Evolution of renal pathology in Fabry disease

Abstract

Fabry disease is a rare lysosomal storage disorder which results from deficient activity of the enzyme α‐galactosidase A. The resultant deposition and progressive accumulation of glycosphingolipids in all types of body tissue leads to severe clinical manifestations involving the heart, CNS and kidney. Renal manifestations are observed relatively early in the course of the disease, and progression to end‐stage renal failure is common in hemizygous males in the third to fifth decades of life. Renal biopsy specimens reveal evidence of diffuse intracytoplasmic glycosphingolipid accumulation, mainly affecting podocytes and epithelial cells of distal tubules, which are strikingly enlarged and vacuolated. On electron microscopy the deposits appear as typical osmiophilic inclusion bodies in the cytoplasm of all kinds of renal cells, and show a characteristic ‘onion skin’ or ‘zebra’ appearance. These pathological features are also evident in heterozygous females. Deposits occur before the development of renal impairment. As patients age, the disease progresses in cells throughout the kidney, and is associated with increasing glycosphingolipid accumulation. Conclusion: The age‐related evolution of renal pathology in Fabry disease is closely correlated with progressive intracellular deposition of glycosphingolipid and ultimately leads to end‐stage renal failure.

Anderson-Fabry Disease: A Multiorgan Disease

“…The evolution of renal Fabry disease is characterized by progressive deterioration of renal function to end-stage renal failure (ESRF). Ultrastructural study of kidney biopsies reveals typical bodies in the cytoplasm of all types of renal cells, characterized by concentric lamellation of clear and dark layers with a periodicity of 35-50 [20] (Fig. 3).…”

“…Possibly, other cardiovascular risk factors may contribute to enhanced athero-thrombogenesis and a worsening of arterial performance. Although some patients with Fabry disease may suffer from stroke by involvement of larger arteries, smallvessel disease causes cerebral complications and probably contributes to complications of the kidney and the heart [31,32,33]. Controversy exists whether the storage in the endothelial cells and the pro-thrombotic state are the origin of arterial damage or whether smooth muscle cell proliferation in the arterial media layer is the initiating step in the cascade that leads to Fabry vasculopathy [34,35].…”

Fabry disease: Guidelines for the evaluation and management of multi-organ system involvement

“…Initial manifestations include impaired filtration rate (GFR), proteinuria, and tubular derangements. 11 Microalbuminuria and blunted concentrating ability have been reported in adolescents. Typically, reduced GFR and proteinuria associated with GL-3 accumulation develop during the third decade in affected males.…”

Neurological Complications of Anderson-Fabry Disease

“…Anderson-Fabry disease clinical manistestations are essentially vascular (or miscrovascular) complications (such as cerebral disease), with a not well understood pathophysiology. Some studies indicate that vascular lesions of Anderson-Fabry disease may be related to endothelial dysfunction, alterations in cerebral perfusion and a pro-thrombotic state [40,20,41,42]. To date not well clear is the issue about the concept if a GB3 storage in the endothelial cells and the pro-thrombotic state is the origin of arterial damage or whether smooth muscle cell proliferation in the arterial media layer could represent the first step of Anderson-Fabry vascular pathology [43,44].…”