Nephrotic Syndrome: From Pathophysiology to Novel Therapeutic Approaches

Abstract

Nephrotic edema stands out as one of the most common complications of nephrotic syndrome. The effective management of hypervolemia is paramount in addressing this condition. Initially, "the underfill hypothesis" suggested that proteinuria and hypoalbuminemia led to fluid extravasation into the interstitial space, causing the intravascular hypovolemia and activation of neurohormonal compensatory mechanisms, which increased the retention of salt and water. Consequently, the recommended management involved diuretics and human-albumin infusion. However, recent findings from human and animal studies have unveiled a kidney-limited sodium-reabsorption mechanism, attributed to the presence of various serine proteases in the tubular lumen-activating ENaC channels, thereby causing sodium reabsorption. There is currently no standardized guideline for diuretic therapy. In clinical practice, loop diuretics continue to be the preferred initial choice. It is noteworthy that patients often exhibit diuretic resistance due to various factors such as high-sodium diets, poor drug compliance, changes in pharmacokinetics or pharmacodynamics, kidney dysfunction, decreased renal flow, nephron remodeling and proteasuria. Considering these challenges, combining diuretics may be a rational approach to overcoming diuretic resistance. Despite the limited data available on diuretic treatment in nephrotic syndrome complicated by hypervolemia, ENaC blockers emerge as a potential add-on treatment for nephrotic edema.

Keywords: ENaC-blockers; diuretic resistance; nephrotic syndrome; serin protease; underfill and overfill hypothesis.

Figure 1

Classes of diuretics and their mechanism of action at different sites in the renal tubule; Abbreviations: carbonic anhydrase (CA), epithelial sodium-channel blockers (ENaCb), mineralocorticoid-receptor antagonists (MRAs), sodium–glucose transport protein 2 (SGLT2), classes of diuretics and their mechanism of action at different sites in the renal tubule; Abbreviations: carbonic anhydrase (CA); anion-exchanger 1 (AE1); aquaporin-2/4 (AQP-2/4); calcium-sensing receptor (CASR); chloride channels with barttin (ClC Ka/b); glucose-transporter 2 (GLUT2); epithelial sodium channels (ENaC); hydrogen ATPase (H+ ATPase); hydrogen-potassium ATPase (H+/K+ ATPase); mineralocorticoid receptor (MR); sodium-potassium pump (Na+/K+ ATPase); electrogenic sodium-bicarbonate cotransporter 1 (NBCe1-A); sodium-chloride symporter (NCC); Na-K-Cl cotransporter (NCCK2); sodium–calcium exchanger (NCX1); sodium-driven chloride/bicarbonate exchanger (NDCBE); sodium–hydrogen antiporter 1/3 (NHE1/3); Na-K-Cl cotransporter (NCCK1); Na(+)-independent Cl(-)/HCO3(-)-exchanger (pendrin); plasma-membrane Ca2+ ATPase (PMCA); renal outer medullary potassium channel (ROMK); sodium–glucose cotransporter-2 (SGLT2); transient receptor potential cation channel subfamily M member 6/7 (TRPM6/7); transient receptor potential cation channel subfamily V member 5 (TRPV5); vasopressin receptor 2 (V2R).

Figure 2

Major adverse events of diuretics and possible diuretic combinations to overcome them. Abbreviations: carbonic anhydrase (CA), epithelial sodium-channel blockers (ENaCb), mineralocorticoid-receptor antagonists (MRAs), sodium–glucose transport protein 2 (SGLT2).

Figure 3

A stepwise approach for diuretic-resistance management of edematous states.

Figure 4

Structures of some loop diuretics, thizides or thiazide-like diuretics and potassium-sparing diuretics.