Summary
Background and objectives
Fabry disease is a rare X-linked disease with multisystemic manifestations. This study investigated the effectiveness of long-term enzyme replacement therapy with agalsidase alfa in Fabry nephropathy treatment.
Design, setting, participants, & measurements
In this observational study, data on patients receiving agalsidase alfa (0.2 mg/kg every other week) were extracted from the Fabry Outcome Survey, an international registry of patients with Fabry disease. Serum creatinine and estimated GFR (eGFR) at baseline and after ≥5 years of treatment were assessed; 24-hour urinary protein excretion and BP measurements were also reviewed. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula. Patients with an eGFR <30 ml/min per 1.73 m2 were excluded.
Results
Renal function was assessed in 208 patients (mean enzyme replacement therapy, 7.4 years; range, 5.0–11.2 years). Mean yearly change in eGFR was −2.2 ml/min per 1.73 m2 in men and −0.7 ml/min per 1.73 m2 in women (95% confidence limits, −2.8; −1.7 and −1.4; 0.0, respectively). Patients with 24-hour protein excretion >1 g/24 h had poorer renal function at baseline and follow-up compared with patients with protein excretion of 500–1000 mg/24 h or with proteinuria <500 mg/24 h. Renal function was worse in patients with baseline arterial hypertension, and there was a more rapid yearly decline compared with normotensive patients.
Conclusions
This study suggests that long-term agalsidase alfa therapy is able to stabilize the rate of Fabry nephropathy progression in women and is associated with a mild to moderate decline of renal function in men.
Introduction
Fabry disease is an X-linked disease in which mutations of the GLA gene result in a deficiency of the enzyme α-galactosidase A and subsequent progressive, intralysosomal deposition of undegraded glycosphingolipid products, primarily globotriaosylceramide, in multiple organs, including the kidneys. The progressive nephropathy that develops is generally more severe in men than in women (1).
The treatment of Fabry disease with enzyme replacement therapy (ERT) has been a common practice since 2001. Positive short-term effects of ERT on different organs have been demonstrated, and ERT can change the natural course of the disease (2–4). ERT, with either agalsidase alfa or beta, has also been shown to slow the progression of Fabry nephropathy (5–7). The current consensus is that ERT should be started in all men and in women with signs of renal involvement (8).
This study aimed to investigate the effectiveness of ERT with agalsidase alfa in treating Fabry nephropathy in a large number of patients enrolled in the Fabry Outcome Survey (FOS) who were treated and followed for a minimum of 5 years. Moreover, the study used a new formula, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, to calculate the estimated GFR (eGFR) (9). This formula has been shown to be more accurate than the Modification of Diet in Renal Disease (MDRD) equation (10,11), particularly for measurement of GFRs >60 ml/min per 1.73 m2 (12).
Materials and Methods
Patients
Data were obtained from FOS, an international database of patients with Fabry disease, in August 2010. All patients in FOS gave written informed consent for the collection and analysis of their data. Inclusion in the database was approved by the ethical committee of the local health institution for each patient.
This analysis included adult patients (>18 years of age at baseline) with data on creatinine concentrations available in FOS at baseline and after ≥5 years of treatment with agalsidase alfa (Replagal; Shire Human Genetic Therapies, Cambridge, MA), consisting of 40-minute infusions at a dosage of 0.2 mg/kg every 2 weeks. An additional analysis was carried out in adult patients for whom proteinuria levels were recorded at baseline and after ≥5 years of treatment. The analyses included all available yearly intermediate renal data for patients fulfilling these criteria. Variables studied included serum creatinine concentrations, eGFR calculated using the CKD-EPI equation (9), 24-hour urinary protein excretion. and arterial BP. Noncompensated measurements of serum creatinine levels recorded in FOS were adjusted according to the Jaffé detection method (13,14).
The eGFR measurements at baseline, as well as during and after ≥5 years of ERT were assessed, and changes in eGFR between time points were computed for each individual patient. The mean of the changes for all patients was then calculated. Rate of decline in eGFR per year was also calculated. Patients with Kidney Disease Outcomes Quality Initiative (KDOQI) stage IV and V renal disease (eGFR <30 ml/min per 1.73 m2) were not included in the study. Diagnoses of hypertension based on BP measurements and details of the use of antihypertensive therapies recorded in FOS were reviewed.
To assess how representative the patient sample in the current investigation was of the total FOS population treated for at least 5 years, eGFR data are also presented for the subgroup of patients receiving ERT who had renal data at baseline and ≥5 years but did not fulfill the criteria for the main analysis, as well as the subgroup of patients who had never been treated with ERT and who had renal data at baseline and ≥5 years.
