Differential macromolecule clearances were used to elucidate the mechanism of
proteinuria in patients with diabetic glomerulopathy. Uncharged
dextrans of graded size, combined with
albumin and
IgG separated into narrow fractions of varying charge by preparative electrofocusing, were used to probe the filtration barrier. Analysis of the fractional clearance profile of
dextrans in the 30- to 60-A interval revealed a small fraction of filtrate volume (0.0023-0.0097) permeating large nonrestrictive glomerular pores and correlating strongly with the fractional clearances of
albumin (r = .88, P less than .001) or
IgG (r = .91, P less than .001). The fractional clearance of the most anionic species of
albumin [isoelectric point (pI) 4.0-4.5] significantly exceeded that of less anionic species (pI 4.5-5.5) at all levels of
proteinuria. A corresponding increase in fractional clearance of anionic (pI 4.5-5.0) over neutral (pI 7.0-7.5)
IgG species was observed in patients with subnephrotic-range
proteinuria. We conclude that a loss of barrier size selectivity underlies
proteinuria in diabetic glomerulopathy. In addition, either facilitated filtration of
polyanions or preferential tubular reabsorption of
polycations can be invoked to explain the final composition of urinary
protein. Similar loss of size selectivity combined with enhanced fractional clearance of anionic
IgG in a group of nondiabetic patients with
nephrotic syndrome indicates that the foregoing abnormality of renal
protein handling is not unique to diabetic glomerulopathy.