Pathologic Diagnosis Of Antibody-mediated Rejection Research Articles

Significance of C4d expression in peritubular capillaries concurrent with microvascular inflammation in for-cause biopsies of ABO-incompatible renal allografts.

Pathologic diagnosis of antibody-mediated rejection (ABMR) in ABO-incompatible (ABOi) transplantation patients is often challenging because patients without ABMR are frequently immunopositive for C4d. The aim of this study was to determine whether C4d positivity with microvascular inflammation (MVI), in the absence of any detectable donor-specific antibodies (DSAs) in ABOi patients, could be considered as ABMR. A retrospective study of 214 for-cause biopsies from 126 ABOi kidney transplantation patients was performed. Patients with MVI score of ≥2 and glomerulitis score of ≥1 (n = 62) were divided into three groups: the absolute ABMR group (DSA-positive, C4d-positive or C4d-negative; n = 36), the C4d-positive group (DSA-negative, C4d-positive; n = 22), and the C4d-negative group (DSA-negative, C4d-negative; n = 4). The Banff scores, estimated glomerular filtration rates (eGFRs), and graft failure rates were compared among groups. C4d-positive biopsies showed higher glomerulitis, peritubular capillaritis, and MVI scores compared with C4d-negative specimens. The C4d-positive group did not show significant differences in eGFRs and graft survival compared with the absolute ABMR group. The results indicate that C4d positivity, MVI score of ≥2, and glomerulitis score of ≥1 in ABOi allograft biopsies may be categorized and treated as ABMR cases.

Quadritherapy vs standard tritherapy immunosuppressant regimen after heart transplantation: A propensity score-matched cohort analysis.

After heart transplant, adding everolimus (EVL) to standard immunosuppressive regimen mostly relies on converting calcineurin inhibitors (CNIs) into EVL. The aim of this study was to describe the effects of combining low-dose EVL and CNIs in maintenance immunosuppression regimen (quadritherapy) and compare it with standard tritherapy associating standard-dose CNIs, mycophenolate mofetil, and corticosteroids. In the 3-year registry cohort of heart transplanted patients, those who received quadritherapy were compared with those who received tritherapy. EVL was added after 3months posttransplant. Three analyses were performed to control for confounders: propensity score matching, multivariable survival, and inverse probability score weighting analyses. Among 213 patients who were included (75 with quadritherapy), propensity score matching selected 64 unique pairs of patients with similar characteristics. In the matched cohort (n=128), quadritherapy was associated with fewer deaths (3 [4.7%] vs 17 [21.9%], P=.007) and biopsy-proven acute rejections (15 [23.4%] vs 31 [48.4%], P=.002). These results were confirmed in the overall cohort (n=213), after multivariable and inverse probability score weighting analyses. Renal function and donor-specific HLA-antibodies remained similar in both groups. Low-dose combination quadritherapy was associated with fewer deaths and rejections, compared with standard immunosuppression tritherapy.

Effect of recipient gender and donor-specific antibodies on antibody-mediated rejection after heart transplantation.

Gender-difference regarding antibody-mediated rejection (AMR) after heart transplantation has been described. However, no study accounted for the presence of preformed donor-specific antibodies (pfDSA), a known risk factor of AMR, more common among women than men. In a single-institution 6-year cohort (2010-2015), time to AMR was assessed, comparing men with women by survival analysis with a 1-year death-censored follow-up. All AMRs were biopsy proven. Confounding variables that were accounted for included mean intensity fluorescence (MFI) of pfDSA, recipient age, HLA-, size- and sex-mismatch. 463 patients were included. Overall incidence of AMR was 10.3% at 1year. After adjusting for confounding variables, independent risk factors of AMR were female recipient gender (adjusted hazard-ratio [adj. HR]=1.78 [1.06-2.99]), P=.03) and the presence of pfDSA (adj. HR=3.20 [1.80-5.70], P<.001). This association remained significant when considering pfDSA by their MFI; female recipient gender had an adj. HR=2.2 (P=.026) and MFI of pfDSA (per 1 MFI-increase) adj. HR=1.0002 (P<.0001). In this cohort, women were at higher risk of AMR than men and this risk increase was additive to that of pfDSA. These findings may suggest a gender-related difference in the severity of pfDSA.

