Agalsidase beta treatment slows estimated glomerular filtration rate loss in classic Fabry disease patients: results from an individual patient data meta-analysis - PubMed (original) (raw)

. 2020 May 22;14(4):1136-1146.

doi: 10.1093/ckj/sfaa065. eCollection 2021 Apr.

Steve Kanters 2, Alaa Hamed 3, Pronabesh DasMahapatra 3, Eugene Poggio 4, Manish Maski 5, Mario Aguiar 5, Elvira Ponce 5, Jeroen P Jansen 6, Dieter Ayers 2, Rachel Goldgrub 2, Robert J Desnick 7

Affiliations

Agalsidase beta treatment slows estimated glomerular filtration rate loss in classic Fabry disease patients: results from an individual patient data meta-analysis

Alberto Ortiz et al. Clin Kidney J. 2020.

Abstract

Background: Fabry disease is a rare, X-linked genetic disorder that, if untreated in patients with the Classic phenotype, often progresses to end-stage kidney disease. This meta-analysis determined the effect of agalsidase beta on loss of estimated glomerular filtration rate (eGFR) in the Classic phenotype using an expansive evidence base of individual patient-level data.

Methods: The evidence base included four Sanofi-Genzyme studies and six studies from a systematic literature review. These were restricted to Classic Fabry patients meeting the eligibility criteria from Phases III and IV agalsidase beta trials, including 315 patients (161 treated). Linear regression was first used to model annual change in eGFR for each patient and the resulting annualized eGFR slopes were modelled with treatment and covariates using quantile regression. These results were then used to estimate median annualized eGFR change in agalsidase beta treated versus untreated groups.

Results: Imbalances across treatment groups were found in baseline age, sex and proteinuria, but not in the use of renin-angiotensin system blockers. The adjusted model suggests that treated (agalsidase beta) patients experienced a slower median eGFR decrease [2.46 mL/min/1.73 m2/year slower; 95% confidence interval (CI) 0.63-4.29; P = 0.0087] than comparable untreated patients. The median eGFR decrease was 2.64 mL/min/1.73 m2/year slower (95% CI 0.53-4.78; P = 0.0141) in treated Classic males.

Conclusions: Using an expansive evidence base and robust modelling approach, these data indicate that agalsidase beta-treated patients with the Classic phenotype conserve their renal function better than untreated patients.

Keywords: Fabry disease; agalsidase beta; chronic kidney disease outcomes; classic phenotype; glomerular filtration rate; individual patient data meta-analysis.

© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.

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Figures

FIGURE 1

FIGURE 1

Study selection flow diagram.

FIGURE 2

FIGURE 2

Comparing sample sizes in consideration for weights. Examples of eGFR trajectories for four patients with different number of observations. The number of observations in the overall study population varied from 2 to 41 across patients. The dependent variable was changed from baseline in eGFR, meaning that all patients started at the origin (0,0 coordinates of a Cartesian graph). The top two panels demonstrate that for patients with small number of measurements, using an inverse variance weighting would either be infeasible or be limited by overfitting. It is for this reason that the weights assuming equal residual variance across patients were favoured.

FIGURE 3

FIGURE 3

Forest plot comparing the adjusted median eGFR slopes in agalsidase beta treated versus untreated. Adjusted median eGFR slopes and interquartile range for the overall treated and untreated groups and the individual studies. After adjusting for the noted imbalances in gender and proteinuria, the treatment effect was found to be significant (P = 0.0087). The median decline in agalsidase beta-treated patients is 1.01 mL/min/1.73/m2/year compared with a decline of 3.47 mL/min/1.73 m2/year in untreated patients. Agalsidase beta-treated patients decreased by a median eGFR of 2.46 mL/min/1.73 m2/year (95% CI 0.63–4.29) slower than a comparable untreated patient. The study by Lin et al. was not shown as there was only one patient and dispersion could not be calculated.

References

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