What is the role of edema in the pathophysiology of pediatric nephrotic syndrome?

Updated: Mar 04, 2020
  • Author: Jerome C Lane, MD; Chief Editor: Craig B Langman, MD  more...
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The classic explanation for edema formation is a decrease in plasma oncotic pressure, as a consequence of low serum albumin levels, causing an extravasation of plasma water into the interstitial space. The resulting contraction in plasma volume (PV) leads to stimulation of the renin-angiotensin-aldosterone axis and antidiuretic hormone. The resultant retention of sodium and water by the renal tubules contributes to the extension and maintenance of edema.

While the classic model of edema (also known as the "underfill hypothesis") seems logical, certain clinical and experimental observations do not completely support this traditional concept. First, the PV has not always been found to be decreased and, in fact, in most adults, measurements of PV have shown it to be increased. Only in young children with MCNS have most (but not all) studies demonstrated a reduced PV.

Additionally, most studies have failed to document elevated levels of renin, angiotensin, or aldosterone—even during times of avid sodium retention. Active sodium reabsorption also continues despite actions that should suppress renin effects (eg, albumin infusion or angiotensin-converting enzyme [ACE] inhibitor administration).

Coupled with these discrepancies is the fact that, in the patient with steroid-responsive nephrotic syndrome, diuresis usually begins before the plasma albumin level has significantly increased and before the plasma oncotic pressure has changed. Some investigators have demonstrated a blunted responsiveness to atrial natriuretic peptide (ANP) despite higher than normal circulating plasma levels of ANP. [32]

Another model of edema formation, the "overfill hypothesis," postulates a primary defect in renal sodium handling. A primary increase in renal sodium reabsorption leads to net salt and water retention and subsequent hypertension.

ANP might play a role in this mechanism; studies have shown an impaired response to ANP in nephrotic syndrome. This ANP resistance, in part, might be caused by overactive efferent sympathetic nervous activity, as well as enhanced tubular breakdown of cyclic guanosine monophosphate.

Other mechanisms that contribute to a primary increase in renal sodium retention include overactivity of the Na+ -K+ -ATPase and renal epithelial sodium channel (RENaC) in the cortical collecting duct and the shift of the Na+/H+ exchanger 3 (NHE3) from the inactive to active pools in the proximal tubule. [32]

A more recent theory of edema formation posits that massive proteinuria leads to tubulointerstitial inflammation and release of local vasoconstrictors and inhibition of vasodilation. This leads to a reduction in single-nephron glomerular filtration rate and sodium and water retention. [32]

Thus, the precise cause of edema and its persistence is uncertain. A complex interplay of various physiologic factors, such as the following, probably contribute:

  • Decreased oncotic pressure

  • Increased activity of aldosterone and vasopressin

  • Diminished ANP level

  • Activities of various cytokines and physical factors within the vasa recti

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