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Mehta A, Beck M, Sunder-Plassmann G, editors. Fabry Disease: Perspectives from 5 Years of FOS. Oxford: Oxford PharmaGenesis; 2006.

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Fabry Disease: Perspectives from 5 Years of FOS.

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Chapter 21Renal manifestations of Fabry disease

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Cross-sectional and cohort studies clearly show that renal manifestations occur early in life in a significant proportion of children, in many women, and in almost all men with Fabry disease. These manifestations ultimately progress to end-stage renal disease in nearly all males and some female patients. The prevalence of cortical and parapelvic renal cysts is also increased in patients with Fabry disease. A total of 132 of the 507 adult patients in FOS – the Fabry Outcome Survey – (26%; 54 females, 78 males) presented with an estimated glomerular filtration rate of less than 60 ml/min/1.73 m2 (chronic kidney disease stages 3–5). In FOS, 22 patients are on dialysis and 26 have a kidney graft. It is anticipated that enzyme replacement therapy will alter the natural history of kidney disease in patients with Fabry disease.

Introduction

Fabry disease affects the kidney in almost all male and in many female patients, resulting in end-stage renal disease (ESRD) and early death. This chapter gives an overview of the clinical course, histopathology and radiological findings in the kidney of patients with Fabry disease. Finally, renal replacement therapy will be discussed in the context of a hereditary nephropathy.

The progressive nature of renal involvement in patients with Fabry disease

Cross-sectional and cohort studies clearly show that renal manifestations (e.g. proteinuria or a decreased glomerular filtration rate [GFR]) occur early in life in a significant proportion of children, in many females and in almost all male patients with Fabry disease. These manifestations progress over time, leading to ESRD in nearly all males and some female patients.

Children

The clinical manifestations of classic Fabry disease between 4 and 16 years of age include mild proteinuria and urinary sediment containing globotriaosylceramide (Gb3). In some cases, this may progress to ESRD during late adolescence [1]. A study of 35 children and adolescents (20 females, 15 males; age range, 1–21 years) from 25 European families demonstrated that all males, and the majority of females, show signs and symptoms of Fabry disease before adulthood. Six of these children (3 males, 3 females, all over 14 years of age) showed renal involvement with proteinuria (13% of males, 14% of females), and one boy had a decreased creatinine clearance of 62 ml/min [2]. More recently, Ries and colleagues reported a mean 24-hour protein excretion of 92 ± 45 mg (range, 33–213 mg) among 25 boys (age, 12.3 ± 3.5 years) who were referred to the National Institutes of Health [3]. The mean estimated GFR (eGFR) in these children was 144 ± 22 ml/min/1.73 m2, and none presented with an eGFR of less than 110 ml/min/1.73 m2. Among 82 children (40 males, 42 females) in FOS, three were reported to have haematuria, eight to have microalbuminuria and 12 to have proteinuria.

Women

Among 20 females from 13 European families (mean age, 38 years; range, 12–65 years), every individual showed clinical manifestations of Fabry disease. A reduced GFR was observed in 11 patients (55%), and one patient also presented with crescentic glomerulonephritis [4]. Another study of 60 obligate carriers from the UK (mean age, 44 years) found clinically relevant disease manifestations in 33% [5]. Two of these patients (3.3%) presented with ESRD at a mean age of 36 years; however, renal function or proteinuria was assessed only in 31.5% of these 60 patients during the last years of follow-up. In Australia, 21% of 38 females with Fabry disease were reported to have renal involvement [6]. Interestingly, in this study anhidrosis was reported to be predictive of renal manifestations in females. In FOS, 86 (35%) of 303 females were reported to have proteinuria, one patient was on dialysis, and two had received a renal transplant.

Men

A large cohort study from the UK, conducted between 1985 and 2000, showed a high prevalence of ESRD of 30.8% among 84 adult hemizygous males [7]. The mean age of patients at initiation of renal replacement therapy was 36.7 years, and the youngest patient was 18 years of age at the start of therapy. Proteinuria (> 0.15 g/24 hours or > 1+ on dipstick testing) was documented in 37 out of 44 patients, and abnormal renal function (serum creatinine > 120 μmol/l, creatinine clearance < 85 ml/min, or GFR ⩽ 120 or > 160 ml/min/m2) was reported in 28 out of 60 patients.

