Fabry nephropathy: a review – how can we optimize the management of Fabry nephropathy?

In Fabry disease, the decline in renal function over time is related to the degree of proteinuria and, in untreated patients, is more rapid when the eGFR is below 60 ml/min/1.73 m². Male sex and hypertension are also significant risk factors for development of renal failure [36]. As with all nephropathies, protein overload may cause an increase in the levels of inflammatory mediators, and interstitial accumulation of these mediators may lead to renal scarring. In patients with undiagnosed Fabry renal disease, a significant number of glomeruli may already be sclerotic [37]. Reduced nephron mass thus increases the risk of further renal damage from hyperfiltration, proteinuria, and activation of angiotensin II [37].

Consequently, regular, reproducible estimates of renal function are essential in the management of Fabry disease. Most centres now use the eGFR calculated using the MDRD (modified diet in renal disease) equation to assess renal function during follow-up [38]. There are limitations to current GFR estimates [39] and the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation is recommended in adults. In children, a CKD-EPI equation developed by Schwartz et al. has been used successfully [40]. GFR can be measured more accurately using the iohexol plasma disappearance curve [40]. Rombach and colleagues suggest that the Stevens’ equation (a creatinine- and cystatin C-based formula) is also helpful, although it is recognized that cystatin C is not uniformly available [39].

Proteinuria is an early sign of Fabry renal disease in both sexes and is often the most frequent clinical manifestation [5, 6]. Importantly, proteinuria is an independent risk factor affecting the extent of renal decline in treated and untreated patients, as well as determining the success of ERT [41‐44].

Among patients in the FOS, proteinuria was present in 44–54% of males and 33–41% of females for whom renal data were available [45]. Similarly, data from 1,262 adult patients (585 males, 677 females) in the Fabry Registry demonstrated overt proteinuria (>300 mg/day) in 43% and 26% of males and females with CKD stage 1, respectively, with higher proportions in patients with more advanced kidney involvement [8]. Consequently, proteinuria should be monitored regularly and treated appropriately.

Renal biopsy is useful in all patients with any degree of proteinuria/albuminuria and/or renal dysfunction to assess the degree of glomerulosclerosis and interstitial damage because of their prognostic significance [2]. In patients with minimal proteinuria and normal renal function, biopsy can also determine if there is significant Gb₃ deposition (especially in podocytes and endothelial cells), or early damage to indicate ERT use. In the classical male patient with signs of renal involvement a renal biopsy can be helpful in providing evidence of prognosis depending on the degree of glomerular sclerosis [41]. In females with even the slightest evidence of Fabry nephropathy, renal biopsy is considered much more important (and by some mandatory) as the presence of significant renal Gb₃ deposits is an indication for initiating ERT. Renal biopsy should also be undertaken if there is the possibility of double pathology (e.g. diabetes or other glomerular diseases such as immunoglobulin A [IgA] nephropathy or thin membrane disease if haematuria is present) and if there is a sudden, unexplained decline in renal function [46, 47].

Fabry disease can be difficult to diagnose solely from standard light microscopy, so semi-thin toluene blue sections or electron microscopy should be performed particularly if there is doubt about the histological diagnosis [13]. The role of re-biopsy is still undetermined, especially for evaluating the results of ERT. However, a study by Tondel et al. found comparing deposition of Gb₃ in glomerular cells from renal biopsies taken at baseline and after 5 years of ERT to be useful in assessing the success of ERT [32]. It is better to compare Gb₃ deposition using semi-thin toluene-blue stained sections and/or electron microscopy, rather than with haematoxylin and eosin or periodic acid Schiff stained slides, where the Gb₃ deposition is dissolved by solvents during processing of the samples. Figure 2A illustrates how foam cells observed with haematoxylin and eosin staining could be confused with other causes of glomerular nephritis. Typical Fabry lesions observed with toluene-blue staining or electron microscopy are shown in Figures 2B–E.

Multiple renal cysts, mostly parapelvic, can be detected using ultrasonography in up to 50% of cases of patients [48]. Although uncommon, haematuria may also occur, but other causes must be excluded [46, 47]. The aetiology of cysts is unknown, but the cause of haematuria is similar to that found in other glomerular diseases.

In the FOS Registry, a high prevalence (57% of male and 47% of female patients) of uncontrolled hypertension was reported in patients with Fabry disease which generally increased with worsening CKD stage [49]. Similarly, in the Fabry Registry, hypertension (systemic blood pressure [BP] ≥130/80 mmHg) was observed more often in those with poor renal function (67% vs 48% of patients with eGFR ≥60 ml/min/1.73 m²) [8].

