Sustained, Long-Term Renal Stabilization After 54 Months of Agalsidase beta Therapy in Patients with Fabry Disease

Department of Medicine, University of Rochester, Rochester, New York, United States
Journal of the American Society of Nephrology (Impact Factor: 9.34). 06/2007; 18(5):1547-57. DOI: 10.1681/ASN.2006080816
Source: PubMed


Fabry disease, an inherited deficiency of the lysosomal enzyme alpha-galactosidase A, causes progressive intralysosomal accumulation of globotriaosylceramide (GL-3) and premature death from renal, cardiac, and cerebrovascular manifestations. To determine the long-term safety and efficacy of recombinant human alpha-galactosidase A, an open-label, phase III extension study was conducted, involving 58 patients who had classic Fabry disease and completed a 20-wk, double-blind, randomized, placebo-controlled, phase III study of agalsidase beta and were transitioned to an extension trial to receive biweekly 1 mg/kg agalsidase beta for up to an additional 54 mo. GL-3 accumulation was evaluated in the capillary endothelia of the skin, kidney, and heart. Renal function was assessed. By month 54, all patients with optional kidney biopsies (n = 8) maintained complete GL-3 clearance in renal capillary endothelial cells and multiple cell types. Continued, complete clearance of skin (31 of 36) and heart (six of eight) capillary endothelium was demonstrated. Mean plasma GL-3 levels remained decreased in the normal range. Median serum creatinine and estimated GFR remained stable (normal) in patients with renal data at month 54 (n = 41). Six patients had renal disease progression; most (four of six) were older than 40 yr and had significant proteinuria at baseline and evidence of sclerotic glomeruli pretreatment. Adverse events were generally mild and unrelated to treatment. The most common treatment-related adverse events were infusion-associated reactions, which decreased over time. Long-term agalsidase beta therapy stabilizes renal function in patients without renal involvement at baseline, maintains reduction of plasma GL-3, and sustains GL-3 clearance in capillary endothelial cells and multiple renal cell types.

