Accumulation of Globotriaosylceramide in Podocytes in Fabry Nephropathy Is Associated with Progressive Podocyte Loss

Abstract

BackgroundIn males with classic Fabry disease, the processes leading to the frequent outcome of ESKD are poorly understood. Defects in the gene encoding α-galactosidase A lead to accumulation of globotriaosylceramide (GL3) in various cell types. In the glomerular podocytes, accumulation of GL3 progresses with age. Of concern, podocytes are relatively resistant to enzyme replacement therapy and are poorly replicating, with little ability to compensate for cell loss.MethodsIn this study of 55 males (mean age 27 years) with classic Fabry disease genotype and/or phenotype, we performed unbiased quantitative morphometric electron microscopic studies of biopsied kidney samples from patients and seven living transplant donors (to serve as controls). We extracted clinical information from medical records and clinical trial databases.ResultsPodocyte GL3 volume fraction (proportion of podocyte cytoplasm occupied by GL3) increased with age up to about age 27, suggesting that increasing podocyte GL3 volume fraction beyond a threshold may compromise survival of these cells. GL3 accumulation was associated with podocyte injury and loss, as evidenced by increased foot process width (a generally accepted structural marker of podocyte stress and injury) and with decreased podocyte number density per glomerular volume. Worsening podocyte structural parameters (increasing podocyte GL3 volume fraction and foot process width) was also associated with increasing urinary protein excretion—a strong prognosticator of adverse renal outcomes in Fabry disease—as well as with decreasing GFR.ConclusionsGiven the known association between podocyte loss and irreversible FSGS and global glomerulosclerosis, this study points to an important role for podocyte injury and loss in the progression of Fabry nephropathy and indicates a need for therapeutic intervention before critical podocyte loss occurs.

Biomarkers in Fabry Disease. Implications for Clinical Diagnosis and Follow-up

“…Moreover, pathogenic mechanisms may differ depending on the cell type or exposed tissue. In renal involvement, podocyte injury caused by Gb3 or lyso-Gb3 accumulation exposure appears to be the initial step that induces different pathogenic mechanisms that may be associated with the progression of nephropathy [3,38,[40][41][42][43][44]. Nevertheless, the substrate can also accumulate in other renal cell types [45,46] and activate parallel signaling cascades that contribute to the development of both glomerular sclerosis and tubulo-interstitial fibrosis.…”

RIPK3 Contributes to Lyso-Gb3-Induced Podocyte Death

“…Moreover, the inclusion of Gb-3 was observed in almost every glomerular cell type and was especially abundant in podocytes [ 11 ], suggesting that podocyte injury might be critical in the pathogenesis of Fabry nephropathy. Gb3 accumulation was associated with progressive podocyte injury and loss, increased foot process width, and foot process effacement [ 12 , 13 ]. The subsequent increase in urinary protein excretion is a risk factor for the progression of Fabry nephropathy [ 14 ].…”

Fabry disease—what cardiologists can learn from the nephrologist: a narrative review

“…During routine paraffine histology processing cytoplasmic Gb3 depositions are removed. With disease progression podocyte foot process effacement becomes apparent, a hallmark for increasing proteinuria (34)(35)(36). Endothelial fenestration decreases and duplication of the glomerular basement membrane is detectable.…”