Statistical Analyses
Patients were grouped by sex and according to baseline renal function, as defined by the KDOQI: stage I (eGFR ≥90 ml/min per 1.73 m2; normal renal function); stage II (eGFR 60–89 ml/min per 1.73 m2); and stage III (eGFR 30–59 ml/min per 1.73 m2) (15). To evaluate the role of 24-hour proteinuria on renal outcomes, patients were divided into three subgroups according to baseline 24-hour proteinuria: patients with urinary protein excretion <500 mg/24 h (mild or no proteinuria), 500–1000 mg/24 h, and >1 g/24 h.
To evaluate the role of arterial hypertension—defined in FOS by individual physicians according to national and local guidelines, generally a BP ≥120/80 mmHg—men and women with different stages of renal function or renal disease were further subdivided into hypertensive and normotensive patients.
All data were reported as mean ± SD as well as median and geometric mean for proteinuria levels. Slopes of eGFR per patient were calculated using mixed-effect model methodology with intercept and slope as random effects. For each patient, all data available from baseline as well as during and after ≥5 years of treatment were included in the model. P<0.05 was considered significant. For paired comparisons, the signed-rank test or paired t test was used, as appropriate. For comparisons of two groups, the Wilcoxon rank–sum test or two-sample t test was used, as appropriate. For ordinal, categorical data, the chi-squared test was used.
Results
Patients
At the time of data collection, FOS contained data on 1120 patients (145 children at FOS entry) treated with agalsidase alfa and 783 patients (159 children at FOS entry) who had not received ERT. Data on creatinine concentrations at baseline, as well as during and after ≥5 years of treatment with agalsidase alfa were available from 208 treated adult patients (134 men; mean time on ERT, 7.4 years; range, 5.0–11.2 years). Mean age at baseline was 38.4±12.28 years (men, 34.5 years; women, 45.6 years). On the basis of eGFR at baseline, renal function was classified as stage I in 87 men and 19 women, stage II in 32 men and 43 women, and stage III in 15 men and 12 women (Tables 1 and 2). Arterial hypertension was present in 66 of 208 patients. Data on proteinuria at baseline as well as during and after ≥5 years of treatment were available from 130 (84 men) of the 208 enrolled treated patients who were adults at baseline (Figure 1).
Table 1.
Estimated GFR (eGFR) in men with Fabry disease at baseline and after ≥5 years of treatment with agalsidase alfa
| Visit | n | Mean eGFR at Baseline (ml/min per 1.73 m2) | Mean eGFR at Year End (ml/min per 1.73 m2) | Mean Change in eGFR to Year End (ml/min per 1.73 m2) | t Test (P Value) |
|---|---|---|---|---|---|
| Stage I (≥90) (n=87)a | |||||
| year 1 | 62 | 111.2±14.4 | 107.9±18.0 | −3.2±12.1 | 0.04 |
| year 2 | 80 | 113.2±15.2 | 107.3±17.6 | −5.9±14.2 | <0.01 |
| year 3 | 80 | 111.8±14.2 | 104.8±17.6 | −7.0±13.8 | <0.01 |
| year 4 | 76 | 113.1±15.0 | 99.9±21.6 | −13.2±16.9 | <0.01 |
| year 5 | 72 | 112.0±14.5 | 96.1±22.1 | −15.8±18.0 | <0.01 |
| year 5+ | 87 | 113.2±14.9 | 92.2±27.2 | −21.0±24.3 | <0.01 |
| Stage II (60–89) (n=32)b | |||||
| year 1 | 23 | 75.1±8.1 | 75.2±13.9 | 0.2±9.9 | 0.93 |
| year 2 | 29 | 76.7±8.6 | 77.1±15.3 | 0.4±9.7 | 0.83 |
| year 3 | 27 | 76.8±8.1 | 73.0±17.9 | −3.8±13.7 | 0.17 |
| year 4 | 31 | 76.9±8.3 | 71.0±18.2 | −5.9±14.5 | 0.03 |
| year 5 | 26 | 78.0±8.3 | 70.0±22.7 | −8.0±19.0 | 0.04 |
| year 5+ | 32 | 77.2±8.4 | 67.0±24.9 | −10.2±21.5 | 0.01 |
| Stage III (30–59) (n=15)c | |||||
| year 1 | 11 | 46.3±9.2 | 45.2±11.0 | −1.0±7.9 | 0.67 |
| year 2 | 15 | 48.4±8.8 | 49.0±20.6 | 0.6±16.6 | 0.89 |
| year 3 | 14 | 49.3±8.3 | 44.7±11.4 | −4.6±8.0 | 0.05 |
| year 4 | 14 | 49.3±8.3 | 34.5±14.7 | −14.8±14.5 | ≤0.01 |
| year 5 | 13 | 49.1±8.6 | 33.6±14.0 | −15.5±14.5 | ≤0.01 |
| year 5+ | 15 | 48.4±8.8 | 34.2±12.0 | −14.2±13.7 | ≤0.01 |
| Total (n=134)d | |||||
| year 1 | 96 | 95.1±26.4 | 92.9±27.4 | −2.2±11.2 | 0.06 |
| year 2 | 124 | 96.8±27.0 | 93.2±27.0 | −3.6±13.8 | ≤0.01 |
| year 3 | 121 | 96.8±25.7 | 90.8±27.2 | −6.0±13.2 | <0.01 |
| year 4 | 121 | 96.5±26.5 | 84.9±29.8 | −11.5±16.3 | <0.01 |
| year 5 | 111 | 96.6±25.8 | 82.7±29.9 | −14.0±18.0 | <0.01 |
| year 5+ | 134 | 97.3±26.5 | 79.7±31.8 | −17.6±23.1 | <0.01 |
Groups are stratified according to Kidney Disease Outcomes Quality Initiative classification of renal function at baseline. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula. Data are presented as mean ± SD. Estimates (average slopes) from the mixed-effect model. CL, confidence limit.
