Molecular mechanism of edema formation in nephrotic syndrome: therapeutic implications

Alain Doucet,Guillaume Favre,Georges Deschênes

doi:10.1007/s00467-007-0521-3

Abstract

Sodium retention and edema are common features of nephrotic syndrome that are classically attributed to hypovolemia and activation of the renin–angiotensin–aldosterone system. However, numbers of clinical and experimental findings argue against this underfill theory. In this review we analyze data from the literature in both nephrotic patients and experimental models of nephrotic syndrome that converge to demonstrate that sodium retention is not related to the renin–angiotensin–aldosterone status and that fluid leakage from capillary to the interstitium does not result from an imbalance of Starling forces, but from changes of the intrinsic properties of the capillary endothelial filtration barrier. We also discuss how most recent findings on the cellular and molecular mechanisms of sodium retention has allowed the development of an efficient treatment of edema in nephrotic patients.

Highlights

Interstitial edema is a common clinical feature of nephrotic syndrome (NS)
Site of sodium retention Most of our current knowledge on the site and mechanism of renal sodium retention in NS comes from experimental models of the disease, in particular the puromycin aminonucleoside (PAN) rat model
Methods allowing in vitro analysis of isolated sub-segments of the Pediatr Nephrol (2007) 22:1983–1990 distal nephron demonstrated a marked stimulation of sodium reabsorption in the cortical collecting duct (CCD) of PAN nephrotic rats [1, 5]

Summary

Introduction

Interstitial edema is a common clinical feature of nephrotic syndrome (NS). It is often massive (up to 30% of body weight) and constitutes a functional constraint, owing to locomotive restriction and eyelid shutting. Hypovolemia is supposed to proceed as follows: proteinuria induces hypoalbuminemia and reduces plasma oncotic pressure, which generates an imbalance of Starling’s forces across capillary walls, leading to interstitial leakage of fluid and decreased efficient volume [15] This mechanism is consistent with the renal site of sodium retention, with the activation of ENaC and the induction of Na,K-ATPase in the collecting duct, and with the hyperaldosteronemia observed in PAN nephrotic rats [13], a large body of clinical evidence argues against this theory. Administration of PAN to these corticosteroid-clamped rats reduces sodium excretion, establishes sodium balance and promotes ascites formation with similar time course and intensity as in adrenal-intact rats [11, 13] These findings exclude a possible role in sodium retention of promiscuous activation of the mineralo-corticoid receptor (MR) by glucocorticoid brought about by decreased 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2).

50 Etanercept

Findings

Conclusion