In general, the BP of patients with Fabry disease is lower than that of the general population, predominantly due to the effects of autonomic dysfunction on cardiac and vascular function [50], although the aetiology of this effect is complex and other factors may be involved. Consequently, the current target for controlling hypertension in the general population (systolic BP <130 mmHg or diastolic BP <80 mmHg) may be too high. Maintenance of a BP <125/75 mmHg in patients with proteinuria levels >1 g/day, and <130/80 mmHg in patients with proteinuria of 0.25–1 g/day has been advocated in CKD [37]. Caution is recommended in reducing BP <100/70 mmHg because this has been shown to increase the risk of cardiovascular and/or renal events [31, 51, 52].

Two ERT products are available for treating Fabry disease: agalsidase alfa (Replagal^®, Shire), produced in a human cell line by gene activation technology [53], and agalsidase beta (Fabrazyme^®, Genzyme), produced in Chinese hamster ovary (CHO) cells [54]. The recommended licensed dose for agalsidase alfa is 0.2 mg/kg/2 weeks and is 1 mg/kg/2 weeks for agalsidase beta.

Current UK guidelines for the management of Fabry disease state that, “No trial has yet addressed the appropriate starting time of treatment or the group of patients most likely to benefit from therapy. However this is a chronic, progressive disorder. The aim of treatment is to prevent progression and where disease is already manifest to try and reverse or stabilise the disease. It is anticipated that treatment will be most successful when started early in the course of the disease. Conversely treatment late in the course of the disease may have limited efficacy.”[38]. Therefore ERT should be started as soon as symptoms/signs occur in an effort to stabilize (or even reverse) pathology. In the UK, ERT treatment is indicated in patients with Fabry disease who have evidence of renal disease (defined as an eGFR <80 ml/min, proteinuria >300 mg/day) and/or microalbuminuria if a renal biopsy shows endothelial deposits [38, 51].

ERT has been shown to improve the clinical outcome of patients with Fabry disease, including stabilization of kidney function and reduction in neuropathic pain [41, 55‐57]. However, because of the heterogeneous disease presentation, no evidence is available to support the optimal timing of ERT or to identify the patient groups in whom disease is likely to be most rapidly progressive or which patients are most likely to gain significant benefit from therapy [58]. Data from the FOS have been used to develop an age- and sex-adjustment of the global Mainz Severity Score Index for Fabry disease. This scoring system corrects for the impact of age and sex on severity. By allowing meaningful comparisons across age and sex [59] it may be possible to determine clinical features that predict future disease severity.

Data from the FOS have also been used to develop organ-specific (cardiac, renal, and neurological) and composite prognostic severity scores [58]. Using the analysis it was possible to differentiate groups of patients with different outcome probabilities. The overall composite score, the Fabry International Prognostic Index (FIPI), distinguished two distinct groups in whom the 50% event-free survival differed by 10 years. The FIPI should prove to be a valuable tool in comparative analyses of outcomes using different therapies [58]. Additionally, a validated disease severity scoring system for Fabry disease has been developed (DS3) to quantify disease burden and monitor disease progression and response to treatment [60].

Data on the renal effects of agalsidase alfa and beta mostly originate from open-label and observational studies, including the FOS and the Fabry Registry [41, 45, 51, 55, 61‐64], with randomized, long-term, controlled data being limited to one placebo-controlled trial [44] and two studies that utilized historical controls [65, 66]. Although registries can provide long-term data on large patient populations, they are limited by their voluntary nature, which can result in incomplete follow-up data [67].

The renal benefits of ERT at tissue and clinical levels were demonstrated in a double-blind, randomized, placebo-controlled study of 26 patients given agalsidase alfa at 0.2 mg/kg/2 weeks for 6 months [55]. Significant improvements were seen in renal structure (increase in the percentage of mesangium) in patients receiving agalsidase alfa compared with placebo [55].

Similarly, agalsidase beta 1 mg/kg/2 weeks resulted in stabilization of the GFR with rapid, marked, reductions in plasma and tissue Gb₃ observed by biochemical and histological means [61]. A randomized, double-blind, placebo controlled Phase IV trial investigating the effects of agalsidase beta (1 mg/kg/2 weeks for up to 35 months [mean, 18.4 months]) on clinical outcomes in 82 adult patients with advanced Fabry disease and mild-to-moderate renal dysfunction found an increased time to first clinical event and stabilized renal function compared with placebo when adjusted for the degree of proteinuria [44].