Slope (95% CL) estimate over time: –2.6 (−3.1; −2.0) ml/min per 1.73 m2 per year (P<0.01).
Slope (95% CL) estimate over time: –1.7 (−2.6; −0.7) ml/min per 1.73 m2 per year (P<0.01).
Slope (95% CL) estimate over time: –2.5 (−3.9; −1.1) ml/min per 1.73 m2 per year (P≤0.01).
Slope (95% CL) estimate over time: –2.2 (−2.8; −1.7) ml/min per 1.73 m2 per year (P<0.01).
Table 2.
Estimated glomerular filtration rate (eGFR) in women with Fabry disease at baseline and after ≥5 years of treatment with agalsidase alfa
| Visit | n | Mean eGFR at Baseline (ml/min per 1.73 m2) | Mean eGFR at Year End (ml/min per 1.73 m2) | Mean Change in eGFR to Year End (ml/min per 1.73 m2) | t Test (P Value) |
|---|---|---|---|---|---|
| Stage I (≥90) (n=19)a | |||||
| year 1 | 14 | 99.4±9.5 | 89.5±13.4 | −9.9±12.2 | 0.01 |
| year 2 | 17 | 101.2±11.3 | 88.2±20.0 | −13.0±18.9 | 0.01 |
| year 3 | 17 | 103.0±11.9 | 93.4±16.6 | −9.6±17.2 | 0.04 |
| year 4 | 16 | 103.4±12.2 | 93.3±20.0 | −10.1±17.0 | 0.03 |
| year 5 | 17 | 101.8±12.1 | 90.4±19.6 | −11.4±15.8 | ≤0.01 |
| year 5+ | 19 | 102.0±11.6 | 87.7±20.5 | −14.4±15.2 | <0.01 |
| Stage II (60–89) (n=43)b | |||||
| year 1 | 34 | 76.2±8.1 | 78.4±12.9 | 2.2±10.8 | 0.25 |
| year 2 | 38 | 75.7±7.9 | 77.5±14.2 | 1.8±11.0 | 0.32 |
| year 3 | 38 | 76.1±8.0 | 75.6±14.3 | −0.6±12.7 | 0.78 |
| year 4 | 41 | 76.1±8.1 | 76.2±14.6 | 0.2±13.2 | 0.94 |
| year 5 | 40 | 76.1±8.3 | 76.7±15.6 | 0.6±13.3 | 0.79 |
| year 5+ | 43 | 75.7±8.2 | 74.4±13.5 | −1.3±12.7 | 0.51 |
| Stage III (30–59) (n=12)c | |||||
| year 1 | 12 | 52.0±6.0 | 55.2±19.7 | 3.2±17.5 | 0.54 |
| year 2 | 11 | 51.2±5.7 | 53.8±10.9 | 2.5±9.6 | 0.40 |
| year 3 | 10 | 51.3±6.0 | 50.5±13.0 | −0.8±9.6 | 0.80 |
| year 4 | 11 | 51.7±6.2 | 53.0±16.0 | 1.3±13.8 | 0.76 |
| year 5 | 12 | 52.0±6.0 | 50.9±13.2 | −1.0±12.4 | 0.78 |
| year 5+ | 12 | 52.0±6.0 | 50.5±13.7 | −1.4±11.8 | 0.68 |
| (n=74)d | |||||
| year 1 | 60 | 76.8±17.6 | 76.3±18.4 | −0.4±13.5 | 0.81 |
| year 2 | 66 | 78.2±18.4 | 76.3±18.8 | −1.9±14.6 | 0.30 |
| year 3 | 65 | 79.3±18.8 | 76.4±19.8 | −3.0±14.0 | 0.09 |
| year 4 | 68 | 78.5±18.6 | 76.5±20.3 | −2.1±14.8 | 0.25 |
| year 5 | 69 | 78.3±18.5 | 75.6±20.5 | −2.7±14.5 | 0.13 |
| year 5+ | 74 | 78.6±18.5 | 73.9±19.4 | −4.7±14.3 | ≤0.01 |
Groups are stratified according to Kidney Disease Outcomes Quality Initiative classification of renal function at baseline. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula. Data are presented as mean ±SD. Estimates (average slopes) from the mixed-effect model. CL, confidence limit.
