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Mehta A, Beck M, Sunder-Plassmann G, editors. Fabry Disease: Perspectives from 5 Years of FOS. Oxford: Oxford PharmaGenesis; 2006.
In the absence of large-scale placebo-controlled trials of enzyme replacement therapy (ERT) in patients with Fabry disease, FOS – the Fabry Outcome Survey – is providing valuable clinical data on the renal benefits of ERT with agalsidase alfa. Long-term longitudinal data in male and female patients with mild to moderate renal disease at baseline has clearly demonstrated a stabilization of renal function, compared with the decline seen in the period before treatment.
Introduction
Abnormalities of renal function are one of the most clinically significant features of Fabry disease and constitute an important cause of premature morbidity and mortality. Renal disease is often observed early in the course of Fabry disease [1] and is characterized by microalbuminuria, proteinuria, hypertension and a decreased glomerular filtration rate (GFR). It may ultimately progress to end-stage renal disease (ESRD) [2–6]. These abnormalities affect both males and females, although ESRD is uncommon in females. The renal manifestations of Fabry disease are discussed fully in Chapter 21.
Until recently, the clinical management of patients with Fabry disease was limited to symptomatic and supportive therapies only. Enzyme replacement therapy (ERT) with agalsidase alfa was licensed by the European Agency for the Evaluation of Medicinal Products in August 2001. The initial trials that led to the introduction of ERT focused on the effects of enzyme replacement on pain. However, patients in the early randomized double-blind trials of both agalsidase alfa [7] and agalsidase beta [8] underwent serial renal biopsies, which revealed that ERT had significant beneficial effects on renal histology. These included reduction in endothelial cell globotriaosylceramide content, reduction in mesangial widening and an increase in the number of histologically normal glomeruli. Most patients in the initial studies had normal renal function. There are no placebo-controlled studies assessing the impact of ERT on renal function in patients with Fabry disease. The effects of this intervention therefore have to be assessed using data from outcomes databases such as FOS – the Fabry Outcome Survey. There are, however, difficulties associated with such outcome studies (Chapter 14). The specific problems relating to assessing the impact of ERT on renal function in a patient database are described below.
Difficulties with registry studies
Measurement of outcome
The first issue is how should outcome be measured? One of the earliest signs of renal involvement in Fabry disease is the loss of the concentrating ability of the kidneys. However, isosthenuria is not easily detectable by routine methods. Proteinuria is another important feature of renal damage, although it is variable from day to day and depends on the GFR; a decline in the GFR, for example, is accompanied by reduced amounts of filtered protein. Thus, proteinuria should be adjusted for the amount of creatinine in the urine. In addition, females with Fabry disease frequently have proteinuria but only rarely develop ESRD, and proteinuria is often found in asymptomatic children. Overall, therefore, proteinuria does not appear to be a good index of the extent of renal damage, although the presence or absence of proteinuria (or the onset of microalbuminuria) may be a useful marker of the onset of damage and an indication to start ERT.
The GFR may be a better indicator of renal function, although there are issues concerning its measurement. It is convenient to estimate GFR from serum creatinine using the short MDRD (Modification of Diet in Renal Disease) formula, but this formula is not applicable to all categories of patients and has not been validated in children or in patients with normal or near-normal renal function. Creatinine clearance is not always an accurate measure of renal function and should be corrected for muscle mass, age, gender and race. In addition, it is essential that urine collections should be complete. Within an outcomes database, the patients who have been included will have undergone diverse measurements, and this variability may introduce further errors. A radioactive chromium-EDTA or DTPA clearance measurement is generally considered the 'gold standard', but has not been applied uniformly in FOS. Patients at an early stage of renal impairment may have a period of hyperfiltration; thus an elevated GFR (> 150 ml/min/1.73 m2 in patients older than 18 years) may indicate early renal involvement.
Effect of concomitant medication
Another issue is that patients' concomitant medication is subject to variation. An improvement in pain may lead to a reduction in analgesic consumption that may, in turn, lead to an improvement in renal function. The successful treatment of blood pressure and, especially, the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers may result in a reduction in progression of renal failure, which is independent of the effect of concomitant ERT.
Database deficiencies
A third issue is that FOS is a multicentre outcomes survey. As such, the database lacks the consistency of a clinical trial, although there are basic similarities in the procedures used at each of the different participating centres. In addition, long-term follow-up data may be incomplete, and there is an ongoing need within such databases to maximize data recording.
Different organ systems
Finally, the effects of ERT are not necessarily consistent across different organ systems. Thus, a patient may demonstrate improvement in cardiac parameters (including reduction in left ventricular mass) and yet show deterioration in GFR, or may report substantial improvements in pain but little or no improvement in cardiac parameters.
Baseline characteristics of the patient cohort
The data reported here are from an analysis of the FOS database conducted in March 2005. At that time, there were 74 centres participating in FOS located in 11 European countries. These centres had enrolled a total of 688 patients, 401 of whom were receiving ERT with agalsidase alfa, with the remainder not receiving ERT. Of these 688 patients, 330 were male (including 50 boys < 18 years of age) and 358 were female (including 69 girls < 18 years of age). The age range of male patients was 0.75–80.9 years and for females was 2.5–78.5 years.
