Functional Nature of Glomerular Injury in Progressive Diabetic Glomerulopathy

Abstract

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 Kf is computed to have been 3-5 times lower and mean pore radius of the major membrane component (r0) 2 A smaller than normal control values. In contrast, the model computes the fraction of filtrate volume permeating the nondiscriminatory shunt pathway (omega 2) 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 omega 2 tended to occur in parallel with fractional protein clearance, regardless of its direction. We conclude that in progressive diabetic glomerulopathy GFR declines because of a loss by glomerular capillaries of ultrafiltration capacity, proteinuria is largely a consequence of increasingly impaired barrier-size selectivity, and the foregoing injuries reflect damage to different parts of the GCW and may become dissociated from one another with the passage of time.

Effects of Converting-Enzyme Inhibition on Barrier Function in Diabetic Glomerulopathy

“…At the elevated filtered protein loads associated with diabetic glomerulopathy, it is likely that fractional tubular reabsorption of filtered protein is severely depressed and that the fractional clearance of a given protein approaches its glomerular ultrafiltrate-to-plasma concentration ratio (22)(23)(24). Because this ratio is a more direct measure of glomerular permeability than the protein excretion rate, it may have greater utility in identifying an improvement of barrier function during CEI therapy (8,25).…”

“…Urinary losses were replaced quantitatively throughout with oral fluids. Eight clearance periods were used rather than our routine number of four to promote the most complete bladder emptying possible in these proteinuric subjects, who frequently exhibited evidence of autonomic bladder neuropathy (8). To prevent the formation of a PAH-glucose adduct in urine, 4-ml urine samples were alkalinized with 23 jxl of 4 M sodium hydroxide (11).…”

“…Iothalamate and PAH concentrations were determined from the peak area of each solute, corresponding to column retention times of 10 and 14 min, respectively. Dextran concentrations were assayed with anthrone after protein-free filtrates of plasma and urine had been separated into narrow fractions by gel-permeation chromatography on precalibrated Ultragel AcA 44 columns (LKB, Pleasant Hill, CA) as described previously (8)(9)(10). Plasma oncotic pressure was measured by membrane osmometry, and concentrations of albumin and IgG in serum were measured by radial immunodiffusion.…”

“…The inability of CEI therapy to consistently lower proteinuria in diabetic glomerular disease may be partly attributable to differences in the treatment protocols and experimental populations in the studies cited. The relative insensitivity of urinary protein excretion rate as a measure of glomerular permeability to proteins may also contribute to the inconsistency of reported responses (8). Glomerular permeability, prevailing plasma protein concentration, and glomerular filtration rate (GFR) can all influence the filtered protein load, and the fraction of this load that is ultimately excreted depends on a variable rate of tubular protein reabsorption.…”

“…We have previously shown that the extent of glomerular permeability to proteins in diabetic glomerular disease is closely related to the degree of size selectivity exhibited by the glomerular barrier (8)(9)(10). To explore the effects of CEI therapy on intrinsic barrier function, we examined the sieving behavior of glomeruli of proteinuric diabetic patients toward uncharged and nonreabsorbable dextrans of broad size distribution.…”