Ovadia Shemesh

A differential solute clearance technique was used to evaluate glomerular capillary wall function in 20 patients with membranous glomerulopathy and massive proteinuria. The clearance of inulin, the filtration fraction, and the fractional clearance of uncharged dextrans of a radius of 28-48 A were depressed significantly below control values in 20 healthy volunteers (P less than 0.01). In contrast, the fractional clearance of dextrans of radius greater than 50 A was elevated markedly. A theoretical model of solute transport that depicts the major portion of the glomerular capillary wall as an isoporous membrane and the minor portion as a nondiscriminatory shunt pathway revealed the calculated glomerular ultrafiltration coefficient to be five times lower and mean pore radius of the major membrane component to be 4 A smaller than control values. However, the fraction of filtrate volume permeating the shunt pathway was three- to fourfold above control values and correlated strongly in individual patients with the fractional clearance of albumin (r = 0.76) and of IgG (r = 0.80). Lowering renal plasma flow by 24% during indomethacin therapy in seven patients resulted in a 74% reduction in proteinuria accompanied by a corresponding diminution of filtrate formed through the shunt pathway. Morphometric analysis of glomerular ultrastructure revealed the magnitude of depression of the glomerular filtration rate and of urinary protein leakage to be related strongly to changes in the epithelial layer of the glomerular capillary wall, but not to the density of subepithelial immune deposits. We conclude that glomerular capillaries in membranous glomerulopathy are characterized by a loss of ultrafiltration capacity and of barrier size-selectivity, and that subepithelial immune deposits do not provide a structural basis for these functional alterations.

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.