Experimental evidence also suggests that Na⁺ and water retention occur in the kidney due to an intrarenal cause independent of salt-retaining mechanisms. As a result, the plasma volume is expanded, and this overfilled plasma volume leaks into the interstitium to cause edema . This is called the “overfill” theory (Fig. 9.1). The major site for Na⁺ reabsorption in patients with nephrotic syndrome is the collecting duct. This formed the basis of molecular theory.

According to this theory, Na⁺ retention in patients with nephrotic syndrome occurs by the overactivity of the epithelial Na⁺ channel (ENaC) in principal cells of the collecting duct. ENaC is inhibited by amiloride. Studies also have shown that the activity of Na/K-ATPase located in the basolateral membrane of the principal cell is enhanced. The net effect is avid Na⁺ reabsorption. It seems that ENaC activity is increased by locally generated plasmin from plasminogen. Plasminogen is filtered at the glomerulus in nephrotic syndrome. When it reaches the cortical collecting duct, it is split into plasmin by urokinase, and plasmin activates the ENaC to reabsorb Na⁺, resulting in low excretion of Na⁺. Thus, edema is formed in nephrotic syndrome .

Finally, the roles of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) have been implicated in the formation of edema in nephrotic syndrome . The levels of both of these hormones are elevated in nephrotic syndrome; however, their diuretic and natriuretic effects are blunted, resulting in retention of Na⁺ and water and edema formation.