title: Allo-immune membranous nephropathy and recombinant aryl sulfatase replacement therapy: a need for tolerance induction therapy.
abstract: Nephrotic syndrome was reported in a highly-sensitized patient receiving enzyme replacement therapy (ERT) for Pompe disease, but the prevalence of ERT-induced renal complications and mechanisms to facilitate readministration of ERT in these patients remain unexplored. This work identifies a new antigen responsible for secondary membranous nephropathy (MN) in a patient with mucopolysaccharidosis type VI caused by aryl sulfatase B (ASB) deficiency. ERT (recombinant human ASB [rhASB]; 1 mg/kg per week) started at the age of 4 years led to a high anti-rhASB titer and dramatically improved clinical manifestations. However, 16 months later, the patient suddenly developed nephrotic syndrome resistant to steroid therapy 1 week after orthopedic surgery. Examination of the kidney biopsy specimen revealed glomerular deposition of IgG (mostly IgG4, C3, and C5b-9) in a granular pattern typical of MN. Double immunofluorescence staining showed that subepithelial granular deposits contained rhASB colocalized with IgG. Ig eluted from the patient's biopsy specimen reacted specifically with rhASB. On discontinuation of ERT, proteinuria progressively decreased, but the patient's clinical condition markedly deteriorated. Induction of tolerance to rhASB was initiated by coadministration of low-dose corticosteroids, rituximab, intravenous Igs, and oral methotrexate. ERT was resumed 8 weeks after starting immunosuppressive therapy without inducing a rebound of antibody titer or an increase in proteinuria. We conclude that the allo-immune response to the recombinant rhASB caused the nephropathy. Considering the critical requirement for ERT in patients with such enzyme deficiencies, immune tolerance induction should be advocated in the patients with allo-immune MN.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche_S 702, Paris, France;
authors.forename: Hanna
authors.initials: H
authors.lastname: Debiec
authors.forename: Vassili
authors.initials: V
authors.lastname: Valayannopoulos
authors.forename: Olivia
authors.initials: O
authors.lastname: Boyer
authors.forename: Laure-Hélène
authors.initials: LH
authors.lastname: Nöel
authors.forename: Patrice
authors.initials: P
authors.lastname: Callard
authors.forename: Hélène
authors.initials: H
authors.lastname: Sarda
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
authors.forename: Patrick
authors.initials: P
authors.lastname: Niaudet
authors.forename: Pierre
authors.initials: P
authors.lastname: Ronco
mesh_terms: D002675:Child, Preschool; D056947:Enzyme Replacement Therapy / Q000009:adverse effects*; D015433:Glomerulonephritis, Membranous / Q000209:etiology*; D006801:Humans; D007108:Immune Tolerance; D007518:Isoantibodies / Q000096:biosynthesis*; D008297:Male; D009087:Mucopolysaccharidosis VI / Q000188:drug therapy; D020051:N-Acetylgalactosamine-4-Sulfatase / Q000276:immunology* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000276:immunology
chemical_list: D007518:Isoantibodies; D011994:Recombinant Proteins; D020051:N-Acetylgalactosamine-4-Sulfatase; C581941:ARSB protein, human