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Fisiopatologia e tratamento de edema em pacientes com síndrome nefrotica

Autor: Jai Radhakrishnan, MD, MS

Editores de seção: Richard J Glassock, MD, MACP, Fernando C Fervenza, MD, PhD
Editor adjunto: Albert Q Lam, MD

Todos os tópicos são atualizados à medida que novas evidências ficam disponíveis e nosso processo de
revisão pelos pares está completo.
Revisão da literatura atual até: julho de 2017. | Este tópico foi atualizado pela última vez: 19 de maio
de 2017.

INTRODUÇÃO - O edema é uma das principais manifestações clínicas da síndrome nefrótica. A

fisiopatologia eo tratamento do edema em pacientes com síndrome nefrótica serão analisados aqui.
Problemas mais gerais como manifestações clínicas, diagnóstico e princípios gerais do tratamento do
edema são discutidos em outros lugares, como é o mecanismo da hipoalbuminemia na síndrome nefrótica.
(Ver "Manifestações clínicas e diagnóstico de edema em adultos" e "Princípios gerais do tratamento de
edema em adultos" e "Visão geral da proteinúria pesada e síndrome nefrótica", seção sobre
"Hipoalbuminemia" .)

DESCRIÇÃO CONTRA A RETENÇÃO DO SÓDIO RENAL - Dois fatores importantes, que levaram à
retenção, foram considerados responsáveis pelo desenvolvimento de edema em pacientes com síndrome
nefrotica; É provável que ambos contribuam para um grau variável em pacientes individuais [ 1,2 ]:

● Retenção primária de sódio induzida diretamente pela doença renal ( hipótese de enchimento
excessivo )

● A retenção secundária de sódio em que a baixa pressão oncótica do plasma devido a hipoalbuminemia
promove o movimento do fluido do espaço vascular para o interstício, levando ao preenchimento da
vasculatura e à ativação do sistema renina-angiotensina-aldosterona ( hipótese de enxofre )

A importância clínica de distinguir entre esses mecanismos é a capacidade de tolerar a terapia diurética. Os
diuréticos são bem tolerados em pacientes com retenção de sódio renal, mas, se o preenchimento básico é
o mecanismo primário, pode levar a uma hipovolemia piora como evidenciado clinicamente por elevação da
creatinina sérica. Como será descrito abaixo, a maioria dos pacientes tolerará a terapia diurética pelo menos
inicialmente.

Lei de Starling - A possível importância do preenchimento arterial parece estar prevista na lei de Starling,
que afirma que a troca de fluidos entre o plasma eo interstício é determinada pelas pressões hidráulicas e
oncóticas em cada compartimento:

Filtragem líquida através da parede capilar

= LpS x (Δ pressão hidráulica - Δ pressão oncótica)

= LpS x [(Pcap - Pif) - s (πcap - πif)]

Onde Lp é a permeabilidade da unidade (ou porosidade) da parede capilar, S é a superfície disponível para
o movimento do fluido, Pcap e Pif são as pressões hidráulicas do fluido capilar e intersticial, πcap e πif são
as pressões oncóticas do fluido capilar e intersticial e S representa o coeficiente de reflexão das proteínas
através da parede capilar (com valores variando de 0 se completamente permeável a 1 se completamente
impermeável). A pressão oncótica intersticial é derivada principalmente de proteínas de plasma filtradas e,
em menor grau, de proteoglicanos no interstício.
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Aplicação à síndrome nefrótica - À primeira vista, uma redução da pressão oncótica plasmática
induzida pela hipoalbuminemia parece favorecer o movimento do fluido para fora do espaço vascular para o
interstício e produzir enxertos arteriais. No entanto, é o gradiente de pressão oncótica transcapilar
(plasma menos intersticio), não a pressão oncótica do plasma sozinha, que atua para manter o fluido dentro
do espaço vascular. A pressão oncótica intersticial normal em seres humanos é de 10 a 15 mmHg (em
comparação com cerca de 26 mmHg no plasma) devido em parte ao acúmulo de uma pequena quantidade
de albumina que é filtrada através da parede capilar [ 1,3 ].