Liver Allograft Provides Immunoprotection for the Cardiac Allograft in Combined Heart-Liver Transplantation.

When transplanted simultaneously, the liver allograft has been thought to have an immunoprotective role on other organs; however, detailed analyses in simultaneous heart-liver transplantation (SHLT) have not been done to date. We analyzed patient outcomes and incidence of immune-mediated injury in 22 consecutive SHLT versus 223 isolated heart transplantation (IHT) recipients between January 2004 and December 2013, by reviewing 3912 protocol- and indication-specific cardiac allograft biopsy specimens. Overall survival was similar (86.4%, 86.4%, and 69.1% for SHLT and 93.3%, 84.7%, and 70.0% for IHT at 1, 5, and 10 years; p = 0.83). Despite similar immunosuppression, the incidence of T cell-mediated rejection (TCMR) was lower in SHLT (31.8%) than in IHT (84.8%) (p < 0.0001). Although more SHLT patients had preexisting donor-specific HLA antibody (22.7% versus 8.1%; p = 0.04), the incidence of antibody-mediated rejection was not different in SHLT compared with IHT (4.5% versus 14.8%, p = 0.33). While the left ventricular ejection fraction was comparable in both groups at 5 years, the incidence and severity of cardiac allograft vasculopathy were reduced in the SHLT recipients (42.9% versus 66.8%, p = 0.03). Simultaneously transplanted liver allograft was associated with reduced risk of TCMR (odds ratio [OR] 0.003, 95% confidence interval [CI] 0-0.02; p < 0.0001), antibody-mediated rejection (OR 0.04, 95% CI 0-0.46; p = 0.004), and cardiac allograft vasculopathy (OR 0.26, 95% CI 0.07-0.84; p = 0.02), after adjusting for other risk factors. These data suggest that the incidence of alloimmune injury in the heart allograft is reduced in SHLT recipients.

Antibody-mediated rejection in cardiac transplantation: emerging knowledge in diagnosis and management: a scientific statement from the American Heart Association.

Antibody-mediated rejection (AMR) of the cardiac allograft is a poorly defined and challenging diagnosis for transplant recipients and their clinicians. Although even its very existence in heart transplantation was debated until relatively recently, improved immunopathologic and serological techniques to detect myocardial capillary complement deposition and circulating anti-HLA (human leukocyte antigen) antibodies have led to the detection of a spectrum of newly uncovered immunologic changes that characterize AMR. The earliest standardized clinical and pathological criteria for the diagnosis of AMR in heart transplantation became available in 2004, the result of a task force assembled by the International Society for Heart and Lung Transplantation (ISHLT). In 2006, the criteria were refined by the ISHLT Immunopathology Task Force (Table 1). These revisions provide 4 categories of diagnostic criteria: clinical, histopathologic, immunopathologic, and serological assessment.1 Despite these published criteria, currently >50% of heart transplant centers make the diagnosis of AMR based on cardiac dysfunction and the lack of cellular infiltrates on the heart biopsy (preconference survey included in the ISHLT consensus article).2 More recently, the ISHLT Consensus Conference on AMR has redefined the pathological diagnosis of AMR.3 The 2013 ISHLT “Working Formulation for the Standardization of Nomenclature in the Pathologic Diagnosis of Antibody-Mediated Rejection in Heart Transplantation” was published in December 2013. This document provided an update to the 2010 consensus conference.4 It is anticipated that this update to the definition of AMR will reduce variations in the diagnosis of AMR, providing a platform for the development of standardized therapies. The goal of the present scientific statement is to provide the heart transplant professional with an overview of the current status of the diagnosis and treatment of AMR in the cardiac allograft based on recent consensus conferences and the published literature. We include recommendations to facilitate evolving standardization and strategies …

(882) - Cardiac Post-Transplant Biopsy Tissue Processing and Reporting Protocols for Rejection: A Comparative Survey of Routine Practice Across Three European Centres

First developed by the International Society for Heart and Lung Transplantation (ISHLT) in 1990, the standardized grading method to determine acute cellular rejection (ACR) on endo-myocardial biopsy has since been reviewed and updated (2004). In 2013, the ISHLT issued a further consensus working formulation for the standardization of nomenclature towards pathological diagnosis of antibody-mediated rejection (AMR) in heart transplantation.This survey describes and compares current reporting protocols at three European cardiac transplant centres (Manchester; Berlin and Vienna).

