title: Distal Angiopathy and Atypical Hemolytic Uremic Syndrome: Clinical and Functional Properties of an Anti-Factor H IgAλ Antibody.
abstract: Abnormal regulation of the alternative pathway of the complement system is a well-described trigger of microangiopathy leading to atypical hemolytic uremic syndrome (aHUS). However, the involvement of complement dysregulation in distal angiopathy has not been reported in adults. We describe the clinical course of a patient with severe distal angiopathy (amputation of all fingers and toes) followed 3 years later by aHUS with end-stage renal disease. This course was attributed to a circulating monoclonal immunoglobulin A λ light chain (IgAλ) with unusual properties: it bound complement factor H (CFH) and impaired CFH-glycosaminoglycan interaction and cell-surface protection. Local complement activation with distal angiopathy and microvascular injury was suggested by deposition of IgA, C4d, and C5b-9 in limb and preglomerular arteries. We therefore postulated that the monoclonal IgAλ inhibited activity of endothelial cell-bound CFH, which led to local activation of complement, vasoconstriction (distal angiopathy), and aHUS. While the patient was dependent on dialysis and plasma exchange, treatment with the anti-C5 antibody eculizumab induced remission of distal angiopathy and aHUS. During eculizumab treatment, kidney transplantation was performed. The patient had normal kidney function at the 3-year follow-up. We suggest that the association of distal angiopathy and aHUS in this patient is clearly linked to anti-CFH properties of the monoclonal IgAλ.
authors.affiliation: Service de Néphrologie Transplantation Dialyse, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France; INSERM U1026, Université de Bordeaux, Bordeaux, France. Electronic address: claire.rigothier@chu-bordeaux.fr.
authors.forename: Claire
authors.initials: C
authors.lastname: Rigothier
authors.affiliation: Service de Néphrologie Transplantation Dialyse, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
authors.forename: Yahsou
authors.initials: Y
authors.lastname: Delmas
authors.affiliation: Complement and Diseases Team, INSERM UMRS 1138, Cordeliers Research Center, Paris, France; Université Paris Descartes Sorbonne Paris-Cité, Paris, France; Université Pierre et Marie Curie (UPMC-Paris-6), Paris, France.
authors.forename: Lubka T
authors.initials: LT
authors.lastname: Roumenina
authors.affiliation: Laboratoire d'Immunologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Contin-Bordes
authors.affiliation: INSERM U1026, Université de Bordeaux, Bordeaux, France; Laboratoire de Pathologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lepreux
authors.affiliation: Service de Néphrologie, Hémodialyse et Transplantation Rénale, Centre Hospitalier Universitaire de Poitiers, Poitiers, France; Centre de référence des amyloses primitives et des maladies de dépôts d'immunoglobulines monoclonales, Poitiers, France.
authors.forename: Frank
authors.initials: F
authors.lastname: Bridoux
authors.affiliation: Centre de référence des amyloses primitives et des maladies de dépôts d'immunoglobulines monoclonales, Poitiers, France; Laboratoire d'Anatomie et cytologie Pathologiques, Centre Hospitalier Universitaire de Poitiers, Poitiers, France.
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Goujon
authors.affiliation: Service de Néphrologie Transplantation Dialyse, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bachelet
authors.affiliation: Service de Néphrologie, Hémodialyse et Transplantation Rénale, Centre Hospitalier Universitaire de Poitiers, Poitiers, France; Centre de référence des amyloses primitives et des maladies de dépôts d'immunoglobulines monoclonales, Poitiers, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Touchard
authors.affiliation: Complement and Diseases Team, INSERM UMRS 1138, Cordeliers Research Center, Paris, France; Assistance Publique-Hopitaux de Paris, Service d'Immunologie biologique, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Frémeaux-Bacchi
authors.affiliation: Service de Néphrologie Transplantation Dialyse, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France; INSERM U1026, Université de Bordeaux, Bordeaux, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Combe
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D065766:Atypical Hemolytic Uremic Syndrome / Q000209:etiology* / Q000276:immunology / Q000628:therapy; D017242:Complement Factor H / Q000276:immunology*; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology*; D007147:Immunoglobulin Light Chains / Q000276:immunology*; D007676:Kidney Failure, Chronic / Q000209:etiology* / Q000276:immunology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D010265:Paraproteinemias / Q000150:complications* / Q000276:immunology / Q000628:therapy; D010951:Plasma Exchange; D011928:Raynaud Disease / Q000209:etiology* / Q000276:immunology / Q000628:therapy; D057049:Thrombotic Microangiopathies / Q000209:etiology / Q000276:immunology / Q000628:therapy
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D007070:Immunoglobulin A; D007147:Immunoglobulin Light Chains; D017242:Complement Factor H; C481642:eculizumab
keywords: Gammopathy; alternative complement pathway; atypical hemolytic uremic syndrome (aHUS); autoantibody; complement activation; complement factor H (CFH); distal angiopathy; factor H antibody; macroangiopathy; microvascular injury