Diagnosis and Treatment Strategies for Fabry Nephropathy

Clinical Case A 23-year-old woman was hospitalized in the nephrology department because of persistent non-nephrotic-range proteinuria (approximately 1 g/day). Family history revealed that her father had chronic glomerulonephritis that developed at a young age and had been undergoing hemodialysis for the past 10 years. During clinical evaluation, the patient reported no complaints. Arterial blood pressure was 120/70 mm Hg and pulse rate was 68 beats/min. Laboratory tests showed a serum creatinine level of 0.7 mg/dL and creatinine clearance of 92 mL/min. Proteinuria was 870 mg/day. Immunological blood tests showed no pathological abnormalities. A kidney biopsy was performed. Light microscopy revealed cellular vacuolization in the glomeruli and renal tubules. Immunological studies showed no pathological abnormalities. Electron microscopy revealed deposits in the lysosomes of podocytes, epithelial cells, and endothelial cells (so-called zebra bodies). Based on these findings, Fabry disease was suspected. Further testing showed normal leukocyte α-galactosidase A activity (α-gal A) (19 nmol/mL protein/hour); DNA analysis revealed a specific gene mutation. No angiokeratomas were found on the skin, but slit-lamp examination revealed cornea verticillata. After 2 weeks, enzyme replacement therapy (ERT) with agalsidase beta at a dose of 1 mg/kg every 2 weeks was initiated. When the patient’s father was re-evaluated, it was found that during his most recent kidney biopsy, the specimen had not been examined by electron microscopy. His leukocyte α-gal A activity had also not been tested. The results of DNA analysis were identical to those of his daughter. What Is Fabry Disease? Fabry disease is a genetically inherited X-linked storage disorder caused by a deficiency or reduced activity of the enzyme α-gal A. When the function of this enzyme is impaired, undegraded glycosphingolipids (GL-3) accumulate in cellular lysosomes. Such accumulation is most characteristic of endothelial cells, cardiomyocytes, fibroblasts, neurons, and renal cells, including podocytes, glomerular endothelial cells, mesangial cells, and tubular cells [1]. In the classic form of Fabry disease, the first symptoms develop during childhood and adolescence and include episodes of neuropathic pain, gastrointestinal disturbances, skin angiokeratomas, proteinuria, and reduced sweating. If left untreated, renal failure, cardiomyopathy, or stroke may develop. In cases of complete α-gal A deficiency, the disease begins earlier, progresses more rapidly, and affects more organs. Such involvement leads to deterioration in quality of life and premature mortality (Table 1) [1–5]. This type of disease is characteristic of men and is less common in women. In very rare cases in which α-gal A activity is reduced (1–5%), patients seek medical attention considerably later and their complaints are generally atypical. These patients most commonly develop cardiac involvement, whereas classic manifestations such as angiokeratomas, hypohidrosis, and ocular abnormalities are absent. Proteinuria is a common finding, but renal dysfunction is rare [6]. Fabry nephropathy develops during childhood or adolescence, and albuminuria and proteinuria may develop as early as the second decade of life. In patients of both sexes, detection of albuminuria is a more sensitive method for identifying renal involvement at an earlier stage [7, 8]. However, as with other chronic kidney diseases, determination of baseline proteinuria allows prediction of disease progression [9–12]. Table 1. Classic Symptoms and Signs of Fabry Disease in Patients of Different Ages Indications for Kidney Biopsy in Fabry Disease Fabry disease belongs to the group of proteinuric diseases; therefore, kidney biopsy is the gold standard for determining disease progression and the degree of renal involvement. In addition, this examination reliably confirms Fabry nephropathy in patients with proteinuria who have angiokeratomas or pain symptoms [13, 14]. Other indications for kidney biopsy include:

• male patients presenting with atypical disease manifestations (e.g., macroscopic hematuria, nephrotic syndrome, end-stage renal disease, or urinalysis without pathological abnormalities) [13, 14]. In classic disease, biopsy is recommended but is not necessary to confirm the diagnosis;
• female patients [15, 16];
• suspected concomitant kidney disease (IgA nephropathy, diabetic nephropathy, systemic lupus erythematosus, crescentic glomerulonephritis, etc.) [17–22];
• monitoring pathological deposits in renal cells and the effects of enzyme replacement therapy on these deposits [23, 24];
• marked deterioration of renal function (decline in glomerular filtration rate [GFR] >3 mL/min/1.73 m² per year) [13, 14, 25].

