Charge Selectivity of Proteinuria in Diabetic Glomerulopathy

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-Å 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 < .001) or IgG (r = .91, P < .001). The fractional clearance of the most anionic species of albumin [isoelectric point (pl) 4.0–4.5] significantly exceeded that of less anionic species (pl 4.5–5.5) at all levels of proteinuria. A corresponding increase in fractional clearance of anionic (pl 4.5–5.0) over neutral (pl 7.0–7.5) IgG species was observed in patients with sub-nephrotic-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.