Fabry nephropathy: 5 years of enzyme replacement therapy--a short review

Fabry disease is an X-linked lysosomal storage disease, resulting from a deficiency of the enzyme α-galactosidase A and subsequent cellular storage of the enzyme substrate globotriaosylceramide (Gb3) [1]. Estimates of the incidence of Fabry disease vary markedly, from 1:<5000 male births in a newborn screening study in Italy [2] to 1:117 000 male births in Australia [3] and 1:833 000 male births in northern Portugal [4]. In general, hemizygous males are more severely affected than heterozygous females. In males, life expectancy is reduced by an average of 20 years [5] and in females by 15 years [6]. Although males tend to suffer symptoms earlier than females, both boys and girls can be affected from an early age [7]. Death usually occurs due to renal, cardiovascular or cerebrovascular complications [5,6,8], with renal dysfunction being the main cause of death in men before the development of renal failure requiring dialysis and transplantation [9]. As enzyme replacement therapy (ERT) has recently become available, it is important to recognize the signs and symptoms of Fabry disease so that early treatment can be started before irreversible organ damage occurs. This short review outlines the renal manifestations of Fabry disease and the results of ERT. Urinary concentration defects, despite being rare, may be the earliest manifestation of renal dysfunction, and are responsible for polyuria and nycturia. Otherwise, the first clinical manifestation of Fabry-related renal disease is proteinuria. In their review of the natural history of renal involvement in 105 male patients, Branton et al. found that 50% of patients presented with proteinuria by 35 years of age and 100% by 52 years of age [9]. In patients with Fabry nephropathy in FOS—the Fabry Outcome Survey—the usual level of proteinuria is 0.5–2.0 g per 24 h. True nephrotic syndrome is not frequent, even in patients who have proteinuria in the nephrotic range [9]. Microscopic haematuria is present in 30% of patients. Chronic renal insufficiency (CRI) develops concomitantly to proteinuria in the majority of male patients. Branton et al. found that 50% of male patients presented with CRI by 42 years of age. After the development of CRI, there was a rapid decline in glomerular filtration rate (GFR) of 12.2 ml/min/year (range, 3–34 ml/min/year), leading to end-stage renal disease (ESRD) after further 4.1 years [9]. It is of note that only 18 of the 105 patients studied had received angiotensin antagonist therapy at any time (6 for hypertension alone, 1 for hypotension and proteinuria, 5 for hypertension with CRI, 3 with proteinuria alone, 1 with congestive heart failure, 2 for reasons unknown) and 11 of the 31 hypertensive patients had medically controlled hypertension. Unpublished data from the Necker Hospital in Paris suggest that the rate of decrease in GFR may be slower in patients with Fabry disease who are receiving these nephroprotective measures as standard. It is interesting that the progressive decline in GFR reported by Branton and colleagues is similar to that seen in untreated diabetic nephropathy and occurs more rapidly than in primary glomerulonephritis [10]. Both these diseases are multisystemic and their nephropathies are caused initially by metabolic deposits—Gb3 in Fabry disease and end-glycosylation products in diabetes. They may both progress in a similar manner to chronic non-diabetic proteinuric nephropathies via a common pathophysiological pathway that is relatively independent of the initial renal insult [11,12]. Contrary to patients with diabetes type I or II, nearly all male patients with Fabry disease will develop CRI during their lifetime. Hypertension is observed in 60% of patients with diabetic nephropathy and, if untreated, contributes to the progression of CRI [13]. Similarly, hypertension has been found in 57% of men and 47% of women with Fabry disease [14]. Finally, as for other monogenic diseases, there is a remarkable variability in the rate of progression of nephropathy [15] that may be partly explained by the role of modifier genes. A renal biopsy may be used to diagnose Fabry disease in patients with renal symptoms or to follow treatment with ERT; however, diagnosis is often based on non-renal manifestations [9]. Such manifestations include characteristic skin lesions (angiokeratomas), acroparaesthesia, cornea verticillata and left ventricular hypertrophy. A diagnosis may also be made as a result of a family history of the disease. Confirmation of the diagnosis by measurement of the plasma and leukocyte activity of α-galactosidase A in male patients and genetic analysis in female patients is necessary. Because Fabry disease is a rare, often unrecognized disease, the nephropathy is often already present by the time diagnosis is made. For example, Branton et al. reported that the mean age at diagnosis of Fabry disease in 44 patients was 16 ± 13 years, even though these patients had a known family history. The age at diagnosis of 50 patients without a known family history of Fabry disease was even higher, at 28 ± 12 years, despite signs of the disease being apparent well before diagnosis. Other studies and data from FOS have also highlighted the delay between onset of symptoms in childhood and diagnosis [5,7], pointing to the need for physicians to rediscover the disease because of the availability of ERT and early nephroprotective measures. Other newly recognized aspects of Fabry nephropathy have been reported recently. In a study of male children with Fabry disease, Ries et al. found that 20 out of 25 patients had microalbuminuria and that 13 out of 25 had an estimated GFR (using the Schwartz formula) above 140 ml/min, suggestive