Slope (95% CL) estimate over time: –1.4 (−2.6; −0.1) ml/min per 1.73 m2 per year (P=0.03).
Slope (95% CL) estimate over time: –0.3 (−1.1; 0.6) ml/min per 1.73 m2 per year (P=0.53).
Slope (95% CL) estimate over time: –0.5 (−2.0; 1.0) ml/min per 1.73 m2 per year (P=0.52).
Slope (95% CL) estimate over time: –0.7 (−1.4; 0.0) ml/min per 1.73 m2 per year (P=0.05).
Figure 1.
Flow chart of patient disposition. Data on creatinine concentrations at baseline and after ≥5 years of treatment were available for 208 of 1120 agalsidase alfa–treated patients. For clinical investigation, the cohort of patients was subdivided according to renal function (Kidney Disease Outcomes Quality Initiative stages), to arterial BP and to urinary protein excretion at baseline. FOS, Fabry Outcome Survey; eGFR, estimated GFR; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration.
This study included 912 patients (525 male; mean age at baseline, 37.7±16.8 years) who had received ERT, but did not fulfill the inclusion criteria for this analysis (due to being aged <18 years, not yet having completed ≥5 years of treatment, having stage IV or V renal disease at baseline, or having missing data on renal function). Of these 912 patients, 57 (46 male; 31 children; mean age at baseline, 25.8±15.4 years) had renal creatinine clearance data at baseline and the ≥5-year time point. The eGFR for this subgroup changed from 92.9±55.4 at the baseline to 76.4±48.7 ml/min per 1.73 m2 at the end of follow-up. In addition, 783 patients (212 male; mean age at baseline, 35.0±18.3 years) had never received ERT (for a variety of reasons including having a low degree of disease severity and ERT not being available). Of these 783 patients, 46 (7 male; 14 children; mean age at baseline, 28.9±17.8 years) had renal data at baseline and the ≥5-year time point. For this subgroup, eGFR changed from 106.2±42.7 at baseline to 94.6±31.0 ml/min per 1.73 m2 at the end of follow-up.
eGFR
In men, there was a small but significant (P<0.01) decline in renal function from baseline over the ≥5 years of treatment, with a mean rate of change (95% confidence limits [95% CL]) of −2.2 [−2.8; −1.7] ml/min per 1.73 m2 per year. In women, there was a stabilization of renal function over the follow-up period, with a mean rate of change (95% CL) of −0.7 (−1.4; 0.0) ml/min per 1.73 m2 per year (P=0.05) (Tables 1 and 2, Figure 2).
Figure 2.
Graph showing the line plots of estimated GFR (eGFR) (mean ± SD) from baseline and throughout the follow-up in patients treated with agalsidase alfa. The upper line represents male patients and the lower line represents female patients. Numbers of patients in each group are shown in parentheses.
Proteinuria
Changes in the level of proteinuria over the ≥5-year follow-up period were minimal. Overall, the extent of change in proteinuria levels within each gender group was limited and therefore not statistically significant (Table 3).
Table 3.
