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Review
. 2025 Mar 21;13(4):767.
doi: 10.3390/biomedicines13040767.

The Role of Kidney Biopsy in Fabry Disease

Irene Capelli  1   2 , Laura Martano  2 , Gian Marco Berti  2 , Gisella Vischini  1 , Sarah Lerario  1 , Vincenzo Donadio  3   4 , Alex Incensi  3 , Valeria Aiello  1 , Francesca Ciurli  1   2 , Benedetta Fabbrizio  5 , Stefano Chilotti  5 , Renzo Mignani  1   2 , Gianandrea Pasquinelli  2   5 , Gaetano La Manna  1   2
Affiliations
Review

The Role of Kidney Biopsy in Fabry Disease

Irene Capelli et al. Biomedicines. .

Abstract

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to α-galactosidase A deficiency and subsequent accumulation of glycosphingolipids, including globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3), in multiple organs. This accumulation can result in multisystemic disease and life-threatening complications. FD presents with a broad phenotypic spectrum, ranging from the classic form, with early and severe symptoms, to a later-onset form with variable manifestations. The severity of the disease in females is more variable due to X-chromosome inactivation (XCI). Renal involvement is a key feature, and kidney biopsy remains a valuable tool for diagnosing FD and assessing the extent of nephropathy. Although molecular genetic testing is the gold standard for diagnosis, kidney biopsy aids in confirming renal involvement, detecting coexisting conditions, and determining the pathogenicity of variants of uncertain significance (VUSs). Moreover, kidney biopsy can serve as a prognostic tool by identifying early markers of nephropathy, such as foot process effacement and glomerular sclerosis, which predict disease progression. Emerging technologies, including machine learning, offer the potential to enhance the analysis of renal histology, improving diagnostic accuracy and patient stratification. Despite the challenges posed by overlapping diseases and potential misdiagnoses, kidney biopsy remains an essential component of FD diagnosis and management, facilitating early detection, the monitoring of disease progression, and the evaluation of therapeutic responses.

Keywords: Fabry nephropathy; biopsy; histopathology; inclusions; podocyte.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Algorithm of diagnosis of FD.
Figure 2
Figure 2
Light microscopy of the cortical renal parenchyma showing segmental vacuolated appearance of podocytes with wrinkling of the loops (indicated by arrow). (a) Hematoxylin and eosin (H&E ×20; scale bar 90 μm); (b) periodic acid-Schiff, (PAS ×20; scale bar 200 μm).
Figure 3
Figure 3
Electron microscopy, numerous myelin figures are observed within the podocyte cytoplasm in the glomerulus. The asterisk indicates an unaffected podocyte.
Figure 4
Figure 4
Toluidine blue stain. Abundant dense darkly stained round inclusions in podocytes of a glomerulus (indicated by arrow). (a) (400×); (b) (1000×).
Figure 5
Figure 5
Pathological mechanisms associated with lysosomal accumulation of Gb3 and Lyso-Gb3 in the kidney, highlighting the involvement of podocytes, vascular endothelium, and tubular cells. In podocytes, the accumulation leads to an increase in volume until their detachment, resulting in proteinuria and sclerosis, while endothelial dysfunction and cellular proliferation result in vasculopathy. Tubular cell damage and interstitial inflammation contribute to tubular atrophy and interstitial fibrosis.
Figure 6
Figure 6
Immunofluorescence staining of Gb3 deposits (red signal) in podocytes of renal cortical parenchyma identified by a collagen staining (green signal).
See this image and copyright information in PMC

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