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Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy.
Kidney Int. 2002 Dec; 62(6):1933-46.KI

Abstract

BACKGROUND

Fabry disease, a lysosomal storage disease caused by deficient lysosomal alpha-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, alpha-galactosidase A (r-halphaGalA), 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-halphaGalA 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-halphaGalA 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-halphaGalA may halt the progression of pathology and prevent renal failure in patients with Fabry disease.

Authors+Show Affiliations

Department of Pathology, Genzyme Corporation, Cambridge, Massachusetts, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Clinical Trial, Phase III
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12427118

Citation

Thurberg, Beth L., et al. "Globotriaosylceramide Accumulation in the Fabry Kidney Is Cleared From Multiple Cell Types After Enzyme Replacement Therapy." Kidney International, vol. 62, no. 6, 2002, pp. 1933-46.
Thurberg BL, Rennke H, Colvin RB, et al. Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy. Kidney Int. 2002;62(6):1933-46.
Thurberg, B. L., Rennke, H., Colvin, R. B., Dikman, S., Gordon, R. E., Collins, A. B., Desnick, R. J., & O'Callaghan, M. (2002). Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy. Kidney International, 62(6), 1933-46.
Thurberg BL, et al. Globotriaosylceramide Accumulation in the Fabry Kidney Is Cleared From Multiple Cell Types After Enzyme Replacement Therapy. Kidney Int. 2002;62(6):1933-46. PubMed PMID: 12427118.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy. AU - Thurberg,Beth L, AU - Rennke,Helmut, AU - Colvin,Robert B, AU - Dikman,Steven, AU - Gordon,Ronald E, AU - Collins,A Bernard, AU - Desnick,Robert J, AU - O'Callaghan,Michael, PY - 2002/11/13/pubmed PY - 2003/5/24/medline PY - 2002/11/13/entrez SP - 1933 EP - 46 JF - Kidney international JO - Kidney Int VL - 62 IS - 6 N2 - BACKGROUND: Fabry disease, a lysosomal storage disease caused by deficient lysosomal alpha-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, alpha-galactosidase A (r-halphaGalA), 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-halphaGalA 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-halphaGalA 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-halphaGalA may halt the progression of pathology and prevent renal failure in patients with Fabry disease. SN - 0085-2538 UR - https://www.unboundmedicine.com/medline/citation/12427118/Globotriaosylceramide_accumulation_in_the_Fabry_kidney_is_cleared_from_multiple_cell_types_after_enzyme_replacement_therapy_ DB - PRIME DP - Unbound Medicine ER -