Mechanisms of proteinuria in diabetic nephropathy: a study of glomerular barrier function.

The fractional clearance of neutral dextrans (theta D) with Einstein-Stokes radii between 30 and 64 A was determined in normal subjects (controls, N = 15) and in diabetic patients with heavy proteinuria (advanced nephropathy, N = 16) or trace proteinuria (early nephropathy, N = 8). When plotted on log normal probability coordinates, the correlation between theta D and radius in controls and in early diabetic nephropathy was linear, suggesting that glomerular pores form one population with a normal distribution. In advanced diabetic nephropathy, however, theta D for large molecules (radius greater than 46 A) was elevated and departed from linearity suggesting a bimodal pore size distribution within the glomerular membrane. A mathematical model was devised, which revealed the mean fraction of glomerular filtrate permeating the upper pore mode to be 0.009 +/- 0.002, and the pores to be totally nondiscriminatory toward molecules with radii up to 64 A. We conclude that the development of large pores (or defects) within the glomerular membrane in advanced diabetic nephropathy permits the unrestricted passage of large plasma proteins into the urine.