Fig.1 
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This 49 year old woman presented with increasing proteinuria over the course of 8 months. Her previous medical history included right nephrectomy (1968) for recurrent pyelonephritis, appendectomy, tonsillectomy, C-sections x 2, hysterectomy. She was treated for hypertension since 1991.
Proteinuria was first detected in January 1995; it increased to 2.1 g/day in June 1995, and to 3.4 g/day in October 1995. The creatinine was within normal range, between 70 and 80 µmol/L. She was otherwise asymptomatic. Physical examination was unremarkable except for obesity. Laboratory values revealed a weakly positive ANA (1:40, speckled pattern), normal complement levels (C3, C4), negative serology for hepatitis B and C, and normal serum electrophoresis. Her serum was noted to be lipemic.
There was a positive family history for early cardiac ischemic disease. Her paternal uncle died of a myocardial infarct at 31 year-old. Her father has suffered from a myocardial infarct at 38 year-old, but was still living. Her mother had had five miscarriages.
A renal biopsy was arranged, to determine the diagnosis and prognosis, and to decide on treatment, if any.
Two cores of renal cortex containing up to 8 glomeruli are obtained. Two glomeruli are globally sclerosed and segmental sclerotic lesions are seen in another two glomeruli [FIG. 1 - HPS stain], and are associated with capsular adhesions. The non-sclerosed glomeruli are within normal limits. Under close inspection, a few glomerular visceral cells appear hypertrophied and have a finely vacuolated cytoplasm [FIG 2. - HPS stain]. Mild interstitial fibrosis is present. Arteries are within normal limits and there is no vacuolation of arterial smooth muscle cells.
To access light micrographs, use Figure 1.
Fig.1 Fig. 2
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Except for mild (1+) glomerular mesangial staining for IgM, there is no glomerular, interstitial or vascular staining for IgG, IgA, C3, C4, kappa, lambda and fibrinogen.
Semi-thin sections stained with methylene blue reveal the presence of dark inclusions in the cytoplasm of some but not all glomerular visceral epithelial cells [FIG. 3]. Ultrastructurally, the inclusions are electron-dense (osmiophilic) [FIG. 4], and appear as concentric lamellar inclusions (myeloid figures and "zebra" bodies) at higher magnification [FIG. 5]. There are no electron-dense immune-type deposits. Foot processes of podocytes are segmentally effaced. Small myeloid inclusions are present in rare glomerular mesangial cells and in a few smooth muscle cells of arterial walls.
To access electron micrographs, use Figure 4.
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A renal biopsy and particularly electron microscopy have been instrumental in establishing the diagnosis in this patient. The superimposed focal and segmental sclerosing lesions might be part and parcel of Fabry's disease, or could be secondary to the fact that the patient has a single kidney. Fabry's disease is a relatively rare (incidence: 1:40,000) X-linked hereditary disorder. There was no known family history in this female patient; the diagnosis was unsuspected clinically.
The cytoplasmic myeloid inclusions in podocytes, seen in electron photomicrographs, although characteristic, are not pathognomonic of Fabry's disease [1]. On a purely morphological basis, similar inclusions might be seen in "silicon nephropathy" [2]. Similar inclusions might occur with the administration of drugs (aminoglycoside antibiotics and chloroquine) but tend to occur preferentially in the cytoplasm of proximal tubular epithelial cells. These inclusions are not reported in patients with hyperlipidemia [3].
The clinical manifestations of Fabry's disease tend to be more limited and variable in female patients. That phenomenon explains the fact that inclusions were limited in number in the patient discussed in this case [4,5]. A definitive diagnosis is made on the basis of a biochemical assay for blood leucocyte alpha-galactosidase A or urinary levels of ceramide digalactosidase or trihexoside.
It is important to note that the glycolipid inclusions are almost entirely extracted by xylene during processing for light microscopy [6], leaving "empty" vacuoles in the cytoplasm of glomerular visceral epithelial cells. However, frozen tissue submitted for immunofluorescence or glutaraldehyde-fixed tissue processed for electron microscopy retain the inclusions and can be stained with PAS reaction. In this manner, the cytoplasmic inclusions in glomerular visceral epithelial cells are beautifully demonstrated [FIG. 6]. Under polarized light, these inclusions are birefractile and have a Maltese-cross pattern [FIG. 7].
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Fig. 7
J.C. Jennette - June 1995 Renal Biopsy Case Review at:
<htpp://ns.gamewoood.net/pathcase/nephpath.html>