Proteinuria levels at ≥5 years in treated patients
| n | Mean Proteinuria at Baseline (mg/24 h) | Mean Proteinuria at Year End (mg/24 h) | Mean Change in Proteinuria to Year End (mg/24 h) | t Test (P Value) | |
|---|---|---|---|---|---|
| Men | |||||
| stage I (≥90) (n=57) | |||||
| year 5 | 40 | 474.0±410.2 | 692.4±788.7 | 218.4±632.3 | 0.04 |
| year 5+ | 57 | 384.9±383.4 | 704.3±934.0 | 319.3±762.5 | ≤0.01 |
| stage II (60–89) (n=19) | |||||
| year 5 | 14 | 1185.9±1323.9 | 1149.8±2310.8 | −36.1±1626.0 | 0.94 |
| year 5+ | 19 | 914.7±1219.3 | 914.0±1852.2 | −0.6±1140.0 | 1.00 |
| stage III (30–59) (n=8) | |||||
| year 5 | 7 | 1407.1±1494.0 | 1315.7±1239.1 | −91.4±648.0 | 0.72 |
| year 5+ | 8 | 1286.0±1425.0 | 924.1±935.7 | −362.0±657.4 | 0.16 |
| total (n=84) | |||||
| year 5 | 61 | 744.4±926.2 | 868.9±1333.2 | 124.5±944.5 | 0.31 |
| year 5+ | 84 | 590.6±832.2 | 772.6±1190.1 | 182.1±871.6 | 0.06 |
| Women | |||||
| stage I (≥90) (n=10) | |||||
| year 5 | 7 | 220.7±233.5 | 146.3±90.9 | −74.4±157.0 | 0.26 |
| year 5+ | 10 | 275.8±321.5 | 184.3±156.1 | −91.5±365.2 | 0.45 |
| stage II (60–89) (n=27) | |||||
| year 5 | 23 | 384.2±493.5 | 339.0±205.8 | −45.2±494.9 | 0.67 |
| year 5+ | 27 | 387.7±493.9 | 307.7±345.5 | −80.0±473.5 | 0.39 |
| stage III (30–59) (n=9) | |||||
| year 5 | 9 | 222.8±192.9 | 314.3±413.3 | 91.4±315.9 | 0.41 |
| year 5+ | 9 | 222.8±192.9 | 1018.9±2022.4 | 796.0±2080.0 | 0.28 |
| total (n=46) | |||||
| year 5 | 39 | 317.6±405.0 | 298.7±259.0 | −18.9±413.0 | 0.78 |
| year 5+ | 46 | 331.1±416.2 | 420.0±944.8 | 88.9±1024.5 | 0.56 |
Groups are stratified according to Kidney Disease Outcomes Quality Initiative classification of renal function at baseline. Data are presented as mean ± SD.
Patients with baseline protein excretion of 500–1000 mg/24 h (group 2) had a slightly lower eGFR at baseline and at follow-up compared with patients with baseline urinary protein excretion <500 mg/24 h (group 1). During the study, the group with proteinuria 500–1000 mg/24 h (group 2) had a yearly slope (95% CL) of renal function of –1.6 (−2.6; −0.7) ml/min per 1.73 m2 per year, and the group with proteinuria <500 (group 1) had a slope (95% CL) value of –1.1 (−1.7; −0.6) ml/min per 1.73m2 per year (P=0.36). The group of patients with proteinuria >1 g/24 h (group 3) had a lower mean eGFR at baseline and after ≥5 years compared with the other protein excretion groups. The yearly slope (95% CL) was –3.9 (−5.0; −2.7) ml/min per 1.73 m2, which was significantly worse than the slopes of group 1 and group 2 (P≤0.01 versus group 1, and P<0.01 versus group 2) (Table 4).
Table 4.
Estimated GFR (eGFR) in patients according to urinary protein excretion at baseline and after ≥5 years of treatment with agalsidase alfa
| KDOQI Stage at Baseline (ml/min per 1.73 m2) | Patients (n) | eGFRa (ml/min per 1.73 m2) | t Test (P Value) | Slope Estimate (ml/min per 1.73 m2 per yr)a | P Value | ||
|---|---|---|---|---|---|---|---|
| Baseline | 5+ yr | Mean Change | |||||
| Group 1: proteinuria <500 mg/24 h at baseline (n=120) | |||||||
| stage I (≥90) | 68 | 109.7±14.1 | 93.8±22.1 | −15.9±17.8 | <0.01 | −1.9 | <0.01 |
| stage II (60–89) | 41 | 76.7±8.6 | 75.5±15.6 | −1.1±12.8 | 0.58 | −0.4 | 0.35 |
| stage III (30–59) | 11 | 53.8±4.8 | 49.1±14.4 | −4.7±10.9 | 0.19 | −1.1 | 0.13 |
| total | 120 | 93.3±23.1 | 83.5±23.8 | −9.8±17.1 | <0.01 | −1.1 | <0.01 |
| Group 2: Proteinuria 500–1000 mg/24 h at baseline (n=28) | |||||||
| stage I (≥90) | 13 | 118.2±19.3 | 88.1±28.4 | −30.2±30.9 | 0.04 | −3.4 | <0.01 |
| stage II (60–89) | 9 | 81.6±8.8 | 83.6±13.7 | 2.0±14.9 | 0.70 | 0.1 | 0.90 |
| stage III (30–59) | 6 | 48.0±10.4 | 37.8±9.2 | −10.2±7.1 | 0.02 | −1.6 | 0.09 |
| total | 28 | 91.4±31.7 | 75.9±29.0 | −15.6±26.7 | ≤0.01 | −1.6 | <0.001 |
| Group 3: Proteinuria >1000 mg/24 h at baseline (n=19) | |||||||
| stage I (≥90) | 5 | 116.9±13.0 | 78.9±41.5 | −38.0±32.3 | 0.06 | −4.6 | <0.01 |
| stage II (60–89) | 9 | 75.8±6.1 | 43.0±20.0 | −32.8±19.8 | ≤0.01 | −4.8 | <0.01 |
| stage III (30–59) | 5 | 43.0±8.0 | 32.9±14.4 | −10.0±19.1 | 0.31 | −2.1 | ≤0.05 |
