Renal Pathology in Fabry Disease

Alroy, Joseph; Sabnis, Sharda G.; Kopp, Jeffrey B.

doi:10.1097/01.asn.0000016684.07368.75

Cited by 211 publications

(137 citation statements)

References 15 publications

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“…Ischaemic damage resulting from microvascular endothelial disease and/or necrosis of vascular smooth muscle cells and/or pericyte injury is the major theory for the pathogenesis of the classical phenotype of Fabry disease [4,8,10,32]. However, we found a largely comparable prevalence of GSL deposits in the vascular and endothelial cells in Fabry mice and patients.…”

Section: Discussionmentioning

confidence: 52%

“…However, the size of GSL deposits was smaller in Fabry mice than is typically seen in humans with Fabry nephropathy. Therefore, progressive increase of lysosomal GSL deposits in podocytes, ultimately causing irreversible cell injury [10,14], may be a critical mechanism in the pathogenesis of human Fabry nephropathy.…”

Section: Discussionmentioning

confidence: 99%

“…Glomerular filtration rate gradually declines and classically affected males progress to end-stage renal disease before their fifth decade [4][5][6][7]. A spectrum of histological lesions can be observed in the kidneys, even in cases with normal glomerular filtration rate and minimal proteinuria [8][9][10][11][12][13][14][15]. These lesions may include intracellular GSL deposits and nonspecific chronic glomerular, vascular, and tubulointerstitial fibro-sclerotic lesions.…”

Section: Introductionmentioning

confidence: 99%

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Kidney histologic alterations in α-Galactosidase-deficient mice

et al. 2011

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Fabry disease is a rare X-linked disorder caused by mutations in the α-galactosidase gene (GLA), the resultant deficiency of lysosomal α-galactosidase enzyme activity leading to systemic accumulation of globotriaosylceramide and other glycosphingolipids. GLA knockout mice ("Fabry mice") were generated as an animal model for Fabry disease but, as they do not manifest progressive chronic kidney disease (CKD), their relevance as a model for human Fabry nephropathy is uncertain. We evaluated the histological alterations in the kidneys of Fabry mice at different ages, as contrasted to those observed in wild-type mice. Furthermore, we compared the renal histological alterations of Fabry mice to the kidney pathology reported in patients with Fabry disease at comparable age ranges and across different CKD stages, using a scoring system that has been developed for Fabry nephropathy. Fabry mice are phenotypically different from wild-type mice, displaying progressive age-related accumulation of glycosphingolipids in all types of renal cells. There were no statistically significant differences between Fabry mice and Fabry patients in the prevalence of glycosphingolipid storage per renal cell type with the exceptions of mesangial (higher in humans) and proximal tubular cells (higher in mice). However, Fabry mice lack the nonspecific histological glomerulosclerotic and interstitial fibrotic renal lesions that best correlate with progressive CKD in Fabry patients, and do not develop large podocyte inclusions. We postulate that the elucidation of the mechanisms underlying these species differences, may contribute important clues to a better understanding of the pathogenesis of Fabry nephropathy.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Kidney histologic alterations in α-Galactosidase-deficient mice

et al. 2011

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“…Elektronenmikroskopisch hat das Gb3 die Form von Myelinstrukturen, die sich im Zytoplasma ablagern und an den Zellkern stoßen. Mit der Progression der Krankheit kommt es zu einer mesangialen Aufweitung und folglich zu segmentaler/globaler Glomerulosklerose mit einer Eindickung der Basalmembranen [9]. Mögliche Mechanismen dieser Entwicklung sind mikrovaskuläre Läsionen sowie Schä-digungen der Podozyten und der tubulären Epithelzellen.…”

Section: Histologische Veränderungenunclassified

“…Gubler et al konnten einen Zusammenhang zwischen Fabry-Nephropathie und ischämischen Läsionen im Zusammenhang mit einer Gb3-Akkumulation auf der Arterienwand zeigen [10]. Gemäß Alroy et al wirkt die intrazelluläre Gb3-Akkumulation toxisch auf die Podozyten, wahrscheinlich durch Verlust ihrer Differenzierung [9]. Außer-dem kann die Gb3-Ablagerung in den tubulären Epithelzellen zu Atrophie und interstitieller Fibrose führen.…”

Section: Histologische Veränderungenunclassified

Wirkung der Enzymersatztherapie (ERT) auf die Nierenfunktion von Patienten mit Morbus Fabry

et al. 2009

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Fabry's disease is an inherited lysosomal storage disorder characterized by the lack of enzyme alpha-galactosidase A (alpha-Gal A) which degrades globotriaosylceramides (Gb3) into products with lower molecular weight. The accumulation of Gb3 in different cell types is responsible for the variety of clinical manifestations. The renal function, estimated via proteinuria, hematuria and reduction of glomerular filtration rate (GRF), is heavily affected. Currently, substitution of alpha-Gal A remains the only therapeutic option for patients with Fabry's disease. Two products are approved for the treatment of Fabry's disease: agalsidase alfa and agalsidase beta. Both of these enzymes have shown a stabilization of renal function in various studies when evaluated by the creatinine clearance, estimated GFR, and serum creatinine. The pro gnosis has proven to be significantly better in cases of mild or moderate renal insufficiency from the baseline. For this reason, an early substitution of the lacking enzyme is necessary. Furthermore, enzyme replacement therapy (ERT) has proven efficient in reducing the amount of intracellular Gb3 and Gb3 in urine. Without treatment, an eGFR reduction of approximately 12 ml/min/year has been reported. After diverse studies of ERT, no significant correlation between enzyme substitution and improvement of patients' proteinuria could be shown. Furthermore, renoprotective drugs have not been consistently applied so far in the ERT trials. In any case, further studies to evaluate the long-term effect of ERT on the morbidity and mortality of patients with Fabry's disease are necessary.

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