Branton and colleagues carefully examined the records of 105 male patients with Fabry disease from the USA who were seen between 1970 and 2000 at the National Institutes of Health [8, 9]. Seventy-eight of these patients developed proteinuria (n = 66, > 0.2 g/24 hours) and/or chronic renal insufficiency (sustained serum creatinine ⩾ 1.5 mg/dl). The age at onset of non-nephrotic proteinuria was 34 ± 10 years (range, 14–55 years), and 50% of the patients developed proteinuria by the age of 35 years. All survivors developed proteinuria by 52 years of age. Nephrotic range proteinuria (> 3 g/24 hours) was seen in 19 out of 78 patients (18%) with renal disease. Thirty-nine patients presented with an increase of serum creatinine above 1.5 mg/dl. The median age at onset of chronic renal failure (creatinine > 1.5 mg/dl) was 42 years (range, 19–54 years) among 33 patients for whom the date of onset was available. During the observation period, 24 out of 105 patients (23%) developed ESRD at a median age of 47 years (range, 21–56 years), and all survivors developed ESRD by the age of 55 years. Arterial hypertension was observed in 30% of the 105 patients. Branton and colleagues also calculated the rate of decline of renal function in 14 patients in whom the onset of chronic renal failure (serum creatinine > 1.5 mg/dl) and the time of initiation of renal replacement therapy were available. The mean decrease in eGFR was −12 ± 8.1 ml/min/1.73 m2 per year (range, −3.3 to −33.7 ml/min/1.73 m2 per year). It is important to recognize that this somewhat rapid decrease in renal function was described in a very small population with a serum creatinine concentration far above 1.5 mg/dl in the majority of cases. It is therefore not appropriate to compare the time course of changes in serum creatinine in Fabry patients who have normal baseline creatinine concentrations with this cohort of patients who had mild to severe impairment of renal function at baseline.

Renal disease in FOS

The largest study of patients with Fabry disease published to date reported proteinuria in 44% of males and 33% of females. In this huge group of 366 patients (201 males, 165 females) in FOS, ESRD was present in 17% of males (10% with renal transplants, 7% on dialysis) and in 1% of females (one patient on dialysis who subsequently received a renal transplant) [10].

At the time of the FOS analysis undertaken for this chapter, at least one serum creatinine level was available from 590 patients (83 children, 507 adults). The most recently reported creatinine concentrations for these patients, according to age and gender, are shown in Figure 1. Serum creatinine, however, is not an optimal tool for assessing kidney disease. It is generally accepted that a direct measurement of GFR is the best overall marker for renal function. Gold standard measurements of GFR (urinary clearance of inulin, iohexol, chromium ethylenediamine tetraacetate, etc.) are time consuming, expensive and not widely available. Serum creatinine-based eGFR values (using the short Modification of Diet in Renal Disease [MDRD] formula [11]) are easy to calculate and it has been proposed that they should be used to provide rough estimates of overall kidney function. They also allow classification of patients into the different categories of chronic kidney diseases (CKD stages 1–5, [12]) (Table 1). The eGFR derived from the short MDRD formula [11], does not, however, show good agreement with measured GFR in patients with Fabry disease who have normal serum creatinine concentrations [13]. Furthermore, this formula underestimates measured GFR in individuals with high–normal (0.7–1.6 mg/dl) serum creatinine concentrations [14], and it has been recommended to report such GFR approximations only when estimated levels are less than 60 ml/min/1.73 m2 (CKD stages 3–5).

Figure 1. Serum creatinine according to age in 590 patients (291 males, 299 females) with Fabry disease enrolled in FOS – the Fabry Outcome Survey.

Figure 1

Serum creatinine according to age in 590 patients (291 males, 299 females) with Fabry disease enrolled in FOS – the Fabry Outcome Survey.

Table 1. Prevalence of chronic kidney disease (CKD) stages 1–5, as classified using the short form of the Modification of Diet in Renal Disease equation to estimate glomerular filtration rate (eGFR, based on the most recent serum creatinine concentration data), among adult patients with Fabry disease enrolled in FOS – the Fabry Outcome Survey.

Table 1

Prevalence of chronic kidney disease (CKD) stages 1–5, as classified using the short form of the Modification of Diet in Renal Disease equation to estimate glomerular filtration rate (eGFR, based on the most recent serum creatinine concentration (more...)