Analyses of data from the FOS showed improvements in renal function based on 1,040 serum creatinine measurements in 201 patients [63]. Time on agalsidase alfa therapy was an independent predictor of serum creatinine levels (inverse association, p = 0.04; multivariate analyses). In patients with CKD stage 2 and 3, ERT halted the progressive decline in renal function within the first year of treatment (longitudinal analyses) [63].

The benefits of ERT with agalsidase beta over 54 months have also been reported: 41 patients with <50% glomerulosclerosis and ≤1 g proteinuria per 24 hours at baseline showed stable renal function [41].

Long-term positive results with ERT were confirmed in an analysis of renal function in a cohort of males and females (n = 150) in FOS receiving agalsidase alfa and adjunctive therapies for up to 5 years [68]. Annualized rates of decline by CKD stages are shown in Figure 3. Responder analysis showed normalization of the eGFR in 68.8–89.1% of those in CKD stages 1–3. The role of agalsidase alfa in preserving renal function is also supported by pooled data from three prospective, randomized, placebo-controlled trials and their open-label extension studies involving 108 adult male patients treated for 1–4 years [56]. The rate of eGFR loss in patients with a baseline eGFR of 30–135 ml/min per 1.73 m² was less than that seen during the placebo period. Multivariate analyses revealed that the eGFR and proteinuria (<1 or ≥1 g/day) at baseline significantly predicted the rate of decline of the eGFR during treatment (Figure 4).

Renal function was evaluated in 151 men and 62 women from the Fabry Registry receiving agalsidase beta at 1 mg/kg/2 weeks for at least 2 years [51]. Multivariate logistic regression analyses were used to identify factors associated with the progression of renal disease. The risk factor most strongly associated with such progression was an averaged urinary protein:creatinine ratio ≥1 g/g and delays in treatment initiation compared with symptom onset.

In the latest long-term study on ERT effectiveness, renal function was assessed in 208 patients (mean time on ERT, 7.4 years). The mean yearly change in eGFR was -2.2 ml/min/1.73 m² in men and -0.7 ml/min/1.73 m² in women [62]. In another study by Tondel et al., which monitored the effects of ERT in 12 patients over 5 years using serial renal biopsies, ERT was associated with the clearance of Gb₃ deposition from glomerular cells, especially in those receiving high doses of ERT. However, this study was carried out in a small number of patients and these results need to be confirmed in a larger study [32]. It also has been suggested that clearance of Gb₃ from podocytes may be affected by heterogeneity between patients in the expression levels of receptors (mannose-6-phosphate receptor, sortilin and megalin) that are responsible for the uptake of alpha-galactosidase A into the lysosomes of podocytes [71].

Patients with impaired renal function have a less favourable outcome than those without renal impairment. A 2-year, open-label study of 26 patients with Fabry disease treated with agalsidase beta (1 mg/kg/2 weeks) reported that 9 patients experienced 12 endpoints, including 2 deaths [72]. All clinical endpoints (cerebrovascular and cardiac events, renal failure, and death) occurred in patients with impaired renal function. Despite ERT, renal function deteriorated and left ventricular posterior wall thickness (PWT) was unaltered. In contrast, patients without renal impairment at baseline had a more favourable outcome post-treatment (no clinical events, renal function remained unchanged, and PWT decreased significantly).

Similarly, in a multivariate logistic regression analysis of renal function from 151 men and 62 women from the Fabry Registry who received agalsidase beta (1 mg/kg/2 weeks) for at least 2 years, adults with Fabry disease were at risk of progressive reduction in the eGFR despite ERT if the urinary protein:creatinine ratio was ≥1 g/g [51]. Men with little urinary protein excretion and those who received ERT sooner after symptom onset had stable renal function.

The findings from these studies suggest that there is a strong case for early intervention because ERT seems less effective in more advanced disease [51, 72]. Two studies evaluating the occurrence of significant negative clinical events (renal, cardiac or neural) provide further support for starting ERT early. In a prospective study of 75 patients undergoing ERT, prolonged ERT delayed the occurrence of complications [65]. The difference between treated and non-treated patients only became obvious after at least 4 years of ERT, which suggests that the risk of complications decreases with increasing treatment duration. These data also indicated that in patients affected by Fabry disease-related complications, ERT is unlikely to modify outcome. In another prospective study of 40 patients undergoing ERT and 40 matched untreated patients, no differences in the occurrence of renal, cardiac, or neural complications were observed between the cohorts. The authors suggested that a long period of ERT is required to evaluate the results but that in advanced stages of the disease ERT can improve symptoms but not slow down the progression. However, from a nephrological point of view, it is worth noting that the incidence of renal failure was lower in the ERT cohort than in the comparator cohort (10% versus 28%, respectively) [66].