Esta distinção é importante, uma vez que a queda gradual da pressão oncótica plasmática na síndrome
nefrótica está associada a um declínio paralelo na pressão oncótica intersticial ( figura 1 ) [ 3 , 4 ], que
minimiza a mudança no gradiente de pressão oncótica transcapilar e, portanto, minimiza o fluido Movimento
fora do espaço vascular e resulta na manutenção relativa do volume plasmático. Os seguintes fatores
contribuem para esta resposta protetora [ 4,5 ]:

● Ahipoalbuminemia está associada a menor entrada de albumina no interstício

● O fluido que se move do espaço vascular para o intersticio diminuirá a concentração de albumina
intersticial por diluição

● 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.

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● 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 and infantile 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 renal 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 (plasmin in particular) 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.

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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 [26,27]. 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 in an attempt to more clearly define the volume status [28]. 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) [28].

Another finding that might favor of a component of underfilling in the nephrotic syndrome is the frequent
presence of nonosmotic release of antidiuretic hormone [29,30]. However, this change is not of major
physiologic importance since, in the absence of renal 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) [31]. 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 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 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 had edema, overt nephrotic syndrome, and a mean plasma albumin concentration of 1.8 g/dL (18
g/L), but no signs of hypovolemia.

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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 [32].

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 renal findings at presentation may be helpful but the
predictive value is uncertain [11,33]:

● 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 [34]. 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: Maximum effective dose 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 [35-37]. Several factors are
thought to play an important role in this relative diuretic resistance:

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● 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 [35,36].

● Some of the diuretic that enters the tubular lumen is bound to filtered albumin and rendered inactive
[38,39]. 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 about 50 percent [38]. 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 [40].

● Studies in rats with drug-induced nephrotic syndrome suggest that the loop of Henle may be relatively
resistant to loop diuretics [41].

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, triamterene
[42,43] or acetazolamide [44] can be combined with loop diuretics in patients with refractory edema. These
issues are discussed in detail elsewhere. (See "Loop diuretics: Maximum effective dose and major side
effects" and "Treatment of refractory edema in adults", section on 'Thiazide plus loop diuretics'.)

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 [45]. Administering albumin and diuretics separately leads to only a
modest increase in mean daily urine volume and sodium excretion in adults [46]. (See "Treatment of
refractory edema in adults", section on 'Infusion with albumin'.)

In children, the addition of albumin appears to produce a more profound diuresis, at least in a subpopulation
of patients [47], 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 [48]. 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 [37]. 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 "Treatment of minimal change disease in
adults", section on 'Glucocorticoid therapy'.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics"
and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have about a given

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condition. These articles are best for patients who want a general overview and who prefer short, easy-to-
read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want
in-depth information and are comfortable with some medical jargon.

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

● 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 renal disease. It is likely that both can contribute to a variable degree in individual patients. (See
'Underfilling versus renal sodium retention' above.)

● 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 addition, patients with symptomatic hypovolemia, compared with asymptomatic patients, have a
higher plasma renin activity, higher plasma aldosterone and norepinephrine concentrations, and more
sodium avidity as evidenced by a lower fractional excretion of sodium. 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.)

● 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.)

● Studies in children with minimal change disease have shown that either underfilling or primary renal
sodium retention can be the mechanism for edema. In adults, the majority of patients present with
primary sodium retention. (See 'Varying mechanisms in childhood minimal change disease' above.)

● The following clinical characteristics have been suggested to help determine whether underfilling or
sodium retention is the predominant mechanism in nephrotic edema (see 'Conclusion' above):

• 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]).

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● 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.)

● 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.)

