Mosaicism of podocyte involvement is related to podocyte injury in females with Fabry disease

Michael Mauer, Emily Glynn, Einar Svarstad, Camilla Tøndel, Marie-Claire Gubler, Michael West, Alexey Sokolovskiy, Chester Whitley, Behzad Najafian, Michael Mauer, Emily Glynn, Einar Svarstad, Camilla Tøndel, Marie-Claire Gubler, Michael West, Alexey Sokolovskiy, Chester Whitley, Behzad Najafian

Abstract

Background: Fabry disease. an X-linked deficiency of α-galactosidase A coded by the GLA gene, leads to intracellular globotriaosylceramide (GL-3) accumulation. Although less common than in males, chronic kidney disease, occurs in ∼ 15% of females. Recent studies highlight the importance of podocyte injury in Fabry nephropathy development and progression. We hypothesized that the greater the % of podocytes with active wild-type GLA gene (due to X-inactivation of the mutant copy) the less is the overall podocyte injury.

Methods: Kidney biopsies from 12 treatment-naive females with Fabry disease, ages 15 (8-63), median [range], years were studied by electron microscopy and compared with 4 treatment-naive male patients.

Results: In females, 51 (13-100)% of podocytes (PC) per glomerulus had no GL-3 inclusions, this consistent with a non-Fabry podocyte phenotype (NFPC). In PC with GL-3 inclusions [Fabry podocyte phenotype (FPC)], GL-3 volume density per podocyte was virtually identical in females and males, consistent with little or no cross-correction between FPC and NFPC. %NFPC per glomerulus (%NFPC/glom) correlated with age in females (r = 0.65, p = 0.02), suggesting a survival disadvantage for FPC over time. Age-adjusted %NFPC/glom was inversely related to foot process width (FPW) (r = -0.75, p = 0.007), an indicator of PC injury. GL-3 volume density in FPC in females correlated directly with FPW.

Conclusions: These findings support important relationships between podocyte mosaicism and podocyte injury in female Fabry patients. Kidney biopsy, by providing information about podocyte mosaicism, may help to stratify females with Fabry disease for kidney disease risk and to guide treatment decisions.

Conflict of interest statement

Competing Interests: BN is a consultant to Genzyme and Amicus Therapeutics, receives investigator initiated research support from Genzyme and Roche, and honoraria and travel support from Genzyme. BN is also a member of the Medical Advisory Board of Amicus Therapeutics. MM is a consultant to Genzyme, and receives investigator initiated research support, honoraria, and travel support from Genzyme. MM is also a member of the Genzyme funded FDA mandated Fabry Registry Board. This interest for MM has been reviewed and managed by the University of Minnesota in accordance with its conflict of interest policies. MM is also a consultant to Amicus. CT and ES received travel support and speakers honoraria from Shire and Genzyme. MLW has received research support, honoraria, and/or travel support from Actelion, Amicus, Excelsior Pharmaceuticals, Genzyme, Glaxo SmithKline, Shire, and Sumitomo Pharma. Behzad Najafian is a PLOS ONE Editorial Board member, and commercial affiliations do not alter the authors' adherence to PLOS ONE Editorial policies and criteria.

Figures

Figure 1. Mosaicism of podocyte Fabry phenotype…
Figure 1. Mosaicism of podocyte Fabry phenotype in a glomerulus from a female patient with Fabry disease.
(A) Montage image of a glomerulus (∼3,000×). Podocyte bodies with visible nuclei are colored blue, podocyte nuclei purple, and GL-3 inclusions yellow. The white rectangle is magnified in B. (B) Magnified view of three podocyte profiles without (at the bottom) and three other podocyte profiles with GL-3 inclusions (on the top). Arrows show GL-3 inclusions in mesangial (M) cells (black) and endothelial (E) cells. P is a podocyte profile with no visible nucleus on this section.
Figure 2. Intra- and inter-subject variability of…
Figure 2. Intra- and inter-subject variability of podocyte mosaicism for Fabry phenotype in females.
X axis shows case numbers (see Table 1). Each vertical dashed line represents a biopsy and each circle represents % podocytes with no GL-3 inclusions in one glomerulus.
Figure 3. Relationship between age and %…
Figure 3. Relationship between age and % podocytes with no GL-3 in females.
Dashed lines represent 0.95 confidence interval.
Figure 4. Relationships between podocyte mosaicism and…
Figure 4. Relationships between podocyte mosaicism and foot process width in age-matched paired females.
Each vertical grey or white band represents an age-matched pair. Each pie chart represents %NFPC/glom as white and %FPC/glom as black area. Abbreviation: FPW: foot process width.

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