of hyperfiltration, a well-known risk factor for glomerular injury that is responsible for increased glomerular permeability to albumin [16]. Moreover, another recent study has shown that there may already be evidence of CRI (estimated GFR of 60–89 ml/min/1.73 m2) in some untreated children with Fabry disease (n = 2/24) [17]. There is clear evidence that the burden of Fabry nephropathy is already present in boys with Fabry disease and probably starts with a (presumed) silent phase, including hyperfiltration and/or microalbuminuria (stage II Fabry nephropathy; Table 1), which progresses to overt proteinuria, CRI and, finally, ESRD, an evolution closely resembling that seen in diabetic nephropathy (Figure 1) [9]. Renoprotective treatment in patients with Fabry disease should therefore be the same as that for patients with type 1 and type 2 diabetes; i.e. these patients should be treated during the silent phase of the disease to slow, halt or even reverse the pathological changes that lead to renal failure. The literature suggests that the course of kidney disease is generally less severe in females; however, some of them will progress to ESRD before the age of 40 years [18]. Proposed stages of progression of Fabry nephropathy in male patients CRI, chronic renal insufficiency; ESRD, end-stage renal disease; ERT, enzyme replacement therapy; Gb3, globotriaosylceramide; GFR, glomerular filtration rate; +, mild; ++, moderate; +++, severe. Proposed stages of progression of Fabry nephropathy in male patients CRI, chronic renal insufficiency; ESRD, end-stage renal disease; ERT, enzyme replacement therapy; Gb3, globotriaosylceramide; GFR, glomerular filtration rate; +, mild; ++, moderate; +++, severe. The interrelationships between functional and morphological markers in diabetic and Fabry nephropathy. Great similarities are found between these conditions. Progressive accumulation of Gb3 in the kidney results in mesangial expansion and glomerulosclerosis, tubular atrophy and interstitial fibrosis—non-specific anomalies seen in most glomerular diseases and diabetic nephropathy [19]. Vascular injury due to Gb3 deposition in the capillaries and arterial wall probably plays a central role in the loss of nephrons, via ischaemic degenerative alterations. As such, Fabry nephropathy is not only a disease associated with deposition, it should also be considered a vascular disease, like diabetic nephropathy. However, it is likely that other mechanisms, secondary to the progressive accumulation of Gb3, are also involved in the pathogenesis of Fabry nephropathy. In patients with Fabry nephropathy, all types of renal glomerular cells show lipid inclusions—as do the endothelial and smooth muscle cells of renal vessels, epithelial cells of the proximal tubule, loop of Henle, distal tubule and interstitial cells [20]. Podocytes, in particular, contain high levels of glycosphingolipid deposits early during childhood, although it remains unclear whether the glomerular filtration barrier is physically compromised, as many women with Fabry disease have podocyte deposits without proteinuria throughout their life. Nevertheless, GFR declines over time, mainly due to ischaemic degenerative changes provoked by vascular involvement and progressive expansion of the mesangial matrix, which occurs concomitant to the development of overt proteinuria. Expansion of the mesangial matrix, in turn, leads to thickening of the glomerular basement membrane and ultimately to glomerulosclerosis [21]. In order to evaluate the renal response to ERT, a scoring system for chronic glomerular, vascular, tubular and interstitial alterations is needed. A series of guidelines for the recognition, evaluation and surveillance of disease-associated morbidities and therapeutic strategies for Fabry disease have been proposed by an international panel of experts [22]. These guidelines recommend that evaluation of kidney function, including of GFR and proteinuria, should be out in with Fabry disease. note that a to treatment of Fabry disease is and between and other with or is considered the therapy for ESRD in patients. A recent analysis of the found of Fabry-related ESRD, patients renal transplantation between and and in with Fabry disease and was similar to of in patients without Fabry disease and rate and the risk of cardiovascular death in untreated not receiving patients with Fabry disease not from of other renal with being in with untreated Fabry disease and in these which may be due to the of for transplantation for the patients should also be treated with ERT, as renal transplantation not the metabolic in other The of ERT with α-galactosidase A the of the natural course of Fabry disease. 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In the study by Branton et al. 18 out of 105 received an angiotensin at any ERT with may to the progression to irreversible kidney failure in patients with or Fabry nephropathy to data from 2 years of a is to evaluate the on transplantation can reverse the glomerulosclerosis seen in diabetic nephropathy in patients with type I more than 5 years of et al. reported a analysis of data from on the progression of renal dysfunction in patients with Fabry disease treated with data from 1 before at the of treatment and 1 after treatment in 20 patients with a GFR of 60–89 ml/min/1.73 with a GFR of ml/min/1.73 and 2 years after treatment in 13 patients of with a GFR of 60–89 ml/min/1.73 5 with a GFR of ml/min/1.73 The results of the analysis that the decline in renal function, observed over the to ERT in patients with a GFR of 60–89 ml/min/1.73 at was after 1 of treatment with renal in patients with both and renal disease at treated with for 2 years (Figure of proteinuria before and after ERT with some