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REFERENCES

1. Perico N, Remuzzi G. Edema of the nephrotic syndrome: the role of the atrial peptide system. Am J
Kidney Dis 1993; 22:355.
2. Humphreys MH. Mechanisms and management of nephrotic edema. Kidney Int 1994; 45:266.
3. Noddeland H, Riisnes SM, Fadnes HO. Interstitial fluid colloid osmotic and hydrostatic pressures in
subcutaneous tissue of patients with nephrotic syndrome. Scand J Clin Lab Invest 1982; 42:139.
4. Koomans HA, Kortlandt W, Geers AB, Dorhout Mees EJ. Lowered protein content of tissue fluid in
patients with the nephrotic syndrome: observations during disease and recovery. Nephron 1985;
40:391.
5. Aukland K, Nicolaysen G. Interstitial fluid volume: local regulatory mechanisms. Physiol Rev 1981;
61:556.
6. Geers AB, Koomans HA, Roos JC, et al. Functional relationships in the nephrotic syndrome. Kidney Int
1984; 26:324.
7. Geers AB, Koomans HA, Roos JC, Dorhout Mees EJ. Preservation of blood volume during edema
removal in nephrotic subjects. Kidney Int 1985; 28:652.
8. Dzau VJ, Colucci WS, Hollenberg NK, Williams GH. Relation of the renin-angiotensin-aldosterone
system to clinical state in congestive heart failure. Circulation 1981; 63:645.
9. Watkins L Jr, Burton JA, Haber E, et al. The renin-angiotensin-aldosterone system in congestive failure
in conscious dogs. J Clin Invest 1976; 57:1606.
10. EISENBERG S. Blood volume in patients with acute glomerulonephritis as determined by radioactive
chromium tagged red cells. Am J Med 1959; 27:241.
11. Meltzer JI, Keim HJ, Laragh JH, et al. Nephrotic syndrome: vasoconstriction and hypervolemic types
indicated by renin-sodium profiling. Ann Intern Med 1979; 91:688.
12. Vande Walle JG, Donckerwolcke RA, van Isselt JW, et al. Volume regulation in children with early
relapse of minimal-change nephrosis with or without hypovolaemic symptoms. Lancet 1995; 346:148.
13. Manning RD Jr, Guyton AC. Effects of hypoproteinemia on fluid volumes and arterial pressure. Am J
Physiol 1983; 245:H284.
https://www.uptodate.com/contents/pathophysiology-and-treatment-of-edema-in-patients-with-the-nephrotic-syndrome/print?source=see_link 8/15
18/08/2017 Pathophysiology and treatment of edema in patients with the nephrotic syndrome - UpToDate

14. Manning RD Jr. Effects of hypoproteinemia on renal hemodynamics, arterial pressure, and fluid volume.
Am J Physiol 1987; 252:F91.
15. Vande Walle JG, Donckerwolcke RA, Koomans HA. Pathophysiology of edema formation in children
with nephrotic syndrome not due to minimal change disease. J Am Soc Nephrol 1999; 10:323.
16. EDER HA, LAUSON HD, CHINARD FP, et al. A study of the mechanisms of edema formation in
patients with the nephrotic syndrome. J Clin Invest 1954; 33:636.
17. LUETSCHER JA Jr, HALL AD, KREMER VL. Treatment of nephrosis with concentrated human serum
albumin. II. Effects on renal function and on excretion of water and some electrolytes. J Clin Invest
1950; 29:896.
18. Ichikawa I, Rennke HG, Hoyer JR, et al. Role for intrarenal mechanisms in the impaired salt excretion of
experimental nephrotic syndrome. J Clin Invest 1983; 71:91.
19. Buerkert J, Martin DR, Trigg D, Simon EE. Sodium handling by deep nephrons and the terminal
collecting duct in glomerulonephritis. Kidney Int 1991; 39:850.
20. Féraille E, Vogt B, Rousselot M, et al. Mechanism of enhanced Na-K-ATPase activity in cortical
collecting duct from rats with nephrotic syndrome. J Clin Invest 1993; 91:1295.
21. Valentin JP, Ying WZ, Sechi LA, et al. Phosphodiesterase inhibitors correct resistance to natriuretic
peptides in rats with Heymann Nephritis. J Am Soc Nephrol 1996; 7:582.
22. Valentin JP, Qiu C, Muldowney WP, et al. Cellular basis for blunted volume expansion natriuresis in
experimental nephrotic syndrome. J Clin Invest 1992; 90:1302.
23. Lee EY, Humphreys MH. Phosphodiesterase activity as a mediator of renal resistance to ANP in
pathological salt retention. Am J Physiol 1996; 271:F3.
24. Svenningsen P, Bistrup C, Friis UG, et al. Plasmin in nephrotic urine activates the epithelial sodium
channel. J Am Soc Nephrol 2009; 20:299.
25. Passero CJ, Mueller GM, Rondon-Berrios H, et al. Plasmin activates epithelial Na+ channels by
cleaving the gamma subunit. J Biol Chem 2008; 283:36586.
26. Besse-Eschmann V, Klisic J, Nief V, et al. Regulation of the proximal tubular sodium/proton exchanger
NHE3 in rats with puromycin aminonucleoside (PAN)-induced nephrotic syndrome. J Am Soc Nephrol
2002; 13:2199.
27. Klisic J, Zhang J, Nief V, et al. Albumin regulates the Na+/H+ exchanger 3 in OKP cells. J Am Soc
Nephrol 2003; 14:3008.
28. Rodríguez-Iturbe B, Colic D, Parra G, Gutkowska J. Atrial natriuretic factor in the acute nephritic and
nephrotic syndromes. Kidney Int 1990; 38:512.
29. Usberti M, Federico S, Meccariello S, et al. Role of plasma vasopressin in the impairment of water
excretion in nephrotic syndrome. Kidney Int 1984; 25:422.
30. Pyo HJ, Summer SN, Niederberger M, et al. Arginine vasopressin gene expression in rats with
puromycin-induced nephrotic syndrome. Am J Kidney Dis 1995; 25:58.
31. Koomans HA, Boer WH, Dorhout Mees EJ. Renal function during recovery from minimal lesions
nephrotic syndrome. Nephron 1987; 47:173.
32. Mayatepek E, Becker K, Gana L, et al. Leukotrienes in the pathophysiology of kwashiorkor. Lancet
1993; 342:958.
33. Schrier RW, Fassett RG. A critique of the overfill hypothesis of sodium and water retention in the
nephrotic syndrome. Kidney Int 1998; 53:1111.
34. Crew RJ, Radhakrishnan J, Appel G. Complications of the nephrotic syndrome and their treatment. Clin
Nephrol 2004; 62:245.

