The glomerular sieve and the mechanisms of proteinuria

The glomerular capillary wall acts as a sieve, allowing the passage of water and small solutes but holding up circulating macromolecules the size of albumin or larger. Recent studies indicate that such macromolecules are held up at the level of the endothelial fenestrae by a functional barrier which depends critically upon the maintenance of normal haemodynamic conditions. The effectiveness of this barrier probably relates to molecular sieving phenomena across the basement membrane, perhaps in conjunction with the formation of a concentration-polarisation layer beneath the endothelium, and possibly in association with charge effects. Accordingly, proteinuria may result not only from structural damage to the capillary wall in glomerular disease but also from general or local changes in glomerular blood flow or ultrafiltration flux, causing disturbances in the functional barrier at the endothelial fenestrae. Because it appears that the epithelial layer offers the major restriction to water flux across the wall, protein leakage at sites of focal loss of the epithelial layer (as found in a variety of human and experimental proteinuric states) may result from a focal "blow-out" of ultrafiltration flux, thereby disrupting the functional barrier at the endothelial fenestrae and dragging macromolecules across to the urinary space.