Renal outcomes of agalsidase beta treatment for Fabry disease: role of proteinuria and timing of treatment initiation

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Abstract

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/1.73m ²/year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of –6.7 mL/min/1.73m ²/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/1.73m ²/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.

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Most cited references 17

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Agalsidase-beta therapy for advanced Fabry disease: a randomized trial.

Stephen Waldek, Robert J Desnick, Marie McDonald … (2007)

Fabry disease (alpha-galactosidase A deficiency) is a rare, X-linked lysosomal storage disorder that can cause early death from renal, cardiac, and cerebrovascular involvement. To see whether agalsidase beta delays the onset of a composite clinical outcome of renal, cardiovascular, and cerebrovascular events and death in patients with advanced Fabry disease. Randomized (2:1 treatment-to-placebo randomization), double-blind, placebo-controlled trial. 41 referral centers in 9 countries. 82 adults with mild to moderate kidney disease; 74 of whom were protocol-adherent. Intravenous infusion of agalsidase beta (1 mg per kg of body weight) or placebo every 2 weeks for up to 35 months (median, 18.5 months). The primary end point was the time to first clinical event (renal, cardiac, or cerebrovascular event or death). Six patients withdrew before reaching an end point: 3 to receive commercial therapy and 3 due to positive or inconclusive serum IgE or skin test results. Three patients assigned to agalsidase beta elected to transition to open-label treatment before reaching an end point. Thirteen (42%) of the 31 patients in the placebo group and 14 (27%) of the 51 patients in the agalsidase-beta group experienced clinical events. Primary intention-to-treat analysis that adjusted for an imbalance in baseline proteinuria showed that, compared with placebo, agalsidase beta delayed the time to first clinical event (hazard ratio, 0.47 [95% CI, 0.21 to 1.03]; P = 0.06). Secondary analyses of protocol-adherent patients showed similar results (hazard ratio, 0.39 [CI, 0.16 to 0.93]; P = 0.034). Ancillary subgroup analyses found larger treatment effects in patients with baseline estimated glomerular filtration rates greater than 55 mL/min per 1.73 m2 (hazard ratio, 0.19 [CI, 0.05 to 0.82]; P = 0.025) compared with 55 mL/min per 1.73 m2 or less (hazard ratio, 0.85 [CI, 0.32 to 2.3]; P = 0.75) (formal test for interaction, P = 0.09). Most treatment-related adverse events were mild or moderate infusion-associated reactions, reported by 55% of patients in the agalsidase-beta group and 23% of patients in the placebo group. The study sample was small. Only one third of the patients experienced clinical events, and some patients withdrew before experiencing any event. Agalsidase-beta therapy slowed progression to the composite clinical outcome of renal, cardiac, and cerebrovascular complications and death compared with placebo in patients with advanced Fabry disease. Therapeutic intervention before irreversible organ damage may provide greater clinical benefit.

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Stroke in Fabry disease frequently occurs before diagnosis and in the absence of other clinical events: natural history data from the Fabry Registry.

Katherine Sims, Juan Politei, Maryam Banikazemi … (2009)

Stroke is a common and serious clinical manifestation of Fabry disease, an X-linked lysosomal storage disorder caused by deficiency of alpha-galactosidase A activity. This study was undertaken to better understand the natural history of cerebrovascular manifestations of Fabry disease. Data from 2446 patients in the Fabry Registry were analyzed to identify clinical characteristics of patients experiencing stroke during the natural history period (ie, before enzyme replacement therapy). A total of 138 patients (86 of 1243 males [6.9%] and 52 of 1203 females [4.3%]) experienced strokes. Median age at first stroke was 39.0 years in males and 45.7 years in females. Most patients (70.9% of males and 76.9% of females) had not experienced renal or cardiac events before their first stroke. Fifty percent of males and 38.3% of females experienced their first stroke before being diagnosed with Fabry disease. Thirty patients (21 males and 9 females) had strokes at age <30 years. Most patients (86.8%) had ischemic strokes, but 16.9% of males and 6.9% of females had hemorrhagic strokes, among those for whom stroke type was reported. At the most recently available follow-up examination after their first stroke, 60% of males and 25.5% of females exhibited stage 3 to 5 chronic kidney disease and 66.1% of males and 59.5% of females had left ventricular hypertrophy. All patients with Fabry disease, regardless of age or gender, should be monitored for possible cerebrovascular complications, as stroke can occur in the absence of other key signs of the disease.

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Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy.