Of the 401 patients who were receiving ERT, 160 were female and 241 were male. These 401 patients included 55 children (31 boys, 24 girls). The age range of treated patients was 3.5–68.9 years for males and 3.5–76.1 years for females.
Duration of ERT and age at the start of treatment
The duration of agalsidase alfa therapy amongst the 401 treated patients is illustrated in Figure 1. In total, 219 patients (71 females, 148 males) had been receiving agalsidase alfa for 2 or more years, and 133 (31 females, 102 males) of these had been treated for 3 or more years. The age of patients at the start of agalsidase alfa therapy is shown in Figure 2, which illustrates the older age of female patients than male patients at the commencement of ERT. Although the mean and median ages at which patients with Fabry disease commenced agalsidase alfa therapy remained essentially unchanged between 2001 and 2004/2005, the range increased, demonstrating a progressively greater proportion of both younger and older patients starting treatment over time.
Figure 1
Duration of treatment with agalsidase alfa in the 401 treated patients enrolled in FOS – the Fabry Outcome Survey – as of March 2005.
Symptom severity at the start of ERT
The Mainz Severity Score Index (MSSI) [9] is an overall measure of the clinical severity of Fabry disease. The scoring system has been adapted for use in FOS (FOS-MSSI), omitting the renal and cardiac laboratory assessments included in the original MSSI score (see Chapter 32). Figure 3 displays the severity of Fabry disease manifestations as assessed by the FOS-MSSI for patients commencing treatment between 2001 and 2004/05. The mean and median pretreatment FOS-MSSI scores declined over time between 2001 and 2004/05, indicating that physicians chose initially to commence agalsidase alfa therapy in the most severely symptomatic patients and later extended ERT to less severely affected patients, including a greater proportion of children and females.
Renal function before the start of ERT
Figure 4 shows renal function, presented as the estimated GFR (eGFR) calculated using the MDRD equation, prior to the start of ERT with agalsidase alfa and classified according to gender and year of commencement of ERT. The analysis includes all patients with eGFR data available at baseline who subsequently received agalsidase alfa (297 of the 401 treated patients). For males, the mean and median severity of renal dysfunction at the start of ERT with agalsidase alfa has decreased over time. Most patients commencing ERT have a baseline eGFR between 60 and 90 ml/min/1.73 m2, which is defined as stage 2 chronic kidney disease (CKD) by the Kidney Disease Outcomes Quality Initiative classification.
Agalsidase alfa therapy and renal function
Figure 5 depicts the change in eGFR among adult patients with Fabry disease who have received agalsidase alfa therapy for 1, 2 or 3 years. All patients had renal involvement before treatment, with eGFR values in the range 30–89 ml/min/1.73 m2. Data are excluded for those patients who were less than 18 years of age at the start of ERT, had normal renal function at baseline or had more than a 3-month interruption of ERT. An annual rate of decline in GFR of approximately 12 ml/minute in untreated patients with Fabry disease was demonstrated by Branton and colleagues [10]. In comparison with this benchmark, agalsidase alfa therapy appears to slow the decline in renal function in adult patients with Fabry disease with a baseline eGFR of 30–89 ml/min/1.73 m2. Mean and median eGFR values at baseline and after 1, 2 and 3 years of agalsidase alfa therapy are summarized by gender in Table 1. The effect of agalsidase alfa in preserving renal function was approximately equal in males and females. After 2 years of treatment, only one out of 28 males experienced a fall in eGFR below 30 ml/min/1.73 m2. Likewise, among the 34 female patients, only one experienced a fall in eGFR below 30 ml/min/1.73 m2 (declining to 29.97 ml/min/1.73 m2) during 2 years of agalsidase alfa therapy.
Figure 6 and Table 2 show the serial changes in eGFR for patients with a baseline eGFR of 30–89 ml/min/1.73 m2 after 2 and 3 years of ERT in a subgroup of patients for whom complete serial eGFR values were available. Again, these data clearly demonstrate a stabilization of renal function after long-term treatment with agalsidase alfa.
Detailed analysis of the FOS database reveals two further lines of evidence, that strongly support a beneficial effect of agalsidase alfa treatment on renal function.
The first of these analyses involved a subgroup of patients for whom GFR data were available from 1 year before treatment, at the start of treatment (baseline) and 1 year after the start of treatment (12 patients with CKD stage 2 and 8 patients with CKD stage 3 at baseline). Renal function in the 12 patients (10 females and 2 males; mean age, 40 years; range, 19–71 years) with baseline CKD stage 2 declined significantly (p < 0.05) in the year before the start of treatment. There was a similar decline in renal function in the eight patients (4 females and 4 males; mean age, 49 years; range, 29–69 years) with CKD stage 3 during the year before the start of treatment, although this did not reach significance.
