Agalsidase benefits renal histology in young patients with Fabry disease

Abstract

The effect of early-onset enzyme replacement therapy on renal morphologic features in Fabry disease is largely unknown. Here, we evaluated the effect of 5 years of treatment with agalsidase alfa or agalsidase beta in 12 consecutive patients age 7-33 years (median age, 16.5 years). We performed renal biopsies at baseline and after 5 years of enzyme replacement therapy; 7 patients had additional biopsies after 1 and 3 years. After a median of 65 months, biopsy findings from all patients showed total clearance of glomerular endothelial and mesangial cell inclusions, and findings from 2 patients showed complete clearance of inclusions from epithelial cells of the distal tubule. The 4 patients who received the highest dose of agalsidase exhibited substantial clearance of podocyte inclusions, and the youngest patient had nearly complete clearance of these inclusions. Linear regression analysis showed a highly significant correlation between podocyte globotriaocylceramide clearance and cumulative agalsidase dose (r=0.804; P=0.002). Microalbuminuria normalized in five patients. In summary, long-term enzyme replacement therapy in young patients can result in complete globotriaocylceramide clearance of mesangial and glomerular endothelial cells across all dosage regimens, and clearance of podocyte inclusions is dose-dependent.

Figure 1.

Albumin-to-creatinine-ratio (ACR), mGFR, and GL3 in plasma and urine during 5 years follow-up.

Figure 2.

Change of GL3 inclusion score in podocytes in relation to cumulative agalsidase dose after 5 years (linear regression analysis); patients 1, 3, and 9 received agalsidase beta, 1.0 mg/kg every other week; patient 5, agalsidase alpha, 0.4 mg/kg every other week, then a switch to agalsidase beta 1.0 mg/kg every other week after 4 years; patient 7, agalsidase alpha, 0.4 mg/kg every other week; patient 12, agalsidase alpha, 0.2 mg/kg per week; patients 2, 4, 6, 8, and 11, agalsidase alpha, 0.2 mg/kg every other week. Patient 10, agalsidase beta, 0.2 mg/kg every other week. *Patient 8 underwent rebiopsy after 1 year. Numbers in red represent patient numbers.

Figure 3.

Baseline biopsy specimen (upper panel) shows full score of GL3 deposits. Rebiopsy after 5 years of ERT, 1 mg/kg every other week (lower panel), shows almost complete clearance of deposits in a 7-year-old boy (patient 1). Shown are light microscopic images of hematoxylin and eosin sections (A), PAS sections (B), and osmicated toluidine semithin sections (C) and electron microscopic image (D). Original magnification: × 1000 in A; × 1000 in B; × 400 in C; × 2000 at baseline and × 1500 at 5 years in D.

Figure 4.

Change of GL3 inclusion score in podocytes in relation to change of albumin-to-creatinine ratio (linear regression analysis). Patient 7 was excluded from the analysis because of mixed glomerular/tubular proteinuria. Numbers in red represent patient numbers.