B L Thurberg, Michael J O’Callaghan, Steven Dikman … (2002)

Fabry disease, a lysosomal storage disease caused by deficient lysosomal alpha-galactosidase A activity, is characterized by globotriaosylceramide (GL-3) accumulation in multiple cell types, particularly the vasculature, leading to end organ failure. Accumulation in the kidney is responsible for progressive decline in renal function in male patients with the classical phenotype, resulting in renal failure in their third to fifth decades of life. With the advent of recombinant protein synthesis technology, enzyme replacement therapy has become a viable alternative to dialysis or renal transplantation, previously the only available treatment options for end-stage renal disease. The pre- and post-treatment renal biopsies were analyzed from fifty-eight Fabry patients enrolled in a Phase 3 double-blind, randomized, placebo-controlled trial followed by a six-month open label extension study of the recombinant human enzyme, alpha-galactosidase A (r-halphaGalA), administered IV at 1 mg/kg biweekly. The purpose of this investigation was to detail the pathologic changes in glycosphingolipid distribution and the pattern of post-treatment clearance in the kidney. Baseline evaluations revealed GL-3 accumulations in nearly all renal cell types including vascular endothelial cells, vascular smooth muscle cells, mesangial cells and interstitial cells, with particularly dense accumulations in podocytes and distal tubular epithelial cells. After 11 months of r-halphaGalA treatment there was complete clearance of glycolipid from the endothelium of all vasculature as well as from the mesangial cells of the glomerulus and interstitial cells of the cortex. Moderate clearance was noted from the smooth muscle cells of arterioles and small arteries. Podocytes and distal tubular epithelium also demonstrated evidence for decreased GL-3, although this clearance was more limited than that observed in other cell types. No evidence of immune complex disease was found by immunofluorescence despite circulating anti-r-halphaGalA IgG antibodies. These findings indicate a striking reversal of renal glycosphingolipid accumulation in the vasculature and in other renal cell types, and suggest that long-term treatment with r-halphaGalA may halt the progression of pathology and prevent renal failure in patients with Fabry disease.

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Author and article information

Journal

Journal ID (nlm-ta): Nephrol Dial Transplant

Journal ID (iso-abbrev): Nephrol. Dial. Transplant

Journal ID (hwp): ndt

Journal ID (publisher-id): ndt

Title: Nephrology Dialysis Transplantation

Publisher: Oxford University Press

ISSN (Print): 0931-0509

ISSN (Electronic): 1460-2385

Publication date (Print): March 2012

Publication date (Electronic): 29 July 2011

Publication date PMC-release: 29 July 2011

Volume: 27

Issue: 3

Pages: 1042-1049

Affiliations

[1 ]University of Alabama at Birmingham, Birmingham, AL, USA

[2 ]IIS-Fundación Jiménez Díaz and Universidad Autonoma de Madrid, Madrid, Spain

[3 ]University of Minnesota, Minneapolis, MN, USA

[4 ]Academic Medical Center, Amsterdam, Netherlands

[5 ]Hospital São João, Faculty of Medicine, Porto, Portugal

[6 ]University of Zurich, Zurich, Switzerland

[7 ]University of Debrecen Medical and Health Science Center, Debrecen, Hungary

[8 ]Department of Nephrology and Dialysis, Infermi Hospital, Rimini, Italy

[9 ]General Hospital Slovenj Gradec, Slovenj Gradec, Slovenia

[10 ]Genzyme Corporation, Cambridge, MA, USA

[11 ]Department of Medicine, Haukeland University Hospital, and Institute of Medicine, University of Bergen, Bergen, Norway

[12 ]Salford Royal NHS Foundation Trust, Manchester, UK

[13 ]Hôpital Raymond Poincaré (AP-HP), University of Versailles, Garches, France

[14 ]University of Würzburg, Würzburg, Germany

Author notes

Correspondence and offprint requests to: David G. Warnock; E-mail: dwarnock@ 123456uab.edu

Article

DOI: 10.1093/ndt/gfr420

PMC ID: 3289896

PubMed ID: 21804088

SO-VID: 3738b613-75d9-456b-8ece-b534a5d544e4

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date received : 14 March 2011

Date accepted : 20 June 2011

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Pages: 8

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Renal outcomes of agalsidase beta treatment for Fabry disease: role of proteinuria and timing of treatment initiation

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Abstract

Background.

Methods.

Results.

Conclusions.

Related collections

Karger: Nephrology

Most cited references 17

Agalsidase-beta therapy for advanced Fabry disease: a randomized trial.

Stroke in Fabry disease frequently occurs before diagnosis and in the absence of other clinical events: natural history data from the Fabry Registry.

Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy.

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