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

Abstract

BackgroundNephropathy 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 designThe 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.Results18 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 m2/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 m2/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.ConclusionsThis 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 numberNCT00446862.

Disease Progression Modeling to Evaluate the Effects of Enzyme Replacement Therapy on Kidney Function in Adult Patients with the Classic Phenotype of Fabry Disease

“…A recent study by Germain and colleagues showed that less affected individuals with a better preserved kidney function at baseline benefited from ERT, experiencing better renal and cardiovascular outcomes during the observational period [36]. Moreover, in male FD patients, enhanced therapeutic outcomes may occur if we increase the ERT dose [35, 37, 38], or frequency of infusions [39], in combination with intensified additional medication such as ARBs and ACE inhibitors [16]. In patients with amenable mutations, pharmacological chaperones have been shown as a useful therapeutic alternative [40, 41].…”

“…Although NLME is frequently applied in clinical drug development, to our knowledge, it is the first time that this method was utilized to characterize progression of the Fabry nephropathy over time, quantify effects of ERT, as well as key covariates on kidney function. Previous studies used linear multivariate regression models for outcome analyses as a common statistical tool [16, 31, 32]. …”

“…Recent studies suggest that FD patients with chronic kidney disease (CKD) stage 3 or 4 may not benefit from ERT as clinically meaningful events continue to occur in these patients despite treatment [15]. Proteinuria seems to be associated with decreased effectiveness of ERT [16, 17]. …”

Fabry Nephropathy: An Evidence-Based Narrative Review

“…Results showed that proteinuria in most classical FD patients was controlled, but that kidney function was not preserved in patients who did not achieve the urine protein to creatinine ratio (UPCR) treatment goal of 0.5 g/g. Kidney function was preserved in a minority of patients who started ERT at a younger age, and who maintained a UPCR < 0.5 g/g with antiproteinuric therapy [86]. There is some evidence supporting that the use of amiloride, a drug with proven effects in podocyte stabilization and proteinuria actions at the distal convoluted tubule, can decrease protein excretion in FD patients [87], but further research is needed.…”

“…When urine protein excretion was controlled to a target of ≤0.5 g/day by carefully titrating ACEI and ARB doses in these adult Fabry patients who were also treated with agalsidase beta at 1 mg/kg every other week (EOW), the rate of loss of eGFR was not significantly different than zero [85]. A few years later, Warnock et al [86] conducted a prospective observational study that examined the safety and efficacy of controlling proteinuria with ACEI or ARB therapy in FD patients who were receiving ERT with agalsidase beta. Results showed that proteinuria in most classical FD patients was controlled, but that kidney function was not preserved in patients who did not achieve the urine protein to creatinine ratio (UPCR) treatment goal of 0.5 g/g.…”