Progressive podocyte injury and globotriaosylceramide (GL-3) accumulation in young patients with Fabry disease

Abstract

Progressive renal failure often complicates Fabry’s disease. However, the pathogenesis of Fabry nephropathy is not well understood. We applied unbiased stereological methods to the study of the electron microscopic changes of Fabry nephropathy and the relationship between glomerular structural parameters and renal function in young Fabry patients. Renal biopsies from 14 (M/F=8/6) enzyme replacement therapy (ERT)-naive Fabry patients (median age 12 years; range 4–19 years) and 9 (M/F=6/3) normal living kidney donor control subjects were studied. Podocyte GL-3 inclusion volume density [Vv(Inc/PC)] increased progressively with age, while there was no significant relationship between age and endothelial [Vv(Inc/Endo)] or mesangial [Vv(Inc/Mes)] inclusion volume densities. Foot process width which was greater in male Fabry patients vs. controls also progressively increased with age, and correlated directly with proteinuria. Endothelial fenestration was reduced in Fabry patients vs. controls. These studies are the first to show relationships between quantitative glomerular structural parameters of Fabry nephropathy and urinary protein excretion. The parallel progression with increasing age in podocyte GL-3 accumulation, foot process widening and proteinuria, strongly suggest that podocyte injury may play a pivotal role in the development and progression of Fabry nephropathy.

Immune‐Mediated Myocarditis in Fabry Disease Cardiomyopathy

“…The marked deficiency or absence of GAL activity results in the systemic accumulation of globotriaosylceramide and related glycosphingolipids within the lysosomes, particularly in microvascular endothelial cells, vascular smooth muscle cells, renal tubular cells, podocytes, and cardiomyocytes 3, 4, 5, 6, 7…”

Fabry Liga: Klinikinis Atvejis Ir Literatūros Apžvalga

“…Atlikus inkstų biopsiją, galimas platus histopatologinių pakitimų spektras. Šviesinės mikroskopijos metu randama podocitų ir epitelinių ląstelių vakuolizacija kartu su mezangiumo išsiplėtimu yra būdin-gas Fabry ligos bruožas, vėliau gali progresuoti iki segmentinės ir globalinės glomerulosklerozės [23]. Elektroninės mikroskopijos metu nustatomi tipiški Fabry ligos pakitimai -"zebra" kūneliai (2 pav.).…”

“…Tai -glikosfingolipidų sankaupos podocituose, glomerulų endotelinėse, mezangiumo ir intersticinėse ląstelėse. Pakitimai podocituose progresuoja su amžiumi ir tiesiogiai koreliuoja su proteinurijos dyžiu [23]. Negydomas progresuojantis inkstų pažeidimas yra dažniau-sia Fabry liga sergančių vyrų mirties priežastis.…”

“…sergančių pacientų [19,23]. Dažniausiai pasireiškia ritmo sutrikimai (nuo sinusinio mazgo iki laidžiosios sistemos pažeidimų), koncentrinė kairiojo skilvelio hipertrofija, diastolinė disfunkcija, su amžiumi progresuoja miokardo fibrozė.…”

Fabry disease in infancy and early childhood: a systematic literature review

“…30 Renal symptoms. Najafian et al 51 reported storage of GL3 in biopsied kidneys as early as age 4 years, with GL3 inclusions in all glomerular cell types. Reports of clinical renal involvement in the pediatric population with Fabry disease are limited but may include microalbuminuria, proteinuria, and reduced glomerular filtration rates.…”