Glomerular size-selectivity and microalbuminuria in early diabetic glomerular disease

Abstract

Sieving coefficients of uncharged dextrans of graded size (radii 30 to 60 Å) were used to characterize barrier size-selectivity in nonazotemic diabetic humans with microalbuminuria (Group 1, N = 11) or macroalbuminuria (Group 2, N = 21). Compared to a non-diabetic control group (N = 21) the low radius end of the sieving profile was depressed, whereas the high radius end was elevated in each diabetic group, more so in Group 2 than Group 1. A heteroporous membrane model revealed the major portion of the glomerular barrier to be perforated by restrictive pores of ~56 Å radius in all three groups. However, in keeping with a parallel trend for GFR, the relative density of restrictive pores was control > Group 1 > Group 2. The remaining minor portion of the barrier was perforated by large, shunt-like pores, the relative prominence of which ranked Group 2 > Group 1 > control. Although the hypothetical, fractional clearance of macromolecules attributable to the shunt-like pores varied directly with fractional clearances of albumin and IgG, the progressive increment in the latter fractional protein clearances in the two diabetic groups was disproportionate. This raises the possibility that factors in addition to barrier size defects contribute to the development, magnitude and composition of proteinuria early in the course of diabetic glomerular disease. Such factors could include: (1) a progressive decrement in fractional reabsorption as the filtered protein load increases, and (2) a concomitant loss of barrier charge-selectivity, permitting albumin but not IgG to escape through restrictive pores, and thereby accounting for an observed excess of albumin over IgG clearance in both micro- and macroalbuminuric stages of diabetic glomerular disease.