Table 1 shows the number of male and female patients according to the different CKD categories, based on eGFR levels. As almost all hemizygotes develop symptomatic renal disease and a significant proportion of heterozygotes with normal GFR will go on to develop signs of kidney damage, such as albuminuria, proteinuria, haematuria or specific findings on kidney biopsy, we have also included patients with an eGFR greater than 60 ml/min and no signs of kidney damage (combined CKD stages 1 and 2). A total of 132 of 507 patients (26%; 54 females, 78 males) presented with eGFR-based CKD stages 3–5. Data on albuminuria or proteinuria were available from 408 patients (adults and children; 192 females, 216 males). Figure 2 shows the most recent data on proteinuria according to age and sex in these 408 patients. Data on the presence or absence of haematuria were available from 391 patients. In total, 46 of the 196 females and 45 of the 195 males studied were reported to have haematuria.

Figure 2. Proteinuria according to age in 408 patients (216 males, 192 females) with Fabry disease enrolled in FOS – the Fabry Outcome Survey.

Figure 2

Proteinuria according to age in 408 patients (216 males, 192 females) with Fabry disease enrolled in FOS – the Fabry Outcome Survey.

Renal phenotype

There have been several reported cases of patients with signs and symptoms of Fabry disease confined to the kidneys. In some cases, however, other organ manifestations have not been excluded [15, 16]. Other reports have shown only mild renal involvement with proteinuria [17, 18], or described patients with renal variants that progressed to ESRD [19]. One report described a 20-year-old male with isolated proteinuria [20]. Family members, however, suffered from ESRD or presented with cardiac involvement. In FOS, to date, no patient has been described with disease confined to the kidneys.

Histopathology

The intracellular accumulation of glycosphingolipids is the histological hallmark of Fabry disease [2123]. Deposition occurs primarily in the cells of blood vessel walls and, to a lesser degree, in renal glomerular and tubular epithelial cells, corneal epithelial cells, myocardial cells and ganglion cells of the autonomic nervous system, among others. The kidney is affected in all hemizygous males, as well as in many heterozygous females.

Light microscopy

In paraffin-embedded sections, glomerular visceral epithelial cells are enlarged and vacuolated, and tubules and blood vessels are also abnormal. In plastic-embedded sections of osmium-fixed tissues treated with toluidine or methylene blue, fine but darkly staining granular inclusions are present, corresponding to the vacuoles.

Immunofluorescence

Routine immunofluorescence microscopy is usually negative. In glomeruli with advanced lesions, however, immunoglobulin M and complement components (C3 and C1q) may be detectable in capillary walls and mesangial regions showing a segmental distribution and granular pattern.

Ultrastructure

Cellular inclusions within lysosomes have been described by various names, including zebra bodies, myelin figures, myelin-like figures or lamellated structures. They are surrounded by a single membrane and can be found in all cells, mainly podocytes and endothelial cells, regardless of the light microscopic features.

A recent study of 58 patients with a GFR of approximately 80 ml/min who were enrolled in a placebo-controlled trial of enzyme replacement therapy (ERT) [24] showed an extensive accumulation of Gb3 in the kidneys before therapy [25]. The cellular inclusions varied considerably in quantity and morphology among the different cell types. Podocytes and distal tubular epithelial cells contained the highest concentrations of Gb3, whereas proximal tubular epithelial cells were relatively unaffected. In some cell types, inclusions appeared as small, dark, dense-beaded granules; in others, they appeared as larger complex laminated bodies. There was also considerable Gb3 accumulation in vascular endothelial cells, vascular smooth muscle cells, mesangial cells, interstitial fibroblasts and phagocytic cells of the renal cortex [25] (Figure 3).

Figure 3. Globotriaosylceramide accumulates in many cell types in the renal glomerulus as dark blue granules and scroll-like whorls, as shown here.

Figure 3

Globotriaosylceramide accumulates in many cell types in the renal glomerulus as dark blue granules and scroll-like whorls, as shown here. Red arrows indicate endothelial accumulation; yellow arrows indicate mesangial cell accumulation; P, indicates podocyte (more...)

