Proteasuria—The impact of active urinary proteases on sodium retention in nephrotic syndrome

Abstract

Sodium retention and extracellular volume expansion are typical features of patients with nephrotic syndrome. In recent years, from in vitro data, endoluminal activation of the epithelial sodium channel (ENaC) by aberrantly filtered serine proteases has been proposed as an underlying mechanism. Recently, this concept was supported in vivo in nephrotic mice that were protected from proteolytic ENaC activation and sodium retention by the use of aprotinin for the pharmacological inhibition of urinary serine protease activity. These and other findings from studies in both rodents and humans highlight the impact of active proteases in the urine, or proteasuria, on ENaC-mediated sodium retention and edema formation in nephrotic syndrome. Targeting proteasuria could become a therapeutic approach to treat patients with nephrotic syndrome. However, pathophysiologically relevant proteases remain to be identified. In this review, we introduce the concept of proteasuria to explain tubular sodium avidity and conclude that proteasuria can be considered as a key mechanism of sodium retention in patients with nephrotic syndrome. K E Y W O R D Saprotinin, ENaC, nephrotic syndrome, proteasuria, proteinuria, proteolysis, serine protease

Sodium retention by uPA‐plasmin‐ENaC in nephrotic syndrome—Authors reply

“…Conventional diuretics, that is, loop diuretics and thiazides, show reduced efficacy in this condition emphasizing the need for a diuretic intervention based on causal understanding. Contrary to the classical view of altered fluid distribution second to a low plasma oncotic pressure, accumulating evidence suggest that oedema formation in NS is because of the aberrant renal sodium retention . It has been shown that pharmacologic blockade of the epithelial sodium channel (ENaC) using amiloride can prevent sodium retention and relieve nephrotic oedema in both rats, mice and humans .…”

“…Contrary to the classical view of altered fluid distribution second to a low plasma oncotic pressure, accumulating evidence suggest that oedema formation in NS is because of the aberrant renal sodium retention. 4 It has been shown that pharmacologic blockade of the epithelial sodium channel (ENaC) using amiloride can prevent sodium retention and relieve nephrotic oedema in both rats, mice and humans. [5][6][7][8] As aldosterone is typically in normal range or suppressed in NS, possibly after a variable and short initial increase, the question is what activates ENaC in NS?…”

Rebuttal to editorial: Sodium retention by uPA in nephrotic syndrome?

“…There is substantial experimental evidence for the concept that proteolytic ENaC activation by proteasuria contributes to renal sodium retention in nephrotic syndrome . In particular, two key observations support this hypothesis: firstly, treatment with the ENaC inhibitor amiloride greatly attenuates renal sodium retention in rat and mouse models of nephrotic syndrome.…”

Bradykinin—from snake poison to therapeutic options

“…In general, kinins induce a decrease in systemic blood pressure through stimulating natriuresis and diuresis in the kidney. Kallikreins are involved in ENaC regulation . Sodium retention in a rodent model of nephrotic syndrome is caused by activated serine proteases in the urine .…”

“…Kallikreins are involved in ENaC regulation. 11 Sodium retention in a rodent model of nephrotic syndrome is caused by activated serine proteases in the urine. 12 Interestingly, kallikrein is detectable in the urine of proteinuric patients and capable of ENaC activation in vitro, suggesting a role in pathologic sodium retention.…”