Pathophysiology and treatment of edema in adults with the nephrotic syndrome

INTRODUCTION — Edema is one of the major clinical manifestations of the nephrotic syndrome. The pathophysiology and treatment of edema in patients with the nephrotic syndrome will be reviewed here. More general issues such as the clinical manifestations, diagnosis, and general principles of the treatment of edema are discussed elsewhere as is the mechanism of hypoalbuminemia in the nephrotic syndrome.

●(See "Clinical manifestations and evaluation of edema in adults".)

●(See "General principles of the treatment of edema in adults".)

●(See "Overview of heavy proteinuria and the nephrotic syndrome", section on 'Hypoalbuminemia'.)

UNDERFILLING VERSUS RENAL SODIUM RETENTION — Two major factors, both of which lead to retention, have been thought to be responsible for the development of edema in patients with the nephrotic syndrome; it is likely that both contribute to a variable degree in individual patients [1,2]:

●Primary sodium retention that is directly induced by the kidney disease (overfill hypothesis)

●Secondary sodium retention in which the low plasma oncotic pressure due to hypoalbuminemia promotes the movement of fluid from the vascular space into the interstitium, leading to underfilling of the vasculature and activation of the renin-angiotensin-aldosterone system (underfill hypothesis)

The clinical importance of distinguishing between these mechanisms is the ability to tolerate diuretic therapy. Diuretics are well tolerated in patients with renal sodium retention but, if underfilling is the primary mechanism, can lead to worsening hypovolemia as evidenced clinically by an elevation in serum creatinine. As will be described below, most patients tolerate diuretic therapy at least initially.

Starling's law — The possible importance of arterial underfilling seems to be predicted from Starling's law, which states that the exchange of fluid between the plasma and the interstitium is determined by the hydraulic and oncotic pressures in each compartment:

Net filtration across the capillary wall

 =  LpS  x  [(P_cap - P_if) - s(Pi_cap - Pi_if)]

where Lp is the unit permeability (or porosity) of the capillary wall, S is the surface area available for fluid movement, P_cap and P_if are the capillary and interstitial fluid hydraulic pressures, Pi_cap and Pi_if are the capillary and interstitial fluid oncotic pressures, and s represents the reflection coefficient of proteins across the capillary wall (with values ranging from 0 if completely permeable to 1 if completely impermeable). The interstitial oncotic pressure is derived primarily from filtered plasma proteins and to a lesser degree proteoglycans in the interstitium.

Application to nephrotic syndrome — At first glance, a reduction in plasma oncotic pressure induced by hypoalbuminemia would seem to favor the movement of fluid out of the vascular space into the interstitium and produce arterial underfilling. However, it is the transcapillary oncotic pressure gradient (plasma minus interstitium), not the plasma oncotic pressure alone, that acts to hold fluid within the vascular space. The normal interstitial oncotic pressure in humans is 10 to 15 mmHg (compared with approximately 26 mmHg in the plasma) due in part to accumulation of some of the small amount of albumin that is filtered across the capillary wall [1,3].

This distinction is important since the gradual fall in plasma oncotic pressure in the nephrotic syndrome is associated with a parallel decline in interstitial oncotic pressure (figure 1) [3,4], which minimizes the change in the transcapillary oncotic pressure gradient and therefore minimizes fluid movement out of the vascular space and results in relative maintenance of the plasma volume. The following factors contribute to this protective response [4,5]:

●Hypoalbuminemia is associated with less albumin entry into the interstitium.

●The fluid that moves from the vascular space into the interstitium will lower the interstitial albumin concentration by dilution.

●There is increased lymphatic flow, which, by bulk flow, will remove albumin as well.

As a result, there is usually little change in the transcapillary oncotic pressure gradient in patients with nephrotic syndrome and therefore little tendency to plasma volume depletion, unless the hypoalbuminemia is severe [6]. Similarly, the plasma volume is typically preserved after diuretic therapy for edema removal in patients with nephrotic syndrome as long as the patient is not overdiuresed [7].

