TY  - JOUR
A1  - Warnock, David G.
A1  - Ortiz, Alberto
A1  - Mauer, Michael
A1  - Linthorst, Gabor E.
A1  - Oliveira, João P.
A1  - Serra, Andreas L.
A1  - Maródi, László
A1  - Mignani, Renzo
A1  - Vujkovac, Bojan
A1  - Beitner-Johnson, Dana
A1  - Lemay, Roberta
A1  - Cole, J. Alexander
A1  - Svarstad, Einar
A1  - Waldek, Stephen
A1  - Germain, Dominique P.
A1  - Wanner, Christoph
T1  - Renal outcomes of agalsidase beta treatment for Fabry disease: role of proteinuria and timing of treatment initiation
JF  - Nephrology Dialysis Transplantation
N2  - Background. The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with agalsidase beta.

Methods. Renal function was evaluated in 151 men and 62 women from the Fabry Registry who received agalsidase beta at an average dose of 1 mg/kg/2 weeks for at least 2 years. Patients were categorized into quartiles based on slopes of estimated glomerular filtration rate (eGFR) during treatment. Multivariate logistic regression analyses were used to identify factors associated with renal disease progression.

Results. Men within the first quartile had a mean eGFR slope of –0.1 mL/min/1.73m2/year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of –6.7 mL/min/1.73m2/year. The risk factor most strongly associated with renal disease progression was averaged urinary protein:creatinine ratio (UP/Cr) ≥1 g/g (odds ratio 112, 95% confidence interval (95% CI) 4–3109, P = 0.0054). Longer time from symptom onset to treatment was also associated with renal disease progression (odds ratio 19, 95% CI 2–184, P = 0.0098). Women in Quartile 4 had the highest averaged UP/Cr (mean 1.8 g/g) and the most rapid renal disease progression: (mean slope –4.4 mL/min/1.73m2/year).

Conclusions. Adults with Fabry disease are at risk for progressive loss of eGFR despite enzyme replacement therapy, particularly if proteinuria is ≥1 g/g. Men with little urinary protein excretion and those who began receiving agalsidase beta sooner after the onset of symptoms had stable renal function. These findings suggest that early intervention may lead to optimal renal outcomes.
KW  - proteinuria
KW  - enzyme replacement therapy
KW  - alpha galactosidase
KW  - Fabry disease
KW  - genetic renal disease
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124697
VL  - 27
IS  - 3
ER  - 
TY  - JOUR
A1  - Weidemann, Frank
A1  - Sanchez-Nino, Maria D.
A1  - Politei, Juan
A1  - Oliveira, João-Paulo
A1  - Wanner, Christoph
A1  - Warnock, David G.
A1  - Oritz, Alberto
T1  - Fibrosis: a key feature of Fabry disease with potential therapeutic implications
JF  - Orphanet Journal of Rare Diseases
N2  - Fabry disease is a rare X-linked hereditary disease caused by mutations in the AGAL gene encoding the lysosomal enzyme alpha-galactosidase A. Enzyme replacement therapy (ERT) is the current cornerstone of Fabry disease management. Involvement of kidney, heart and the central nervous system shortens life span, and fibrosis of these organs is a hallmark of the disease. Fibrosis was initially thought to result from tissue ischemia secondary to endothelial accumulation of glycosphingolipids in the microvasculature. However, despite ready clearance of endothelial deposits, ERT is less effective in patients who have already developed fibrosis. Several potential explanations of this clinical observation may impact on the future management of Fabry disease. Alternative molecular pathways linking glycosphingolipids and fibrosis may be operative; tissue injury may recruit secondary molecular mediators of fibrosis that are unresponsive to ERT, or fibrosis may represent irreversible tissue injury that limits the therapeutic response to ERT. We provide an overview of Fabry disease, with a focus on the assessment of fibrosis, the clinical consequences of fibrosis, and recent advances in understanding the cellular and molecular mechanisms of fibrosis that may suggest novel therapeutic approaches to Fabry disease.
KW  - Fabry
KW  - fibrosis
KW  - podocyte
KW  - Lyso-Gb3
KW  - kidney
KW  - enzyme replacement therapy
KW  - alpha-galactosidase-A
KW  - focal semental glomerulosclerosis
KW  - cardiovascular magnetic-resonance
KW  - left-ventricular hypertrophy
KW  - biopsy findings
KW  - agalsidase-beta
KW  - natural-history data
KW  - cardiac energy metabolism
KW  - randomized controlled trial
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124773
SN  - 1750-1172
VL  - 8
IS  - 116
ER  -