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

Research output: Contribution to journalArticle

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Abstract

Background: Fabry disease. an X-linked deficiency of a-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 = 20.75, 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.

Original languageEnglish (US)
Article numbere112188
JournalPloS one
Volume9
Issue number11
DOIs
StatePublished - Nov 11 2014

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Fabry Disease
Podocytes
Mosaicism
phenotype
Wounds and Injuries
Biopsy
kidney diseases
Genes
Phenotype
Galactosidases
biopsy
Electron microscopy
kidneys
galactosidases
electron microscopy
inactivation
genes
Foot
mutants
Kidney

Cite this

Mauer, M., Glynn, E., Svarstad, E., Tøndel, C., Gubler, M. C., West, M., ... Najafian, B. (2014). Mosaicism of podocyte involvement is related to podocyte injury in females with Fabry disease. PloS one, 9(11), [e112188]. https://doi.org/10.1371/journal.pone.0112188

Mosaicism of podocyte involvement is related to podocyte injury in females with Fabry disease. / Mauer, Michael; Glynn, Emily; Svarstad, Einar; Tøndel, Camilla; Gubler, Marie Claire; West, Michael; Sokolovskiy, Alexey; Whitley, Chester; Najafian, Behzad.

In: PloS one, Vol. 9, No. 11, e112188, 11.11.2014.

Research output: Contribution to journalArticle

Mauer, M, Glynn, E, Svarstad, E, Tøndel, C, Gubler, MC, West, M, Sokolovskiy, A, Whitley, C & Najafian, B 2014, 'Mosaicism of podocyte involvement is related to podocyte injury in females with Fabry disease', PloS one, vol. 9, no. 11, e112188. https://doi.org/10.1371/journal.pone.0112188
Mauer, Michael ; Glynn, Emily ; Svarstad, Einar ; Tøndel, Camilla ; Gubler, Marie Claire ; West, Michael ; Sokolovskiy, Alexey ; Whitley, Chester ; Najafian, Behzad. / Mosaicism of podocyte involvement is related to podocyte injury in females with Fabry disease. In: PloS one. 2014 ; Vol. 9, No. 11.
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abstract = "Background: Fabry disease. an X-linked deficiency of a-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 = 20.75, 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.",
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AU - Gubler, Marie Claire

AU - West, Michael

AU - Sokolovskiy, Alexey

AU - Whitley, Chester

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AB - Background: Fabry disease. an X-linked deficiency of a-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 = 20.75, 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.

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