The response is appreciably different after the rapid administration of large volumes of saline to patients with marked hypovolemia due to bleeding (eg, ruptured aortic aneurysm). In this setting, there is an acute dilutional reduction in the plasma albumin concentration without time for the interstitial albumin concentration to fall. As a result, the transcapillary oncotic pressure gradient is reduced and peripheral edema due to fluid movement out of the vascular space can occur before the restoration of normal intracardiac filling pressures.

It is important to appreciate that the absence of demonstrable plasma volume depletion when a nephrotic patient is edematous does not preclude an important role for underfilling. Initial underfilling can activate compensatory mechanisms (such as enhanced renin release) that then return the plasma volume toward normal at the price of extracellular volume expansion and edema. Such a sequence clearly occurs in heart failure [8,9]. Furthermore, patients with the nephrotic syndrome do not have the clear signs of volume expansion (and occasionally pulmonary edema) as can be seen with renal sodium retention due to acute glomerulonephritis [10].

Evidence supporting underfilling — The following findings support an important role for hypoalbuminemia and underfilling in the pathogenesis of edema in some patients with the nephrotic syndrome:

●Some patients, primarily those with minimal change disease, have low rates of sodium excretion and elevated plasma renin activity, findings suggestive of volume depletion [6,11,12] (see 'Volume regulatory hormones' below). One study, for example, evaluated 30 children with early relapse of minimal change disease who were studied within a few days of the onset of relapse as indicated by persistent 3+ findings on the urine dipstick for protein; 21 had edema at the time of evaluation and were evaluated for symptoms or signs of hypovolemia which included tachycardia, peripheral vasoconstriction (eg, cold hands and feet), and oliguria [12].

Compared with the eight asymptomatic patients, the 13 patients with hypovolemic signs or symptoms had a higher plasma renin activity, higher plasma aldosterone and norepinephrine concentrations, and more sodium avidity as evidenced by a lower fractional excretion of sodium. The differences between the two groups could not be explained by differences in proteinuria or the degree of hypoproteinemia.

●The normal serum total protein concentration is 6 to 8 g/dL (60 to 80 g/L), a little more than one-half of which (3.5 to 5.0 g/dL [35 to 50 g/L]) is normally comprised of albumin. The findings in the preceding study of children with early relapse of minimal change disease are consistent with dog studies in which severe reductions in the total protein concentration (mean 2.4 g/dL [24 g/L], normal 7.2 g/dL [72 g/L]) produced by plasmapheresis plus isotonic fluid replacement led to significant reductions in plasma volume and blood pressure and increases in plasma renin activity and plasma aldosterone concentration [13,14]. These hemodynamic changes were not seen with moderate reductions in total protein concentration to approximately 4.8 g/dL (48 g/L) [13].

●Starling's law predicts that, with increasingly severe hypoalbuminemia, washout of the interstitial oncotic pressure would eventually be complete and that further reductions in the plasma oncotic pressure would lower the transcapillary oncotic pressure gradient and tend to produce underfilling. Support for this hypothesis comes from a study of 22 children with nephrotic syndrome not due to minimal change disease [15]. Sixteen children had stable edema without marked sodium retention or changes in volume regulatory hormones; these patients had a mean plasma albumin concentration of 2.1 g/dL (21 g/L). In contrast, six had clinical (tachycardia, vasoconstriction, pallor, oliguria) and hormonal evidence of hypovolemia; these patients, four of whom had congenital nephrotic syndrome of the Finnish type, had a mean plasma albumin concentration of 0.8 g/dL (8 g/L). (See "Congenital nephrotic syndrome".)

●The administration of albumin to raise the plasma oncotic pressure can increase sodium excretion and lead to resolution of edema [16,17]. However, this response is not seen in all patients and is not predictably seen in the same patient studied on several occasions [17].

Evidence supporting primary renal sodium retention — Studies in experimental animals with unilateral nephrotic syndrome or glomerulonephritis suggest that primary sodium retention in these disorders is due to increased sodium reabsorption in the collecting tubules (figure 2) [18,19], which is also the site of action of atrial natriuretic peptide (ANP) and the related kidney hormone urodilatin. This has been called the overfill hypothesis since primary renal sodium retention leads to volume expansion, as opposed to underfilling, as discussed in the preceding section.

