Allo-immune Membranous Nephropathy and Recombinant Aryl Sulfatase Replacement Therapy: A Need for Tolerance Induction Therapy

J Am Soc Nephrol. 2014 Apr;25(4):675-80. doi: 10.1681/ASN.2013030290. Epub 2013 Nov 21.

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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child, Preschool
  • Enzyme Replacement Therapy / adverse effects*
  • Glomerulonephritis, Membranous / etiology*
  • Humans
  • Immune Tolerance
  • Isoantibodies / biosynthesis*
  • Male
  • Mucopolysaccharidosis VI / drug therapy
  • N-Acetylgalactosamine-4-Sulfatase / immunology*
  • N-Acetylgalactosamine-4-Sulfatase / therapeutic use
  • Recombinant Proteins / immunology

Substances

  • Isoantibodies
  • Recombinant Proteins
  • N-Acetylgalactosamine-4-Sulfatase
  • ARSB protein, human