The renal effects of ERT in different disease stages have also been analysed in a meta-analysis of six studies with a mean follow-up of 5 years [67]. This analysis demonstrated a smaller mean decline in renal function in males treated with ERT than in untreated males when the GFR was <60 ml/min/1.73 m². However, in males with a baseline GFR of >60 ml/min/1.73 m² and in females the decline in renal function was comparable between the ERT and untreated groups.

Although there is limited long-term, controlled evidence of a clinical benefit of ERT on renal function, we feel that there is adequate, less rigorous evidence to indicate that ERT is of benefit, especially when started early in the course of the disease. However, to optimize the results from ERT, it should be used, when appropriate, with other adjuvant therapies.

Long-term ERT can be associated, mostly in male patients, with the occurrence of antibodies against the infused enzyme [73]. While there are problems in interpreting antibody levels and comparing them between the two products due to differences in measurement methodologies and “cut off” points [73], some potentially useful data are available. IgG antibodies occur with both products, but seem to be generally higher with agalsidase beta [73]. In an open-label extension study of agalsidase beta, infusion-related reactions (rigors, temperature-change sensation, fever, nausea, headache and nasal congestion) were the most common enzyme-related adverse events [74]. With the exception of one patient, all the reactions were mild and decreased over time, similar to observations reported from the FOS registry 5-year follow up [68]. The initial increase in frequency of infusion-related reactions seems to parallel the seroconvertion rate [41]. Although high antibody titres to either product could have an inhibitory effect on agalsidase A activity in vitro, the relationship to clinical response is much more difficult to assess [73]. Most studies reported so far have looked at the relationship between antibody titres and surrogate markers such as Gb₃ or lyso-Gb₃ in urine or plasma [73, 75]. Therefore, although the long-term effects of antibodies on ERT have yet to be determined, the prescribing nephrologist should be aware of the issues and potential problems.

The optimal dosage and regimen for ERT in Fabry disease are unclear. The licensed doses for agalsidase alfa and agalsidase beta are 0.2 mg/kg/2 weeks and 1 mg/kg/2 weeks, respectively. Clearance of Gb₃ from podocytes has been shown to be dose-dependent, with higher doses associated with greater clearance [32]. Regarding frequency of dosing, in patients demonstrating a continuing decline in renal function, switching from bi-weekly dosing to weekly dosing of agalsidase alfa (0.2 mg/kg) has been found to improve eGFR, with the mean rate of change in eGFR slowing from -8.0 ml/min per 1.73 m²/year to -3.3 ml/min per 1.73 m²/year [69]. A recent short-term study assessing three doses of agalsidase alfa (0.2 mg every 2 weeks; 0.1 mg and 0.2 mg every week) showed a trend for the higher dose to be most effective suggesting a longer-term study was needed [76]. A study of agalsidase beta involving 21 male patients receiving the standard dose of 1 mg/kg body weight for 6 months followed by a reduced dose of 0.3 mg/kg body weight for a further 18 months showed that 100% of patients cleared Gb₃ by 6 months while only 70% were still clear at 18 months [77].

