Physiological aspects of the glomerular permeability to large proteins

Abstract

The normal glomerular capillary wall has a high permselectivity, allowing almost free passage of water and small solutes while larger proteins are markedly restricted. The aim of the study was to investigate the relative importance of size, charge and shape for the glomerular permeability of proteins. Isolated rat kidneys were perfused in situ with a Tyrode albumin solution at 8*C to inhibit metabolic tubular functions. Molecular shape was found to be much more important than hitherto reported. Thus, the fractional clearance (q) of bikunin, an elongated plasma protein, was 80 times greater than that of albumin despite similarities in size and charge. Furthermore, q for bikunin was more or less constant over a wide range of glomerular filtration rates, probably reflecting the fact that bikunin is a rather stiff molecule.The glomerular barrier is charge selective, even in the large pore pathway. Thus, q for the cationic isoenzyme of lactate dehydrogenase, LDH5, was five times higher than for the negatively charged LDH1 and 2.5 times higher than for albumin. The charge density of the glomerular membrane was calculated to be 35 mEq L-1 and a similar value was found using neutral and anionic horseradish peroxidase (HRP). In the latter study, the charge barrier could be reversibly altered using perfusate with different ionic strengths but similar osmolality. The HRP clearance ratio (neutral/anionic) increased from 2.8 to 4.2 during perfusion with a low ionic strength solution (34 mM) compared to a normal ionic strength solution (152 mM), suggesting a reduced charge density of 12 mEq L-1. Moreover, the effects of hyperosmolar perfusion were studied in terms of morphological and functional properties. No signs of changes in glomerular permeability were found.To conclude, there seem to be two serial barriers in the glomerular membrane: a dynamic gel with a density of fixed negative charges of 35 mEq L-1, which may be the endothelial glycocalyx and a more static heteroporous membrane with functional pores around 45Å and far less frequent pores of radius 75-85Å. The molecular shape and/or flexibility is, however, of utmost importance and may actually outweigh the effects of size and charge.