N@PoC

Nephrology @ Point of Care 2016; 2(1): e47-e55

DOI: 10.5301/pocj.5000204

eISSN 2059-3007 QUESTIONS @ POINT OF CARE

Edema in renal diseases – current view on pathogenesis

Irina Bobkova1,2, Natalia Chebotareva1, Lydiya Kozlovskaya3, Evgenij Shilov2
1
Nephrology Department of Research Center, I.M. Sechenov First Moscow State Medical University, Moscow - Russia
2
Department of Nephrology and Dialysis of Professional Education Institute, I.M. Sechenov First Moscow State Medical University, Moscow -
Russia
3
Department of Internal, Occupational Diseases and Pulmonology, I.M. Sechenov First Moscow State Medical University, Moscow - Russia

ABSTRACT
Edema is a common complication of numerous renal disease. In the recent past several aspects of the pathophys-
iology of this condition have been elucidated. We herein present a case of nephrotic syndrome in a 30 year-old
men. The discussion revolves around the following key questions on fluid accumulation in renal disease:
1. What is edema? What diseases can cause edema?
2. What are the mechanisms of edema in nephrotic syndrome?
2a. The “underfill” theory
2b. The “overfill” theory
2c. Tubulointerstitial inflammation
2d. Vascular permeability
3. What are the mechanisms of edema in nephritic syndrome?
4. How can the volume status be assessed in patients with nephrotic syndrome?
5. What are therapeutic strategies for edema management?
6. What are the factors affecting response to diuretics?
7. How can we overcome the diuretics resistance?
7a. Effective doses of loop diuretics
7b. Combined diuretic therapy
7c. Intravenous administration of diuretics
7d. Albumin infusions
7e. Alternative methods of edema management
8. Conclusion.
Keywords: Edema, ENa+C, NHE3, Na,K-ATPase, Nephrotic syndrome, Sodium retention

Case presentation markable. One month before admission minimal proteinuria

was found.
A 30-year-old male patient was referred to the nephrol- Physical examination did not reveal any significant signs
ogy clinic with massive periorbital, upper and lower extrem- and symptoms beyond edema.
ities and scrotal edema, 10 kg weight gain, foamy urine and Urinalysis demonstrated nephrotic range proteinuria
reduction of the urine output. His edema was resistant to (10 g/day) without any abnormalities of the urinary sedi-
oral furosemid administration (80 mg/day). His blood pres- ment. Total blood count showed hemoglobin 12.5 g/dL,
sure was 110/70 mmHg. The past medical history was unre- an erythrocyte sedimentation rate of 40 mm/h, hemato-
crit 54%. The main biochemical data are summarized in
Table I.
Accepted: September 6, 2016 No monoclonal component was found either in the serum
Published online: October 10, 2016 or the urine. Thromboembolic events were not observed.
Ultrasonography revealed two normal-sized kidneys and
Corresponding author: presence of ascites. Chest plain radiography revealed bilat-
Irina Bobkova eral hydrothorax.
Gagarina street, 11a Limitation of the oral sodium intake to 2.5 g daily was
23. Krasnoznamensk
Moscow Region recommended. The intravascular volume was corrected by
Russian Federation intravenous infusions of 20% albumin (2 mL/min for 1-1.5
143090 Moscow, Russia hours). Intravenous infusions of furosemide (initial bolus -
irbo.mma@mail.ru 60 mg, followed by continuous infusions - 60 mg/h) were