https://www.uptodate.com/contents/pathophysiology-and-treatment-of-edema-in-patients-with-the-nephrotic-syndrome/print?source=see_link 9/15
18/08/2017 Pathophysiology and treatment of edema in patients with the nephrotic syndrome - UpToDate

35. Smith DE, Hyneck ML, Berardi RR, Port FK. Urinary protein binding, kinetics, and dynamics of
furosemide in nephrotic patients. J Pharm Sci 1985; 74:603.
36. Keller E, Hoppe-Seyler G, Schollmeyer P. Disposition and diuretic effect of furosemide in the nephrotic
syndrome. Clin Pharmacol Ther 1982; 32:442.
37. Wilcox CS. New insights into diuretic use in patients with chronic renal disease. J Am Soc Nephrol
2002; 13:798.
38. Kirchner KA, Voelker JR, Brater DC. Intratubular albumin blunts the response to furosemide-A
mechanism for diuretic resistance in the nephrotic syndrome. J Pharmacol Exp Ther 1990; 252:1097.
39. Kirchner KA, Voelker JR, Brater DC. Binding inhibitors restore furosemide potency in tubule fluid
containing albumin. Kidney Int 1991; 40:418.
40. Agarwal R, Gorski JC, Sundblad K, Brater DC. Urinary protein binding does not affect response to
furosemide in patients with nephrotic syndrome. J Am Soc Nephrol 2000; 11:1100.
41. Kirchner KA, Voelker JR, Brater DC. Tubular resistance to furosemide contributes to the attenuated
diuretic response in nephrotic rats. J Am Soc Nephrol 1992; 2:1201.
42. Deschênes G, Guigonis V, Doucet A. [Molecular mechanism of edema formation in nephrotic
syndrome]. Arch Pediatr 2004; 11:1084.
43. Hoorn EJ, Ellison DH. Diuretic Resistance. Am J Kidney Dis 2017; 69:136.
44. Fallahzadeh MA, Dormanesh B, Fallahzadeh MK, et al. Acetazolamide and Hydrochlorothiazide
Followed by Furosemide Versus Furosemide and Hydrochlorothiazide Followed by Furosemide for the
Treatment of Adults With Nephrotic Edema: A Randomized Trial. Am J Kidney Dis 2017; 69:420.
45. Chalasani N, Gorski JC, Horlander JC Sr, et al. Effects of albumin/furosemide mixtures on responses to
furosemide in hypoalbuminemic patients. J Am Soc Nephrol 2001; 12:1010.
46. Fliser D, Zurbrüggen I, Mutschler E, et al. Coadministration of albumin and furosemide in patients with
the nephrotic syndrome. Kidney Int 1999; 55:629.
47. Dharmaraj R, Hari P, Bagga A. Randomized cross-over trial comparing albumin and frusemide infusions
in nephrotic syndrome. Pediatr Nephrol 2009; 24:775.
48. Kapur G, Valentini RP, Imam AA, Mattoo TK. Treatment of severe edema in children with nephrotic
syndrome with diuretics alone--a prospective study. Clin J Am Soc Nephrol 2009; 4:907.

