The 2013 International Society for Heart and Lung Transplantation Working Formulation for the standardization of nomenclature in the pathologic diagnosis of antibody-mediated rejection in heart transplantation
TL;DR: The consensus findings from a series of meetings held between 2010-2012 to develop a Working Formulation for the pathologic diagnosis, grading, and reporting of cardiac antibody-mediated rejection are reported.
Abstract: During the last 25 years, antibody-mediated rejection of the cardiac allograft has evolved from a relatively obscure concept to a recognized clinical complication in the management of heart transplant patients. Herein we report the consensus findings from a series of meetings held between 2010-2012 to develop a Working Formulation for the pathologic diagnosis, grading, and reporting of cardiac antibody-mediated rejection. The diagnostic criteria for its morphologic and immunopathologic components are enumerated, illustrated, and described in detail. Numerous challenges and unresolved clinical, immunologic, and pathologic questions remain to which a Working Formulation may facilitate answers.
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Cedars-Sinai Medical Center1, University of Alberta2, Johns Hopkins University School of Medicine3, Harvard University4, Emory University5, Mayo Clinic6, University of Pittsburgh7, University of Maryland, Baltimore8, Cleveland Clinic9, University of Manitoba10, Washington University in St. Louis11, University of North Carolina at Chapel Hill12, University of California, Los Angeles13
TL;DR: The 12th Banff Conference on Allograft Pathology was held in Comandatuba, Brazil, from August 19-23, 2013, and was preceded by a 2-day Latin American Symposium on Transplant Immunobiology and Immunopathology.
1,121 citations
University of Pittsburgh1, University of Edinburgh2, University of Birmingham3, Baylor University Medical Center4, University of California, San Francisco5, Queen Elizabeth Hospital Birmingham6, Harvard University7, Royal Prince Alfred Hospital8, Cleveland Clinic9, Oslo University Hospital10, Kyoto University11, University Health Network12, Mayo Clinic13, Mount Sinai Hospital14, Icahn School of Medicine at Mount Sinai15, University of São Paulo16, University of Cambridge17, Columbia University18, Cincinnati Children's Hospital Medical Center19, Universidade Federal do Rio Grande do Sul20, Loma Linda University21, Ain Shams University22, Hospital of the University of Pennsylvania23, University Medical Center Groningen24, Toronto General Hospital25, University of Chicago26, Beni-Suef University27, Kobe University28, Temple University29, Lahey Hospital & Medical Center30, Duke University31, University of North Carolina at Chapel Hill32, University of California, Los Angeles33, Cliniques Universitaires Saint-Luc34, Northwestern University35, St. Joseph's Hospital and Medical Center36, Sahlgrenska University Hospital37, Beth Israel Deaconess Medical Center38, University of Kansas39, Hadassah Medical Center40, University of Southern California41, University of Miami42, Dokuz Eylül University43, University of Pennsylvania44, University of Alberta Hospital45, University of Texas Medical Branch46, University of Rome Tor Vergata47, University of Patras48, Karolinska University Hospital49, Tulane University50
TL;DR: New recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization are included.
397 citations
TL;DR: This review focuses on current standards for management of antibody-mediated rejection in solid-organ transplant recipients and emphasizes the importance of informed consent for the use of antibodies for organ transplantation.
Abstract: Antibody-Mediated Rejection of Solid-Organ Allografts This review focuses on current standards for management of antibody-mediated rejection in solid-organ transplant recipients and emphasizes adva...
307 citations
TL;DR: The most recent International Society for Heart and Lung Transplantation (ISHLT) Consensus Conference on Antibody-Mediated Rejection (AMR) as discussed by the authors defined four diagnostic criteria: clinical, histopathologic, immunopathologic and serological assessment.
Abstract: 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 …
226 citations
TL;DR: It is demonstrated that a differential expression of miRNA occurs in rejecting allograft patients, not only at the tissue level but also in the serum, suggesting their potential relevance as non-invasive biomarkers in heart transplant rejection.
Abstract: Aim Rejection is one of the major causes of late cardiac allograft failure and at present can only be diagnosed by invasive endomyocardial biopsies. We sought to determine whether microRNA profiling could serve as a non-invasive biomarker of cardiac allograft rejection.
Methods We included 113 heart transplant recipients from four referral French institutions (test cohort, n = 60, validation cohort, n = 53). In the test cohort, we compared patients with acute biopsy-proven allograft rejection ( n = 30) to matched control patients without rejection ( n = 30), by assessing microRNAs expression in the heart allograft tissue and patients concomitant serum using RNA extraction and qPCR analysis. Fourteen miRNAs were selected on the basis of their implication in allograft rejection, endothelial activation, and inflammation and tissue specificity.
