Sustained, Long-Term Renal Stabilization After 54 Months of Agalsidase β Therapy in Patients with Fabry Disease

Globotriaosylceramide (GL-3) clearance from kidney, heart, and skin capillary endothelium in all patients. Histologic specimens that were obtained at pretreatment, month 6, and month 54 (optional for kidney and heart) were evaluated for the presence of GL-3. Results show that for the majority of patients, initial GL-3 clearance (score of 0) seen at month 6 was maintained during the 54-mo treatment period. Numbers above bar graphs represent the number of patients with zero scores out of the total number evaluated. cap. endo., capillary endothelium.

Agalsidase β therapy reduced GL-3 accumulation to zero at 54 mo in various types of kidney cells. For distal convoluted tubule (DCT)/collecting duct cells, baseline scores were obtained at the beginning of the double-blind trial and at month 54 on a 0 to 3 scale. For all other cell types, pretreatment scores were obtained before agalsidase β treatment as defined in Materials and Methods. Mesangial cells were scored on a scale of 0 to 2, and other cell types were scored on a scale of 0 to 3.

Long-term agalsidase β therapy decreases GL-3 accumulation in podocytes. (A) Kidney biopsy that was obtained before agalsidase β therapy exhibits dark-staining granules in podocytes. (B) By month 54, fewer GL-3 inclusions are evident from a specimen that was obtained from the same patient. Methylene blue/azure II stain (13). Magnification, ×400.

Median estimated GFR (eGFR; ml/min per 1.73 m²) over time. Patients in the “as treated” population maintained a stable median eGFR during the 54-mo treatment period, which was observed in both the placebo/agalsidase β and the agalsidase β/agalsidase β treatment groups (left) as well as in the overall, combined population (right).

High (>1 g/24 h) baseline proteinuria is associated with higher rate of eGFR decline and increased probability of renal events. (A) Subgroup analyses of patients in the “as treated” population who were stratified by baseline proteinuria (≤1 g/24 h versus >1 g/24 h) showed differences in the rate of eGFR decline during the 54-mo treatment period. (B) Increased baseline proteinuria values seem to correlate with the probability of renal event (a 50% increase in serum creatinine from the pretreatment assessment and the increased value was >1.4 mg/dl). Note that baseline proteinuria was determined before entry into the double-blind study for all patients.

Pretreatment glomerulosclerosis involving ≥50% glomeruli is associated with higher rate of eGFR decline and increased risk for renal events. (A) Subgroup analyses of patients in the “as treated” population show that those with pretreatment glomerulosclerosis (≥50% sclerotic glomeruli) had a higher rate of decline in eGFR compared with patients with <50% sclerotic glomeruli at pretreatment. (B) As pretreatment glomerulosclerosis increases, the likelihood of having a renal event (a 50% increase in serum creatinine over the pretreatment assessment and an increased value >1.4 mg/dl) also increases.