Mechanisms of Proteinuria in Diabetic Nephropathy II: A Study of the Size-Selective Glomerular Filtration Barrier

Abstract

We evaluated the size-selective properties of the glomerular barrier in 30 patients in whom diabetic nephropathy was associated with urinary IgG losses. Neutral dextrans of graded size were used to characterize glomerular membrane-pore structure. A fractional IgG clearance (relative to freely permeable inulin) smaller or greater than 0.001 was used to distinguish patients with minor (group 1, N = 14) and major (group 2, N = 16) urinary IgG leakage, respectively. Fractional clearances of dextrans (θD) of smaller size (radii 20–40 Å) were similar, but those of larger dextrans (radii 42–60 Å) were elevated in group 2 relative to group 1 patients. When plotted on log-normal probability coordinates, the correlation between θD and radius in healthy subjects is linear, suggesting that glomerular pores form one population with a normal distribution. In diabetic nephropathy with urinary IgG leakage, however, θD for large molecules was elevated and departed from linearity, suggesting a bimodal pore size distribution within the glomerular membrane. A pore model of solute transport revealed (1) the upper pore mode was highly permeable to large dextrans equivalent in size to IgG and (2) the fraction of glomerular filtrate permeating the large pores was greater in group 2 than in group 1 patients with diabetic nephropathy, 6% versus 3%, respectively. We conclude that urinary IgG leakage in diabetic nephropathy is determined by the development of a subpopulation of enlarged pores. The magnitude of urinary IgG losses appears to be a function of the membrane area-fraction occupied by the enlarged pores.