A novel unbiased method reveals progressive podocyte globotriaosylceramide accumulation and loss with age in females with Fabry disease

Behzad Najafian, Aurelio Silvestroni, Alexey Sokolovskiy, Camilla Tøndel, Einar Svarstad, Bogdan Obrisca, Gener Ismail, Myrl D. Holida, Michael Mauer

Research output: Contribution to journalArticlepeer-review

Abstract

While females can suffer serious complications of Fabry disease, most studies are limited to males to avoid confounding by mosaicism. Here, we developed a novel unbiased method for quantifying globotriaosylceramide (GL3) inclusion volume in affected podocytes (F+) in females with Fabry disease independent of mosaicism leading to important new observations. All podocytes in male patients with Fabry are F+. The probability of observing random profiles from F+ podocytes without GL3 inclusions (estimation error) was modeled from electron microscopic studies of 99 glomeruli from 40 treatment-naïve males and this model was applied to 28 treatment-naïve females. Also, podocyte structural parameters were compared in 16 age-matched treatment-naïve males and females with classic Fabry disease and 11 normal individuals. A 4th degree polynomial equation best described the relationship between podocyte GL3 volume density and the estimation error (R2 =0.94) and was confirmed by k-fold cross-validation. In females, this model showed that age related directly to F+ podocyte GL3 volume (correlation coefficient (r = 0.54) and podocyte volume (r = 0.48) and inversely to podocyte number density (r = -0.56), (all significant). F+ podocyte GL3 volume was significantly inversely related to podocyte number density (r = -0.79) and directly to proteinuria. There was no difference in F+ podocyte GL3 volume or volume fraction between age-matched males and females. Thus, in females with Fabry disease GL3 accumulation in F+ podocytes progresses with age in association with podocyte loss and proteinuria, and F+ podocyte GL3 accumulation in females with Fabry is similar to males, consistent with insignificant cross-correction between affected and non-affected podocytes. Hence, these findings have important pathophysiological and clinical implications.

Original languageEnglish (US)
Pages (from-to)173-182
Number of pages10
JournalKidney international
Volume102
Issue number1
DOIs
StatePublished - Jul 2022

Bibliographical note

Funding Information:
BN is a recipient of investigator-initiated grants from Amicus Therapeutics and Sanofi Genzyme; has research contracts with Avrobio, Sanofi Genzyme, Freeline, and 4DMT; is a consultant to Amicus Therapeutics, Freeline Therapeutics, Sanofi Genzyme, Sangamo, Avrobio, and 4DMT; and has received honoraria for speaking at nonpromotional educational meetings sponsored by Amicus Therapeutics and Sanofi. CT is a consultant for Sanofi Genzyme, Amicus, Chiesi, Freeline Therapeutics, and Avrobio; participates as an investigator in clinical Fabry studies initiated from Sanofi Genzyme, Protalix, Idorsia, and Freeline Therapeutics; and has received speaker’s honoraria from Sanofi Genzyme, Amicus, Takeda, and Chiesi. All honoraria received go to Haukeland University Hospital. ES received speaker’s fees from Amicus, Sanofi Genzyme, and Takeda. MDH received speaker-related fees from Protalix and Chiesi. MM is the recipient of investigator-initiated research grants from Sanofi/Genzyme and Amicus∗; has performed research kidney biopsy laboratory studies for Sanofi/Genzyme, Freeline, and Amicus; is a consultant to Genzyme, Amicus, Freeline Therapeutics, Avrobio, and Sangamo for clinical trial design in Fabry disease∗; and has been a speaker at Sanofi/Genzyme and Amicus nonpromotional educational meetings. (∗These interests have been reviewed and managed by the University of Minnesota in accordance with its conflict of interest policies). All the other authors declared no competing interests.

Funding Information:
We would like to thank Frida Maiers, Zour Yang, Karen Zaruba, and Ann Palmer for electron microscopy studies and Cathy Bagne for research coordination. This work was supported by an investigator-initiated grant (BN) from Amicus Therapeutics and a grant (MM and BN) from the National Institutes of Health Lysosomal Disease Network (U54NS065768), a part of the National Center for Advancing Translational Sciences (NCATS) Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Diseases Research, NCATS, funded through a collaboration between NCATS and the National Institute of Neurological Disorders and Stroke and the National Institute of Diabetes and Digestive and Kidney Diseases .

Funding Information:
We would like to thank Frida Maiers, Zour Yang, Karen Zaruba, and Ann Palmer for electron microscopy studies and Cathy Bagne for research coordination. This work was supported by an investigator-initiated grant (BN) from Amicus Therapeutics and a grant (MM and BN) from the National Institutes of Health Lysosomal Disease Network (U54NS065768), a part of the National Center for Advancing Translational Sciences (NCATS) Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Diseases Research, NCATS, funded through a collaboration between NCATS and the National Institute of Neurological Disorders and Stroke and the National Institute of Diabetes and Digestive and Kidney Diseases.

Publisher Copyright:
© 2022 International Society of Nephrology

Keywords

  • Fabry
  • GL3
  • biopsy
  • globotriaosylceramide
  • mosaicism
  • pathology
  • podocyte

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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