AJKD Atlas of Renal Pathology: FabryNephropathy
Behzad Najafian, MD,1 Agnes B. Fogo, MD,2Mark A. Lusco, MD,2 and Charles E. Alpers, MD 1
Clinicaland Pathologic Features
Clinical manifestations are heterogeneous.Classic cases present with peripheral neuropathy, skin vascular dilatations(angiokeratoma corporis diffusum), corneal opacities, abdominal pain anddiarrhea, arrhythmias, ventricular hypertrophy, strokes, and kidney failure.The initial clinical manifestations of kidney involvement are microalbuminuriaand proteinuria, which may start in the teenage years. This is followed byprogressive glomerular filtration rate decline. Untreated patients (especiallymen) develop end-stage renal disease in their 40s and 50s.
Light microscopy: The characteristicaccumulated glycosphingolipid (GSL) inclusions are removed during tissueprocessing for paraffin embedding. Therefore, the cells, especially podocytes,parietal epithelial cells, and distal tubular epithelial cells, appearvacuolated. Hyaline-like material accumulates in the media of arteries andarterioles (Fabry arteriopathy) and sometimes in the mesangial regions.
Immunofluorescence: Negative.
Electron microscopy: Highly electron-densemultilamellar inclusions of GSL (myelin figures made of concentric layers andzebra bodies, which have elongated striped appearance) are present in variouscell types. The inclusions also stain darkly by toluidine blue on semi-thinsections. Abundant inclusions are present in podocytes, parietal epithelialcells, and distal tubular cells. Mesangial and endothelial cell inclusions maynot be present in patients treated with enzyme replacement therapy or in womenwho are disease carriers. Arteries and arterioles show inclusions in smooth musclecells and hyaline-like material, consistent with Fabry arteriopathy.
Etiology/Pathogenesis
Fabry disease is an X-linked lysosomalstorage disease due to deficiency of alpha-galactosidase A. This results inaccumulation of GSLs, especially globotriaosylceramide (GL3), in the form ofintralysosomal inclusions.
DifferentialDiagnosis
Cytoplasmic inclusions similar to Fabryinclusions can also be seen in iatrogenic phospholipidosis secondary toamphophilic drugs, such as chloroquine, amiodarone, and hydroxychloroquine.Foamy podocytes by light microscopy can also be seen in other lysosomal storagediseases. However, inclusions in those conditions appear different from Fabryinclusions by electron microscopy.
KeyDiagnostic Features
-Foamy podocytes and distal tubular cellson paraffin sections by light microscopy
-Darkly stained round multilamellarinclusions on toluidine blue–stained sections
-Intracellular inclusions (myelin figuresand zebra bodies), with greatest abundance in podocytes by electron microscopy
Figure1. Fabry nephropathy with prominent vacuolizationof podocytes (hematoxylin and eosin stain). Reproduced with permission fromAJKD 37(4):e25. Continued
Figure2. Fabry nephropathy with darkly stained roundinclusions in podocytes (red arrow), mesangial cells (yellow arrow), andendothelial cells (white arrow) in a glomerulus. There is an arteriole withFabry inclusions in smooth muscle cells (asterisk; toluidine blue stain).
Figure3. Fabry nephropathy with deposition ofhyaline-like material in the media of an interlobular artery (arrows),consistent with Fabry arteriopathy (periodic acid–Schiff stain).
Figure4. Fabry nephropathy with typical Fabryglycosphingolipid inclusions shaped as multilamellated myelin figures (redarrow) and zebra bodies (yellow arrows) in podocytes. There are also smallerinclusions in endothelial cells (black arrow) and mesangial cells (white arrow;electron microscopy). - Atlas of Renal Pathology II e36 Am J Kidney Dis. 2015;66(5):e35-e36
