Erythrocytosis associated with IgA nephropathy

Camille Cohen; Séverine Coulon; Kanit Bhukhai; Antoine Neuraz; Michael Dussiot; Guillemette Fouquet; Marie-Bénédicte Le Stang; Martin Flamant; François Vrtovsnik; Aurélie Hummel; Bertrand Knebelmann; Laurent Mesnard; Eric Rondeau; Thiago T Maciel; Fabrizia Favale; Nicole Casadevall; Thao Nguyen-Khoa; Stéphane Moutereau; Christophe Legendre; Marc Benhamou; Renato C Monteiro; Olivier Hermine; Khalil El Karoui; Ivan C Moura

doi:10.1016/j.ebiom.2021.103785

Erythrocytosis associated with IgA nephropathy

EBioMedicine. 2022 Jan:75:103785. doi: 10.1016/j.ebiom.2021.103785. Epub 2021 Dec 24.

Authors

Camille Cohen¹, Séverine Coulon², Kanit Bhukhai³, Antoine Neuraz⁴, Michael Dussiot⁵, Guillemette Fouquet⁵, Marie-Bénédicte Le Stang⁶, Martin Flamant⁷, François Vrtovsnik⁸, Aurélie Hummel⁹, Bertrand Knebelmann¹, Laurent Mesnard¹⁰, Eric Rondeau¹⁰, Thiago T Maciel⁵, Fabrizia Favale¹¹, Nicole Casadevall¹¹, Thao Nguyen-Khoa¹², Stéphane Moutereau¹³, Christophe Legendre¹, Marc Benhamou⁶, Renato C Monteiro⁶, Olivier Hermine¹⁴, Khalil El Karoui¹⁵, Ivan C Moura⁵

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ INSERM UMR1163, CNRS ERL8254, Laboratoire d'excellence GR-Ex, Université René-Descartes, Imagine Institute, Paris, France.
⁶ INSERM UMR1149 ; CNRS ERL8252 ; Université de Paris, Laboratoire d'excellence INFLAMEX ; Service d'Immunologie, FHU Apollo, Hôpital Bichat-Claude Bernard, AP-HP; Paris, France.
⁷ 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.
⁸ 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.
⁹ Service de Néphrologie et Transplantation rénale, AP-HP, Hôpital Necker, Paris, France.
¹⁰ Urgences Néphrologiques et Transplantation Rénale, AP-HP, Hôpital Tenon, Paris, France.
¹¹ Service d'hématologie biologique, AP-HP, Hôpital Saint Antoine, Paris, France.
¹² Service de biochimie, AP-HP, Hôpital Necker, Paris, France.
¹³ Service de biochimie, AP-HP, Hôpital Henri Mondor, Paris-Est Université Créteil, France.
¹⁴ 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. Electronic address: ohermine@gmail.com.
¹⁵ Service de Néphrologie et Transplantation rénale, AP-HP, Hôpital Henri Mondor, Institut Mondor de recherche biomédicale (IMRB), Paris-Est Université Créteil, France. Electronic address: khalil.el-karoui@aphp.fr.

Abstract

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).

Keywords: Erythrocytosis; IgA; IgA nephropathy; Polycythemia.

MeSH terms

Animals
Biomarkers
Galactose
Glomerulonephritis, IGA* / complications
Glomerulonephritis, IGA* / genetics
Humans
Immunoglobulin A
Mice
Polycythemia* / complications
Polycythemia* / genetics
Retrospective Studies

Substances

Biomarkers
Immunoglobulin A
Galactose