Abstract
BACKGROUND: In males with classic Fabry disease, the processes leading to the frequent outcome of ESKD are poorly understood. Defects in the gene encoding α-galactosidase A lead to accumulation of globotriaosylceramide (GL3) in various cell types. In the glomerular podocytes, accumulation of GL3 progresses with age. Of concern, podocytes are relatively resistant to enzyme replacement therapy and are poorly replicating, with little ability to compensate for cell loss. METHODS: In this study of 55 males (mean age 27 years) with classic Fabry disease genotype and/or phenotype, we performed unbiased quantitative morphometric electron microscopic studies of biopsied kidney samples from patients and seven living transplant donors (to serve as controls). We extracted clinical information from medical records and clinical trial databases. RESULTS: Podocyte GL3 volume fraction (proportion of podocyte cytoplasm occupied by GL3) increased with age up to about age 27, suggesting that increasing podocyte GL3 volume fraction beyond a threshold may compromise survival of these cells. GL3 accumulation was associated with podocyte injury and loss, as evidenced by increased foot process width (a generally accepted structural marker of podocyte stress and injury) and with decreased podocyte number density per glomerular volume. Worsening podocyte structural parameters (increasing podocyte GL3 volume fraction and foot process width) was also associated with increasing urinary protein excretion-a strong prognosticator of adverse renal outcomes in Fabry disease-as well as with decreasing GFR. CONCLUSIONS: Given the known association between podocyte loss and irreversible FSGS and global glomerulosclerosis, this study points to an important role for podocyte injury and loss in the progression of Fabry nephropathy and indicates a need for therapeutic intervention before critical podocyte loss occurs.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 865-875 |
| Number of pages | 11 |
| Journal | Journal of the American Society of Nephrology : JASN |
| Volume | 31 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 1 2020 |
Bibliographical note
Funding Information:Dr. Mauer is a recipient of investigator-initiated Sanofi Genzyme research grants. His laboratory performs kidney/skin biopsy laboratory studies for Sanofi Genzyme. He is also a consultant to Sanofi Genzyme for clinical trial design. He is a speaker at Sanofi Genzyme educational meetings. These interests have been reviewed and managed by the University of Minnesota in accordance with its conflict of interest policies. Dr. Mauer is also a consultant to and his laboratory performs kidney biopsy studies for Amicus Therapeutics and he is a consultant to Freeline Therapeutics. Dr. Mauer also reports other grants from Amicus Therapeutics, grants from National Institutes of Health, and Sanofi Genzyme, during the conduct of the study, Consultant fees from Freeline Therapeutics, and Sanofi Genzyme, outside the submitted work. Dr. Najafian is a recipient of investigator-initiated grants from Amicus Therapeutics and Sanofi Genzyme; has research contracts with Avrobio and Sanofi Genzyme; and is a consultant to Amicus Therapeutics, Freeline Therapeutics, and Sanofi Genzyme. Dr. Oliveira has received financial support for research from Sanofi Genzyme, honoraria for lecturing from Sanofi Genzyme and Shire, and honoraria for consultancies and advisory board membership from Sanofi Genzyme. Dr. Svarstad has received speakers’ fees and travel support from Amicus Therapeutics, Sanofi Genzyme, and Shire; and has participated in Amicus Therapeutics and Sanofi Genzyme Advisory Boards. Dr. Svarstad also reports personal fees from Amicus Therapeutics, grants from Sanofi Genzyme, personal fees from Sanofi Genzyme, and personal fees from Takeda Shire, outside the submitted work. Dr. Tøndel reports other support from Amicus, Freeline Therapeutics, Protalix, Sanofi Genzyme, and Shire during the conduct of the study. Dr. Tøndel has also received speakers’ fees and travel support from Amicus Therapeutics, Sanofi Genzyme, and Shire; and has participated in studies supported by Freeline Therapeutics, Protalix, Sanofi Genzyme, and Shire.
Funding Information:
Sanofi Genzyme provided funding in the form of investigator-initiated grants on this subject. This study was supported by the National Institutes of Health Lysosomal Disease Network (a part of the National Center for Advancing Translational Sciences Rare Diseases Clinical Research Network) grant U54NS065768.
Publisher Copyright:
Copyright © 2020 by the American Society of Nephrology.
Keywords
- chronic kidney disease
- Fabry disease
- pathology
- podocyte
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't
- Research Support, N.I.H., Extramural