Structural determinants of glomerular permeability

Recent progress in relating the functional properties of the glomerular cap illary wall to its unique structure is reviewed. The fenestrated endotheliu m, glomerular basement membrane (GBM), and epithelial filtration slits form a series arrangement in which the flow diverges as it enters the GBM from the fenestrae and converges again at the filtration slits. A hydrodynamic m odel that combines morphometric findings with water flow data in isolated G BM has predicted overall hydraulic permeabilities that are consistent with measurements in vivo. The resistance of the GBM to water flow, which accoun ts for roughly half that of the capillary wall, is strongly dependent on th e extent to which the GBM surfaces are blocked by cells. The spatial freque ncy of filtration slits is predicted to be a very important determinant of the overall hydraulic permeability, in keeping with observations in several glomerular diseases in humans. Whereas the hydraulic resistances of the ce ll layers and GBM are additive, the overall sieving coefficient for a macro molecule (its concentration in Bowman's space divided by that in plasma) is the product of the sieving coefficients for the individual layers. Models for macromolecule filtration reveal that the individual sieving coefficient s are influenced by one another and by the filtrate velocity, requiring gre at care in extrapolating in vitro observations to the living animal. The si ze selectivity of the glomerular capillary has been shown to be determined largely by the cellular layers, rather than the GBM. Controversial findings concerning glomerular charge selectivity are reviewed, and it is concluded that there is good evidence for a role of charge in restricting the transm ural movement of albumin. Also discussed is an effect of albumin that has r eceived little attention, namely, its tendency to increase the sieving coef ficients of test macromolecules via steric interactions. Among the unresolv ed issues are the specific contributions of the endothelial glycocalyx and epithelial slit diaphragm to the overall hydraulic resistance and macromole cule selectivity and the nanostructural basis for the observed permeability properties of the GBM.