Results
One hundred fifty-one men and 62 women met the inclusion criteria, including a baseline UP/Cr value and three or more eGFR values (see Materials and methods); 95% of the men and 92% of the women had two or more UP/Cr values reported during the treatment period. The median age at initiation of agalsidase beta treatment was 38 years for men and 43 years for women. Men were followed for 5 ± 1.9 years (mean ± SD) and women for 4 ± 1.6 years.
The 38 men in Q1 (those with the most stable renal function) had a mean eGFR slope of −0.1 mL/min/1.73m/year, whereas the 37 men in Q4 (those with the fastest renal disease progression) had a mean eGFR slope of −6.7 mL/min/1.73m/year. Clinical characteristics for these patients are shown in Table 1. Men in Q1 had lower mean averaged UP/Cr levels than those in Q4: 0.7 versus 1.7 g/g. Men in Q1 also had higher mean baseline eGFR levels than men in Q4: 99 versus 72 mL/min/1.73m (i.e. eGFR at the time treatment was initiated). Men in Q1 initiated agalsidase beta treatment sooner after the onset of Fabry symptoms than men in Q4: median 20 versus 35 years. Mean averaged blood pressure levels were similar across quartiles.
Clinical characteristics of women are shown in Table 2. Like men, women in Q4 tended to have higher UP/Cr levels than women in Q1. There were no apparent differences across quartiles in baseline eGFR levels, time from symptom onset to first infusion or age at first infusion in women. Averaged blood pressure levels in women were within or slightly above the normal range across quartiles.
In both genders, fewer patients in Q1 had experienced a stroke or cardiovascular event (as defined in Materials and methods) prior to the initiation of agalsidase beta treatment compared to patients in Q4 (Figure 1). Patients in each quartile were categorized by mutation type and by specific genotype (Table 3). Men with nonsense mutations (n = 16) were more likely to be in Q3–Q4 (n = 12, 75%) than in Q1–Q2 (n = 4, 25%). Conversely, men with missense mutations (n = 71) were more likely to be in Q1–Q2 (n = 44, 62%) than Q3–Q4 (n = 27, 38%). The five most prevalent missense genotypes are shown in Table 3. Most patients had unique genotypes and there was no clear association between any specific genotype and renal function.
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Figure 1.
Patients with rapid renal disease progression experienced clinical events prior to the initiation of agalsidase beta treatment. Patients were grouped into quartiles (Q), based on eGFR slope. Data are expressed as the percentage of patients within each eGFR slope quartile who had a stroke or cardiovascular event (as defined in Materials and Methods section) prior to the initiation of agalsidase beta treatment. The numbers above each bar indicate number of patients who had clinical events prior to the initiation of treatment/total number of patients in each quartile. Data for males are shown in light grey bars and data for females are shown in dark grey bars.
Results of the logistic regression model comparing men in Q1 to men in Q4 are shown in Table 4. Among the 75 men in Q1 and Q4, those who had averaged UP/Cr levels ≥1.0 g/g had a 112-fold increase in the risk of having more rapid renal disease progression (i.e. being in Q4) than did men who had averaged UP/Cr levels <0.3 g/g (odds ratio 112, 95% CI 4.0–3108.9, P = 0.0054). In addition to averaged UP/Cr, the time from symptom onset to first agalsidase beta infusion was also strongly associated with renal disease progression. Men in whom the time from symptom onset to first infusion was greater than the median (24 years) had a 19-fold increase in the risk of being in Q4 than men who initiated treatment sooner (odds ratio 19, 95% CI 2.0–183.9, P = 0.0098). When UP/Cr was removed from the regression model, lower baseline eGFR also emerged as a significant risk factor for renal disease progression in men; men with eGFR <60 mL/min/1.73m at baseline had a 12-fold increase in the risk of being in Q4 than men who had higher eGFR levels (odds ratio 12, 95% CI 1.2–114.0, P = 0.0316).
A proportional odds regression model was used to evaluate factors associated with renal disease progression in men across quartiles, as shown in Table 5. As in the logistic regression model of Q1 versus Q4, higher averaged UP/Cr (≥1 versus <0.3 g/g) was the variable most strongly associated with renal disease progression in men across quartiles. Among the 151 men in this cohort, those with averaged UP/Cr ≥1 g/g had a 4.5-fold higher risk of renal disease progression (i.e. more negative eGFR slope) compared to those with UP/Cr <0.3 g/g (odds ratio 4.5, 95% CI 1.9–10.7, P = 0.0006). The time from symptom onset to initiation of treatment was also a significant factor; men who initiated treatment >24 years after symptom onset had a 2.9-fold higher risk of renal disease progression compared to those who initiated treatment sooner (odds ratio 2.9, 95% CI 1.3–6.7, P = 0.0113). When UP/Cr was removed from the proportional odds regression model, lower baseline eGFR, the occurrence of a stroke or cardiovascular event prior to initiation of treatment and time from symptom onset to initiation of treatment were significant factors associated with renal disease progression in men (Table 5).
It was more difficult to develop a suitable logistic regression model for predictors of eGFR slope among the smaller number of women in this cohort (n = 15 or 16 in each quartile). For this reason, women in Q1–Q3 were combined, as their mean averaged UP/Cr levels and baseline eGFR values were similar (see Materials and methods and Table 2). When covariates were limited to averaged UP/Cr, age at first infusion and time from symptom onset to initiation of treatment, averaged UP/Cr was found to be associated with renal disease progression in women (Table 6). Among all 62 women, those who had averaged UP/Cr levels ≥1.0 g/g had a 12-fold increased risk of having more rapid renal disease progression (i.e. being in Q4) than did women who had averaged UP/Cr levels <0.3 g/g (odds ratio 11.7, 95% CI 1.1–119.7, P = 0.0388). When UP/Cr was removed from the regression model, age at first infusion also appeared as a significant risk factor. Women who received their first infusion at age ≥40 years had a 7-fold increase in the risk of being in Q4 compared to women who received their first infusion at a younger age (odds ratio 7.4, 95% CI 1.12–48.3, P = 0.0375). Time from symptom onset to first infusion was not a significant predictor of renal disease progression in women; however, only a subset of women had reported the age at which they first experienced symptoms of Fabry disease (n = 42).