Reclassification of C4d-Positive Endomyocardial Biopsy (EMB) According to New International Society for Heart and Lung Transplantation (ISHLT) 2013 Categories for Reporting Pathologic Antibody-Mediated Rejection (pAMR): Preliminary Data from a Polish Single-Center Study.

The International Society for Heart and Lung Transplantation (ISHLT) has recently proposed a new protocol for reporting pathologic diagnosis of antibody-mediated rejection (pAMR). The new criteria precisely defined antibody panels and morphologic features indicative of AMR. The aim of this study was to reclassify endomyocardial biopsy specimens (EMBs) that had previously been classified as C4d-positive (AMR1) according to the former ISHLT 2004 protocol and to verify whether the new, stricter criteria have any impact on number of AMR diagnosis. We retrospectively analyzed 1374 EMBs from 212 patients who underwent heart transplantation in the years 2001-2013 and who were diagnosed at the Department of Pathology, The Children's Memorial Health Institute. Recorded data were: histopathologic features indicative of AMR (endothelial swelling, interstitial edema, intracapillary macrophages and leucocytes); C4d stain patterns, and presence of cellular rejection (ACR) or Quilty effect in any biopsy. All EMBs were reevaluated according to new ISHLT 2013 criteria and pAMR was specified. There were 77 EMBs from 46 (21.69%) patients that were initially diagnosed as AMR1 based on any C4d-positive stain. After reclassification according to ISHLT 2013: 22 (28.57%) EMBs were evaluated as pAMR 1(H+); 14 (18.18%) EMBs were pAMR 1(I+); 13 (16.88%) EMBs were pAMR 2, and 28 (36.36%) EMBs were pAMR0. Endothelial swelling was observed in 45 (58.44%) EMBs; interstitial edema in 32 (41.55%) EMBs, and intracapillary activated mononuclear cells in 26 (33.77%) EMBs. Then, all 1374 EMBs from 212 patients were reclassified and we noticed that pAMR1H+ was found in 95 (44.81%) patients; pAMR1I+ in 12 (5.66%) patients; pAMR2 in 8 (3.77%) patients; pAMR0 in 95 (45.75%) in patients, and pAMR3 was not present. New, more restrictive ISHLT 2013 criteria for reporting pathologic antibody-mediated rejection (pAMR) decrease number of AMR diagnosis in a selected Polish population, but they increase number of silent/sub-silent AMR diagnoses.

Pathologic diagnosis of antibody-mediated rejection in endomyocardial biopsy after heart transplantation based on renewed International Society for Heart and Lung Transplantation criteria.

Heart transplantation is a well-established life-saving treatment for patients presenting with end-stage cardiac failure. Despite improved efficacy of the procedure, allograft rejection continues to be a major cause of mortality and morbidity in cardiact allograft patients. Although acute cellular rejection (ACR) is quite unusual nowadays, acute antibody-mediated rejection (AMR) remains a significant problem. The role of pathologists in detection of AMR is very important, especially in sub-clinical cases. In 1990, histologic hallmarks of AMR were first stated by International Society for Heart and Lung Transplantation (ISHLT) and detailed histopathologic features and immunopathologic criteria were established in 2005. Recently (2013) ISHLT revised nomenclature and classification of AMR. Aim of this paper was to present practical changes coming from new criteria as well as to highlight difficulties concerning AMR assessment in endomyocardial biopsies (EMB).

