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Long-Term Dose-Dependent Agalsidase Effects on Kidney Histology in Fabry Disease
Rannveig Skrunes1,2, Camilla Tøndel3,2, Sabine Leh4,2
1Departments of Medicine.
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.
Insights
Enzyme replacement therapy with agalsidase effectively reduces podocyte globotriaosylceramide in Fabry disease, with greater reduction seen at higher cumulative doses. However, limited clearing of vascular globotriaosylceramide suggests potential long-term concerns.
Area of Science:
- Nephrology
- Genetics
- Pharmacology
Background:
- Fabry disease is a rare genetic disorder.
- Enzyme replacement therapy (ERT) is a treatment for Fabry disease.
- Globotriaosylceramide (Gb3) accumulates in various tissues in Fabry disease.
Purpose of the Study:
- To evaluate the dose-dependent effects of agalsidase therapy on globotriaosylceramide (Gb3) accumulation in kidney biopsies.
- To assess the long-term impact of different agalsidase dosing regimens on Fabry disease progression.
Main Methods:
- A cohort of 20 patients with classic Fabry disease received long-term ERT with agalsidase (α or β).
- Patients were divided into lower fixed-dose and higher dose groups.
- Serial kidney biopsies, clinical assessments, and biomarker analysis were performed over up to 14 years.
Main Results:
- Significant reduction in podocyte globotriaosylceramide (Gb3) was observed in both dose groups, correlating with cumulative agalsidase dose.
- Higher agalsidase doses led to greater Gb3 reduction in podocytes and significant clearance of arterial/arteriolar intima Gb3.
- Residual plasma globotriaosylsphingosine levels correlated with cumulative dose in men, being lower in the higher dose group.
Conclusions:
- Long-term agalsidase therapy effectively reduces podocyte Gb3 in Fabry disease, with dose-dependency observed.
- Limited clearance of vascular Gb3 suggests potential long-term vascular complications may persist.
- Cumulative agalsidase dose is a key factor in Gb3 reduction and residual plasma globotriaosylsphingosine levels.