From June 2009 to 2012, production and quality issues led to a worldwide shortage of agalsidase beta resulting in adult patients receiving reduced doses of agalsidase beta (approved dose 1 mg/kg/2 weeks, reduced dose 0.3-0.5 mg/kg/2 weeks), or switching to agalsidase alfa (administered dose 0.2 mg/kg/2 weeks) [78]. In 2010, the European Medicines Agency (EMA) focused their attention on patients treated with lower doses of agalsidase beta noting an increase in adverse events in these patients; specifically “a pattern of adverse events resembles the natural, but accelerated, course of Fabry disease”[78]. The effectiveness of specific ERT doses has also been evaluated in groups of patients switched from agalsidase beta to agalsidase alfa during this period. In 2011, Smid et al. reported that there were no relevant clinical differences in patients treated with variable doses of beta and/or alfa agalsidase, although both patients switching to agalsidase alfa (following a dose reduction of agalsidase beta) and those who continued on a reduced agalsidase beta dose had increased levels of lyso-Gb₃ suggesting increased disease activity [79]. This study also showed a minimal but significant decrease in two of the quality of life subscales in the SF-36 questionnaire. End-organ damage and clinical symptoms during dose reduction of agalsidase beta or switch to agalsidase alfa has also been assessed in an observational study (N = 105) [80]. During a median follow-up of 12 months, predefined measures of organ function were stable in those continuing on agalsidase beta 1 mg/kg/2 weeks. In contrast, there was a significant decrease in renal function as assessed by eGFR in those receiving a reduced dose of agalsidase beta, as well as an increase in the number of patients experiencing pain attacks or pain crises. There was also an increase in microabuminuria and Fabry disease-related symptoms (pain aggravation and gastrointestinal symptoms) among patients switching to agalsidase alfa. Considering all data published on the clinical effects of agalsidase alfa, it is surprising how in this report the patients treated with agalsidase alfa had such a significant worsening of their symptoms in such a short time.

In other studies from Japan [81] and Italy [82] no clinical and/or laboratory differences (Gb₃ levels) were observed after the switch from agalsidase beta to agalsidase alfa. Similar results were reported for a cohort of 40 patients in Australia although lower energy levels were observed in the male patients [83]. It is important to emphasize that all the studies on switching from agalsidase beta to agalsidase alfa were carried out in a small number of patients and for short periods of time (<2 years).

Reduction of proteinuria using drugs inhibiting the RAS is an essential and potent tool for improving renal outcome in patients with Fabry disease with CKD. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II receptor antagonists (ARBs), have been demonstrated to be renoprotective in chronic nephropathy [37]. Protein levels can be reduced with ACE inhibitors/ARBs to <0.5 g/day, and are associated with significant stabilization of renal glomerular function [36, 84]. Care should be taken to titrate doses to avoid hypotension [34, 51, 52]. The additional cardioprotective action of RAS inhibitors provides a further rationale for their use in patients with CKD [37]. These drugs will help control BP and are important for preserving renal function. Management should also include lipid-lowering and anti-platelet agents as indicated, together with appropriate prophylaxis against stroke [38]. Additionally, since cardiac arrhythmias do not respond to ERT, care should be taken to detect arrhythmias, as such events can lead to sudden cardiac death, particularly in women [9, 85].

Survival of patients on dialysis with Fabry disease and ESRD is poor. Three-year survival has been shown to be 60% in Europe [86] compared with 63% in the USA [87]. Although this was better than 3-year survival in a diabetic control population (53%), it was significantly lower than in the non-diabetic control group (74%) [87]. This is almost certainly due to the added disease burden from the cardiovascular complications of Fabry disease [88]. Thus, ERT should be considered on an individual patient basis in an attempt to reduce the risk of cardiovascular events.

Renal transplantation was initially considered as a potential treatment for alleviating some of the symptoms of Fabry disease by providing a source of alpha-galactosidase A enzyme. However, this was found not to be the case, with circulating alpha-galactosidase A levels remaining low after transplantation [89]. Nevertheless, the results of renal transplantation in patients with Fabry disease are excellent: 5-year graft survival has been reported as 74%, which was superior to that of patients with ESRD due to other causes (69%), but comparable with a matched cohort [90]. Patient survival at 5 years was 81%, which was slightly lower than that of the matched cohort (90%) [90]. The results of this study were comparable with those of an earlier study, in which 5-year graft survival and 5-year patient survival were 75% and 83%, respectively [27]. In fact, the results of renal transplantation are so encouraging that it should be considered as the first-line option to correct renal dysfunction in patients with Fabry disease and ESRD [91]. However, despite the positive data supporting renal transplantation, Fabry disease has been shown to confer a higher risk of death versus diabetic control patients (odds ratio 2.15) [88].

There are few data on ERT in patients with ESRD, either on dialysis or with a functioning renal transplant. However, ERT administered to patients with ESRD on dialysis or with a history of renal transplantation has demonstrated a favourable safety profile and the same dosing regimen can be used as for patients with Fabry disease without ESRD [92]. Furthermore, there is evidence that ERT can be administered during haemodialysis, without loss of the enzyme in the dialysate [93].

Organ involvement occurs later in life and with a lower prevalence in women than in men, but the signs and symptoms of Fabry disease should be treated in women because organ involvement is progressive and causes significant disease burden [5]. Few published studies have been dedicated specifically to women with Fabry disease [94]. However, a 4-year study of agalsidase alfa 0.2 mg/kg/2 weeks in 36 symptomatic women (mean age, 47 years) highlighted its long-term effectiveness [95].

