CLINICAL HISTORY

A middle-aged male with hypertension under therapy and overweight was affected by chronic kidney disease stage IIIb (eGFR 35 mL/min/1.73 m², estimated by the CKD-EPI formula) and presented with proteinuria in the nephrotic range (4.4 g/24 h). 

BIOPSY DESCRIPTION 

The biopsy was limited as there were only five patent glomeruli, and ten glomerular scars (Figure 1).

While some glomeruli displayed normal morphology (Figure 2A), other glomeruli showed segmental sclerosis associating obliterated capillaries with increased extracellular matrix (Figure 2B). In addition, some glomeruli displayed capsular synechia, detected as a broad adhesion of a sclerotic glomerular capillary segment to Bowman’s capsule (Figure 2C). In several glomeruli, prominent podocytes were detectable. On the silver stain, no basement membrane remodelling was present. Arteries displayed a moderate concentric pauci-cellular intimal fibrosis, and arterioles showed severe wall hyalinosis. The interstitium presented a low to moderate grade of fibrosis with focal distribution (around 40% of the biopsy). In association with these fibrotic areas, tubular atrophy was detectable. Nonatrophic tubules seem well conformed otherwise.

At higher magnification, segmentally sclerotic and non-sclerotic glomeruli displayed a variable, discrete to frank vacuolization of podocyte cytoplasm (Figure 3 A-C, best seen on AFOG trichrome stain).

Indirect immunohistochemistry performed on protease digested paraffin sections with antibodies against IgG, IgM, IgA, C3, and C1q revealed moderate signals of IgM and C1q in sclerotic glomerular segments.

Electron microscopy material did not have any exploitable glomerular structure.

Figure 1: Lower magnification micrograph showing 3 glomeruli with segmental sclerosis (black arrowhead). In addition, there is moderate interstitial fibrosis and tubular atrophy. scale bar= 200mm PAS-staining.(B).

Figure 2: Higher magnification view of morphologically normal glomerulus (A); glomerulus with segmental sclerosis, capsular synechia, and parietal epithelial cell changes including hyperplasia (empty arrowhead), prominent nuclei (asterix), pseudotubular structures (oval) and even the rare event of a parietal epithelial cell mitosis (black arrow); and another glomerulus with segmental sclerosis in adjunction with hyalinosis. At closer inspection, one can appreciate the foamy aspect of vacuolized podocyteic cytoplasm (black arrowhead). Scale bar= 50mm PAS-staining. 

Figure 3: Higher magnification micrographs demonstrating podocyte cytoplasmic vacuoles. A. AFOG trichrome stain scale bar= 50mm). B. PAS stain scale bar= 10mm C. AFOG stain sscale bar= 10mm.

DIAGNOSIS:

At this stage of the exploration, the histological findings were highly suggestive of the renal involvement by a storage disorder (first on the list was Fabry disease) with secondary segmental sclerosis.

CLINICAL FOLLOW-UP

DISCUSSION

Fabry disease (FS) is an X-linked lysosomal storage disorder. GLA gene mutation leads to deficiency in alpha-galactosidase A enzymatic activity, resulting in organ damage from accumulation of glycosphingolipid, particularly  globotriaosylceramide [1].

GLA gene inactivation seems to lead to the production of secondary mediators promoting podocyte injury, triggering chronic progressive nephropathy, resulting in glomerulosclerosis and kidney failure [2]. 

The renal histopathology of FD highlights hypertrophic podocytes, parietal epithelial cells, and distal tubular epithelial cells with cytoplasmic vacuolization.  By electron microscopy, there are multilamellar inclusions of glycosphingolipids, described as myelin figures or zebra bodies [3].  We did not have EM in this particular case,  but provide illustration of such ultrastructural podocyte changes in Figure 4 from another case.

Bosquetti et al. demonstrated that treatment with chloroquine at sub-lethal doses (1.0 µg/mL) can induce the same alterations in podocytes, including lysosomal lipid accumulation, as those found in Fabry patients [4].

 Clinical presentation of FD can be classified as classic or non- classic (also known as late-onset). Classic FD is due to complete or near completely absent alpha-galactosidase A activity with childhood onset of neuropathic pain, cornea verticillata, gastrointestinal symptoms, hypohidrosis, angiokeratoma, proteinuric chronic kidney disease leading to renal failure, hypertrophic cardiomyopathy, cardiac arrhythmia, hypoacusis, and stroke. The non-classic phenotype is seen in males with >1% alpha-galactosidase A activity and results in later adult onset of cardiac and renal disease, without skin or cerebrovascular disease.  Enzyme replacement therapy with or without chaperone therapy can prevent and/or delay the progression of FD organ injury. 

Figure 4: Typical EM appearance of podocytes in FD. - 45A Scale bar=50mm, 45B Scale bar=2mm. The figures show global podocytic changes with numerous intracytoplasmic, lamellated structures with concentric pattern of the lysosomal inclusions at higher magnifications (zebra/myeloid bodies – black arrowhead) and effacement of foot processes.

References:

1. Besekar SM, Jogdand SD, Naqvi WM. Fabry disease and its management: a literature analysis. Cureus. 2023;15(4):e37048. doi:10.7759/cureus.37048
2. Monte Neto JTD, Kirsztajn GM. The role of podocyte injury in the pathogenesis of Fabry disease nephropathy. J Bras Nefrol. 2024;46(3):e20240035. doi:10.1590/2175-8239-JBN-2024-0035en
3. Alroy J, Sabnis S, Kopp JB. Renal pathology in Fabry disease. J Am Soc Nephrol. 2002;13 Suppl 2:S134-S138. doi:10.1097/01.ASN.0000016684.07368.75
4. Bosquetti B, Santana AA, Gregório PC, Cunha RSD, Miniskiskosky G, Budag J, Franco CRC, Ramos EAS, Barreto FC, Stinghen AEM. The role of α3β1 integrin modulation on Fabry disease podocyte injury and kidney impairment. Toxins (Basel). 2023;15(12):700. doi:10.3390/toxins15120700
5. Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30. doi:10.1186/1750-1172-5-30