title: One Year of Enzyme Replacement Therapy Reduces Globotriaosylceramide Inclusions in Podocytes in Male Adult Patients with Fabry Disease.
abstract: Fabry nephropathy is associated with progressive accumulation of globotriaosylceramide (GL3) in podocytes. Reducing this GL3 burden may reduce podocyte injury. Sensitive methods to quantify podocyte GL3 content may determine whether a given strategy can benefit podocytes in Fabry disease. We developed an unbiased electron microscopic stereological method to estimate the average volume of podocytes and their GL3 inclusions in 6 paired pre- and post-enzyme replacement therapy (ERT) biopsies from 5 men with Fabry disease. Podocyte GL3 content was regularly reduced (average 73%) after 11-12 months of ERT. This was not detectable using a semi-quantitative approach. Parallel to GL3 reduction, podocytes became remarkably smaller (average 63%). These reductions in podocyte GL3 content or size were not significantly correlated with changes in foot process width (FPW). However, FPW after ERT was significantly correlated with the magnitude of the decrease in podocyte GL3 content from baseline to 11-12 months of ERT. Also podocytes exocytosed GL3 inclusions, a phenomenon correlated with their reduction in their GL3 content. Demonstrable after11-12 months, reduction in podocyte GL3 content allows for early assessment of treatment efficacy and shorter clinical trials in Fabry disease.
authors.affiliation: Department of Pathology, University of Washington, Seattle, United States of America.
authors.forename: Behzad
authors.initials: B
authors.lastname: Najafian
authors.affiliation: Department of Clinical Medicine, University of Bergen, Bergen, Norway.|Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Camilla
authors.initials: C
authors.lastname: Tøndel
authors.affiliation: Department of Clinical Medicine, University of Bergen, Bergen, Norway.|Department of Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Einar
authors.initials: E
authors.lastname: Svarstad
authors.affiliation: Department of Pathology, University of Washington, Seattle, United States of America.
authors.forename: Alexey
authors.initials: A
authors.lastname: Sokolovkiy
authors.affiliation: Department of Pathology, University of Washington, Seattle, United States of America.
authors.forename: Kelly
authors.initials: K
authors.lastname: Smith
authors.affiliation: Departments of Pediatrics and Medicine, University of Minnesota, Minneapolis, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Mauer
mesh_terms: D000293:Adolescent; D000328:Adult; D048429:Cell Size / Q000187:drug effects; D056947:Enzyme Replacement Therapy; D005089:Exocytosis / Q000187:drug effects; D000795:Fabry Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014281:Trihexosylceramides / Q000378:metabolism*; D055815:Young Adult
chemical_list: D014281:Trihexosylceramides; C018549:globotriaosylceramide