Clinical and Prognostic Correlates of pAMR Grading in Patients with Suspect Antibody Mediated Rejection

Purpose Antibody mediated rejection (AMR) is a serious emerging issue in the management of heart transplant (HT) recipients. Although consensus criteria currently define pathological diagnosis of AMR (pAMR), the clinical drawbacks of the pAMR criteria in term of graft function and prognosis, as well as pAMR relationship with donor specific antibodies, (DSA) are unexplored. Methods and Materials In this study we analyze the correlation between pAMR grading, hemodynamic features, DSA detection, and subsequent prognosis in a cohort of consecutive HT recipients with suspected AMR. Results We included 184 patients, with estimated 7-year graft survival of 84±4%, after biopsy. Luminex assay was available in 86 patients, of whom 24 (28%) positive for DSA. pAMR was diagnosed in 72 (39%) recipients (61, pAMR1 and 11 pAMR2). Capillary wedge pressure was higher in patients with pAMR≥1 than in those with pAMR 0 (P=0.03) but we found no difference in hemodynamic data between pAMR 1 and 2. Patients with DSA had a lower cardiac output (P=0.02). However, DSA did not correlate with pAMR grading, but were more often detected in patients with mixed rejection (cellular and AMR), than in those with pAMR alone (P=0.03). Significant angiographic vasculopathy (CAV) accounted for 30% of total deaths, regardless of any rejection grade, and was associated with 12% yearly mortality. pAMR grading per se, on the other hand, was not associated with graft survival, while mixed rejection accounted for a 3.6 times increased risk of graft-related death, in patients without CAV (P=0.04). Conclusions While showing that pathological signs of AMR were associated with a worse hemodynamic profile, with however no differences between pAMR 1 and 2 grades, this study provide suggestive evidence that DSA co-activate both cellular and antibody-mediated graft injury, and that mixed rejection, not AMR alone, drives poor outcome. These data shed new light on the clinical significance of pAMR grading, and brings attention to the adverse consequences of mixed rejection, as opposed to “pure” AMR.

103 Pathologic Diagnosis of Antibody-Mediated Rejection of the Lung Allograft

The role of an antibody-mediated process in lung allograft rejection has not been elucidated. The purpose of this study is to evaluate the correlation of capillary inflammation and complement deposition in patients with anti-HLA Antibodies (DSAs), non-Donor Specific Antibodies (non-DSAs) and controls with no antibodies.

Pathological diagnosis of antibody-mediated rejection in renal allograft without c4d staining, how much reliable?

Background:C4d as a part of complement activation process is a marker for detecting antibody-mediated rejection (ABMR) and its positivity accompanied by positive donor specific antibody (DSA), and morphologic view of humoral rejection has been suggested to detect ABMR since 2003.Materials and Methods:41 specimens of transplanted kidney biopsies gathered from 2006 to 2008 were evaluated for morphological changes on light microscopy, and nephro-pathologist made distinct diagnosis for all of specimens then c4d staining was done for all of them. The association between primary diagnosis without c4d staining and c4d scoring on peritubular capillaries and glomerular capillaries were evaluated to determine whether morphological changes were enough for distinct diagnosis or not.Results:Acute tubular necrosis (ATN) 27%, interstitial fibrosis and tubular atrophy (IF&TA) 17%, and T cell mediated rejection (TCMR) 22% were the commonest diagnosis on light microscopy, and 17% of all biopsies had diffuse positive c4d staining. There was not any report of ABMR in morphological evaluation while c4d positive staining was seen in some specimens (17%). It may result from masking of ABMR by other morphological changes such as TCMR and no specific histologic changes for ABMR on light microscopy.Conclusion:We would like to emphasize that c4d staining should be done for all of renal allograft biopsies, and pathologists all over the world should consider the probability of ABMR masked by other morphological changes on light microscopic evaluation.

The ISHLT working formulation for pathologic diagnosis of antibody-mediated rejection in heart transplantation: Evolution and current status (2005–2011)

From the Department of Pathology, Stanford University, Stanford, California; Universita of Padua Medical School, Padua, Italy; Royal Brompton and Harefield NHS Trust, London, United Kingdom; Hopital Europeen Georges Pompidou, Paris, France; David Geffen School of Medicine at the University of California-Los Angeles, Los Angeles, California; Intermountain Medical Center, Salt Lake City, Utah; Queen Elizabeth Hospital, Birmingham, United Kingdom; University of Utah, Salt Lake City, Utah; Cleveland Clinic, Cleveland, Ohio; Papworth Hospital, Papworth, United Kingdom; Brigham & Women’s Hospital, Boston, Massachusetts; Cedars Sinai Heart Institute, Los Angeles, California; University of Maryland School of Medicine, Baltimore, Maryland.