After 1 year of treatment, however, the progressive loss of GFR had been stabilized in both groups of patients (Figure 7a [11]).
In 13 of these 20 patients, follow-up data for 2 years after the start of treatment were available (8 patients with CKD stage 2 and 5 patients with CKD stage 3 at baseline). Again, in contrast to the decline in GFR before the start of ERT, renal function remained stable in both groups over 2 years (Figure 7b [11]). There was no clear effect of concomitant therapy in these 20 patients; five used ACE inhibitors or angiotensin receptor blockers at the start of ERT, another five used these drugs at other times, and information on concomitant renal-protective medication was not available for the remaining ten patients.
The second analysis of FOS data involved a multivariate study of 1040 serum creatinine measurements from 201 patients with Fabry disease, aged 20–60 years. All patients had serum creatinine concentrations below 2 mg/dl and had received ERT with agalsidase alfa for up to 4.7 years. Both pretreatment and treatment data were used to examine independent predictors of changes in serum creatinine.
Independent positive associations were found between serum creatinine concentrations and age, gender and body mass index (BMI) (all p < 0.01) and an inverse association was noted between serum creatinine and time on agalsidase alfa therapy (p < 0.05, R2 = 23%) (Table 3), as defined by the following equation:
Table 3
Independent associations of serum creatinine with time on agalsidase alfa enzyme replacement therapy (ERT) in 201 patients with Fabry disease in FOS – the Fabry Outcome Survey.
Effect of agalsidase alfa on renal function in children
To assess renal function in paediatric patients with Fabry disease, the Counahan–Barratt equation [12] was used to determine the eGFR at baseline and after 1 year of agalsidase alfa therapy. Figure 8 gives the mean eGFR at baseline and after 1 year of agalsidase alfa therapy for 21 of 55 paediatric patients treated with agalsidase alfa for whom serum creatinine data were available. Mean and median values for eGFR at baseline and after 1 year of agalsidase alfa therapy are summarized by gender in Table 4.
At baseline, 12 of the 21 patients had eGFR values less than 90 ml/min/1.73 m2 and seven patients had normal eGFR values in the range of 90–135 ml/min/1.73 m2. The remaining two patients (boys aged 3.4 and 12.7 years) had baseline eGFR values above 135 ml/min/1.73 m2. From the preliminary paediatric data presented in Figure 8 and Table 4, it can be concluded that renal function, on average, remained stable in this subgroup of patients receiving agalsidase alfa therapy for 1 year, as would be expected at this early stage of the disease. The small decrease in mean eGFR was driven by the two children with a high eGFR at baseline. Both of these boys showed apparent 'improvement' in their renal function after 1 year of agalsidase alfa therapy, as indicated by a large decrease in their eGFR from above 135 ml/min/1.73 m2 to less than 99 ml/min/1.73 m2. This preliminary conclusion, however, must be considered tentative in view of the small number of patients and the recognized unreliability of eGFR values above 90 ml/min/1.73 m2.
Effect of agalsidase alfa on proteinuria
Figure 9 depicts the effects of agalsidase alfa treatment on proteinuria (measured as total protein in 24-hour urine collections). In 40 patients with longitudinal data on proteinuria at the start and after 1 and 2 years of treatment, no significant change could be detected (Figure 9a). Similarly, in a group of 12 patients with longitudinal data available over a 3-year treatment period, ERT with agalsidase did not affect the mean or median levels of proteinuria. It should be remembered, however, that there are limitations concerning the use of proteinuria as an accurate measure of renal damage.
Discussion and conclusions
ERT with agalsidase alfa leads to stabilization of renal function in patients with CKD stages 1 and 2. Among 17 male patients receiving ERT and with a baseline eGFR in the range 30–60 ml/min/1.73 m2 (stage 3 CKD), mean eGFR declined by less than 4 ml/min/1.73 m2 per year. The rate of decline in GFR of 12.2 ml/min/1.73 m2 per year reported by Branton et al. [10] in a cohort of 39 comparable untreated male patients with Fabry disease is clearly much higher than the values observed in patients who were receiving ERT with agalsidase alfa in FOS. In fact, more than half (62.5%) of the 39 patients reported by Branton et al. progressed to ESRD within 4 years, whereas none of the patients in FOS progressed to ESRD during 30–54 months of treatment. Renal function in both men and women with a baseline eGFR of 60–90 ml/min/1.73 m2 (stage 2 CKD) was stabilized after 1–2 years of ERT following a deterioration in the year before treatment. Further long-term analyses of renal data from the increasing numbers of patients receiving agalsidase alfa in FOS should not only further demonstrate the beneficial effects on renal function in adults, but should also help to determine whether ERT prevents the development of renal disease in patients starting treatment in childhood.
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- Effect of enzyme replacement therapy with agalsidase alfa on renal function in p...Effect of enzyme replacement therapy with agalsidase alfa on renal function in patients with Fabry disease: data from FOS – the Fabry Outcome Survey - Fabry Disease
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