Molecular configuration and glomerular size selectivity in healthy and nephrotic humans

We studied eight healthy volunteers and eight nephrotic subjects to compare the glomerular sieving coefficients (theta) of dextran, a linear polymer of glucopyranose, with those of Ficoll, a spherical polysucrose. Over a molecular radius (rs) interval of 20-70 A, theta for a given Ficoll was uniformly lower than corresponding theta for a dextran of equivalent rs. For each macromolecular species, the theta of molecules with rs > 50 A was selectively enhanced in nephrotic vs. healthy subjects. Analysis of either dextran or Ficoll sieving curves with pore theory revealed the glomerular barrier to have a bimodal pore size distribution: a lower mode of restrictive pores with a lognormal distribution of radii and an upper mode of large shuntlike pores. Nephrotics differed from controls in that the lower mode was broadened and shifted to pores of smaller mean size, but the prominence of shuntlike pores was enhanced by an order of magnitude. Both the mean radius of restrictive pores and the magnitude of the shunt pathway were substantially smaller when estimated from Ficoll than dextran sieving. We interpret the more realistic values for pore parameters derived from Ficoll than dextran sieving to indicate 1) that the normal glomerular barrier prevents albuminuria by virtue of a combination of both charge- and size-selective properties and 2) that a combined impairment of both barrier charge selectivity and size selectively are required to account for the observed level and composition of proteinuria in our nephrotic subjects.