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Clin J Am Soc Nephrol. 2017 Sep 7;12(9):1470-1479. doi: 10.2215/CJN.01820217. Epub 2017 Jun 16.

Long-Term Dose-Dependent Agalsidase Effects on Kidney Histology in Fabry Disease.

Author information

1
Departments of Medicine, rannvsk@online.no.
2
Department of Clinical Medicine, University of Bergen, Bergen, Norway; and.
3
Pediatrics.
4
Pathology, and.
5
Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
6
Heart Disease and.
7
Pediatrics and.
8
Departments of Endocrinology and Metabolism and.
9
Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands.
10
Departments of Medicine.

Abstract

BACKGROUND AND OBJECTIVES:

Dose-dependent clearing of podocyte globotriaosylceramide has previously been shown in patients with classic Fabry disease treated with enzyme replacement. Our study evaluates the dose-dependent effects of agalsidase therapy in serial kidney biopsies of patients treated for up to 14 years.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:

Twenty patients with classic Fabry disease (12 men) started enzyme replacement therapy at a median age of 21 (range =7-62) years old. Agalsidase-α or -β was prescribed for a median of 9.4 (range =5-14) years. The lower fixed dose group received agalsidase 0.2 mg/kg every other week throughout the follow-up period. The higher dose group received a range of agalsidase doses (0.2-1.0 mg/kg every other week). Dose changes were made due to disease progression, suboptimal effect, or agalsidase-β shortage. Serial kidney biopsies were performed along with clinical assessment and biomarkers and scored according to recommendations from the International Study Group of Fabry Nephropathy.

RESULTS:

No statistical differences were found in baseline or final GFR or albuminuria. Kidney biopsies showed significant reduction of podocyte globotriaosylceramide in both the lower fixed dose group (-1.39 [SD=1.04]; P=0.004) and the higher dose group (-3.16 [SD=2.39]; P=0.002). Podocyte globotriaosylceramide (Gb3) reduction correlated with cumulative agalsidase dose (r=0.69; P=0.001). Arterial/arteriolar intima Gb3 cleared significantly in the higher dose group, all seven patients with baseline intimal Gb3 cleared the intima, one patient gained intimal Gb3 inclusions (P=0.03), and medial Gb3 did not change statistically in either group. Residual plasma globotriaosylsphingosine levels remained higher in the lower fixed dose group (20.1 nmol/L [SD=11.9]) compared with the higher dose group (10.4 nmol/L [SD=8.4]) and correlated with cumulative agalsidase dose in men (r=0.71; P=0.01).

CONCLUSIONS:

Reduction of podocyte globotriaosylceramide was found in patients with classic Fabry disease treated with long-term agalsidase on different dosing regimens, correlating with cumulative dose. Limited clearing of arterial/arteriolar globotriaosylceramide raises concerns regarding long-term vascular effects of current therapy. Residual plasma globotriaosylsphingosine correlated with cumulative dose in men.

KEYWORDS:

Adolescent; Adult; Biomarkers; Biopsy; Child; Disease Progression; Enzyme Replacement Therapy; Fabry Disease; Follow-Up Studies; Humans; Isoenzymes; Male; Middle Aged; Podocytes; Trihexosylceramides; Young Adult; albuminuria; alpha-Galactosidas; chronic kidney disease; genetic renal disease; glomerular filtration rate; podocyte

PMID:
28625968
PMCID:
PMC5586567
DOI:
10.2215/CJN.01820217
[Indexed for MEDLINE]
Free PMC Article

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