Antiproteinuric therapy and Fabry nephropathy: factors associated with preserved kidney function during agalsidase-beta therapy

Abstract

Background: Nephropathy is an important feature of classical Fabry disease, which results in alpha-galactosidase A deficiency and cellular globotriaosylceramide accumulation. We report the safety and efficacy of antiproteinuric therapy with ACE inhibitors or angiotensin II receptor blockers (ARBs) in a study of classical Fabry patients receiving recombinant agalsidase-beta therapy.

Methods and design: The goal was maintenance of urine protein to creatinine ratio (UPCR) <0.5 g/g or a 50% reduction in baseline UPCR for 24 patients at eight study sites. The change in estimated glomerular filtration rate (eGFR) was assessed over 21 months of treatment.

Results: 18 out of 24 patients achieved the UPCR goal with eGFR slopes that were significantly better than six patients who did not achieve the UPCR goal (-3.6 (-4.8 to -1.1) versus -7.0 (-9.0 to -5.6) mL/min/1.73 m(2)/year, respectively, p=0.018). Despite achieving the UPCR goal, 67% (12/18 patients) still progressed with an eGFR slope <-2 mL/min/1.73 m(2)/year. Regression analysis showed that increased age at initiation of agalsidase-beta therapy was significantly associated with worsened kidney outcome. Hypotension and hyperkalaemia occurred in seven and eight patients, respectively, which required modification of antiproteinuric therapy but was not associated with serious adverse events.

Conclusions: This study documents the effectiveness of agalsidase-beta (1 mg/kg/2 weeks) and antiproteinuric therapy with ACE inhibitors and/or ARB in patients with severe Fabry nephropathy. Patients had preservation of kidney function if agalsidase-beta treatment was initiated at a younger age, and UPCR maintained at or below 0.5 g/g with antiproteinuric therapy.

Trial registration number: NCT00446862.

Keywords: Clinical genetics; Metabolic disorders; Renal Medicine.

Figure 1

Box plots of urine protein to creatinine ratio (UPCR). (A) Stratified at UPCR goal. (B) Stratified by Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate (eGFR) intercept at 60 mL/min per 1.73 m². The UPCR goal was defined as UPCR for first treatment visit ≤0.5 g/g or averaged treatment UPCR ≤50% of baseline UPCR (visit –3). The eGFR intercept was calculated with a mixed-effect linear model across all treatment visits. eGFR slopes, mL/min/1.73 m²/year. The horizontal line is the median value and the upper and lower limits of the boxes are 75th and 25th centiles, respectively. The number of participants in each category is shown in parentheses above the upper cap of the 90th centile values.

Figure 2

Box plots of Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate (eGFR) slopes. (A) Stratified at urine protein to creatinine ratio (UPCR) goal. (B) Stratified by eGFR slope at −2.0 mL/min per 1.73 m²/year. The UPCR goal was defined as UPCR for first treatment visit ≤0.5 g/g, or averaged treatment UPCR ≤50% of baseline UPCR (visit –3), or averaged treatment UPCR <0.5 g/g. The eGFR slopes and intercepts were calculated with a mixed-effect linear model across all treatment visits. eGFR slopes, mL/min/1.73 m²/year. The horizontal line is the median value and the upper and lower limits of the boxes are 75th and 25th centiles, respectively. The number of participants in each category is shown in parentheses above the upper cap of the 90th centile values.