February 2023 Case

Elderly male presents with chronic kidney disease, bilateral renal cysts, urinary retention due to an enlarged prostate, and echogenic kidneys.  In Fall of 2022, he had negative UPEP and serologic studies, a serum creatinine of 1.27 mg/dL following hydration, a UPC of 1.0 and no hematuria.   

Podocyte myelin figure-like inclusions, consistent with Fabry disease.

Fabry disease is X-linked, caused by pathogenic variants in the alpha-galactosidase A (alpha-Gal A; galactosidase alpha [GLA]) gene (Xq22.1), which encodes lysosomal hydrolase alpha-galactosidase A (alpha-Gal A). This enzyme primarily catalyzes the hydrolytic cleavage of the terminal galactose from alpha D-galactosyl moieties of glycolipids such as globotriaosylceramide (Gb3)¹. Deficiency of Alpha-Gal A results in lysosomal accumulation of Gb3 in a wide variety of cells, such as autonomic ganglia, dorsal root ganglia, renal glomerular (primarily podocytes), renal tubular and interstitial cells, cardiac muscle cells, and vascular smooth muscle cells ^2,3.  Fabry disease is the most prevalent lysosomal storage disorder of the glycosphingolipid metabolic pathway and has been associated with over a thousand mutations in the GLA gene ⁴.  

The hydrophilic deacylated derivative globotriaosylsphingosine (lysoGb3) is cytotoxic, proinflammatory, and profibrotic, which leads to disease manifestations such as severe neuropathic or limb pain (acroparesthesias), telangiectasias and angiokeratomas, gastrointestinal symptoms, kidney dysfunction, cardiovascular disease (such as left ventricular hypertrophy,  aortic and mitral regurgitation, conduction defects and coronary artery disease), and corneal opacities (cornea verticillata)^5,6. The clinical manifestations vary, ranging from the severe classic phenotype in males to asymptomatic disease in some females. Female heterozygotes have a variable disease presentation that ranges from an asymptomatic to severe phenotype resembling that seen in males. This phenotypic variation may be partly due to skewed (nonrandom) X-chromosome inactivation⁷. Males with classic Fabry disease are hemizygous and have little or no functional alpha-Gal A enzyme activity (<1 percent of the normal mean) with virtually all podocytes showing myelin figures. Our patient is male and presented with increased creatinine and non-nephrotic range proteinuria, without the classic clinical presentation of Fabry disease. The renal biopsy findings are unusual with only segmental podocyte inclusions, suggesting a mosaic form of Fabry disease may be present ⁸. Genetic testing for Fabry disease was recommended and it is pending.

Kidney dysfunction such as proteinuria, isosthenuria, polyuria, and polydipsia are common in patients with Fabry disease. A significant number of patients develop chronic kidney disease (CKD) and eventually end-stage kidney disease (ESKD). Some patients may present with disease limited to the kidney (renal variant), and Fabry disease may be underdiagnosed among patients with ESKD⁹. Kidney biopsy is helpful in establishing the diagnosis of Fabry disease. It is not uncommon that the diagnosis of Fabry disease is made incidentally when a kidney biopsy is obtained to evaluate the cause of proteinuria and/or kidney insufficient in patients with no known family history or no clinical presentation of Fabry disease at the time of biopsy, such as in our patient.

Kidney biopsy pathologic findings by light microscopy (LM) and electron microscopy (EM) are quite characteristic in Fabry disease. LM shows visceral glomerular epithelial cells (podocytes) and distal tubular epithelial cells with expanded cytoplasm and a marked foamy appearance (vacuolization), most prominent on the trichrome stain and seem as blue inclusions on toluidine blue stained plastic embedded LM of the EM specimen¹⁰. EM reveals podocytes that have prominent and expanded cytoplasm that contains numerous rounded electron-dense lipid inclusions (myelin figures, aka zebra bodies). Myelin figures or zebra bodies represent deposits of Gb3 primarily within enlarged secondary lysosomes as lamellated membrane structures¹¹. These inclusions, composed of concentric layers with a periodicity of 3.5 to 5 nm and often an onion skin appearance, are considered a hallmark of glycolipid storage disorders¹². These lipid inclusions may be seen in all glomerular cell types (most prominently podocytes), arteriolar smooth muscle cells, and tubular cells (mostly distal tubules) ¹¹. Podocyte foot process effacement may range from focal to diffuse. Immunofluorescence staining does not typically contribute to the diagnosis but may be useful in excluding other coindicident kidney disorders.

The ultrastructural findings of Fabry disease on kidney biopsy are highly characteristic and diagnostic. However, similar inclusions have been described in drug/medication-induced phospholipidosis secondary to quinine containing medications (chloroquine, hydroxychloroquine, anti-malarial agents), amiodarone, mercuric chloride, cisplatin, silicon, cadmium, and possibly other medications ¹³.  The location of the inclusions is sometimes helpful in making the distinction between these diseases. Lamellar inclusions associated with gentamicin occur in proximal tubules, whereas in Fabry disease, the inclusions are most striking in podocytes and distal tubules ¹⁴.

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