Functional Nature of Glomerular Injury in Progressive Diabetic Glomerulopathy

We describe in physiological terms the increasing glomerular capillary wall (GCW) dysfunction of 20 patients with diabetic glomerulopathy and heavy proteinuria. The clearances of uncharged polysaccharide markers of graded size were used to probe the glomerular filter on three occasions over a 24-mo period. The findings were analyzed with a theoretical model of solute transport that depicts most of the GCW as an isoporous membrane and the minor portion as a nondiscriminatory shunt pathway. Initially, the mean glomerular ultrafiltration coefficient K_f is computed to have been 3-5 times lower and mean pore radius of the major membrane component (r₀) 2 Å smaller than normal control values. In contrast, the model computes the fraction of filtrate volume permeating the nondiscriminatory shunt pathway (ω₂) to have been sixfold elevated above control values and to have correlated strongly in individual patients with the fractional clearances of albumin (r = .72) and of IgG (r = .73). Sequential studies after 12 and 24 mo revealed an invariable decline in glomerular filtration rate (GFR). Fractional clearances of albumin and IgG increased with time in most patients but declined in a few instances (20-25%). Change in ω₂ tended to occur in parallel with fractional protein clearance, regardless of its direction. We conclude that in progressive diabetic glomerulopathy 1) GFR declines because of a loss by glomerular capillaries of ultrafiltration capacity, 2) proteinuria is largely a consequence of increasingly impaired barrier-size selectivity, and 3) the foregoing injuries reflect damage to different parts of the GCW and may become dissociated from one another with the passage of time.