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e48 Edema in renal diseases

TABLE I - T he biochemical data of the patient with nephrotic TABLE II - List of the diseases, presenting with edema
syndrome
Renal diseases Nephrotic and nephritic syndromes in acute
Serum total protein (g/dL) 4.0 and chronic glomerulonephritis (idiopathic or
secondary) and other glomerulopathies; acute
Serum albumin (g/dL) 1.9 and chronic renal failure
Serum cholesterol (mmоl/L) 11.0 Cardiovascular Chronic heart failure as a result of coronary
Serum creatinine (mg/dL) 0.9 diseases arteries disease, cardiomyopathy, rheumatic
and congenital heart valve defects, etc.
GFR (mL/min) 83
Hepatic Hepatic cirrhosis, thrombosis of hepatic
Serum Na+ (mEq/L) 140 diseases veins, etc.
Serum K+ (mEq/L) 4,2 Intestinal Diarrhea, malabsorption in chronic enteritis,
diseases Whipple’s disease, intestinal amyloidosis, etc.
Urine Na+ (mEq/L) 10
Endocrine Hypothyroidism, syndrome of inappropriate
Urine K+ (mEq/L) 240 diseases antidiuretic hormone secretion, premenstrual
Urine creatinine (mg/dL) 640 syndrome cyclical edema, etc.
FENa+ (%) 0,01 Vascular Vein thrombosis, thrombophlebitis, tumor
diseases compression, etc.
Uk+/(UNa+ + UK+) (%) 96%
Diseases of Lymphostasis as a result of filariasis,
GFR = glomerular filtration rate (estimated by CKD-EPI formula); FENa+ = the lymphatic nonspecific lymphangitis, metastatic lymphatic
fractional excretion of sodium (was calculated by the formula (urine Na+ system vessels, etc.
× serum creatinine/Serum Na+ × urine creatinine) × 100; ratio Uk+/(UNa +
UK+) - index of RAAS activation with stimulation of Na+/K+ exchange in the Allergic Effects of different allergens (food, drug, pollen,
distal nephron. diseases cosmetics, etc.)
Idiopathic Imbalance of sympathetic nervous system
edema trophic function, of estrogen-progesterone
started. The restriction of sodium intake and the diuretic in women system; increased adrenal sensitivity to
strategy resulted in a positive natriuresis with moderate angiotensin II, and renal tubules sensitivity to
aldosterone and ADH
reduction of edema and a body-weight loss of 900-1000
mg/day. Side effects Ca+-channel blockers, estrogens, minoxidil,
A kidney biopsy was performed and on light microscopy of mediations rosiglitazone, corticosteroids; anabolic
normal glomeruli were found. Immunofluorescent micros- steroids, etc.
copy did not reveal any immune complex deposits. Elec- ADH = antidiuretic hormone.
tron microscopy confirmed the absence of electron-dense
deposits and demonstrated hypertrophy and vacuolization
of some podocytes and foot process effacement. Based on
these findings minimal change disease was diagnosed. What are the mechanisms of edema in nephrotic
The patient was started with oral prednisone 60 mg/day syndrome?
(1 mg/kg), while the diuretic therapy was discontinued. A
urinary output of 3 L/day was observed in a week after the Edema is one of the cardinal clinical features of nephrotic
initiation of steroids. Two weeks later remission of NS was syndrome (NS), and may range from localized puffiness to
achieved. The full dose of prednisone was continued for the massive anasarca.
next two weeks. After achieving a complete remission, it The pathophysiological mechanisms of edema formation in
was tapered slowly over 6 months. NS were discussed over several decades. Abnormal accumula-
tion of interstitial fluid results from the combination of:
What is edema? What diseases can cause edema?
• abnormal renal sodium retention (primary and secondary)
Edema is defined as an abnormal accumulation of fluid in • increased capillary wall permeability (related to the re-
the interstitial space of the body. lease of vascular permeability factor and other cytokines).
Edema is the reason for visiting the doctor, and for a care-
ful differential diagnosis. Various diseases (renal, cardiac, Given the wide spectrum of renal diseases leading to the
hepatic, thyroid glands and others) may be causative (sum- NS, more than one single mechanism may be responsible
marized in Tab. II). for the renal salt retention observed in these diverse condi-
The leading causes of renal edema are nephrotic and ne- tions (1-6).
phritic syndromes (Tab. II).
Confirmation of the renal nature of the edema requires a The “underfill” theory
precise diagnosis of the renal disease with an assessment of
its clinical and morphological activity. All this information is According to classic theory, also called the “underfill” hy-
important for defining the treatment strategy, including the pothesis, sodium retention in NS is secondary to hypovolemia.
administration of diuretics. Urinary protein losses lead to the decrease of plasma albumin

