Fractional clearances of uncharged dextran 40 and anionic proteins were performed in an attempt to elucidate the defect in glomerular barrier function responsible for heavy proteinuria in diabetic nephropathy. Notwithstanding urinary albumin excretion (UalbV) at 3634 +/- 608 microgram/min, the fractional clearance for dextran molecules with Einstein-Stokes radii (r) between 22 and 36 A was depressed in 12 patients with advanced diabetic nephropathy, which suggests a reduction in mean glomerular pore size or density. Equivalent restriction to transglomerular passage of dextrans with a r < 36 A in 7 patients with minimal change nephropathy was associated with a similarly enhanced proteinuria (UalbV, 3333 +/ 759 microgram/min). The dissociation between fractional clearances for neutral and anionic macromolecules in both disorders is consistent with loss of glomerular electrostatic charge. In diabetic nephropathy, however, the fractional clearances for large dextrans and test proteins considerably exceeded corresponding values in minimal change nephropathy when r greater than or equal to 36 A. Furthermore, the fractional clearances for test proteins were two orders of magnitude smaller than that for equivalent-sized dextrans in minimal change nephropathy, whereas this difference was much less in diabetic nephropathy. Thus, a selective increase in transglomerular passage of large molecules and a progressive loss of ability to discriminate between large molecules of different configuration distinguish the glomerular capillary wall in diabetic nephropathy from that in minimal change nephropathy.