With progression of the disease, fusion of podocyte foot processes can be observed. Focal glomerular and tubular epithelial necrosis, as well as thickening of glomerular and tubular basement membranes, were also reported [21, 26] and will finally result in segmental and global glomerulosclerosis, tubular atrophy and interstitial fibrosis [21]. In FOS, the results of biopsies of native kidneys of 19 patients (7 females, 12 males) were reported. All but two patients were reported to show lesions related to Fabry disease. The other cases were reported to present with focal segmental glomerulosclerosis (1 male aged 40 years, 1 female aged 43 years).

Renal imaging

Systematic examination of renal morphology in Fabry disease, using sonography, computed tomography or magnetic resonance imaging, was introduced recently [27, 28].

A large uncontrolled study of 122 patients showed a high prevalence of cortical and parapelvic cysts, as well as an increased echogenicity, decreased cortical thickness and decreased corticomedullary differentiation of the kidney [27]. Details of this study are given in Table 2. Another small case–control study also pointed to a high prevalence of parapelvic cysts in Fabry disease [28], as detected by computed tomography and magnetic resonance imaging (Table 3). Thus, the finding of renal cysts, especially parapelvic cysts, may suggest the presence of Fabry disease. Renal ultrasound data from 122 patients enrolled in FOS (Figure 4) confirmed these observations [29]. The analysis of FOS data did not, however, differentiate between cortical and parapelvic cysts. All three studies found an increase in the prevalence of renal cysts with age. The cause of cyst formation in Fabry disease, however, is currently unknown.

Table 2. Prevalence of cortical and parapelvic renal cysts in patients with Fabry disease. Adapted with permission from [27].

Table 2

Prevalence of cortical and parapelvic renal cysts in patients with Fabry disease. Adapted with permission from [27].

Table 3. Parapelvic renal cysts as detected by magnetic resonance imaging in patients with Fabry disease and matched controls. Adapted with permission from Macmillan Publishers Ltd [28].

Table 3

Parapelvic renal cysts as detected by magnetic resonance imaging in patients with Fabry disease and matched controls. Adapted with permission from Macmillan Publishers Ltd [28].

Figure 4. Prevalence of renal cysts detected by ultrasound among 122 patients (65 males, 57 females) enrolled in FOS – the Fabry Outcome Survey – according to age and gender.

Figure 4

Prevalence of renal cysts detected by ultrasound among 122 patients (65 males, 57 females) enrolled in FOS – the Fabry Outcome Survey – according to age and gender.

The prevalence of simple renal cysts in the general population also increases with every decade of life (Table 4) [30]. In this context, it is worth mentioning that the occurrence of one or more simple cysts was associated with slightly reduced renal function in a population of hospitalized patients with cysts compared with patients without cysts [31]. Other causes of renal cyst formation include several inherited polycystic kidney diseases, including autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, familial nephronophthisis and medullary cystic kidney disease [32], which can all lead to ESRD. In patients with ESRD, acquired cystic kidney disease (defined by the presence of three or more cysts per kidney in an individual on dialysis and the absence of an inherited polycystic kidney disease) may be present in about 10% of patients at the start of dialysis and affects a greater proportion of patients thereafter [33, 34]. The prevalence of acquired cystic kidney disease is directly related to the duration of dialysis (Figure 5), and the presence of acquired cystic kidney disease also increases the risk of renal cancer.

Table 4. Prevalence of simple renal cysts in healthy individuals (n = 14 314). Adapted with permission from [30].

Table 4

Prevalence of simple renal cysts in healthy individuals (n = 14 314). Adapted with permission from [30].

Figure 5. Prevalence of acquired cystic kidney disease (ACKD) in patients on dialysis.

Figure 5

Prevalence of acquired cystic kidney disease (ACKD) in patients on dialysis. Reproduced with permission from [34].

Renal replacement therapy in patients with Fabry disease

A significant proportion of patients with Fabry disease is treated by dialysis or kidney transplantation [35]. In this context, small case series indicate that patients suffering from ESRD, either on dialysis [36, 37] or with a functioning renal graft [38], tolerate ERT very well and may even benefit from this treatment.

Dialysis in Fabry disease

Before the widespread availability of dialysis, the mean age at death of hemizygous patients was 41 years [39]. Dialysis has increased life-expectancy in patients with Fabry disease [7]. However, a report on the prevalence of Fabry disease that identified 83 cases among 440 665 dialysis patients from Europe (0.0188%; 87% male) showed a less favourable 5-year survival rate of 41% in patients with Fabry disease, compared with 68% in patients with standard nephropathies [40]. Comparable data were reported by Thadhani et al., who showed a similar prevalence, with 42 cases of Fabry disease among 250 352 dialysis patients enrolled in the United States Renal Data System (USRDS) (0.0167%; 88% male) [41]. In this study, the 3-year survival for patients with Fabry disease was 63%, compared with 74% for non-diabetic controls and 53% for diabetic controls.

