**2. Kidney manifestations in Fabry disease**

Nephropathy caused by intracellular accumulation of globotriaosylceramide (Gb3) in the kidney, is one of the main features of Fabry disease. Kidney manifestations occur in at least 50% of male patients and approximately 20% of female patients [16]. A urinary concentration defect, microalbuminuria, and later overt proteinuria and progressive decline of kidney function are important signs of Fabry nephropathy [23].

#### **2.1 Proteinuria**

Proteinuria is the most important biomarker in Fabry nephropathy. Studies showed urinary protein excretion is strongly associated with renal disease progression in men and women with Fabry disease [24]. Proteinuria may be glomerular or tubular in origin and usually appears during the second to third decades of life in affected individuals [23, 25, 26]. Early-onset of proteinuria is not rare and it has been reported in male and female adolescents and in boys as young as 6 years [23]. Approximately 90% of males with Fabry disease developed proteinuria by the age of 50 years [27]. Approximately 30–35% of females with Fabry disease have overt proteinuria with an age of onset that is usually later than in males [27–29]. Though proteinuria is an early complication of renal injury, it may not be overt in some patients even with advanced kidney disease [28].

*Enzyme-Replacement Therapy in Fabry Disease DOI: http://dx.doi.org/10.5772/intechopen.103799*

The mechanism of proteinuria has not been entirely clear. Gb3 deposits in podocytes have not been directly related to the magnitude of proteinuria [23]. The degree of proteinuria is a major prognostic determinant for more rapidly progressive Fabry nephropathy, particularly in adult male patients, and may also directly contribute to the progression of renal disease [23].

Nephrotic-range proteinuria is uncommon. In a long-term natural history study from the National Institutes of Health (NIH), nephrotic proteinuria was found in 18% of patients with renal disease. The age at onset of nephrotic proteinuria was 40 ± 7 years (range 26–55 yr). The full presentation of nephrotic syndrome was uncommon even in patients who had heavy proteinuria [27].

## **2.2 Renal tubular dysfunction**

Gb3 accumulation in the kidney occurs in all renal cells but preferentially in the glomeruli, distal tubular cells, and vascular smooth muscle cells. Injury of distal tubular cells leads to urinary concentration defects presenting with polyuria, nocturia, and polydipsia, which may be the early signs of Fabry kidney disease [27, 30]. Interestingly, one case report has suggested that screening for mulberry cells (regarded as distal tubular epithelial cells in which Gb3 has accumulated) during urinalysis could be a simple, inexpensive, and noninvasive method for diagnosing Fabry nephropathy in the absence of proteinuria [31, 32]. Gb3 deposition in proximal tubules may rarely lead to proximal renal tubular acidosis or even Fanconi syndrome. The urine sediment in Fabry disease may contain oval fat bodies, which are renal tubular epithelial cells or cell fragments with lipid inclusions. Under microscopy using crossed polarization filters, these oval fat bodies demonstrate a typical Maltese cross configuration with a lamellar appearance [27].

#### **2.3 Chronic kidney disease**

Initially, patients with Fabry disease may have glomerular hyperfiltration at a rate similar to diabetic nephropathy [23, 33]. However, when the number of damaged nephrons reaches a critical level that cannot maintain adequate glomerular filtration, there will be a rapid decline in GFR [23]. CKD is prevalent in untreated patients with Fabry disease and typically progresses to end-stage renal disease (ESRD). In a cross-sectional retrospective analysis of the natural history of glomerular filtration rate (estimated-eGFR), albuminuria, and proteinuria in 1262 adult patients (585 males, 677 females) using data from the Fabry Registry before treatment with ERT, chronic kidney disease (CKD) stages 1 or 2 were found in 72% of males and 87% of females. CKD with eGFR <60 ml/min/1.73 m [2] was found in 28% of males and 13% of females, while in patients aged >40 years, the percentage increased to 45 and 20% [28]. Without ERT, progression rates of renal insufficiency can be as high as seen in diabetic nephropathy [23]. In the NIH series described above, 39 of 105 patients developed CKD defined as a serum creatinine concentration ≥ 1.5 mg/dL, and the median age of CKD onset and ESRD was 42 years and 47 years, respectively, with a time of progression from onset of CKD to ESRD 4 ± 3 years (range 1–13 yr) [27].

#### **2.4 Hypertension**

Hypertension is not a common early finding in patients with Fabry disease but becomes more prevalent with disease progression [23]. In the NIH series, hypertension was present in 31 patients (30%) with onset at age 38 ± 11 years (range 14–54 yr). Thirty-five percent of patients developed hypertension before the onset of CKD, 12% of patients had a simultaneous diagnosis of hypertension and CKD, and 53% of patients developed hypertension 5 ± 5 years after the onset of CKD [27], suggesting that the onset of CKD was followed by the development of hypertension in most patients.

## **2.5 Renal sinus and parapelvic cysts**

Renal cysts are common, particularly in older men. Studies from potential living kidney donors showed that a cortical, medullary, or parapelvic cyst ≥5 mm was present in 12%, 14%, and 2.8%, respectively [34]. Renal sinus and parapelvic cysts are more prevalent in patients with Fabry disease compared to the general population and are considered as a distinguishing feature in Fabry disease [35]. In a crosssectional case-control study with 24 patients affected with classic Fabry disease (mean age 36.1 ± 8.1 years, median 37 years, range 20–48 years), prospective renal imaging evaluation with magnetic resonance imaging (MRI) and computed tomography (CT) showed 50% of Fabry disease patients had renal sinus cysts, compared to one individual (7%) in the control group [35]. The etiology and mechanism of sinus cyst formation in Fabry disease remain unclear.

### **2.6 Renal pathology**

Renal biopsy is important not only for confirming the diagnosis, but also to show renal damage that can occur in some patients with minimal or no evidence of renal disease on standard tests [23]. By light microscopy, the cells, especially podocytes, parietal epithelial cells, and distal tubular epithelial cells, appear vacuolated because the accumulated glycosphingolipid inclusions are removed during tissue processing for paraffin embedding. Hyaline-like material accumulates in the media of arteries and arterioles and sometimes in the mesangial regions [36]. Immunofluorescence is typically negative. By electron microscopy, podocytes are filled with osmiophilic, granular-to-lamellated membrane structures (zebra bodies) [23, 27, 36].

## **3. Enzyme-replacement therapy (ERT)**

Before ERT was available, a reduced life span of about 25 years in males and 10 years in females was expected compared with the general population [2, 37]. Clinical research with follow-up data clearly demonstrates a modifying effect of ERT on serious organ complications and mortality. ERT has been available for the treatment of Fabry disease since 2001 in Europe and since 2003 in the USA. Licensed ERT treatments include agalsidase alfa (Replagal™, Shire Human Genetic Therapies/Takeda Pharmaceuticals Europe Ltd., London, UK), agalsidase beta (Fabrazyme™, Sanofi Genzyme, Cambridge, MA), and agalsidase beta biosimilar (Fabagal™, Isu-Abxis, South Korea). Agalsidase beta is licensed in both the USA and Europe, while agalsidase alfa is not licensed in the USA. Fabagal is approved in South Korea [22]. Agalsidase alfa is produced in a genetically engineered human cell line and agalsidase beta is produced in a Chinese hamster ovary cell line [38].
