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Long-Term Dose-Dependent Agalsidase Effects on Kidney Histology in Fabry Disease.
Clin J Am Soc Nephrol. 2017 Sep 07; 12(9):1470-1479.CJ

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.

Authors+Show Affiliations

Departments of Medicine, rannvsk@online.no. Department of Clinical Medicine, University of Bergen, Bergen, Norway; and.Department of Clinical Medicine, University of Bergen, Bergen, Norway; and. Pediatrics.Department of Clinical Medicine, University of Bergen, Bergen, Norway; and. Pathology, and.Pathology, and.Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.Heart Disease and.Pediatrics and. Departments of Endocrinology and Metabolism and.Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands.Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands.Departments of Medicine. Department of Clinical Medicine, University of Bergen, Bergen, Norway; and.

Pub Type(s)

Journal Article
Observational Study

Language

eng

PubMed ID

28625968

Citation

Skrunes, Rannveig, et al. "Long-Term Dose-Dependent Agalsidase Effects On Kidney Histology in Fabry Disease." Clinical Journal of the American Society of Nephrology : CJASN, vol. 12, no. 9, 2017, pp. 1470-1479.
Skrunes R, Tøndel C, Leh S, et al. Long-Term Dose-Dependent Agalsidase Effects on Kidney Histology in Fabry Disease. Clin J Am Soc Nephrol. 2017;12(9):1470-1479.
Skrunes, R., Tøndel, C., Leh, S., Larsen, K. K., Houge, G., Davidsen, E. S., Hollak, C., van Kuilenburg, A. B. P., Vaz, F. M., & Svarstad, E. (2017). Long-Term Dose-Dependent Agalsidase Effects on Kidney Histology in Fabry Disease. Clinical Journal of the American Society of Nephrology : CJASN, 12(9), 1470-1479. https://doi.org/10.2215/CJN.01820217
Skrunes R, et al. Long-Term Dose-Dependent Agalsidase Effects On Kidney Histology in Fabry Disease. Clin J Am Soc Nephrol. 2017 Sep 7;12(9):1470-1479. PubMed PMID: 28625968.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Long-Term Dose-Dependent Agalsidase Effects on Kidney Histology in Fabry Disease. AU - Skrunes,Rannveig, AU - Tøndel,Camilla, AU - Leh,Sabine, AU - Larsen,Kristin Kampevold, AU - Houge,Gunnar, AU - Davidsen,Einar Skulstad, AU - Hollak,Carla, AU - van Kuilenburg,André B P, AU - Vaz,Frédéric M, AU - Svarstad,Einar, Y1 - 2017/06/16/ PY - 2017/02/15/received PY - 2017/05/12/accepted PY - 2017/6/20/pubmed PY - 2018/5/22/medline PY - 2017/6/20/entrez KW - Adolescent KW - Adult KW - Biomarkers KW - Biopsy KW - Child KW - Disease Progression KW - Enzyme Replacement Therapy KW - Fabry Disease KW - Follow-Up Studies KW - Humans KW - Isoenzymes KW - Male KW - Middle Aged KW - Podocytes KW - Trihexosylceramides KW - Young Adult KW - albuminuria KW - alpha-Galactosidas KW - chronic kidney disease KW - genetic renal disease KW - glomerular filtration rate KW - podocyte SP - 1470 EP - 1479 JF - Clinical journal of the American Society of Nephrology : CJASN JO - Clin J Am Soc Nephrol VL - 12 IS - 9 N2 - 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. SN - 1555-905X UR - https://www.unboundmedicine.com/medline/citation/28625968/Long_Term_Dose_Dependent_Agalsidase_Effects_on_Kidney_Histology_in_Fabry_Disease_ L2 - http://cjasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=28625968 DB - PRIME DP - Unbound Medicine ER -