Over the past few years, several case-finding studies have clearly shown that Fabry disease has been previously under-recognized in patients receiving dialysis. Systematic measurement of enzyme activity in whole blood, plasma, leukocytes or eluates of dried blood spots in large cohorts of dialysis patients disclosed a more than tenfold higher prevalence of Fabry disease among patients with ESRD than would be expected based on historical registry data [15, 4248] (see also Chapter 17). It is worth mentioning that, to date, 22 patients on dialysis (4 of them after the start of ERT) are enrolled in FOS.

Kidney transplantation in Fabry disease

Some 40 years ago the first kidney transplantations in European patients with Fabry disease were performed in France in 1966 [49] and Switzerland in 1967 [50]. At this time, it was believed that renal transplantation may correct the metabolic defect in patients with Fabry disease [5157]. This hypothesis was challenged by Clark et al. who suggested that the decrease in Gb3 storage observed may reflect reduced production rather than enhanced clearance by the transplanted kidney [58]. A few years later, longitudinal studies showed that the activity of α-galactosidase A does not increase after successful kidney transplantation [59, 60].

Initially, it was thought that kidney transplantation was not justified in patients with Fabry disease [61]. One reason for this was reports of severe cardiac complications following successful kidney transplantation [62] and a high prevalence of life-threatening infectious episodes [63]; however, several case reports showed a favourable course following kidney transplantation [60, 6470]. Recurrence of disease in the graft was rarely reported and occurred in most instances only many years after transplantation and was considered to be without major impact on patient or graft survival [7175]. Interestingly, a study in a small series of transplanted patients with Fabry disease found an increased prevalence of activated protein C resistance associated with an increased risk of thrombosis and rejection [76].

In a study from the European Renal Association–European Dialysis and Transplant Association registry of 33 patients, graft survival at 3 years was no worse than in patients with other nephropathies (72% versus 69%), and patient survival after transplantation was comparable to that of patients under 55 years of age with standard nephropathies [40]. Excellent graft and patient survival was also reported from the USRDS registry [77, 78], Therefore, Fabry disease is currently not judged to be a contraindication for renal transplantation [35, 79, 80]. In FOS, 26 patients who had received kidney transplants (25 at entry into FOS, 1 after the start of ERT) were included at the time of this analysis.

Kidney donation from a living relative in patients with Fabry disease

Kidney donation from a living relative of a patient with Fabry disease is a very delicate issue, and clinical experience is documented in only a few case reports [49, 8183].

Heterozygotes with normal kidney function and no outward signs and symptoms of Fabry disease, but who show evidence of extensive Gb3 accumulation on kidney biopsy, have been recommended not to be used as donors [84]. This approach appears reasonable, because such kidneys may be prone to a rapid accumulation of glycolipids once transplanted in a hemizygous or heterozygous patient with ESRD. Furthermore, the donor may bear an increased risk of progression to ESRD. Hemizygous males should not be considered as kidney donors, even if there are no signs of kidney damage; however, they can receive a kidney from a living asymptomatic heterozygous relative (providing that kidney biopsy in the donor does not show extensive Gb3 accumulation). However, the donation of a kidney by an asymptomatic heterozygous to a hemizygous patient may carry the risk of graft loss within a few years. Female patients with Fabry disease who have ESRD can receive a kidney from asymptomatic related heterozygotes. Receipt of a kidney from a living relative is not reported in FOS.

Conclusions

Data obtained from FOS and from other studies demonstrate that the kidney can be affected early in life, even during childhood, in males and females with Fabry disease. Progressive deterioration of renal function results in ESRD in the majority of hemizygotes at around the age of 50 years. ESRD may also be seen in some heterozygotes. Survival when on dialysis is impaired in patients with Fabry disease compared with patients with other kidney diseases; however, kidney transplantation offers comparable graft and patient survival to that observed in patients with other nephropathies. The ultimate goal of ERT and other therapies should be the prevention of disease manifestations.

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