| total | 19 | 78.0±28.9 | 49.8±30.7 | −28.2±24.8 | <0.01 | −3.9 | <0.01 |
Groups are stratified according to Kidney Disease Outcomes Quality Initiative (KDOQI) classification of renal function at baseline. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula. Results of statistical analyses are as follows. Total proteinuria at baseline: group 1 versus group 2 (93.3±23.1 versus 91.4±31.7 ml/min per 1.73 m2, respectively; P=0.77); group 1 versus group 3 (93.3±23.1 versus 78.0±28.9 ml/min per 1.73 m2 per year, respectively; P=0.01); group 2 versus group 3 (91.4±31.7 versus 78.0±28.9 ml/min per 1.73 m2 per year, respectively; P=0.15). Total proteinuria at ≥5 years: group 1 versus group 2 (83.5±23.8 versus 75.9±29.0 ml/min per 1.73 m2, respectively; P=0.15); group 1 versus group 3 (83.5±23.8 versus 49.8±30.7 ml/min per 1.73 m2, respectively; P<0.01); group 2 versus group 3 (75.9±29.0 versus 49.8±30.7 ml/min per 1.73 m2, respectively; P≤0.01). eGFR slope (ml/min per 1.73 m2 per year): group 1 versus group 2 (–1.1 versus –1.6 ml/min per 1.73 m2 per year; p=0.36); group 1 versus group 3 (–1.1 versus –3.9 ml/min per 1.73 m2 per year; P<0.01); group 2 versus group 3 (–1.6 versus −3.9 ml/min per 1.73 m2 per year; P≤0.01). Data are presented as mean ± SD.
Estimates (average slopes) from the mixed-effect model including all intermediate yearly data.
Arterial Hypertension
In hypertensive patients, baseline systolic and diastolic BPs were 131.9±17.2 mmHg and 80.7±12.1 mmHg, respectively. In normotensive patients, baseline systolic and diastolic BPs were 118.0±12.9 and 69.1±9.8 mmHg, respectively. After ≥5 years, systolic and diastolic BPs were 123.3±15.7 and 75.9±11.4 mmHg, respectively, in patients with hypertension at baseline, and 120.0±14.2 and 73.2±9.6 mmHg, respectively, in patients who were normotensive at baseline.
Baseline eGFR was significantly lower in hypertensive than normotensive patients, and patients with hypertension experienced a greater decline in renal function, expressed as the eGFR slope (95% CL), compared with normotensive patients (−2.4 [−3.1; −1.7] versus −1.2 [−1.7; −0.6] ml/min per 1.73 m2 per year, respectively; P<0.01). Furthermore, hypertensive patients had a lower eGFR than normotensive patients at follow-up (Table 5).
Table 5.
Arterial hypertension and renal function during treatment with agalsidase alfa
| KDOQI Stage at Baseline (ml/min per 1.73 m2) | Patients (n) | eGFR ml/min per 1.73 m2 | t Test (P Value) | Slope Estimate (ml/min per 1.73 m2 per yr)a | P Value | ||
|---|---|---|---|---|---|---|---|
| Baseline | 5+ yr | Mean Change | |||||
| Hypertension at baseline (n=66) | |||||||
| stage I (≥90) | 23 | 102.7±8.9 | 76.8±28.2 | −25.9±26.9 | <0.01 | −3.4 | <0.01 |
| stage II (60–89) | 32 | 76.0±8.3 | 65.0±18.9 | −11.0±17.7 | 0.01 | −1.7 | 0.01 |
| stage III (30–59) | 11 | 50.2±6.1 | 38.5±10.7 | −11.6±8.8 | 0.01 | −2.1 | <0.01 |
| total | 66 | 81.0±20.1 | 64.7±25.0 | −16.3±21.4 | <0.01 | −2.42 | <0.01 |
| No hypertension at baseline (n=142) | |||||||
| stage I (≥90) | 83 | 113.5±15.5 | 95.4±24.1 | −18.1±21.7 | <0.01 | −2.1 | <0.01 |
| stage II (60–89) | 43 | 76.6±8.3 | 75.9±18.6 | −0.7±16.1 | 0.78 | −0.2 | 0.64 |
| stage III (30–59) | 16 | 49.8±8.8 | 43.4±17.4 | −6.4±16.9 | 0.15 | −1.3 | 0.06 |
| total | 142 | 95.2±26.6 | 83.6±27.5 | −11.5±21.1 | <0.01 | −1.2 | <0.01 |
Groups are stratified according to Kidney Disease Outcomes Quality Initiative classification of renal function at baseline. The estimated GFR (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula. Results of statistical analyses are as follows. Total eGFR at baseline: hypertension versus no hypertension (81.0±20.1 versus 95.2±26.6 ml/min per 1.73 m2, respectively; P<0.01). Total eGFR at 5+ years: hypertension versus no hypertension (64.7±25.0 versus 83.6±27.5 ml/min per 1.73 m2, respectively; P<0.01). Total eGFR slope/year: hypertension versus no hypertension (–2.4 versus–1.2 ml/min per 1.73 m2 per year; respectively; P<0.01. Data are presented as mean ± SD.
