Fabry disease: progression of nephropathy, and prevalence of cardiac and cerebrovascular events before enzyme replacement therapy

Abstract

Background: In Fabry disease, progressive glycolipid accumulation leads to organ damage and early demise, but the incidence of renal, cardiac and cerebrovascular events has not been well characterized.

Methods: We conducted a retrospective chart review of 279 affected males and 168 females from 27 sites (USA, Canada, Europe). The pre-defined study endpoints included progression of renal, cardiac and cerebrovascular involvement and/or death before the initiation of enzyme replacement therapy.

Results: The mean rate of estimated glomerular filtration rate (eGFR) decline for patients was -2.93 for males, and -1.02 ml/min/1.73 m(2)/year for females. Prevalence and severity of proteinuria, baseline eGFR <60 ml/min/1.73 m(2) and hypertension were associated with more rapid loss of eGFR. Advanced Fabry nephropathy was more prevalent and occurred earlier among males than females. Cardiac events (mainly arrhythmias), strokes and transient ischaemic attacks occurred in 49, 11, 6% of males, and in 35, 8, 4% of females, respectively. The mean age at death for 20 male patients was 49.9 years.

Conclusions: Baseline proteinuria, reduced baseline eGFR, hypertension and male gender were associated with more rapid progression of Fabry nephropathy. The eGFR progression rate may increase with advancing nephropathy, and may differ between subgroups of patients with Fabry disease.

Fig. 1

eGFR regression slopes with 95% CI for male and female patients who progressed to ESRD during the observation period, compared to those who did not progress to ESRD, based on medical record review. ESRD was defined by institution of renal replacement therapy (dialysis or transplant) or achieving a serum creatinine >6 mg/dl. The eGFR (ml/min/1.73 m²) and progression rates (ml/min/1.73 m²/year) were averaged for all patients who had at least three serum creatinine determinations available from the medical record review. Modelling lines for patients who progressed to ESRD were extended back to start at the minimum age for baseline eGFR, i.e. ∼20 years for males and ∼30 years for females (see Table 5). The lines end on average at about the age of ESRD for these patients, i.e. ∼40 years. Modelling lines for patients without ESRD were extended to cover the ages where the data ended, i.e. ∼70 years for some females and ∼60 years for some males.

Fig. 2

eGFR progression slopes (ml/min/1.73 m²/year) for male and female patients stratified by baseline 24-h urinary protein excretion (g/24 h). The y-axis represents eGFR (ml/min/1.73 m²) and the x-axis in each panel represents a 12-month span. SEM = standard error of the mean.

Fig. 3

(A) Kaplan–Meier estimate of time to first renal, cardiac, stroke event or death. Events were defined as detailed in the section ‘Data collection and analysis’. (B) Kaplan–Meier estimate of time to first cardiac arrhythmia. Male and female patients are shown as separate lines in each panel. Cardiac arrhythmias were defined as detailed in the section ‘Data collection and analysis’.

Fig. 4

Kaplan–Meier-estimated survival rates for male Fabry patients (n = 279).