Mechanisms of sodium retention in nephrotic syndrome

Gitte R Hinrichs, Boye L Jensen, Per Svenningsen

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PURPOSE OF REVIEW: Proteinuria in nephrotic syndrome is associated with sodium retention and edema. Recent studies from mice, rats and humans have shown that the sodium retention depends on urinary serine proteases and that it can be mitigated by blockers (amiloride, triamterene) of the epithelial sodium channel ENaC. The present review outlines the mechanisms of protease-stimulated sodium retention during proteinuric diseases.

RECENT FINDINGS: Inhibition of protease activity in nephrotic mice using aprotinin alleviates sodium retention. From both human and mice studies, an increased proteolytic cleavage of the γENaC subunit plays a role in ENaC activation. In animal models, urokinase-plasmin contributes but not as sole mediators of sodium retention. Across experimental models, human case reports and small intervention trials, amiloride alleviates nephrotic sodium retention and low-renin hypertension with high efficacy.

SUMMARY: Although the exact mechanisms for proteolytic ENaC activation are not resolved, multiple, redundant proteases are involved. Experimental and clinical evidence indicate that aberrant proteolytic ENaC activation is a primary driver of sodium retention in nephrotic syndrome and contributes to hypertension in conditions with low-grade proteinuria. Thus, we foresee increased and personalized use of amiloride treatment of nephrotic and other proteinuric disease patients with associated sodium retention and hypertension.

Original languageEnglish
JournalCurrent Opinion in Nephrology & Hypertension
Issue number2
Pages (from-to)207-212
Publication statusPublished - Mar 2020


  • Edema
  • Epithelial sodium channel
  • Extracellular vesicle
  • Proteinuria
  • Serine proteases
  • Animals
  • Humans
  • Nephrotic Syndrome/metabolism
  • Sodium/metabolism
  • Epithelial Sodium Channels/physiology
  • Hypertension/etiology

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