Blessed were the days when it all made sense and the apparent mechanism for 
edema formation in nephrotic syndrome was straightforward: the kidneys lost 
protein in the urine, which lowered the plasma oncotic pressure. Thus, fluid 
leaked into the interstitium, depleting the intravascular volume with subsequent 
activation of renin/aldosterone and consequent avid renal sodium retention. As 
simple as that! Unfortunately, a number of clinical and laboratory observations 
have raised serious concerns about the accuracy of this "underfill" hypothesis. 
Instead, an "overfill" hypothesis was generated. Under this assumption, the 
nephrotic syndrome not only leads to urinary protein wasting, but also to 
primary sodium retention with consequent intravascular overfilling, with the 
excess fluid spilling into the flood plains of the interstitium, leading to 
edema. Recently, an attractive mechanism was proposed to explain this primary 
sodium retention: proteinuria includes plasma proteinases, such as plasmin, 
which activate the epithelial sodium channel in the collecting duct, ENaC. In 
this edition, further evidence for this hypothesis is being presented by 
confirming increased plasmin content in the urine of children with nephrotic 
syndrome and demonstrating ENaC activation. If correct, this hypothesis would 
provide a simple treatment for the edema: pharmacological blockade of ENaC, for 
instance, with amiloride. Yet, how come clinicians have not empirically 
discovered the presumed power of ENaC blockers in nephrotic syndrome? And why is 
it that some patients clearly show evidence of intravascular underfilling? The 
controversy of over- versus underfilling demonstrates how much we still have to 
learn about the pathophysiology of nephrotic syndrome.