Agalsidase alfa and kidney dysfunction in Fabry disease

Abstract

In male patients with Fabry disease, an X-linked disorder of glycosphingolipid metabolism caused by deficient activity of the lysosomal enzyme alpha-galactosidase A, kidney dysfunction becomes apparent by the third decade of life and invariably progresses to ESRD without treatment. Here, we summarize the effects of agalsidase alfa on kidney function from three prospective, randomized, placebo-controlled trials and their open-label extension studies involving 108 adult male patients. The mean baseline GFR among 54 nonhyperfiltrating patients (measured GFR <135 ml/min per 1.73 m(2)) treated with placebo was 85.4 +/- 29.6 ml/min per 1.73 m(2); during 6 mo of placebo, the mean annualized rate of change in GFR was -7.0 +/- 32.9 ml/min per 1.73 m(2). Among 85 nonhyperfiltrating patients treated with agalsidase alfa, the annualized rate of change was -2.9 +/- 8.7 ml/min per 1.73 m(2). Treatment with agalsidase alfa did not affect proteinuria. Multivariate analysis revealed that GFR and proteinuria category (< 1 or > or = 1 g/d) at baseline significantly predicted the rate of decline of GFR during treatment. This summary represents the largest group of male patients who had Fabry disease and for whom the effects of enzyme replacement therapy on kidney function have been studied. These data suggest that agalsidase alfa may stabilize kidney function in these patients.

Figure 1.

Distribution of the 108 patients who had GFR measured before and after placebo ( ), agalsidase alfa (□), or both placebo and agalsidase alfa. The number of patients is noted in each treatment box.

Figure 2.

GFR during treatment with agalsidase alfa in male patients with Fabry disease, divided into subgroups according to baseline GFR.

Figure 3.

Effect of agalsidase alfa on GFR in male patients with Fabry disease and with baseline GFR between 30 and 90 ml/min per 1.73 m². EOW, every other week.

Figure 4.

Relationship between eGFR and simultaneously measured GFR in men with Fabry disease (n = 314 pairs of measurements). The dotted line is the line of identity. The dashed line represents the results of linear regression across the entire range of GFR. This correlation is described by the following equation: eGFR (ml/min per 1.73 m²) = 17.3 ml/min per 1.73 m² + 0.95 · GFR (ml/min per 1.73 m²) (r² = 0.623, P < 0.001). The bold line represents the results of linear regression for GFR values <90 ml/min per 1.73 m² and is described by the following equation: eGFR (ml/min per 1.73 m² = −2.79 ml/min per 1.73 m² + 1.26 · GFR (ml/min per 1.73 m²).

Figure 5.

A summary of rates of change of GFR in Fabry disease with or without ERT. The dotted line designated “a” represents the entry criterion for inclusion into a study of aggressive ERT. The dotted line designated “b” shows the decline in GFR in the population without Fabry disease after age 30 yr. The rate of change for the Breunig study was calculated from data presented in the article for patients with baseline eGFR between 30 and <135 ml/min per 1.73 m². Similarly, the results presented for this study exclude patients with baseline GFR ≥135 ml/min per 1.73 m². The number of patients in each study and the mean duration of follow-up are indicated in parentheses. The differences between the rates of change of GFR or eGFR in ERT-treated patients who had baseline proteinuria values <1 g/d in the three studies shown above were not statistically significant by t test (this study versus Germain, P = 0.53; this study versus Breunig, P = 0.93; Germain versus Breunig, P = 0.77).