Case report
Fabry disease: renal involvement limited to podocyte pathology and proteinuria in a septuagenarian cardiac variant. Pathologic and therapeutic implications

https://doi.org/10.1053/j.ajkd.2003.09.022Get rights and content

Abstract

In men with classical Fabry disease (α-galactosidase A [α-Gal A] deficiency), kidney failure occurs as early as the second decade of life. In contrast, men with the mild “cardiac variant” have late-onset cardiac involvement and proteinuria but usually do not have renal failure. To investigate the nature of renal involvement in the cardiac variant of Fabry disease, the renal function and morphology were assessed in a 75-year-old affected man. He had mild congestive heart failure, a reduced left ventricular ejection fraction, and hypercholesterolemia but lacked the classical Fabry disease manifestations, including angiokeratoma, acroparesthesias, corneal and lenticular opacities, and hypohidrosis. At age 75 years, he had significant proteinuria, and mildly decreased renal function (serum creatinine, 1.8 mg/dL [159 μmol/L]), presumably secondary to hypertensive arteriosclerosis. He had about 4% residual α-Gal A activity in leukocytes, and mutation analysis identified the N215S missense mutation, the common lesion in cardiac variants. Histologic and ultrastructural studies of kidney tissue showed that lysosomal glycosphingolipid deposition was extensive in podocytes, rare in tubular epithelial cells, and absent in mesangial, interstitial, and vascular endothelial and smooth muscle cells. This cardiac variant serves as an “experiment of nature” showing that the residual α-Gal A activity precludes glycosphingolipid deposition in the renal endothelial and other cells that lead to early renal failure in classically affected men, whereas marked podocyte accumulation is associated with proteinuria and possibly late-onset renal dysfunction. These findings have important implications for the renal effectiveness of enzyme replacement therapy in classically affected patients and for the aggressive treatment of proteinuria in Fabry disease.

Section snippets

Case report

The proband was a 75-year-old man of German descent who had a history of hypertension, hypercholesterolemia, and a myocardial infarction. At age 65, he had a urinary protein level of 0.3 g/L. Five months before examination, he had dyspnea upon exertion. His ventricular ejection fraction had decreased markedly from low normal to 35% and remained at that level thereafter. His father died of cardiac failure at age 81 years, whereas his mother had heart failure and died at age 62 years.

At age 75,

Morphologic studies

The biopsy tissues were fixed in 10% buffered formaldehyde and paraffin embedded. Paraffin sections (2 to 4 μm) were stained with hematoxylin and eosin and periodic acid-Schiff (PAS) for light microscopy. Additional tissue was fixed in 2.5% glutaraldehyde in 0.1% Millonig's phosphate buffer. After washing, the tissues were further fixed in 1% osmium tetroxide, dehydrated, and epon embedded. Thin sections were stained on copper palladium grids with uranyl acetate and lead citrate. Stained

Renal morphology

By light microscopy, the biopsy tissues contained cortex and corticomedullary junction with a total of 7 glomeruli, all of which had enlarged podocytes with abundant foamy cytoplasm (Fig 1). The endothelium, mesangium, and glomerular basement membrane were unremarkable. There was focal, mild interstitial fibrosis, and tubular atrophy. Arterioles showed mild to moderate hyalinosis. The biopsy specimen had focal arteriolar smooth muscle vacuoles without eosinophilic inclusions of the classical

Discussion

In 1991, von Scheidt et al17 reported the clinical, morphologic, and biochemical features of the cardiac variant. They described a 54-year-old white male who had isolated myocardial involvement, but none of the classic manifestations of Fabry disease, including angiokeratoma, acroparesthesias, hypohidrosis, corneal and lenticular opacities, or renal insufficiency. An endocardial biopsy showed ultrastructural changes suggestive of Fabry disease, a diagnosis that was confirmed by the

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    Supported in part by grants from the National Institutes of Health, including a Merit Award (5 R37 DK34045), a grant (5 M01 RR00071) for the Mount Sinai General Clinical Research Center, and a grant (5 P30 HD28822) for the Mount Sinai Child Health Research Center.

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