Renal complications of Fabry disease in children

Abstract

Fabry disease is an X-linked α-galactosidase A deficiency, resulting in accumulation of glycosphingolipids, especially globotriaosylceramide, in cells in different organs in the body. Renal failure is a serious complication of this disease. Fabry nephropathy lesions are present and progress in childhood while the disease commonly remains silent by routine clinical measures. Early and timely diagnosis of Fabry nephropathy is crucial since late initiation of enzyme replacement therapy may not halt progressive renal dysfunction. This may be challenging due to difficulties in diagnosis of Fabry disease in children and absence of a sensitive non-invasive biomarker of early Fabry nephropathy. Accurate measurement of glomerular filtration rate and regular assessment for proteinuria and microalbuminuria are useful, though not sensitive enough to detect early lesions in the kidney. Recent studies support the value of renal biopsy in providing histological information relevant to kidney function and prognosis, and renal biopsy could potentially be used to guide treatment decisions in young Fabry patients. This review aims to provide an update of the current understanding, challenges, and needs to better approach renal complications of Fabry disease in children.

Figure 1

Electron Micrograph of a glomerulus from an 11-years-old boy with Fabry disease. The patient had normal GFR and a urine protein/creatinine ratio of about 40 mg/g at biopsy. There are abundant GL-3 inclusions (long black arrows) in podocytes (PC). Similar inclusions are found in endothelial cells (white arrow) and mesangial cells (spiral arrow). Short black arrows show widened foot processes over a capillary (Cap) loop. Arrowheads show loss of fenestration in an endothelial cell. Magnification: 35,000 x.

Figure 2

A. Mild Fabry arteriopathy characterized by focal replacement of smooth muscle cells in the vascular wall by hyaline-like material (arrow) in a kidney biopsy from a 12-years-old girl with Fabry disease, PAS stain, 40x. The patient had normal GFR and a urine protein/creatinine ratio of 90 mg/g at biopsy. B. More severe Fabry arteriopathy from an autopsy case. Arrows show that a substantial portion of the muscular wall is replaced y the hyaline-like material, H&E, 20x.

Figure 3

Relationships between urine protein creatinine ratio (UPCR) and age with foot process width (FPW) and podocyte GL-3 inclusion density [Vv(Inc/PC)] in young Fabry patients. Both Vv(Inc/PC) and FPW increased with age and correlated with UPCR, although these relationships were more prominent in male patients (black circles) compared to females (white circles). (adapted and modified from Najafian et al., Ref. 18).