Mosaicism of podocyte involvement is related to podocyte injury in females with Fabry disease.
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.
Department of Pediatrics, University of Minnesota, Minneapolis, United States of America; Department of Medicine, University of Minnesota, Minneapolis, United States of America.
Michael
M
Mauer
Department of Pathology, University of Washington, Seattle, United States of America.
Emily
E
Glynn
Department of Medicine, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway.
Einar
E
Svarstad
Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
Camilla
C
Tøndel
U983, Université René Descartes, Hôpital Necker-Enfants Malades AP-HP, Paris, France.
Marie-Claire
MC
Gubler
Division of Nephrology, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
Michael
M
West
Department of Pathology, University of Washington, Seattle, United States of America.
Alexey
A
Sokolovskiy
Department of Pediatrics, University of Minnesota, Minneapolis, United States of America.
Chester
C
Whitley
Department of Pathology, University of Washington, Seattle, United States of America.
Behzad
B
Najafian
D000293:Adolescent; D000328:Adult; D002648:Child; D018450:Disease Progression; D000795:Fabry Disease / Q000150:complications / Q000473:pathology*; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007668:Kidney / Q000473:pathology*; D008875:Middle Aged; D009030:Mosaicism; D050199:Podocytes / Q000473:pathology*; D051436:Renal Insufficiency, Chronic / Q000209:etiology / Q000473:pathology*; D055815:Young Adult