Several different abnormalities in tubular function have been identified in the nephrotic syndrome, which could increase sodium reabsorption:

●There is increased activity of the Na-K-ATPase pump in the cortical collecting tubule but not other nephron segments [20]. This pump provides the energy for active sodium transport by pumping reabsorbed sodium out of the cell into the peritubular capillary. However, it is not clear if this represents a primary effect or is simply a secondary marker for increased sodium transport at this site.

●Both experimental and human studies have documented relative resistance to atrial natriuretic peptide and urodilatin in the nephrotic syndrome [1,21-23]. This defect is due at least in part to increased phosphodiesterase activity in the collecting tubules, leading to more rapid degradation of the second messenger of ANP, cyclic GMP (guanosine monophosphate). Infusion of a phosphodiesterase inhibitor largely reverses this defect and restores the normal natriuretic response to volume expansion [21,22]. The mechanism by which phosphodiesterase activity is increased in the nephrotic syndrome is not known but phosphodiesterase-mediated resistance to ANP has also been described in heart failure and cirrhosis [23].

●Increased activity of the epithelial sodium channel (ENaC) may contribute to sodium retention [24,25]. Serine proteases are aberrantly filtered in the nephrotic syndrome, leading to increased concentration in the urine. Plasminogen (which is activated by epithelial urokinase-type plasminogen activator [uPA] to plasmin) in nephrotic urine may activate ENaC via proteolytic cleavage of the gamma chain, providing a potential mechanism by which filtered proteins cause sodium retention. It also explains the observation that remission from the nephrotic syndrome is generally preceded by a decrease in urinary protein excretion. In an animal model of nephrotic syndrome, mice treated with the serine protease inhibitor aprotinin normalized urinary serine protease activity and prevented sodium retention [26]. Other proteases, including cathepsin-B, have also been reported to increase ENaC activity in experimental nephrotic syndrome [27]. When rats with nephrosis were treated with the ENaC inhibitor amiloride, sodium retention was mitigated [28]. Case reports of the efficacy of ENaC inhibitors in patients with resistant nephrotic edema have also been described [29,30].

Another possible contributor to renal sodium retention is enhanced proximal tubular reabsorption via increased activity of the sodium-hydrogen exchanger (NHE3) that mediates a large part of proximal sodium reabsorption [31,32]. However, even if proximal sodium reabsorption were increased, it might not contribute to sodium retention, since, as mentioned above in the unilateral nephrotic syndrome model, delivery to the end-distal tubule appears to be the same in nephrotic and non-nephrotic kidneys (figure 2) [18].

Volume regulatory hormones — The plasma levels of volume regulatory hormones have been measured in nephrotic patients to more clearly define the volume status [33]. Normal subjects ingesting and excreting 20 mEq of sodium per day have a high plasma renin activity (PRA) and low atrial natriuretic peptide (ANP) levels. In comparison, most nephrotic patients (at the same low level of sodium excretion) have renin and ANP levels that are equivalent to those in normal subjects ingesting 120 to 150 mEq/day (figure 3).

These findings suggest at least a component of primary renal sodium retention since sodium excretion is much lower than expected from the plasma hormone levels. However, nephrotic patients with edema do not have the hormonal profile (very low PRA, very high ANP) seen in acute glomerulonephritis, which is thought to represent an example of pure volume expansion due to renal sodium retention (figure 3) [33].

Another finding that might favor of a component of underfilling in the nephrotic syndrome is the frequent presence of nonosmotic release of antidiuretic hormone [34,35]. However, this change is not of major physiologic importance since, in the absence of kidney failure, nephrotic patients do not usually develop the water retention and hyponatremia seen in patients with heart failure and cirrhosis, conditions in which decreased effective circulating volume provides the stimulus for hormonal activation. (See "Hyponatremia in patients with heart failure" and "Hyponatremia in patients with cirrhosis".)