Estimates (average slopes) from the mixed-effect model including all intermediate yearly data.
Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers
The effects of drugs interfering with the renin–angiotensin system (angiotensin-converting enzyme [ACE] inhibitors and/or angiotensin receptor blockers [ARBs]) on the progression of nephropathy and on proteinuria were retrospectively investigated. There was no difference in the rate of progression of renal damage between those patients who were taking these drugs (84 patients) and those not taking these medications (124 patients) after the start of ERT. Indeed, the mean yearly change in eGFR was −2.5±3.2 ml/min per 1.73 m2 in patients receiving ACE inhibitors and/or ARBs and −1.1±2.5 ml/min per 1.73m2 per year in those not receiving these drugs. Proteinuria was not affected by the use of ACE inhibitors and/or ARBs; urinary protein excretion was actually 671±723 mg/24 h at baseline and 940±1226 mg/24 h at ≥5 years in patients taking ACE inhibitors and/or ARBs (n=58) and 360±696 mg/24 h at baseline and 413±970 mg/24 h at follow-up in patients not treated with these drugs (n=72).
Discussion
Since the introduction of ERT in 2001, the short-term effectiveness of this therapy in the treatment of Fabry disease–related nephropathy has been well established (16). Data on the long-term benefits of ERT on renal function are more limited. This study used the CKD-EPI formula to estimate GFR in place of the MDRD formula. It has been suggested that this new formula may overcome some of the limitations of the MDRD formula, such as the systematic underestimation of GFRs ≥60 ml/min per 1.73 m2 (10,11,17). This is particularly important given that most articles on ERT and Fabry nephropathy describe patients with GFRs higher or lower than 60 ml/min per 1.73 m2 (12). Furthermore, compared with other formulae, the CKD-EPI has recently been shown to provide the best estimate of GFR in patients with Fabry disease (18). Thus, the present data on the changes in eGFR are likely to be more accurate (19,20) than those reported in previous studies.
In this study, a large group of patients were followed for a mean period of 7.4 years, which is a longer follow-up than that reported in previous similar studies. Results confirm the benefits of ERT in patients with Fabry disease–related nephropathy. The mean yearly change in eGFR was −2.2 ml/min per 1.73 m2 per year in men, whereas the yearly decline in eGFR was within the normal physiologic range in women in whom ERT stabilized renal function (21). We also evaluated the yearly slope of decline in renal function and observed stabilization in the yearly reduction of eGFR, which reached a constant annual rate. The effectiveness of ERT with agalsidase alfa is supported by data from a previous FOS analysis (22,23). In an earlier study based on data as of October 2007, and using the MDRD formula, Mehta et al. reported a mean rate of change in eGFR of −3.17 ml/min per 1.73 m2 per year in men and −0.89 ml/min per 1.73 m2 per year in women (22). The smaller decline in renal function in men in this study may be due, in part, to the use of the new more precise CKD-EPI formula, but may also be related to the fact that the male population studied was followed for a longer time period than in the Mehta et al. study. Indeed, it may be hypothesized that the longer follow-up period in this study exposed a sustained effect of the ERT.
In a recent study, the natural progression of nephropathy was retrospectively described in a large group of patients with Fabry disease who were assessed before ERT became available (24). The mean rates of change in eGFR reported by Schiffmann et al. were notably higher than those obtained in this study. Indeed, in men, the rates were −3.0 and −6.8 ml/min per 1.73 m2 per year in patients with an eGFR higher and lower than 60 ml/min per 1.73 m2, respectively. All of our values for the rates of change in eGFR in men were lower than −2.6 ml/min per 1.73 m2 per year and, interestingly, the overall mean rate of change in eGFR was just −2.2 ml/min per 1.73 m2 per year. In women with an eGFR <60 ml/min per 1.73 m2, the rate of change of GFR was −0.9 ml/min per 1.73 m2 per year (−0.5 ml/min per 1.73 m2 per year in this study); in women with an eGFR >60 ml/min per 1.73 m2, the rate of change of GFR was −2.1 ml/min per 1.73 m2 per year (stage I, –1.4 ml/min per 1.73 m2 per year; stage II, −0.3 ml/min per 1.73 m2 per year in this study).