An investigational therapeutic strategy, which is currently being explored, is the use of chaperon molecules to stabilize the chemical structure of the residual agalsidase alfa or to prolong the half-life of the infused enzyme [96, 97]. At present, clinical studies in Fabry patients are very limited and as yet no licensed chaperone drugs are available [98].

Biomarkers have an important role in the assessment of disease activity and response to treatment in other lysosomal storage diseases. However, despite encouraging research, a biomarker has yet to be identified that is relevant to clinical outcomes in Fabry disease [67, 75, 99]. Nevertheless, biomarkers may play an important part as indicators of diagnosis and when to commence therapy in Fabry disease patients. They may also be useful in determining the progression of Fabry disease. Urinary protein and albumin excretion are the most important biomarkers of Fabry disease nephropathy [36, 44]. Urinary Gb₃ levels are consistently elevated in most patients with Fabry disease (although marked inter-patient variability has been observed). Urinary Gb₃ levels decrease during ERT in men, women, and children with Fabry disease. However, despite this response, urinary Gb₃ cannot be considered to be a suitable biomarker of clinical efficacy because baseline levels do not correlate with disease severity, and do not predict clinical efficacy [100].

Recently, plasma [101] and urinary [102] lyso-Gb₃ have been identified as new potential biomarkers. In a study of 10 male and 8 female patients with Fabry disease, plasma lyso-Gb₃ was increased in males, and was higher in cases of the classic form of Fabry disease than in variant Fabry hemizygotes [101]. In females, plasma lyso-Gb₃ was moderately increased in symptomatic and asymptomatic cases, with a correlation between the increase in plasma lyso-Gb₃ and decrease in alpha-galactosidase A activity. Lyso-Gb₃ analogues were also isolated in the urine of 63 patients with Fabry disease [102]. Increased urinary excretion of lyso-Gb₃ in patients with Fabry disease correlated well with several indicators of disease severity, and may be a reliable independent biomarker for the clinically important characteristics of Fabry disease. However, there was no correlation between urinary lyso-Gb₃ and eGFR. Therefore, one cannot assume that lyso-Gb₃ is a reliable biomarker of renal involvement [101].

In 2012, Rombach et al. confirmed elevated levels of lyso-Gb₃ in the plasma and/or urine of patients with Fabry disease and described a reduction of plasma levels of lyso-Gb₃ after 1 year of ERT [75]. This decline in lyso-Gb₃ was associated with a reduction in left ventricular mass in females and a lower risk of developing white matter lesions in the nervous system for both sexes [75]. Recently, new potential biomarkers, Gb₃ analogues, have been identified in the plasma of untreated male Fabry disease patients, but their clinical meaning still has to be validated [103].

The utility of Cystatin C as a biomarker in Fabry disease has also been evaluated [104]. In an observational, multicentre study of 89 patients (n = 42 females; n = 47 males) with Fabry disease and varying degrees of disease severity, serum Cystatin C levels were measured. The authors concluded that Cystatin C is a good and cost-effective prognostic indicator of early renal dysfunction and/or heart failure in Fabry disease [104].

Urinary uromodulin excretion has been examined in 15 male patients with Fabry disease [105]. In untreated patients, changes ranged from a normal to marked decrease or absence of urinary uromodulin frequently accompanied by aberrantly processed uromodulin. These patterns normalized in all patients on ERT and some on substrate reduction therapy. This suggests that uromodulin may also be a potential biochemical marker of renal therapeutic response to ERT.

Urine proteomic analysis based on capillary electrophoresis coupled to mass spectrometry has recently been used to identify a biomarker profile in patients with Fabry disease [106]. In 35 treatment-naïve adult female patients with Fabry disease an abnormal urine profile was identified, which was almost completely corrected following ERT [106]. A further two protein biomarkers have been identified in the urine of children with Fabry disease and type-1 diabetes using label-free quantitative proteomics. Prosaposin and ganglioside GM₂ activator protein were significantly elevated in patients with Fabry disease and ERT was associated with a significant reduction in urinary excretion of these proteins. Therefore, these urinary biomarker models may useful as diagnostic tools for patients with Fabry disease, as well as for monitoring response to ERT [107]. However, there is still work to be done to identify a biomarker that truly reflects disease activity and progression, as well as enabling responses to ERT to be measured.