Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy

Abstract

Globotriaosylceramide accumulation in the Fabry kidney is ance was more limited than that observed in other cell types. cleared from multiple cell types after enzyme replacement therapy.No evidence of immune complex disease was found by immuno-Background. Fabry disease, a lysosomal storage disease caused fluorescence despite circulating anti-r-h␣GalA IgG antibodies. by deficient lysosomal ␣-galactosidase A activity, is character-Conclusions. These findings indicate a striking reversal of ized by globotriaosylceramide (GL-3) accumulation in multiple renal glycosphingolipid accumulation in the vasculature and in cell types, particularly the vasculature, leading to end organ other renal cell types, and suggest that long-term treatment failure. Accumulation in the kidney is responsible for progreswith r-h␣GalA may halt the progression of pathology and sive decline in renal function in male patients with the classical prevent renal failure in patients with Fabry disease. 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 Fabry disease is an X-linked recessive disorder in which only available treatment options for end-stage renal disease.affected males are deficient in the lysosomal enzyme Methods. The pre-and post-treatment renal biopsies were ␣-galactosidase A. This deficiency leads to accumulation analyzed from fifty-eight Fabry patients enrolled in a Phase 3 double-blind, randomized, placebo-controlled trial followed by

Chloroquine-induced lipidosis mimicking Fabry disease

“…1,2,6 Use of toluidine blue-or methylene blue-stained sections of glutaraldehyde fixed and plastic-embedded sections allows for easy identification of cellular inclusions that appear and are dense granular. 1,5 Phospholipidosis similar to that observed in Fabry disease has been associated with various drugs; among these, amiodarone 8 and chloroquine 9,10 are especially well documented in the literature. Chloroquine, an antimalarial agent also infrequently used in the treatment of various rheumatologic illnesses, has been shown in several animal and human studies to be extensively sequestered in tissues, with the liver, spleen, kidneys, and lungs being the main repositories.…”

“…[4][5][6] As a result of this enzyme deficiency, Gb 3 accumulates within many cells resulting in cellular dysfunction and organ system failure. 6 Primary sites affected by Gb 3 accumulation include renal glomerular and tubular epithelial cells, myocardial cells and valvular fibrocytes, neurons of the dorsal root ganglion and autonomic nervous system, and endothelial, perithelial, and smooth muscle cells of the vascular system.…”

“…6 Primary sites affected by Gb 3 accumulation include renal glomerular and tubular epithelial cells, myocardial cells and valvular fibrocytes, neurons of the dorsal root ganglion and autonomic nervous system, and endothelial, perithelial, and smooth muscle cells of the vascular system. 5,6 Fabry disease has an incidence range of 1 in 40 000 to 60 000 in males. 4 Carrier (heterozygous) females also can be affected to a mild or severe degree because of differential X-chromosomal inactivation (Lyonization).…”

Sustained, Long-Term Renal Stabilization After 54 Months of Agalsidase β Therapy in Patients with Fabry Disease

“…The degree of GL-3 deposition was rated using an ordinal scale as reported previously (8,14). GL-3 accumulation in podocytes and distal convoluted tubule/collecting ducts was assessed at month 6 and scored relative to baseline values; at month 54, the ordinal scoring system was used.…”

“…Histologic evaluation of the capillary endothelium of the heart and kidney for GL-3 accumulation was conducted at month 6 (or month 12, if the month 6 biopsy was postponed) and optionally at month 54, if deemed medically appropriate, using LM. Other cell types from the kidney (14,15) were also evaluated using LM.…”