Topic 3044 Version 16.0

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GRAPHICS

Little change in oncotic pressure gradient in nephrotic

syndrome

Relation between plasma and interstitial oncotic pressures in patients with the
nephrotic syndrome due to minimal change disease before (open circles) and after
(closed circles) steroid-induced remission of the proteinuria. Both parameters are
reduced in the nephrotic state, resulting in little change in the transcapillary oncotic
pressure gradient and therefore little tendency to promoting edema formation.

Data from Koomans, HA, Kortlandt, W, Geers, AB, Dorhout Mees, EJ, Nephron 1985;
40:391.

Graphic 74352 Version 1.0

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Increased collecting tubule sodium reabsorption in nephrotic

syndrome

Micropuncture studies (in which samples are taken via micropipettes from different
nephron segments) of sodium handling in unilateral nephrotic syndrome in the rat.
Although less sodium is filtered in the nephrotic kidney, less is reabsorbed so that the
quantity of sodium remaining in the tubular lumen at the end of the distal tubule is the
same in the two kidneys. Thus, sodium reabsorption must be increased in the collecting
tubules to account for the two-thirds reduction in total sodium excretion in the nephrotic
kidney when compared to the normal kidney.

Data from Ichikawa, I, Rennke, HG, Hoyer, JR, et al, J Clin Invest 1983; 71:91.

Graphic 82649 Version 1.0

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Volume regulatory hormones in glomerular disease

Levels of plasma renin activity (ng/L per sec) and atrial natriuretic peptide
(fmol/mL) in normal subjects ingesting 20 and 130 meq of sodium per day and
in patients with acute glomerulonephritis and nephrotic syndrome excreting 25
meq of sodium per day. Patients with nephrotic syndrome (fourth panel) show
signs of renal sodium retention since they have a hormonal profile similar to
those in normal subjects excreting 130 meq/day (second panel) despite having
a much lower rate of sodium excretion. There is also evidence for a contribution
from underfilling as these patients do not have the profile of pure volume
expansion (very low renin, very high ANP) seen in acute glomerulonephritis.

Data from Rodriguez-Iturbe, B, Colic, D, Parra, G, Gutkowska, J, Kidney Int 1990;

38:512.

Graphic 50596 Version 1.0

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Time course of natriuresis during recovery from minimal

change disease

Fractional excretion of sodium (FENa, percent), plasma creatinine concentration

(PCr, mg/dL), plasma renin activity, and plasma albumin concentration (PAlb,
g/dL) in patients with minimal change disease both before therapy and at the
time of peak diuresis during corticosteroid-induced remission. The FENa rose, in
association with reductions in the plasma creatinine concentration and plasma
renin activity, and a minimal elevation in the plasma albumin concentration.

Data from Koomans, HA, Boer, WH, Dorhout Mees, EJ, Nephron 1987; 47:173.

Graphic 55827 Version 1.0

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Contributor Disclosures
Jai Radhakrishnan, MD, MS Nada para divulgar Richard J Glassock, MD, MACP Speaker's Bureau:
Genentech [Vasculitis (Rituximab)]. Consultor / Conselho Consultivo: Bristol-Myers-Squibb [Nefrite Lúpica,
FSGS (Abatacept)]; ChemoCentryx [Vasculite, diabetes (Acocapan)]; Retrophin [FSGS (Sparsentan)]. Equity
Ownership / Stock Options: Reata (Bardoxolone). Fernando C Fervenza, MD, PhD Grant / Research /
Clinical Trial support: Genentech [Nefropatia Membranosa, GN Fibrilar (Rituximab)]; Mallinckrodt [Nefropatia
IgA (gel de injeção de corticotropina)]. Albert Q Lam, MD Nada a divulgar

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