Page 100 - Read Online

Page 12 of 34 West et al. Rare Dis Orphan Drugs J 2024;3:22 https://dx.doi.org/10.20517/rdodj.2023.61

PATHOLOGY OF FABRY NEPHROPATHY
The pathology in Fabry disease has been described in detail by several authors. The changes are pan renal in
nature, involving glomeruli, the tubulointerstitial compartment, and blood vessels of all sizes. These changes
occur in early childhood in both sexes with Gb3 deposits identified as lamellar bodies in all renal cell
types [24,69,78-80] .

Macroscopic features
The glomeruli may appear pale and bulging due to lipid accumulation. In cores obtained on renal biopsy,
[81]
the glomeruli may appear bloodless and pale instead of the normal pink due to excess lipids . Parapelvic
[22]
cysts are frequently described and the prevalence of these can be over 45% as patients age .
Light microscopic features
Glomerular podocyte cytoplasm may appear pale and vacuolated due to lipid deposits dissolving during
processing [Figure 3]. The lipid deposits are seen as blue granules on electron microscopy thin sections
stained with toluidine blue [Figure 4]. Glomeruli often show focal segmental sclerosis progressing to global
sclerosis. Other concurrent glomerular diseases may be present. Distal tubular epithelial cells may also
appear pale and vacuolated. Interstitial foam cells may be seen. The proximal tubular epithelial cells appear
to be minimally involved. Vessels may show nodules of hyalinization. Endothelial cells may show large
glycolipid deposits, which can enlarge the cells with encroachment on the lumen of capillaries; this has been
hypothesized to contribute to downstream ischemia in the kidney, skeletal muscle, and myocardium.
Whether renal ischemia occurs is unknown. Vascular sclerosis is common with thickening of the intima
and media in small arterioles and large arteries. As the disease progresses, non-specific chronic changes may
be present, such as global sclerosis, interstitial fibrosis, tubular atrophy, interstitial lymphocytic infiltration,
and arteriosclerosis.

Immunofluorescence features
Non-specific positivity for IgM and C3 may be present in segmental scars, but there are no immune
[82]
complex deposits. The lipid deposits exhibit a yellow fluorescence under UV light .

Electron microscopic features
Electron-dense laminated lipid deposits, known as zebra bodies, myeloid bodies, or lamellar bodies, are
present most prominently in the podocytes [Figure 5], but may also be seen in almost any cell in the kidney,
including mesangial cells, the parietal layer of Bowman’s capsule, tubular epithelial cells, interstitial
fibroblasts, endothelial cells, and vascular media. These lamellar bodies are enlarged lysosomes 1-3 μm in
diameter with accumulated Gb3 and other glycolipids that are in concentric alternating layers of light and
dark with a periodicity of 35-50 Å . Such deposits can be identified before birth and increase in size and
[24]
[83]
number with age .
While lamellar bodies are a distinctive feature of Fabry nephropathy, they are not diagnostic by themselves.
They are reported in a number of other acquired or hereditary renal conditions including radiocontrast
injury and other lysosomal diseases, e.g., Neimann-Pick disease, among others [Table 3].

In a single-center retrospective analysis of 4,400 renal biopsies over 11 years, there were 32 cases (0.73%)
with lamellar bodies, only 6 of which were ultimately shown to be Fabry nephropathy while the majority
was a mixture of possible DIP and other renal pathology . While the pathology of DIP is very similar to
[50]
that of Fabry nephropathy, there may be fewer podocytes involved with fewer lamellar bodies and no
involvement of other renal cell types compared with Fabry nephropathy .
[50]