patients an and a of proteinuria is a well-known factor in the progression of CRI, the of the nephropathy [11,12]. the 20 patients for 2 years, 5 used or at another 5 used these at any time and the was for patients. A analysis on data from patients with levels 2 a between and time on further the that may of renal in patients with Fabry disease who have or renal in estimated glomerular filtration rate in 20 patients before and 1 after the of enzyme replacement therapy (ERT) with 1 before at and 1 after the of ERT in 12 patients with a mean GFR of 60–89 ml/min/1.73 and patients with a mean of ml/min/1.73 in in 13 patients before and during 2 years after the of ERT with 1 before at and 1 and 2 years after the of ERT in patients with a mean GFR of 60–89 ml/min/1.73 and 5 patients with a mean of ml/min/1.73 are shown as mean and and and with from et al. of In a more recent et al. reported renal data in patients with Fabry disease with GFR, receiving for to They that and estimated GFR at in the patients for data disease in only patients in estimated GFR from to per of over 40 years of age and had proteinuria and evidence of at of receiving during the further 18 patients also received over the that high proteinuria or glomerulosclerosis at to the rate of decline in estimated the of ERT with on proteinuria in Fabry disease is not In the study by et al. that Gb3 was by a of from renal interstitial endothelial cells in out of patients after of and in out of patients after of In the (range, = of Gb3 was also reported in the distal glomerular endothelial mesangial cells and cells of the however, was not in the interstitial cells and smooth these data suggest that early and with can renal in patients with renal without proteinuria or severe at the of A recent study the of in patients with Fabry disease that proteinuria was reduced by therapy and that was during ERT Although there was an initial decline in estimated GFR after the of was for with 3 or kidney disease at and probably due to of the of ERT, renal as by estimated GFR The average progression rate of estimated GFR during treatment with was ± per per in patients with 1 or 2 kidney disease and ± per per in patients with 3 or kidney disease at Although study not include a receiving ERT alone, these data the of and ERT in the treatment of renal disease in patients with Fabry disease. et al. studied the of ERT in patients with Fabry disease as between and or an estimated receiving 2 for to 35 The results of the study that ERT was to progression to the clinical as any clinical of renal, and cerebrovascular complications and death with (n = even in patients with overt kidney This that progression to severe manifestations was Nevertheless, the that that therapeutic before the onset of irreversible organ damage is study of treatment with in 25 patients with severe symptoms and organ manifestations mean presented data on renal after a mean treatment time of ± in 20 patients with kidney These reported clear in the response to ERT on the of the patients. GFR to be by ERT in patients with renal at ml/min/1.73 GFR was not the rate of progression was reduced with in patients with renal at GFR, ± ml/min/1.73 that there is a of kidney damage is irreversible and CRI despite ERT. A recent study by et al. evidence that it may be to reverse renal by the and of In of to a of 11 male patients, in there was a decline in renal (estimated GFR decline 5 per despite years of therapy After to there was a in the rate of decline of estimated GFR in patients and an in patients. that the main factor responsible for was of with a from the concomitant of although the patients for estimated GFR had proteinuria to the of the patients with proteinuria in of a of the loss of GFR after These data suggest that for a of patients, an increased or of be However, is before a from to in patients, as data from the study by suggest a loss of GFR despite a of of in some patients with GFR who had proteinuria or glomerulosclerosis There is a need for further studies in which the risk for progressive CRI in patients with Fabry disease are It is interesting to note that an study of a who had been treated with for years, Gb3 storage despite ERT Gb3 was in the membrane and of endothelial even in the of lysosomal This that Gb3 remains in cells and even after years of ERT and have to the at in Fabry disease. there is only study of the of ERT on renal in children [17]. A recent study of treatment with renal in a of 24 children with Fabry disease 5 on renal at estimated GFR, ± m2) and found that renal after of treatment estimated GFR, ± ml/min/1.73 in a of patients who had hyperfiltration at estimated GFR to the range ERT. who had proteinuria at was receiving an studies of of ERT in children are to evaluate whether the progressive decline in renal that is characteristic of Fabry disease can be by A recent study has the of α-galactosidase A in renal cells and the manner in which enzyme is In the α-galactosidase A is found in all tubular cells and interstitial cells not renal endothelial cells and In with Fabry disease, of α-galactosidase A occurs in proximal and interstitial cells not in vascular endothelial A for the is a rapid of renal endothelial which has been at for the endothelial cells with of Gb3 as a of ERT from the and have shown that patients with Fabry-related ESRD who are receiving dialysis have a rate than non-diabetic the for ERT in these patients. In an study of the of in patients receiving dialysis (n = = 3 treatment was well and associated with an in symptoms and slower progression of left ventricular the of ERT are apparent in other organ in patients receiving dialysis suggests that these patients should be treated with ERT. 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