title: Markers of Endothelial-to-Mesenchymal Transition: Evidence for Antibody-Endothelium Interaction during Antibody-Mediated Rejection in Kidney Recipients.
abstract: Antibody-mediated rejection (ABMR) is a leading cause of allograft loss. Treatment efficacy depends on accurate diagnosis at an early stage. However, sensitive and reliable markers of antibody-endothelium interaction during ABMR are not available for routine use. Using immunohistochemistry, we retrospectively studied the diagnostic value of three markers of endothelial-to-mesenchymal transition (EndMT), fascin1, vimentin, and heat shock protein 47, for ABMR in 53 renal transplant biopsy specimens, including 20 ABMR specimens, 24 cell-mediated rejection specimens, and nine normal grafts. We validated our results in an independent set of 74 unselected biopsy specimens. Endothelial cells of the peritubular capillaries in grafts with ABMR expressed fascin1, vimentin, and heat shock protein 47 strongly, whereas those from normal renal grafts did not. The level of EndMT marker expression was significantly associated with current ABMR criteria, including capillaritis, glomerulitis, peritubular capillary C4d deposition, and donor-specific antibodies. These markers allowed us to identify C4d-negative ABMR and to predict late occurrence of disease. EndMT markers were more specific than capillaritis for the diagnosis and prognosis of ABMR and predicted late (up to 4 years after biopsy) renal graft dysfunction and proteinuria. In the independent set of 74 renal graft biopsy specimens, the EndMT markers for the diagnosis of ABMR had a sensitivity of 100% and a specificity of 85%. Fascin1 expression in peritubular capillaries was also induced in a rat model of ABMR. In conclusion, EndMT markers are a sensitive and reliable diagnostic tool for detecting endothelial activation during ABMR and predicting late loss of allograft function.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR)_S1155, Paris, France; INSERM, UMR_S1136, Institut Pierre-Louis d'Epidémiologie et de Santé Publique, Equipe EPAR, Paris, France;
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Xu-Dubois
authors.affiliation: Assistance Publique-Hôpitaux de Paris (AP-HP), Tenon Hospital, Renal Intensive Care Unit and Kidney Transplantation, Paris, France;
authors.forename: Julie
authors.initials: J
authors.lastname: Peltier
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Université Paris 06, UMR_S1155, Paris, France; AP-HP, Tenon Hospital, Department of Pathology, Paris, France;
authors.forename: Isabelle
authors.initials: I
authors.lastname: Brocheriou
authors.affiliation: INSERM UMR_S940 University Institute of Hematology, Paris, France;
authors.forename: Caroline
authors.initials: C
authors.lastname: Suberbielle-Boissel
authors.affiliation: Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; and.
authors.forename: Arjang
authors.initials: A
authors.lastname: Djamali
authors.affiliation: Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; and.
authors.forename: Shannon
authors.initials: S
authors.lastname: Reese
authors.affiliation: INSERM, UMR_S1160, Paris, France, University Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Nuala
authors.initials: N
authors.lastname: Mooney
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR)_S1155, Paris, France;
authors.forename: Zela
authors.initials: Z
authors.lastname: Keuylian
authors.affiliation: INSERM, UMR_S1160, Paris, France, University Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Lion
authors.affiliation: Assistance Publique-Hôpitaux de Paris (AP-HP), Tenon Hospital, Renal Intensive Care Unit and Kidney Transplantation, Paris, France;
authors.forename: Nacéra
authors.initials: N
authors.lastname: Ouali
authors.affiliation: INSERM, UMR_S1136, Institut Pierre-Louis d'Epidémiologie et de Santé Publique, Equipe EPAR, Paris, France;
authors.forename: Pierre P
authors.initials: PP
authors.lastname: Levy
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR)_S1155, Paris, France;
authors.forename: Chantal
authors.initials: C
authors.lastname: Jouanneau
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR)_S1155, Paris, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Tenon Hospital, Renal Intensive Care Unit and Kidney Transplantation, Paris, France; Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Université Paris 06, UMR_S1155, Paris, France;
authors.forename: Eric
authors.initials: E
authors.lastname: Rondeau
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR)_S1155, Paris, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Tenon Hospital, Renal Intensive Care Unit and Kidney Transplantation, Paris, France; Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Université Paris 06, UMR_S1155, Paris, France; alexandre.hertig@aphp.fr.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Hertig
mesh_terms: D000906:Antibodies / Q000276:immunology*; D015415:Biomarkers; D004730:Endothelium, Vascular / Q000166:cytology* / Q000276:immunology*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014181:Transplantation Immunology
chemical_list: D000906:Antibodies; D015415:Biomarkers
keywords: antibody-mediated rejection; endothelium; rejection; transplant pathology