ETIOLOGIC FACTORS IN FOCAL GLOMERULAR SCLEROSIS

点击翻译按钮获取中文摘要

The presence of a circulating factor that increases glomerular macromolecular permeability in patients with focal sclerosing glomerulonephritis (FSGS) is supported by recurrence of proteinuria in the immediate post-transplant period and by the observation that plasmapheresis is often effective in reversing this proteinuria. Attempts to identify the factor responsible for glomerular injury in FSGS have been largely unsuccessful. We have developed a sensitive in vitro assay for glomerular protein permeability and have employed this assay to demonstrate the presence of a factor in serum or plasma of patients with FSGS which increases glomerular macromolecular permeability. Incubation of glomeruli in media containing active sera increases albumin permeability from a normal value of 0 to as high as 0.9. The presence of this activity prior to transplantation is strongly associated with early recurrence of proteinuria and progressive renal insufficiency following renal transplantation. Preliminary studies suggest that the active component is a protein of molecular weight 110-120 kD. Its activity is rapid in onset and is concentration dependent. Activity is neutralized by the presence of normal serum; this finding may explain the difficulty that others have had in demonstrating its presence by infusion into intact animals. The goals of the proposed studies are: 1) to purify and characterize the albumin permeability enhancing factor from sera of FSGS patients using ammonium sulphate precipitation, gel filtration, ion exchange column chromatography, HPLC, gel electrophoresis and, if necessary, isoelectric focusing and capillary electrophoresis; 2) to determine the amino acid composition and amino acid sequence of the factor in order to compare it to known proteins. The availability of a bioassay for activity provides a unique opportunity to identify and characterize the factor responsible for proteinuria and, in later studies, to develop an immunologic assay for the factor, to identify its source, to define its targets and mechanism of action, and, finally, to develop rational and effective treatment for patients with FSGS.