Clinical meaning
Nephrotic syndrome is defined by massive proteinuria (greater than 3.5 g/day in adults), hypoalbuminemia, hyperlipidemia, lipiduria, and peripheral edema, all resulting from disruption of the glomerular filtration barrier. The glomerular filtration barrier consists of three layers: the fenestrated capillary endothelium, the glomerular basement membrane (GBM, a collagen IV and laminin matrix providing charge and size selectivity), and the podocyte foot processes connected by slit diaphragms containing nephrin and podocin proteins. In nephrotic syndrome, damage to podocytes and/or the slit diaphragm allows albumin and other plasma proteins to pass freely into the tubular filtrate. In minimal change disease (most common in children), circulating permeability factors (likely T-cell derived cytokines) cause reversible podocyte foot process effacement without visible GBM changes on light microscopy. In focal segmental glomerulosclerosis (FSGS), podocyte injury and loss lead to segmental scarring of the glomerular tuft. In membranous nephropathy, anti-phospholipase A2 receptor (PLA2R) autoantibodies form immune complexes on the subepithelial surface of the GBM, activating complement (C5b-9 membrane attack complex) and damaging podocytes. The consequences of massive proteinuria create a cascade of complications: hypoalbuminemia results from urinary protein losses exceeding the liver's synthetic capacity (normally 12 g/day). Reduced plasma oncotic pressure from hypoalbuminemia causes fluid shift into the interstitial space (Starling forces), producing dependent edema; simultaneously, intravascular volume depletion activates the RAAS, promoting sodium and water retention that further worsens edema. The liver compensatorily increases protein synthesis, including overproduction of lipoproteins (VLDL, LDL), combined with decreased lipoprotein lipase activity, producing severe hyperlipidemia. Critically, urinary loss of antithrombin III, protein C, and protein S creates a hypercoagulable state — nephrotic syndrome carries a 25% risk of thromboembolic complications including renal vein thrombosis, deep vein thrombosis, and pulmonary embolism. Urinary loss of immunoglobulins (especially IgG) increases susceptibility to encapsulated bacterial infections (Streptococcus pneumoniae, Haemophilus influenzae).