title: Mechanism of the antiproteinuric effect of indomethacin in nephrotic humans.
abstract: To elucidate the mechanisms by which indomethacin lowers proteinuria, we studied 20 patients with the nephrotic syndrome. We performed differential macromolecule clearances before and after 3 days of therapy (150 mg/24 h). The fractional clearances of albumin and immunoglobulin G (IgG) decreased by 42 +/- 7 and 44 +/- 10%, respectively (P less than 0.05). Separation of IgG into fractions by preparative electrofocusing in eight selected individuals revealed a proportionate reduction of fractional clearances among anionic (pI = 5.0), neutral (pI = 7.5), and cationic species (pI = 8.5) of IgG. Indomethacin elevated the fractional clearance of uncharged dextrans of radius 28-44 A, while depressing those of dextrans of radius 50-60 A. A heteroporous model that depicts the major portion of the glomerular capillary wall as an isoporous membrane (pore radius = 56 A) and the minor portion as a nondiscriminatory shunt, revealed the former to be unchanged and the latter to be less prominent following indomethacin. A lower fraction of total filtrate volume permeating the shunt, together with a concomitant lowering of overall glomerular filtration rate by 24%, reduced the absolute rate of flux of macromolecule-rich fluid through the shunt pathway from 0.40 to 0.25 ml.min-1.73(-2) (P less than 0.01). We conclude that indomethacin lowered the filtered protein load by restoring barrier size-selectivity while reducing the rate of glomerular ultrafiltration.
authors: Department of Medicine, Stanford University Medical Center, California 94305.
authors: H
authors: H
authors: Golbetz
authors: V
authors: V
authors: Black
authors: O
authors: O
authors: Shemesh
authors: B D
authors: BD
authors: Myers
mesh_terms: D000293:Adolescent; D000328:Adult; D003911:Dextrans / Q000493:pharmacokinetics; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007213:Indomethacin / Q000627:therapeutic use*; D007525:Isoelectric Focusing; D007526:Isoelectric Point; D008297:Male; D008875:Middle Aged; D009404:Nephrotic Syndrome / Q000150:complications / Q000188:drug therapy*; D011507:Proteinuria / Q000209:etiology / Q000517:prevention & control*
chemical_list: D003911:Dextrans; D007213:Indomethacin