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West et al. Rare Dis Orphan Drugs J 2024;3:22 https://dx.doi.org/10.20517/rdodj.2023.61 Page 11 of 34

altered with failure of permselectivity and increasing proteinuria. This ultimately leads to focal and then
global glomerulosclerosis with loss of nephron function.

It has been postulated that Gb3 accumulation and uptake into proximal tubular cells can trigger focal
tubular atrophy and interstitial fibrosis, in addition to the inflammation and fibrosis that can be induced by
increased proteinuria itself . In a study of 15 human Fabry disease kidney biopsies, Rozenfeld (2020)
[69]
showed increased TGF-β1 production mainly from proximal tubular cells rather than glomerular cells
including podocytes . There was also increased production of fibroblast growth factor (FGF-2) and
[70]
vascular endothelial growth factor (VEGF), the latter expressed in the glomerulus and blood vessels; this is
consistent with the fact that TGF-β1 activates FGF-2 expression in endothelial cells which then promotes
VEGF production. VEGF is known to cause thickening of the glomerular basement membrane, glomerular
enlargement, and mesangial proliferation, in addition to foot process effacement in other glomerular
diseases. Caspase-3 positive staining was also observed to be consistent with apoptosis since caspase
activates this process, which is known to be caused by the combination of TGF-β1 and VEGF.
Myofibroblasts, which produce protein components of the fibrillar matrix that contributes to fibrosis, and
are stimulated by TGF-β1, were identified on pericytes surrounding peritubular capillaries, mesangial cells,
and glomeruli. All these observations are consistent with the role of TGF-β1 as the key profibrotic cytokine
in Fabry nephropathy and that it indirectly triggers apoptosis in renal tubular cells.

Proteinuria is the major predictor of GFR loss in patients with Fabry disease and has been linked to
increased glomerular sclerosis [71,72] . This suggests a critical role of podocyte injury in Fabry nephropathy.
The podocytes, being terminally differentiated and thus not able to replicate, have a greater cell burden of
glycolipid deposits than other kidney cells and become significantly enlarged. As such, they may suffer
earlier and greater injury than other renal cell types in Fabry disease. For this reason, Fabry disease can be
thought of as a podocytopathy.

Najafian et al. have performed quantitative stereoscopic morphometric electron microscopic studies of
kidney biopsies in Fabry disease patients that showed Gb3 accumulation in podocytes in males associated
with progressive podocyte injury and loss, with increased foot process width, decreased podocyte density,
and increased proteinuria [73,74] . They also showed that in females with Fabry disease, Gb3 accumulation in
podocytes progresses with age in association with podocyte loss and proteinuria, and this process is similar
[75]
to that in males .
There are secondary processes triggered by Fabry disease that are subsequently unresponsive to ERT and
[63]
contribute to ongoing cell and tissue injury, including in the kidney . These may also contribute to the
suboptimal response of the kidneys to treatment with ERT or pharmacologic chaperone therapy. Recently,
increased alpha-synuclein protein (SNCA) was identified in human podocytes in Fabry nephropathy. This
accumulation appears to be independent of increased Gb3 levels and does not respond to ERT. Studies in a
human podocyte cell line with GLA knockout confirmed the role of SNCA in podocyte injury with
lysosomal impairment in Fabry disease. SNCA inhibition improved both lysosomal structure and function
beyond that of ERT alone . It is unknown whether SNCA accumulates in tissues other than the kidney in
[76]
Fabry disease and whether this is a maladaptive or adaptive response . Doubt has been raised as to the role
[77]
of SNCA in Fabry nephropathy based on the lack of renal damage in Parkinson’s disease, a condition with
[77]
SNCA overexpression, and evidence of an SNCA protective effect in renal tubular disease . Adjunctive
treatments targeting these secondary processes in Fabry nephropathy need to be developed in the future to
accompany ERT and chaperone therapy.