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Abstract: TH-PO798

Accumulation of Globotriaosylceramide (GL3) in Podocytes (PC) in Fabry Nephropathy (FN) Is Associated with Progressive PC Loss

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Najafian, Behzad, University of Washington, Seattle, Washington, United States
  • Tøndel, Camilla, Haukeland University Hospital, Bergen, Norway
  • Svarstad, Einar, Haukeland University Hospital, Bergen, Norway
  • Oliveira, João Paulo, Faculty of Medicine, University of Porto, Porto, Portugal
  • Mauer, Michael, University of Minnesota, Minneapolis, Minnesota, United States
Background

Males with classic Fabry disease (FD) have a high incidence of end stage renal disease (ESRD). Processes leading to ESRD are poorly understood. α-galactosidase A gene defects lead to GL3 accumulation in the glomerulus, but this is progressive with age only in PC. PC are relatively resistant to enzyme replacement therapy and replicate poorly when lost. We aimed to examine if PC GL3 accumulation in FD is associated with PC loss.

Methods

Unbiased morphometric electron microscopic renal biopsy studies were performed in 58 males ages 27±13 years with classic FD genotype and/or phenotype.

Results

With increasing age there was an increasing fraction of PC cytoplasm occupied by GL3 inclusions [Vv(Inc/PC)], but this plateaued at age ~30. However mean PC volume (VPC) and total volume of GL3 inclusions/PC [V(Inc/PC)] continued to increase. V(Inc/PC) correlated with PC injury and loss evidenced by increased foot process width (FPW) and decreased PC number density per volume of glomerulus [Nv(PC/glom)]. The relationship between Nv(PC/glom) vs. V(Inc/PC) was best depicted by a power regression [V(Inc/PC)=0.189×Nv(PC/glom)-0.954 ] or 2 linear regression lines with an initial steep and a later milder slope. Piecewise linear regression analysis explained 81% of the variance of Nv(PC/glom) by V(Inc/PC), providing a breakpoint of V(Inc/PC) = 2009 µm3. Patients with V(Inc/PC) > breakpoint showed an inverse correlation between age and Nv(PC/glom) (r=-0.70, p=0.008) and direct correlations between age and V(Inc/PC) (r=0.57, p=0.04) and VPC (r=0.67, p=0.01). Also, urinary protein excretion rate (UPER), a strong predictor of adverse renal outcomes in FD, correlated inversely with Nv(PC/glom) (r=-0.64, p=0.03) and directly with VPC (r=0.79, p=0.002), and FPW correlated inversely with Nv(PC/glom) (r=-0.74, p=0.04) in patients with V(Inc/PC) > breakpoint. However, in subjects with V(Inc/PC) ≤ the breakpoint there was no statistically significant relationship between age or UPER and PC parameters.

Conclusion

Given the known association between PC loss and irreversible focal and global glomerulosclerosis, this study supports an important role for PC loss, which beyond a certain point, is associated with the clinical progression of FN and argues for therapeutic intervention before critical PC loss has occurred.

Funding

  • Other NIH Support –