Results We identified seven miRNAs that were differentially expressed between normal and rejecting heart allografts: miR-10a, miR-21, miR-31, miR-92a, miR-142-3p miR-155, and miR-451 ( P < 0.0001 for all comparisons). Four out of seven miRNAs also showed differential serological expression (miR-10a, miR-31, miR-92a, and miR-155) with strong correlation with their tissular expression. The receiver-operating characteristic analysis showed that these four circulating miRNAs strongly discriminated patients with allograft rejection from patients without rejection: miR-10a (AUC = 0.975), miR-31 (AUC = 0.932), miR-92a (AUC = 0.989), and miR-155 (AUC = 0.998, P < 0.0001 for all comparisons). We confirmed in the external validation set that these four miRNAs highly discriminated patients with rejection from those without. The discrimination capability of the four miRNAs remained significant when stratified by rejection diagnosis (T-cell-mediated rejection or antibody-mediated rejection) and time post-transplant.
Conclusion This study demonstrates that a differential expression of miRNA occurs in rejecting allograft patients, not only at the tissue level but also in the serum, suggesting their potential relevance as non-invasive biomarkers in heart transplant rejection.
161 citations
References
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TL;DR: This article summarizes the revised consensus classification of lung allograft rejection and recommends the evaluation of antibody-mediated rejection, recognizing that this is a controversial entity in the lung, less well developed and understood than in other solid-organ grafts, and with no consensus reached on diagnostic features.
Abstract: In 1990, an international grading scheme for the grading of pulmonary allograft rejection was adopted by the International Society for Heart and Lung Transplantation (ISHLT) and was modified in 1995 by an expanded group of pathologists. The original and revised classifications have served the lung transplant community well, facilitating communication between transplant centers with regard to both patient management and research. In 2006, under the direction of the ISHLT, a multi-disciplinary review of the biopsy grading system was undertaken to update the scheme, address inconsistencies of use, and consider the current knowledge of antibody-mediated rejection in the lung. This article summarizes the revised consensus classification of lung allograft rejection. In brief, acute rejection is based on perivascular and interstitial mononuclear infiltrates, Grade A0 (none), Grade A1 (minimal), Grade A2 (mild), Grade A3 (moderate) and Grade A4 (severe), as previously. The revised (R) categories of small airways inflammation, lymphocytic bronchiolitis, are as follows: Grade B0 (none), Grade B1R (low grade, 1996, B1 and B2), Grade B2R (high grade, 1996, B3 and B4) and BX (ungradeable). Chronic rejection, obliterative bronchiolitis (Grade C), is described as present (C1) or absent (C0), without reference to presence of inflammatory activity. Chronic vascular rejection is unchanged as Grade D. Recommendations are made for the evaluation of antibody-mediated rejection, recognizing that this is a controversial entity in the lung, less well developed and understood than in other solid-organ grafts, and with no consensus reached on diagnostic features. Differential diagnoses of acute rejection, airway inflammation and chronic rejection are described and technical considerations revisited. This consensus revision of the working formulation was approved by the ISHLT board of directors in April 2007.
2,139 citations
TL;DR: The process of humoral rejection is multifaceted and has different manifestations in the various types of organ transplants.
439 citations
327 citations
Cedars-Sinai Medical Center1, University of Erlangen-Nuremberg2, University of Hamburg3, University of Padua4, Stanford University5, Harefield Hospital6, Primary Children's Hospital7, Columbia University8, University of Bern9, Mayo Clinic10, University of Michigan11, University of California, Los Angeles12, Cleveland Clinic13, Johns Hopkins University14, University of Alabama at Birmingham15, Medical University of South Carolina16, University of Alberta17, University of Pittsburgh18, Medical University of Vienna19
TL;DR: A clinical definition for AMR (cardiac dysfunction and/or circulating donor-specific antibody) was no longer believed to be required due to recent publications demonstrating that asymptomatic (no cardiac dysfunction) biopsy-proven AMR is associated with subsequent greater mortality and greater development of cardiac allograft vasculopathy.
Abstract: Background The problem of AMR remains unsolved because standardized schemes for diagnosis and treatment remains contentious. Therefore, a consensus conference was organized to discuss the current status of antibody-mediated rejection (AMR) in heart transplantation. Methods The conference included 83 participants (transplant cardiologists, surgeons, immunologists and pathologists) representing 67 heart transplant centers from North America, Europe, and Asia who all participated in smaller break-out sessions to discuss the various topics of AMR and attempt to achieve consensus. Results A tentative pathology diagnosis of AMR was established, however, the pathologist felt that further discussion was needed prior to a formal recommendation for AMR diagnosis. One of the most important outcomes of this conference was that a clinical definition for AMR (cardiac dysfunction and/or circulating donor-specific antibody) was no longer believed to be required due to recent publications demonstrating that asymptomatic (no cardiac dysfunction) biopsy-proven AMR is associated with subsequent greater mortality and greater development of cardiac allograft vasculopathy. It was also noted that donor-specific antibody is not always detected during AMR episodes as the antibody may be adhered to the donor heart. Finally, recommendations were made for the timing for specific staining of endomyocardial biopsy specimens and the frequency by which circulating antibodies should be assessed. Recommendations for management and future clinical trials were also provided. Conclusions The AMR Consensus Conference brought together clinicians, pathologists and immunologists to further the understanding of AMR. Progress was made toward a pathology AMR grading scale and consensus was accomplished regarding several clinical issues.
314 citations