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

Clinical journal of the American Society of Nephrology: CJASN

Kristin Kampevold Larsen¹  Carla Hollak¹  Sabine Leh²  Rannveig Skrunes⁴  Gunnar Houge⁸ 

[1] and..;and..†Department of Clinical Medicine, University of Bergen, Bergen, Norway;**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;Departments of *Medicine,..†Department of Clinical Medicine, University of Bergen, Bergen, Norway;§Pathology, and..;¶Heart Disease and..;‖Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway;†Department of Clinical Medicine, University of Bergen, Bergen, Norway

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

DOI  :  10.2215/CJN.01820217

学科分类：泌尿医学

来源: American Society of Nephrology

【 摘 要 】

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.

【 授权许可】

CC BY