Response to glucocorticoids in minimal change disease — Observations in patients with minimal change disease have suggested a relatively minor role for hypoalbuminemia (unless severe) in the development of nephrotic edema in many patients. When remission is induced by glucocorticoids, the peak diuresis typically occurs before there is a substantial rise in the plasma oncotic pressure (figure 4) [36]. It is possible, however, that even a small elevation in the plasma albumin concentration is sufficient to reverse underfilling and permit a diuresis. Thus, these observations do not necessarily exclude a pathogenetic role for underfilling.

Varying mechanisms in childhood minimal change disease — A study in children with minimal change disease sheds some light on the often conflicting findings noted above since it suggests that patients with the same disease may have different mechanisms of edema [12]. Thirty children with minimal change disease in remission were monitored carefully and studied within a few days of the onset of relapse as indicated by persistent 3+ findings on the urine dipstick for protein. When first evaluated, three different groups were noted:

●Nine children appeared to have primary renal sodium retention. They were relatively normoalbuminemic (mean plasma albumin concentration 3.7 g/dL [37 g/L]), had a reduced fractional excretion of sodium (0.5 versus 1.1 percent in remission), and signs of modest volume expansion (weight gain, increased blood volume) but no overt edema since the degree of volume expansion was not yet great enough.

●Thirteen children appeared to have underfilling. In addition to edema, overt nephrotic syndrome, and a mean plasma albumin concentration of 1.6 g/dL (16 g/L), they also had one or more symptoms suggestive of volume depletion (tachycardia, peripheral vasoconstriction, oliguria), marked elevations in the plasma renin activity and plasma concentrations of aldosterone and norepinephrine, low plasma concentration of atrial natriuretic peptide, and a low glomerular filtration rate. In one child, the symptoms and neurohumoral activation were transiently improved by albumin infusion.

●Eight children had edema, overt nephrotic syndrome, and a mean plasma albumin concentration of 1.8 g/dL (18 g/L), but no signs of hypovolemia.

The factors responsible for the differences between the last two groups with the same degree of hypoalbuminemia are not well understood. One possibility is that patients with rapid protein loss may have a reduction in the transcapillary oncotic pressure gradient because there has not been sufficient time for the interstitial oncotic pressure to fall. If this were the case, then underfilling should be transient, disappearing as the interstitial oncotic pressure fell in parallel to the change in the plasma oncotic pressure.

Hypoalbuminemia in other edematous disorders — Observations in conditions other than the nephrotic syndrome have been used to evaluate the role of hypoalbuminemia and presumed underfilling in the pathogenesis of edema. As examples:

●Patients with cirrhosis are frequently hypoalbuminemic but typically present with ascites (due to postsinusoidal obstruction), not prominent peripheral edema.

●Edema is common in the malnutrition syndrome kwashiorkor. Although this complication has been ascribed to hypoalbuminemia, it has been suggested that increased generation of cysteinyl leukotrienes may be of major importance by increasing capillary permeability [37].

Conclusion — It seems likely that the relative importance of underfilling due to hypoalbuminemia and overfilling due to primary renal sodium retention varies among patients and, perhaps at different times, in the same patient [12]. Some have suggested that the kidney findings at presentation may be helpful but the predictive value is uncertain [11,38]:

●Patients with elevated intravascular volume due to primary renal sodium retention are more likely have a glomerular filtration rate less than 50 percent of normal, a plasma albumin concentration greater than 2 g/dL (20 g/L), and hypertension.

●Patients with underfilling are more likely to have a glomerular filtration rate greater than 75 percent of normal and either minimal change disease of acute onset or severe hypoalbuminemia (often below 1 g/dL [10 g/L]) [12,15].

Independent of the mechanism of nephrotic edema, underfilling can occur after the initiation of diuretic therapy as discussed below. (See 'Diuretics and sodium restriction' below.)

