Pathophysiology, Evaluation, and Management of Edema in Childhood Nephrotic Syndrome

Abstract

Generalized edema is a major presenting clinical feature of children with nephrotic syndrome (NS) exemplified by such primary conditions as minimal change disease (MCD). In these children with classical NS and marked proteinuria and hypoalbuminemia, the ensuing tendency to hypovolemia triggers compensatory physiological mechanisms, which enhance renal sodium (Na(+)) and water retention; this is known as the "underfill hypothesis." Edema can also occur in secondary forms of NS and several other glomerulonephritides, in which the degree of proteinuria and hypoalbuminemia, are variable. In contrast to MCD, in these latter conditions, the predominant mechanism of edema formation is "primary" or "pathophysiological," Na(+) and water retention; this is known as the "overfill hypothesis." A major clinical challenge in children with these disorders is to distinguish the predominant mechanism of edema formation, identify other potential contributing factors, and prevent the deleterious effects of diuretic regimens in those with unsuspected reduced effective circulatory volume (i.e., underfill). This article reviews the Starling forces that become altered in NS so as to tip the balance of fluid movement in favor of edema formation. An understanding of these pathomechanisms then serves to formulate a more rational approach to prevention, evaluation, and management of such edema.

Keywords: children/pediatrics; edema; management; nephrotic syndrome; pathophysiology.

Figure 1

Pathophysiology of edema formation in NS. In disorders with massive proteinuria and marked hypoalbuminemia but minimal or absent renal inflammatory infiltrate, as in most children with minimal-change disease (MCD), the reduction in capillary colloid oncotic pressure (πcap) favors net fluid exit from the vascular to the interstitial fluid compartment thereby reducing effective circulatory blood volume, denoted as “underfill.” This then triggers secondary, or compensatory, Na⁺ retention and hemodynamic alterations aimed at achieving blood pressure homeostasis. By contrast, various glomerulonephritides and inflammatory renal disorders, such as acute post-streptococcal glomerulonephritis, may be associated with variable degrees of proteinuria and with pathologic release of mediators, which promote primary renal Na⁺ and water retention, as well as vasoconstrictive hormones that are released despite an intact or even expanded intravascular volume. These factors together with reduction in glomerular ultrafiltration coefficient (K_f, or LpS in the Starling equation), lead to reduced glomerular filtration rate (GFR) and combine to further limit Na⁺ excretion, resulting in an “overfill” state and rise in capillary hydraulic pressure (Pcap). In turn, this causes net fluid accumulation in the interstitial fluid compartment. Note that nephrotic urine may be a common pathway for primary Na⁺ retention in both undefill and overfill disorders (refer to text and Tables 1–3 for the mediators sub-serving each of these main mechanisms of edema formation).