Genetic disorders – Development
Kidney International (2002) 62, 1933–1946; doi:10.1046/j.1523-1755.2002.00675.x
Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy
Beth L Thurberg, Helmut Rennke1, Robert B Colvin1, Steven Dikman1, Ronald E Gordon, A Bernard Collins, Robert J Desnick and Michael O'Callaghan
Departments of Pathology and Preclinical Biology, Genzyme Corporation, Cambridge, and Department of Pathology, Brigham and Women's Hospital, and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts; Departments of Pathology and Human Genetics, Mount Sinai School of Medicine, New York, New York, USA
Correspondence: Dr Michael O'Callaghan, Department of Preclinical Biology, Genzyme Corporation, P.O. Box 9322, One Mountain Road, Framingham, Massachusetts 01701-9322, USA. E-mail: mike.ocallaghan@genzyme.com
1Dr. Rennke, Dr. Colvin, and Dr. Dikman contributed equally to this study
Received 22 March 2002; Revised 24 June 2002; Accepted 22 July 2002.
Abstract
Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy.
Background
Fabry disease, a lysosomal storage disease caused by deficient lysosomal 
-galactosidase A activity, is characterized by globotriaosylceramide (GL-3) accumulation in multiple cell types, particularly the vasculature, leading to end organ failure. Accumulation in the kidney is responsible for progressive decline in renal function in male patients with the classical phenotype, resulting in renal failure in their third to fifth decades of life. With the advent of recombinant protein synthesis technology, enzyme replacement therapy has become a viable alternative to dialysis or renal transplantation, previously the only available treatment options for end-stage renal disease.
Methods
The pre- and post-treatment renal biopsies were analyzed from fifty-eight Fabry patients enrolled in a Phase 3 double-blind, randomized, placebo-controlled trial followed by a six-month open label extension study of the recombinant human enzyme, -galactosidase A (r-hGalA), administered IV at 1 mg/kg biweekly. The purpose of this investigation was to detail the pathologic changes in glycosphingolipid distribution and the pattern of post-treatment clearance in the kidney.
Results
Baseline evaluations revealed GL-3 accumulations in nearly all renal cell types including vascular endothelial cells, vascular smooth muscle cells, mesangial cells and interstitial cells, with particularly dense accumulations in podocytes and distal tubular epithelial cells. After 11 months of r-hGalA treatment there was complete clearance of glycolipid from the endothelium of all vasculature as well as from the mesangial cells of the glomerulus and interstitial cells of the cortex. Moderate clearance was noted from the smooth muscle cells of arterioles and small arteries. Podocytes and distal tubular epithelium also demonstrated evidence for decreased GL-3, although this clearance was more limited than that observed in other cell types. No evidence of immune complex disease was found by immunofluorescence despite circulating anti-r-hGalA IgG antibodies.
Conclusions
These findings indicate a striking reversal of renal glycosphingolipid accumulation in the vasculature and in other renal cell types, and suggest that long-term treatment with r-hGalA may halt the progression of pathology and prevent renal failure in patients with Fabry disease.
Keywords:
renal disease, Fabry disease, X-linked recessive disorder, neutral glycosphingolipids, renoprotection, end-stage renal disease, Phase 3 trial