TREATMENT — The above discussion on the roles of underfilling and primary renal sodium retention was provided to describe the mechanisms of edema formation in the nephrotic syndrome. However, distinction between these mechanisms prior to the initiation of diuretic therapy (eg, measurement of plasma renin activity, plasma aldosterone, and plasma natriuretic peptides) is not made in routine clinical practice. Clinically, children may present with underfilling or primary sodium retention, whereas primary sodium retention predominates in adults. (See "Symptomatic management of nephrotic syndrome in children", section on 'Diuretics'.)

Diuretics and sodium restriction — All patients with nephrotic edema are initially treated with diuretic therapy and dietary sodium restriction (approximately 2 g/day) and monitored for clinical signs of hypovolemia [39]. The excess fluid can usually be removed, at least initially, without inducing clinically significant plasma volume depletion as defined by an otherwise unexplained elevation in serum creatinine or clinical manifestations of hypovolemia (eg, weakness, orthostatic hypotension, and/or cool extremities) [7]. Careful monitoring is required and diuretic therapy should be at least temporarily discontinued if these manifestations occur. (See "Etiology, clinical manifestations, and diagnosis of volume depletion in adults", section on 'Clinical manifestations' and "Loop diuretics: Dosing and major side effects", section on 'Major side effects'.)

Most patients respond well to loop diuretics, although there is generally a lesser natriuresis than seen in normal subjects even when the glomerular filtration rate is normal or near normal [40-42]. Several factors are thought to play an important role in this relative diuretic resistance:

●All the commonly used diuretics are highly protein-bound. This limits the diuretic to the vascular space, thereby maximizing its rate of delivery to the kidney. The degree of protein-binding is reduced with hypoalbuminemia, resulting in a larger extravascular space of distribution and a slower rate of delivery to the kidney [40,41].

●Some of the diuretic that enters the tubular lumen is bound to filtered albumin and rendered inactive [43,44]. In experimental in vivo microperfusion of the loop of Henle, the addition of albumin to the perfusate in a concentration similar to that seen in the tubular lumen in the nephrotic syndrome diminishes the response to intraluminal furosemide by approximately 50 percent [43]. However, it is uncertain if this mechanism is important in humans. In one study of seven patients with nephrotic syndrome, blocking of albumin binding to furosemide by the administration of sulfisoxazole had no effect on the diuretic response [45].

●Studies in rats with drug-induced nephrotic syndrome suggest that the loop of Henle may be relatively resistant to loop diuretics [46].

The net effect is that the effective diuretic dose is usually higher in patients with nephrotic syndrome compared with other edematous disorders. As an example, the maximum dose of intravenous furosemide is 40 to 80 mg in edematous patients with heart failure or cirrhosis who have a relatively normal glomerular filtration rate, but may be as high as 80 to 120 mg in patients with the nephrotic syndrome and a relatively normal glomerular filtration rate [12]. Patients who do not respond adequately may require the addition of a thiazide diuretic to block sodium reabsorption at several sites in the nephron. Alternatively, ENaC inhibitors such as triamterene and amiloride may be utilized in refractory patients [29,30,47,48]. Acetazolamide [49] has been similarly used with loop diuretics in patients with refractory edema. The issue of refractory edema is discussed in detail elsewhere. (See "Loop diuretics: Dosing and major side effects" and "Causes and treatment of refractory edema in adults".)

It has been suggested that the diuresis can be enhanced in patients with marked hypoalbuminemia by infusing a solution in which a loop diuretic has been added to salt-poor albumin, creating loop diuretic-albumin complexes that keep the diuretic within the vascular space, thereby increasing the rate of loop diuretic secretion into the tubular lumen. However, the addition of albumin to furosemide in this manner has not been shown to improve diuresis [50]. Administering albumin and diuretics separately leads to only a modest increase in mean daily urine volume and sodium excretion in adults [51]. (See "Causes and treatment of refractory edema in adults".)

