Scoring system for renal pathology in Fabry disease: report of the International Study Group of Fabry Nephropathy (ISGFN)

Abstract

Background: In Fabry nephropathy, alpha-galactosidase deficiency leads to accumulation of glycosphingolipids in all kidney cell types, proteinuria and progressive loss of kidney function.

Methods: An international working group of nephrologists from 11 Fabry centres identified adult Fabry patients, and pathologists scored histologic changes on renal biopsies. A standardized scoring system was developed with a modified Delphi technique assessing 59 Fabry nephropathy cases. Each case was scored independently of clinical information by at least three pathologists with an average final score reported.

Results: We assessed 35 males (mean age 36.4 years) and 24 females (43.9 years) who mostly had clinically mild Fabry nephropathy. The average serum creatinine was 1.3 mg/dl (114.9 micromol/l); estimated glomerular filtration rate was 81.7 ml/min/1.73 m(2) and urine protein to creatinine ratio was 1.08 g/g (122.0 mg/mmol). Males had greater podocyte vacuolization on light microscopy (mean score) and glycosphingolipid inclusions on semi-thin sections than females. Males also had significantly more proximal tubule, peritubular capillary and vascular intimal inclusions. Arteriolar hyalinosis was similar, but females had significantly more arterial hyalinosis. Chronic kidney disease stage correlated with arterial and glomerular sclerosis scores. Significant changes, including segmental and global sclerosis, and interstitial fibrosis were seen even in patients with stage 1-2 chronic kidney disease with minimal proteinuria.

Conclusions: The development of a standardized scoring system of both disease-specific lesions, i.e. lipid deposition related, and general lesions of progression, i.e. fibrosis and sclerosis, showed a spectrum of histologic appearances even in early clinical stage of Fabry nephropathy. These findings support the role of kidney biopsy in the baseline evaluation of Fabry nephropathy, even with mild clinical disease. The scoring system will be useful for longitudinal assessment of prognosis and responses to therapy for Fabry nephropathy.

Fig. 1

Interstitial fibrosis (%): comparison of semi-quantitative scoring to morphometric assessment. Bland–Altman plot compares the difference (index of chronic damage – semi-quantitative score; solid horizontal line) with their mean. The limits of agreement (±2 SD) are shown as dashed horizontal lines.

Fig. 2

Vacuolization and glycosphingolipid deposits in Fabry nephropathy. (A) The glomerulus shows vacuolization of podocytes (arrowheads), and mild corrugation of glomerular basement membranes, with periglomerular and interstitial fibrosis (periodic acid-Schiff, x400). (B) The glomerulus shows massive expanded deposits in most podocytes (arrowheads) and also in mesangial and endothelial cells and parietal epithelial cells in this male Fabry patient (toluidine blue, ×400). (C) The glomerulus shows occasional small deposits in podocytes (arrowheads) and rare deposits in mesangial areas in this female patient (toluidine blue, ×400). (D) There are prominent deposits in some proximal tubular cells and peritubular capillary endothelium (toluidine blue, ×1000). (E) Numerous deposits in distal tubules and very rare deposits in proximal tubules. The vascular smooth muscle of a large artery (top left corner) also shows deposits, as do parietal epithelial cells lining the Bowman's capsule (bottom) (toluidine blue, ×1000). (F) Numerous deposits in distal tubules with rare deposits in proximal tubules and frequent deposits in peritubular capillaries and interstitium (toluidine blue, ×200).

Fig. 3

Vascular lesions in Fabry nephropathy. Numerous inclusions in endothelial cells and vascular smooth muscle cells in this large artery are seen in the toluidine blue-stained semi-thick scout section (toluidine blue, ×1000).

Fig. A1

Scoring sheet for Fabry nephropathy by light microscopy.