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    • "The reasons for stopping ERT changed from terminal illness or death in the first years to disease progression with irreversible organ damage in more recent years. Despite high expectations and the first positive results from the pivotal studies on the effect of ERT in FD [19] [20], subsequent studies have shown that ERT may not benefit all FD patients, in particular not those with severe disease demonstrated by irreversible organ involvement such as severe proteinuria, a high number of sclerotic glomeruli, severely decreased GFR or cardiac fibrosis [5] [6] [7] [8] [9]. Studies demonstrating limited effectiveness of ERT in patients with irreversible organ damage resulted in the EU consensus recommendation that in case of end stage renal disease (without an option for renal transplant) in combination with advanced heart failure cessation of ERT may be considered [12]. "
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    ABSTRACT: Fabry disease (FD) is a progressive, multi-organ, lysosomal storage disease. Enzyme replacement therapy (ERT) is available for the treatment of the disease. While the reasons to initiate ERT have been frequently discussed, discontinuation of ERT is rarely reported. In this paper we describe our experiences with stopping ERT in FD. From 1999 through 2015, twenty-one patients discontinued ERT. These patients were generally older and more severely affected in comparison those who continued ERT. The reason to discontinue ERT switched from death or terminal illness in the first years towards treatment failure in more recent years. Three cases are described in more detail. We conclude that discontinuation of ERT should or may be considered in subgroups of FD patients although further studies on the effectiveness of ERT in subgroups of patients and the course of the disease after discontinuation of ERT are needed.
    No preview · Article · Dec 2015 · Molecular Genetics and Metabolism
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    • "In patients with minimal proteinuria and normal renal function, biopsy can also determine if there is significant Gb3 deposition (especially in podocytes and endothelial cells), or early damage to indicate ERT use. In the classical male patient with signs of renal involvement a renal biopsy can be helpful in providing evidence of prognosis depending on the degree of glomerular sclerosis [41]. In females with even the slightest evidence of Fabry nephropathy, renal biopsy is considered much more important (and by some mandatory) as the presence of significant renal Gb3 deposits is an indication for initiating ERT. "
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    ABSTRACT: Fabry disease is a rare, X-linked, lysosomal storage disease caused by mutations in the gene encoding the enzyme alpha-galactosidase A. Complete or partial deficiency in this enzyme leads to intracellular accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids in many cell types throughout the body, including the kidney. Progressive accumulation of Gb3 in podocytes, epithelial cells and the tubular cells of the distal tubule and loop of Henle contribute to the renal symptoms of Fabry disease, which manifest as proteinuria and reduced glomerular filtration rate leading to chronic kidney disease and progression to end-stage renal disease. Early diagnosis and timely initiation of treatment of Fabry renal disease is an important facet of disease management. Initiating treatment with enzyme replacement therapy (ERT; agalsidase alfa, Replagal(R), Shire; agalsidase beta, Fabrazyme(R), Genzyme) as part of a comprehensive strategy to prevent complications of the disease, may be beneficial in stabilizing renal function or slowing its decline. Early initiation of ERT may also be more effective than initiating therapy in patients with more advanced disease. Several strategies are required to complement the use of ERT and treat the myriad of associated symptoms and organ involvements. In particular, patients with renal Fabry disease are at risk of cardiovascular events, such as high blood pressure, cardiac arrhythmias and stroke. This review discusses the management of renal involvement in Fabry disease, including diagnosis, treatments, and follow-up, and explores recent advances in the use of biomarkers to assist with diagnosis, monitoring disease progression and response to treatment.
    Full-text · Article · May 2014 · BMC Nephrology
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    • "Of the 1501 identified articles, 76 articles were considered relevant and were studied in more detail. Of these, 27 were excluded because data were presented for males and females combined (Shah et al 2005a; Kampmann et al 2008b; Niemann et al 2010; Germain et al 2007; Tahir et al 2007; Beck et al 2004; Imbriaco et al 2009; Weidemann et al 2009; Koskenvuo et al 2008; Pisani et al 2005; Weidemann et al 2003; Beer et al 2006; Kalliokoski et al 2006; Spinelli et al 2004; Kovacevic-Preradovic et al 2008; Wilcox et al 2004; Banikazemi et al 2007; Messalli et al 2012; Collin et al 2012; Reisin et al 2011; Ramaswami et al 2007; Schiffmann et al 2010; Wraith et al 2008; Shah et al 2005b; Tondel et al 2013; Engelen et al 2012; Wuest et al 2011). Eleven studies were excluded because the data were used in extension studies (including registry studies) or pooled analyses(Schiffmann et al 2001; Eng et al 2001; Schwarting et al 2006; Feriozzi et al 2009; Schiffmann et al 2006; Baehner et al 2003; Eng "
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    ABSTRACT: Current available evidence on long-term effectiveness of enzyme replacement therapy (ERT) for Fabry disease is limited. More insight is needed whether ERT effectiveness differs in patients with and without baseline end-organ damage. Through a systematic review, untreated and ERT treated males and females with Fabry disease were compared for main clinical outcomes: renal function, left ventricular mass (LVmass), cerebral white matter lesions (WMLs) and end-organ complications. Through a meta-analysis ERT effectiveness was estimated in different disease stages. Two reviewers assessed quality of the included studies according to guidelines for prognosis research. Data were synthesized using a random effects meta-analysis. Thirty-one studies were systematically reviewed while six studies were included in the meta-analysis. In patients with a GFR > 60 ml/min/1.73 m(2), decline of renal function was similar for treated and untreated patients. Only ERT treated males with a GFR < 60 ml/min/1.73 m(2) had a slower rate of decline in renal function, possibly attributable to anti-proteinuric therapy. Regardless of left ventricular hypertrophy (LVH) at baseline, LVmass remained stable or increased in males despite ERT, however at a slower rate compared to untreated male patients. In ERT treated females with LVH LVmass decreased, and remained stable in females without LVH. WMLs can not be prevented by ERT. Stroke, cardiac and end-stage renal complications develop, though the incidence of new complications seems to be reduced during ERT. ERT is effective in reducing LVH, but has a limited effect on renal function. Improved treatment options are needed for Fabry disease.
    Full-text · Article · Feb 2014 · Journal of Inherited Metabolic Disease
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