In children, the addition of albumin appears to produce a more profound diuresis, at least in a subpopulation of patients [52], particularly those with a reduced effective arterial blood volume. In one study, for example, 20 children with nephrotic syndrome were treated with diuretics or, if the fractional excretion of sodium (FENa) was less than 0.2 percent (used to identify a reduced effective arterial blood volume), diuretics plus albumin infusion [53]. With diuretics plus albumin infusion, patients with a FENa less than 0.2 percent achieved a similar diuresis as diuretic therapy in patients who had a higher FENa.

Angiotensin inhibition — Almost all patients with proteinuric chronic kidney disease are given, in addition to appropriate therapy for the underlying disease, an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) in an attempt to slow the progressive loss of kidney function. A possible additional benefit of such therapy among diuretic-resistant patients is a lesser degree of albuminuria, which might increase the plasma albumin concentration and enhance the response to diuretics [42]. Minimal change disease is a major exception to this approach since remission can usually be induced with glucocorticoid therapy. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Renin-angiotensin system inhibitors' and "Minimal change disease: Treatment in adults", section on 'Choice of initial therapy'.)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Edema (swelling) (Beyond the Basics)" and "Patient education: The nephrotic syndrome (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Overview – Edema (swelling) is the major clinical manifestation of the nephrotic syndrome. There are two mechanisms responsible for the development of edema in patients with the nephrotic syndrome: low plasma levels of albumin which promotes the movement of fluid out of the vascular, leading to underfilling of the vasculature and secondary sodium retention; and primary sodium retention induced by the kidney disease. It is likely that both can contribute to a variable degree in individual patients. (See 'Underfilling versus renal sodium retention' above.)

●Pathophysiology

•Underfilling – Although an important role of arterial underfilling appears to be predicted from Starling's law, the gradual fall in plasma oncotic pressure in the nephrotic syndrome is associated with a parallel decline in interstitial oncotic pressure, which minimizes the change in the transcapillary oncotic pressure gradient. This minimizes fluid movement out of the vascular space, resulting in many patients in relative maintenance of the plasma volume. (See 'Starling's law' above.)

However, underfilling does occur, particularly in children with minimal change disease of acute onset or severe hypoalbuminemia (often below 1 g/dL [10 g/L]). Such patients may have symptoms or signs of hypovolemia, including tachycardia, peripheral vasoconstriction (eg, cold hands and feet), and oliguria. In the absence of symptoms or signs, the major manifestation of underfilling is an otherwise unexplained elevation in serum creatinine with diuretic therapy in patients who still have edema. (See 'Evidence supporting underfilling' above.)

•Primary renal sodium retention – The presence of primary renal sodium retention as a cause for nephrotic edema is supported by both experimental models and observations in nephrotic patients. Experimental models suggest that the sodium retention is due to increased sodium reabsorption in the collecting tubules. (See 'Evidence supporting primary renal sodium retention' above.)

●Treatment

•Diuretics and sodium restriction – We recommend that patients with nephrotic edema who do not have otherwise unexplained signs of symptoms of hypovolemia (eg, tachycardia, peripheral vasoconstriction, cold hands and feet) be treated with diuretic therapy and dietary sodium restriction (approximately 2 g of sodium per day) (Grade 1A). Excess fluid can usually be removed without inducing clinically significant plasma volume depletion. The effective diuretic dose is usually higher in patients with nephrotic syndrome compared with other edematous disorders and the addition of a thiazide diuretic or, alternatively, triamterene or acetazolamide, may be required in patients with refractory edema. In nephrotic children with clinical signs of reduced effective arterial blood volume or a low fractional excretion of sodium (ie, less than 0.2 percent), the addition of albumin may be considered. (See 'Treatment' above.)

•Angiotensin inhibition – Almost all patients with proteinuric chronic kidney disease are given, in addition to therapy specific for the underlying cause of the nephrotic syndrome, an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) in an attempt to slow the progressive loss of kidney function. Minimal change disease is a major exception to this approach since remission can usually be induced with glucocorticoid therapy. A possible additional benefit of angiotensin inhibition in diuretic-resistant patients is a decrease in the severity of albuminuria, which might increase the plasma albumin concentration and enhance the response to diuretics. (See 'Angiotensin inhibition' above.)