 12-16 And from a practical perspective, proper recognition and staging of CR is essential for long-term patient management, because toxic side effects of long-term immunosuppression force clinicians to significantly lower or discontinue immunosuppression. 17-20 Moreover, given the inevitable decline in kidney and heart allograft structure and function because of CR, study of the relatively low incidence of CR in liver allografts, and the ability of the liver to recover from CR, will likely lead to valuable insights into transplantation immunobiology in general.
Liver Transplantation
A "central pathology" or "site" reading of biopsy slides is used in liver transplant clinical trials to determine rejection. We evaluated inter-rater reliability of readings of "rejection or not" using digitized slides from the Medication Adherence in Pediatric Liver Transplant Recipients (MALT) study. 4 masked experienced pathologists read the digitized slides and then reread them after a study-specific histologic end-point development program. Agreement was expressed throughout as a Kappa or Fleiss Kappa statistic (ҡ). A ҡ > 0.6 was predefined as desirable. Readings were correlated with immunosuppressant adherence (The Medication Level Variability Index, MLVI), and maximal liver enzyme levels during the study period. Interrater agreement between site and central review in MALT, and between 4 pathologists later on, was low (ҡ=0.44, Fleiss ҡ = 0.41, respectively). Following the end-point development program, agreement improved and became acceptable (ҡ = 0.71). The final reading was better-aligned with maximal GGT levels and MLVI
Acute humoral rejection and C4d immunostaining in ABO blood type-incompatible liver transplantation
Liver Transplantation, 2006
Complement C4d deposition in graft capillaries has been reported to be associated with antibody-mediated rejection in kidney and other solid organ transplantation. The correlation of C4d deposits and humoral rejection in liver transplants, however, is not well understood. We investigated the C4d immunostaining pattern in 34 patients whose liver biopsy was taken within the first 3 postoperative weeks for suspected acute rejection after ABO blood type-incompatible liver transplantation. The staining pattern was classified as positive (portal stromal staining), indeterminate (endothelial staining only), and negative (no staining). Positive C4d immunostaining was seen in 17 (50%) patients and was significantly associated with high (ϫ64 or more) postoperative antidonor A/B antibody (immunoglobulin M (IgM)) titers (88 vs. 35%, P ϭ 0.002) and poorer overall survival rate (41 vs. 88%, P ϭ 0.007). Ten of 11 (91%) cases with histological acute humoral rejection (periportal edema and necrosis (PEN) or portal hemorrhagic edema) were positive for C4d, all of which showed high postoperative antibody titers. The other histologies associated with C4d positivity was purulent cholangitis (n ϭ 4), coagulative hepatocyte necrosis (n ϭ 1), acute cellular rejection (n ϭ 1), and hepatocanalicular cholestasis (n ϭ 1). Full clinical recovery was observed in only 6 of 17 (35%) C4d-positive patients, and tended to be associated with a lower rejection activity index (RAI). In conclusion, our study indicates that C4d deposits in the portal stroma can be a hallmark of acute humoral rejection in ABO-incompatible liver transplantation, and allograft damage can be reversible in a minority of cases. Liver Transpl 12: 457-464, 2006. Abbreviations: Ig, immunoglobulin; PEN, periportal edema and necrosis; RAI, rejection activity index.