Interestingly, despite receiving ERT, the patients in stage I with minimal proteinuria showed a significant reduction of mean change of eGFR; however, the yearly slope was only a little bit higher than the total value. This reduction could be an indirect evidence, of a renal dysfunction (7,25) in the early phase of Fabry nephropathy; ERT should reduce hemodynamic alterations.
The negative effect of proteinuria (>1 g/24 h) on the evolution of nephropathies has long been recognized (26), and has also been noted in patients with Fabry disease (5,7,27). In a recent article by Wanner et al. (28), patients who presented with rapid renal deterioration were found to have significantly higher mean averaged urinary protein to urinary creatinine ratios than patients with slower progression (1.5 versus 0.2 for men; 1.4 versus 0.5 for women; P<0.0001). In addition, it has been widely reported that ERT does not reduce proteinuria in patients with Fabry nephropathy (5–7,27,29–31) and only association with ACE inhibitors seems to be effective (32). Our data confirm, accordingly with recent literature (33,34), the fact that patients with proteinuria >1 g/24 h have a faster decline of eGFR and we recommend reducing proteinuria in those patients as much as possible by utilizing antiproteinuric drugs. Moreover, after our previous experience (35), we looked at the prognostic meaning of having proteinuria levels <1 g/24 h. In this study, patients with baseline proteinuria <500 had again a minor yearly slope of eGFR than patients with baseline proteinuria of 500–1000 mg/24 h, but this difference was not statistically significant after >5 years of follow-up. However, this finding supports that reduction of proteinuria is always associated with a better renal prognosis.
Arterial hypertension is another risk factor for the progression of renal diseases, and antihypertensive therapy is usually associated with a reduction in the rate of progression (36). A significant percentage of patients with Fabry disease have overt hypertension associated with renal involvement and its prevalence increases with the reduction of renal function (1,24). In this study, we observed that eGFR at baseline was lower in hypertensive than normotensive patients. During the study, the reduction in eGFR in hypertensive patients was significantly greater than in normotensive patients, although mean arterial pressure, both systolic and diastolic, indicated appropriate BP control. That said, there was a wide SD around the mean and therefore BP control may not have been achieved in a substantial number of patients. In other words, our data confirm the negative effect of the presence of arterial hypertension in the progression of Fabry nephropathy. In addition, a nonoptimal BP control is associated with higher levels of proteinuria and a faster progression toward renal failure.
Therapy with ACE inhibitors and/or ARBs is recommended in all renal diseases to treat proteinuria and arterial hypertension as well as to prevent progression toward renal failure (37,38). However, we did not find any significant differences in renal data between patients receiving ACE inhibitors and/or ARBs and those not receiving these drugs. These unexpected findings may be explained by the limitations inherent to observational studies (retrospective design, large SDs, etc) and to the use of ACE inhibitors and/or ARBs, which was largely to control BP and the doses were not generally titrated to reduce proteinuria to <500 mg/24 h. Furthermore, evidence exists in the literature demonstrating a greater protective role of ACE inhibitors on the progression of kidney diseases in patients with more severe proteinuria, and only small or no beneficial effects in patients with milder proteinuria (39), as occurs in Fabry nephropathy. Interestingly, it was demonstrated in a recent article (40) that ERT interacts with ACE and inhibits its activity, possibly by removing the galactose residues from the enzyme. Furthermore, patients with Fabry disease treated with ERT have upregulated ACE activity. This interaction could make the effects of ACE inhibitors and/or ARBs unusual in patients with Fabry disease. However, at this time, the role of ACE inhibitors and/or ARBs for reducing proteinuria and/or the progression of renal dysfunction in Fabry nephropathy has not yet been completely defined.
Because it is a survey analysis, this study has some known limitations, including the lack of a control group as well as a small number of patients with proteinuria measurements. However, this analysis in a large study population confirms, using a new and more appropriate formula for evaluating eGFR, that ERT with agalsidase alfa is able to stabilize or slow the progression of renal damage in patients with Fabry disease. Careful control of established risk factors for renal disease, most notably proteinuria and hypertension, should also be mandatory.
Disclosures
S.F., J.T., M.C., G.S.-P., and M.W. received speaker fees, travel grants, and research support from Shire HGT and Genzyme. K.N. received travel grants and research support from Shire HGT, Genzyme, and Amicus.
Acknowledgments
The authors thank all of the FOS investigators who have submitted data from their patients to the FOS database. The FOS database is under the independent control of the FOS International Board. Editorial assistance to the authors was provided by Dr. Harriet Crofts (Oxford PharmaGenesis Ltd, Oxford, UK).
Data collection and analysis in FOS were supported by Shire Human Genetic Therapies (HGT). Funding for editorial assistance was provided by Shire HGT.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
Access to UpToDate on-line is available for additional clinical information at www.cjasn.org.
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