INSERM U1151 « mechanisms and therapeutic strategies of chronic kidney diseases », Hôpital Necker, Université de Paris, Paris, France; Service de Néphrologie et Transplantation rénale, AP-HP, Hôpital Necker, Paris, France
Séverine Coulon
INSERM UMR1163, CNRS ERL8254, Laboratoire d'excellence GR-Ex, Université René-Descartes, Imagine Institute, Paris, France; Service de Pharmacie, Grand Hôpital de l'Est Francilien, Coulommiers, France
Kanit Bhukhai
INSERM UMR1163, CNRS ERL8254, Laboratoire d'excellence GR-Ex, Université René-Descartes, Imagine Institute, Paris, France; Present address: Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand
Antoine Neuraz
Département d'Informatique Biomédicale, AP-HP, Hôpital Necker, Centre de Recherche des Cordeliers, INSERM UMR 1138 Equipe 22, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Michael Dussiot
INSERM UMR1163, CNRS ERL8254, Laboratoire d'excellence GR-Ex, Université René-Descartes, Imagine Institute, Paris, France
Guillemette Fouquet
INSERM UMR1163, CNRS ERL8254, Laboratoire d'excellence GR-Ex, Université René-Descartes, Imagine Institute, Paris, France
Marie-Bénédicte Le Stang
INSERM UMR1149 ; CNRS ERL8252 ; Université de Paris, Laboratoire d'excellence INFLAMEX ; Service d'Immunologie, FHU Apollo, Hôpital Bichat-Claude Bernard, AP-HP; Paris, France
Martin Flamant
INSERM UMR1149 ; CNRS ERL8252 ; Université de Paris, Laboratoire d'excellence INFLAMEX ; Service d'Immunologie, FHU Apollo, Hôpital Bichat-Claude Bernard, AP-HP; Paris, France; Service de Physiologie, AP-HP, Hôpital Bichat-Claude Bernard, Paris, France
François Vrtovsnik
INSERM UMR1149 ; CNRS ERL8252 ; Université de Paris, Laboratoire d'excellence INFLAMEX ; Service d'Immunologie, FHU Apollo, Hôpital Bichat-Claude Bernard, AP-HP; Paris, France; Service de Néphrologie, AP-HP, Hôpital Bichat-Claude Bernard, Paris, France
Aurélie Hummel
Service de Néphrologie et Transplantation rénale, AP-HP, Hôpital Necker, Paris, France
Bertrand Knebelmann
INSERM U1151 « mechanisms and therapeutic strategies of chronic kidney diseases », Hôpital Necker, Université de Paris, Paris, France; Service de Néphrologie et Transplantation rénale, AP-HP, Hôpital Necker, Paris, France
Laurent Mesnard
Urgences Néphrologiques et Transplantation Rénale, AP-HP, Hôpital Tenon, Paris, France
Eric Rondeau
Urgences Néphrologiques et Transplantation Rénale, AP-HP, Hôpital Tenon, Paris, France
Thiago T. Maciel
INSERM UMR1163, CNRS ERL8254, Laboratoire d'excellence GR-Ex, Université René-Descartes, Imagine Institute, Paris, France
Fabrizia Favale
Service d'hématologie biologique, AP-HP, Hôpital Saint Antoine, Paris, France
Nicole Casadevall
Service d'hématologie biologique, AP-HP, Hôpital Saint Antoine, Paris, France
Thao Nguyen-Khoa
Service de biochimie, AP-HP, Hôpital Necker, Paris, France
Stéphane Moutereau
Service de biochimie, AP-HP, Hôpital Henri Mondor, Paris-Est Université Créteil, France
Christophe Legendre
INSERM U1151 « mechanisms and therapeutic strategies of chronic kidney diseases », Hôpital Necker, Université de Paris, Paris, France; Service de Néphrologie et Transplantation rénale, AP-HP, Hôpital Necker, Paris, France
Marc Benhamou
INSERM UMR1149 ; CNRS ERL8252 ; Université de Paris, Laboratoire d'excellence INFLAMEX ; Service d'Immunologie, FHU Apollo, Hôpital Bichat-Claude Bernard, AP-HP; Paris, France
Renato C. Monteiro
INSERM UMR1149 ; CNRS ERL8252 ; Université de Paris, Laboratoire d'excellence INFLAMEX ; Service d'Immunologie, FHU Apollo, Hôpital Bichat-Claude Bernard, AP-HP; Paris, France
Olivier Hermine
INSERM UMR1163, CNRS ERL8254, Laboratoire d'excellence GR-Ex, Université René-Descartes, Imagine Institute, Paris, France; Service d'Hématologie clinique, AP-HP, hôpital Necker, Paris, France; Corresponding author at: INSERM-UMR1163, Institut Imagine, 24 Bd du Montparnasse, 75015 Paris, France.
Khalil El Karoui
Service de Néphrologie et Transplantation rénale, AP-HP, Hôpital Henri Mondor, Institut Mondor de recherche biomédicale (IMRB), Paris-Est Université Créteil, France; Corresponding author at: INSERM-UMR1163, Institut Imagine, 24 Bd du Montparnasse, 75015 Paris, France.
Ivan C. Moura
INSERM UMR1163, CNRS ERL8254, Laboratoire d'excellence GR-Ex, Université René-Descartes, Imagine Institute, Paris, France
Summary: Background: Erythrocytosis is a hematological disorder usually related to hematopoietic stem cell somatic mutations. However, unexplained erythrocytosis remains frequent. In this study, we evaluated the involvement of IgA1, a regulator of erythropoiesis also implicated in IgA nephropathy (IgAN) pathophysiology, in unexplained polycythemia/erythrocytosis (PE) of IgAN patients. Methods: IgAN-PE patients’ serum was collected, analyzed and used to study IgA1 effect on proliferation and differentiation of erythroid progenitors. Hematological parameters of transgenic mice for human alpha1 heavy chain were studied. Multicentric observational cohorts of chronic kidney disease (CKD) patients, including both native kidney diseases and renal transplants, were studied to analyze patient hemoglobin levels. Findings: We retrospectively identified 6 patients with IgAN and unexplained PE. In large CKD cohorts, IgAN was associated with PE in 3.5% of patients (p<0.001 compared to other nephropathies). IgAN was an independent factor associated with higher hemoglobin levels (13.1g/dL vs 12.2 g/dL, p=0.01). During post-transplant anemia, anemia recovery was faster in IgAN patients. Elevated polymeric/monomeric IgA1 ratio as well as high Gd-IgA1 rate were observed in circulating IgA1 of the 6 IgAN-PE patients as compared with control or IgAN patients without PE. IgA1 from these patients increased the sensitivity of erythroid progenitors to Epo. In mice, we also observed an elevation of hematocrit in alpha1 knock-in mice compared to wild type controls. Interpretation: These data identify a new etiology of erythrocytosis and demonstrate the role of pIgA1 in human erythropoiesis. This syndrome of IgA-related erythrocytosis should be investigated in case of unexplained erythrocytosis and renal disease. Funding: This work was supported by INSERM (French national institute for health and medical research), Labex GRex and Imagine Institute (Paris, France)
