One year of enzyme replacement therapy reduces globotriaosylceramide inclusions in podocytes in Male adult patients with Fabry disease

Behzad Najafian, Camilla Tøndel, Einar Svarstad, Alexey Sokolovkiy, Kelly Smith, Michael Mauer

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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.

Original languageEnglish (US)
Article numbere0152812
JournalPloS one
Volume11
Issue number4
DOIs
StatePublished - Apr 2016

Bibliographical note

Funding Information:
Competing Interests: BN is a recipient of investigator initiated Genzyme research grants, a consultant to Genzyme, and received speaker's honoraria and travel support from Genzyme. He is also a member of the Medical Advisory Board of Amicus and performs kidney biopsy studies for Amicus. These interests have been reviewed and managed by the University of Washington in according to its conflict of interest policies. CT has no conflict of interest. ES received speaker fees and travel support from Shire and Genzyme. AS and KS have no conflict of interest. MM is a member and Chair of the Genzyme sponsored North American Fabry Registry Advisory Board*, a recipient of investigator initiated Genzyme research grants, a consultant to Genzyme for clinical trial design*, and a speaker at Genzyme educational meetings*. He is also a consultant to and performs kidney biopsy studies for Amicus and a grant reviewer for Shire. *This interest has been reviewed and managed by the University of Minnesota in according to its conflict of interest policies. This did not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Funding Information:
Funding: This work was supported by a grant (MM) from the National Institutes of Health Lysosomal Disease Network [(U54NS065768), a part of the NCATS Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Diseases Research (ORDR), NCATS, funded through a collaboration between NCATS and the National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute of Diabetes and Digestive and Kidney Diseases

Funding Information:
We would like to thank Ms. Frida Meiers and Karen Zaruba for electron microscopy studies and Ms. Cathy Bagne for research coordination. This work was supported by a grant from the National Institutes of Health Lysosomal Disease Network [(U54NS065768), a part of the NCATS Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Diseases Research (ORDR), NCATS, funded through a collaboration between NCATS and the National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)] and by an investigator initiated grant from Genzyme (a Sanofi company). Sanofi Genzyme provided the biopsy material and corresponding clinical data for 5 cases from the Fabrazyme® phase III clinical trial.

Funding Information:
This work was supported by a grant (MM) from the National Institutes of Health Lysosomal Disease Network [(U54NS065768), a part of the NCATS Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Diseases Research (ORDR), NCATS, funded through a collaboration between NCATS and the National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)], no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript, and by an investigator initiated grant from Genzyme (a Sanofi company) to MM. Genzyme provided five paired biopsies with associated clinical information, but had no role in study design, research data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2016 Najafian et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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