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

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


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.

Publication types

  • Observational Study

MeSH terms

  • Adolescent
  • Adult
  • Biopsy
  • Child
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Enzyme Replacement Therapy / adverse effects*
  • Fabry Disease / diagnosis
  • Fabry Disease / drug therapy*
  • Fabry Disease / enzymology
  • Female
  • Glomerular Filtration Rate / drug effects
  • Humans
  • Isoenzymes / administration & dosage*
  • Isoenzymes / adverse effects
  • Kidney / drug effects*
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney / physiopathology
  • Male
  • Middle Aged
  • Norway
  • Time Factors
  • Treatment Outcome
  • Trihexosylceramides / metabolism
  • Young Adult
  • alpha-Galactosidase / administration & dosage*
  • alpha-Galactosidase / adverse effects


  • Isoenzymes
  • Trihexosylceramides
  • globotriaosylceramide
  • alpha-Galactosidase
  • agalsidase beta