Clinical trial data indicate that the risk of complications associated with percutaneous kidney biopsy is very low [26, 27]. Initial and Follow-Up Evaluation Plan for Patients Once the diagnosis of Fabry disease has been confirmed, a detailed personal and family medical history should be obtained. Pain, gastrointestinal disturbances, angiokeratomas and their distribution, and all other symptoms should be documented at the time of diagnosis and subsequently reassessed at least once a year. Younger patients should be monitored more frequently. Annual follow-up should include a clinical examination and blood and urine tests. Because Fabry disease is systemic, the evaluation plan should include all clinical and instrumental tests that may help identify structural changes or functional impairment in any organ in both symptomatic and asymptomatic patients (Table 2) [28]. This is particularly important when considering enzyme replacement therapy (ERT). It is important to remember that the disease may manifest very differently in women, ranging from the classic severe form to an asymptomatic variant with occasional atypical signs [15, 29]. Given that manifestations of the disease become more severe with age, symptomatic female patients should be evaluated as frequently as male patients, whereas those with asymptomatic disease should be evaluated once a year. Table 2. Guidelines for the Evaluation of Patients With Fabry Disease Fabry Disease Among Patients Undergoing Dialysis In Europe, renal replacement therapy is provided to 1,000 per 1 million inhabitants [30]. Approximately 30% of these patients receive treatment without an accurate diagnosis of the underlying kidney disease. It has been established that 12.4% of patients receiving renal replacement therapy have rare diseases [31]. Fabry disease is one of the most common rare diseases causing end-stage renal failure. According to clinical trial data, Fabry disease is diagnosed in 0.017–0.35% of patients with end-stage renal failure [32–37]. The main reasons why Fabry disease remains undiagnosed include failure to perform a kidney biopsy in patients with end-stage kidney disease, incorrect evaluation of biopsy specimens, failure to perform electron microscopy, concomitant overlapping kidney diseases, and misinterpretation of pain in pediatric patients. Consequently, the disease is diagnosed late, in the third or fourth decade of life, when the heart and kidneys are usually already irreversibly damaged and ERT is therefore less effective. Enzyme Replacement Therapy Fabry disease is genetically inherited and usually begins in childhood; therefore, ERT in children should be initiated after the first episode of pain or gastrointestinal disturbance or after the development of albuminuria. If the patient is asymptomatic but a significant mutation or familial phenotype is identified, therapy is also recommended to be initiated immediately. Adult patients should begin ERT as early as possible after diagnosis. In patients with severe renal impairment (e.g., proteinuria >1 g/day, GFR 2) or in patients already receiving renal replacement therapy, the use of ERT remains a matter of debate. European Renal Best Practice has issued recommendations for the treatment of Fabry nephropathy. One recommendation states that in patients with marked proteinuria or a GFR of 2, ERT may be administered if extrarenal manifestations of the disease are present [39]. Patients undergoing hemodialysis are advised to receive the medication during hemodialysis sessions. Kidney transplantation is recommended for patients who meet the appropriate criteria; however, after transplantation, ERT is administered only when extrarenal clinical manifestations are present. These recommendations, however, are based not on randomized clinical trials but only on long-term clinical experience and have therefore generated considerable discussion and disagreement within the specialist community. To date, ERT remains the main treatment for Fabry disease. Two types of preparations are approved in Europe: agalsidase alfa (Replagal®) and agalsidase beta (Fabrazyme®) [42, 43]. Clinical studies involving patients whose GFR at the time of diagnosis was ≥60 mL/min/1.73 m² found that GFR declined twice as much in the control group as in the group receiving agalsidase alfa. Among patients whose baseline GFR was 2, this difference was even somewhat greater [44–51]. Attention has also been drawn to the importance of the administered dose. Recent randomized studies in children and adolescents revealed that patients receiving the highest doses of agalsidase had the lowest levels of albuminuria, with albuminuria usually disappearing completely, while kidney biopsy specimens showed the most pronounced clearance of deposits [25, 52]. Studies evaluating the efficacy of agalsidase beta found that initiating treatment during the early stages of renal dysfunction was more effective in slowing disease progression than initiating therapy later [53, 54]. For this reason, all concomitant kidney diseases are considered poor prognostic factors. Read more in Inkstų ir širdies kraujagyslių ligos, 2018. Prepared according to: Mingani R. Nephrology@Point of Care 2016;2(1):e39-e46. Gabija Visockytė Vilnius University Faculty of Medicine