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

Kidney Int. 2022 Jul;102(1):173-182. doi: 10.1016/j.kint.2022.03.023. Epub 2022 Apr 26.


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.

Keywords: Fabry; GL3; biopsy; globotriaosylceramide; mosaicism; pathology; podocyte.

Publication types

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

MeSH terms

  • Fabry Disease* / complications
  • Female
  • Humans
  • Male
  • Podocytes*
  • Proteinuria / etiology
  • Trihexosylceramides


  • Trihexosylceramides
  • globotriaosylceramide