Early renal changes in hemizygous and heterozygous patients with Fabry's disease

Gubler, Marie–Claire; Lenoir, G.; Grünfeld, Jean‐Pierre; Ulmann, André; Droz, Dominique; Habib, R; Naizot, C; Adafer, E; Grandhomme, C.

doi:10.1038/ki.1978.32

Cited by 176 publications

(170 citation statements)

References 25 publications

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“…In particular, storage in the TALH had a mosaic character. Similar variability in storage has been described before (Gubler et al 1978). As in previous studies on UMOD expression in control kidney, we observed prominent expression of UMOD in the TALH and less so in the DCT in normal kidneys (Hoyer and Seiler 1979;Peach et al 1988;Schenk et al 1971;Sikri et al 1981).…”

Section: Discussionsupporting

confidence: 90%

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Abnormal expression and processing of uromodulin in Fabry disease reflects tubular cell storage alteration and is reversible by enzyme replacement therapy

Vyleťal

Hůlková

Živná

et al. 2008

J of Inher Metab Disea

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Summary Uromodulin (UMOD) malfunction has been found in a range of autosomal dominant tubulointerstitial nephropathies associated with hyperuricaemia, gouty arthritis, medullary cysts and renal failure—labelled as familial juvenile hyperuricaemic nephropathy, medullary cystic disease type 2 and glomerulocystic kidney disease. To gain knowledge of the spectrum of UMOD changes in various genetic diseases with renal involvement we examined urinary UMOD excretion and found significant quantitative and qualitative changes in 15 male patients at various clinical stages of Fabry disease. In untreated patients, the changes ranged from normal to a marked decrease, or even absence of urinary UMOD. This was accompanied frequently by the presence of aberrantly processed UMOD lacking the C‐terminal part following the K432 residue. The abnormal patterns normalized in all patients on enzyme replacement therapy and in some patients on substrate reduction therapy. Immunohistochemical analysis of the affected kidney revealed abnormal UMOD localization in the thick ascending limb of Henle's loop and the distal convoluted tubule, with UMOD expression inversely proportional to the degree of storage. Our observations warrant evaluation of tubular functions in Fabry disease and suggest UMOD as a potential biochemical marker of therapeutic response of the kidney to therapy. Extended comparative studies of UMOD expression in kidney specimens obtained during individual types of therapies are therefore of great interest.

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Section: Discussionsupporting

confidence: 90%

“…The distal tubule and the Henle loop are thus considered to be affected most prominently in Fabry disease (Okuda 2000). The storage pattern in heterozygotes did not differ substantially from that in hemizygous male patients (Farge et al 1985;Gubler et al 1978).…”

Section: Discussionmentioning

confidence: 93%

Abnormal expression and processing of uromodulin in Fabry disease reflects tubular cell storage alteration and is reversible by enzyme replacement therapy

Vyleťal

Hůlková

Živná

et al. 2008

J of Inher Metab Disea

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“…This is the first report of a patient with classic Fabry disease, with only acroparesthesia, who had normal urinalysis but manifested foot process effacement from podocyte injury. Previous studies reported several patients with detectable proteinuria and renal damage such as foot process effacement and glomerular sclerosis (Gubler et al 1978;Tondel et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Foot Process Effacement with Normal Urinalysis in Classic Fabry Disease

et al. 2011

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Fabry disease is an X-linked glycosphingolipidosis caused by deficient synthesis of the enzyme a-galactosidase A, which results in glycosphingolipidosis, predominantly globotriaosylceramide, progressively accumulating in systemic tissue. A dominant complication of Fabry disease is nephropathy. The average age for the development of clinical nephropathy is 27 years in male patients, with up to half of all patients developing endstage renal failure by their 50s. A recent study revealed podocytes play important roles in antiproteinuria. Podocyte injury leads to foot process effacement and proteinuria. The foot process effacement induces podocyte depletion from the glomerular wall, glomerulosclerosis, and results in end-stage renal failure. We report on a 13-year-old boy with classic Fabry disease, who developed foot process effacement and podocyte depletion even before proteinuria appeared. At the time, his only symptom of Fabry disease was acroparesthesia. He was administered Agalsidase b (1 mg/kg/dose div) every other week and 14 months after treatment, his renal function remained normal. This is the first report of a patient with classic Fabry disease, with only acroparesthesia, who had normal urinalysis but manifested foot process effacement and podocyte depletion. Podocytes are highly differentiated cells with a limited capacity for cell division and replacement. The large individual variation and often progressive nature of this disease raises concerns about the appropriate timing for initiating enzyme replacement therapy (ERT). Recent data have shown a limited effect of ERT on progressive organ damage. In our case, ERT was initiated before proteinuria appeared, with good outcome.

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“…Urinary Gb 3 has its origin mostly in kidney tubular cells of the kidney and urinary collecting system. These assumptions are based on the presence of Gb 3 in lysosomes of renal tubular cells shed in the urine and an 80% reduction in urinary Gb 3 after transplantation and nephrectomy (11)(12)(13). Dense accumulation of Gb 3 has been observed in podocytes from Fabry disease patients, which could be partially reversed by long-term enzyme replacement therapy (ERT).…”

Section: What Do We Know?mentioning

confidence: 99%

Biomarkers of Fabry Disease Nephropathy

Schiffmann¹,

Waldek²,

Benigni³

et al. 2010

Clinical Journal of the American Society of Nephrology

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It is suggested that biomarkers of renal complications of Fabry disease are likely to be useful for diagnosis and to follow the natural disease progression or the effect of specific therapeutic interventions. Traditionally, globotriaosylceramide (Gb 3 ) in urine has been used to evaluate the effect of specific therapy, such as enzyme replacement therapy (ERT). Although urinary Gb 3 decreases significantly with ERT, it has not yet been shown to be a valid surrogate marker in treatment trials. We propose a detailed study of the nature and origin of Gb 3 combined with a prospective collaborative trial that combines Gb 3 changes with the effect of ERT on clinical nephrological outcome measures. Existing biomarkers such as general proteinuria/ albuminuria or specific proteins such as N-acetyl-␤-D-glucosaminidase should be evaluated along with novel proteomic or metabolomic studies for biomarker discovery using mass spectrometry or nuclear magnetic resonance. Standard scoring of all pathologic aspects of kidney biopsies may also be a promising way to assess the effect of therapy.

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Early renal changes in hemizygous and heterozygous patients with Fabry's disease

Cited by 176 publications

References 25 publications

Abnormal expression and processing of uromodulin in Fabry disease reflects tubular cell storage alteration and is reversible by enzyme replacement therapy

Abnormal expression and processing of uromodulin in Fabry disease reflects tubular cell storage alteration and is reversible by enzyme replacement therapy

Foot Process Effacement with Normal Urinalysis in Classic Fabry Disease

Biomarkers of Fabry Disease Nephropathy

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