Proteinuria Mechanisms: Glomerular Injury

Proteinuria results from disruption of the glomerular filtration barrier, a three-layered structure consisting of fenestrated endothelial cells, the glomerular basement membrane (GBM), and podocyte foot processes with their slit diaphragms. Under normal conditions, this barrier restricts filtration by both size and charge: the GBM contains heparan sulfate proteoglycans that create a negative charge barrier repelling albumin (also negatively charged), while the slit diaphragm proteins nephrin, podocin, and CD2AP form a physical size barrier preventing passage of molecules > 70 kDa. Glomerular proteinuria occurs through several mechanisms: (1) Loss of charge selectivity — as in minimal change disease, where podocyte foot process effacement and loss of anionic charge barrier allows selective albuminuria (nephrotic-range proteinuria with bland urine sediment); (2) Loss of size selectivity — as in focal segmental glomerulosclerosis (FSGS) and membranous nephropathy, where structural damage to the GBM and podocytes allows larger proteins to pass (non-selective proteinuria); (3) Immune complex deposition — as in lupus nephritis and IgA nephropathy, where immune deposits in the mesangium or subepithelial/subendothelial space activate complement, damage the filtration barrier, and cause inflammatory proteinuria with active...