© 2016 The Authors. Published by Wichtig International

Bobkova et al
concentration and lowering of the plasma oncotic pressure
resulting in imbalance of the Starling forces (Fig. 1). These
events lead to fluid redistribution from the intravascular space
towards the interstitial space, causing the decrease in effec-
tive arterial blood volume. The plasma volume contraction
triggers adaptive neurohumoral responses through activation
of the sympathetic nervous system (particularly efferent renal
nerves), stimulation of the renin-angiotensin-aldosterone sys-
tem (RAAS), an increase of antidiuretic hormone (ADH) release,
renal sodium and water retention. The decrease in atrial na-
triuretic peptide (ANP) secretion facilitates salt retention and
subsequent edema formation (Fig. 1).
However, there are many arguments against this theory.
Clinical observations indicate that most of the edematous
patients with the different histological forms of NS have either
a normal or even expanded intravascular volume, whereas
only a minority of nephrotic patients have a depleted intra-
vascular volume (7, 8). So, some patients with early phases
of severe NS (usually in rapidly developing relapse of minimal
changes disease (9-11)) demonstrate a temporary hypovole-
mia, because the mobilization of interstitial albumin to the
blood is not sufficiently fast to prevent it, there is disequi-
librium between plasma and extravascular albumin stores.
Later, when the albumin redistribution becomes complete, a
new equilibrium is established, during which blood volume is
maintained.
There is increasing experimental and clinical evidence
that hypoalbuminemia cannot explain the development of
edema in NS (for reviews see (1, 2)). In particular, it has been
shown that young analbuminemic Nagase rats do not de-
velop edema despite low plasma oncotic pressure (12). This
© 2016 The Authors. Published by Wichtig International
e49
Fig. 1 - Pathophysiological mech-
anism of edema formation in
nephrotic syndrome.
phenomenon has also been demonstrated in humans with NS
(13, 14).
Furthermore, decrease in plasma oncotic pressure does
not affect the volume of the intravascular space in NS (15,
16), and intravenous administration of albumin to induce vol-
ume expansion promotes only mild natriuresis (12).
These data suggest that there might have been sodium
retention in patients with NS, not mediated by volume
depletion.
The “overfill” theory
Unlike the “underfill” hypothesis, the “overfill” concept
presumes a primary intrinsic defect of salt and water excre-
tion in the nephrotic kidney (1, 2). This theory postulates that
there are also consequences of the proteinuria other than
just hypoalbuminemia, which lead to enhanced tubular so-
dium reabsorption, progressive extracellular fluid volume
expansion and edema formation by an overflow mechanism
(Fig. 1).
The cellular mechanisms of this primary sodium retention
in NS are associated with:
• activation of the expression of Na+/H+exchanger3
(NHE3) in the apical membrane of the proximal tubules
by the tubular albumin (17-19)
• proteinuria-induced stimulation of the basolateral Na,K-
ATPase pump in the collecting ducts (20-22)
• activation of the apical epithelial amiloride-sensitive so-
dium channels (ENa+C) in the collecting ducts induced by
urine proteases (plasminogen/plasmin) (2, 23-26)
e50
• tubular resistance to ANP (the result of an increased
cyclic guanosine monophosphate (cGMP) phosphodies-
terase activity and depletion of cGMP, which is the ANP
second messenger) (2, 27-29).
Tubulointerstitial inflammation
There is also strong evidence that tubulointerstitial inflam-
mation and glomerulo-interstitial cross-talks are involved in
sodium retention and nephrotic edema formation (30). It has
been demonstrated that proteinuria induces infiltration of the
interstitium by inflammatory cells (T-cells and monocyte/mac-
rophages). Production of vasoactive mediators by these cells (in-
crease of angiotensin II and decrease of nitric oxide) can cause
a reduction in glomerular ultrafiltration coefficient and single
nephron GFR (30, 31) as well as a decline in sodium filtration
with an increase of tubular reabsorption, resulting in primary
sodium retention (Fig. 2). Interstitial inflammation in longstand-
ing NS, stimulating tubulointerstitial fibrosis and atubular glom-
eruli formation, can lead to a more permanent decrease in
glomerular filtration rate (GFR) and thus to sodium retention.
Vascular permeability
The asymmetric expansion of the interstitial volume in
NS is explained by changes in intrinsic properties of the en-
dothelial capillary barriers, including its increased hydraulic
conductivity and permeability to proteins, rather than to an
imbalance of the Starling forces (2, 32-34). Increase of capil-
lary permeability could be related to the release of numerous
vascular permeability factors and other cytokines, from im-
mune cells, including histamine, endotoxins, anaphylatoxins,
catecholamines, vascular endothelial growth factor, interleu-
kin-1, interleukin-2, and tumor necrosis factor-alpha.
Edema in renal diseases
Fig. 2 - The role of tubulointerstitial
inflammation in the pathogenesis
of nephrotic edema. Adapted from
Rodriguez-Iturbe et al (30). Kf =
ultrafiltration coefficient, GFR = glo-
merular filtration rate, AT-II = angio-
tensin II, NO = nitric oxide.
What are the mechanisms of edema in nephritic
syndrome?
Acute glomerulonephritis is the prototypical form of ne-
phritic edema (35). Overexpansion of the vascular compart-
ment is responsible for the hemodynamic characteristics of
patients with nephritic syndrome (increased effective arterial
blood volume, plasma volume, blood pressure, and cardiac
output) (36). Hypervolemia and edema in such patients re-
sult from primary salt retention and GFR reduction due to
glomerulopathy. The glomerular damage leads to urinary
protein loss with following increase of tubular albumin reab-
sorption and urine proteases concentration, which activates
renal salt and water retention. The glomerular lesion results
in the reduction of Kf, which is driven by the effective capillary
wall hydraulic permeability and total capillary surface area
per glomerulus (37). At the onset of the disease the GFR re-
mains normal for some period of time. The initially preserved
GFR is maintained by the equilibrium between the increased
transcapillary hydraulic pressure, which is the driving force
for filtration, and the reduced Kf. The progressive GFR dete-
rioration observed in more advanced stages of this disorder
is the consequence of the further reduction of Kf. The signifi-
cant fall of Kf leading to subsequent reduction of GFR results
in the decrease of sodium filtration with sodium and water
retention.
How can the volume status be assessed in patients
with nephrotic syndrome?
Evaluation of the volume status is crucially important for
edema management. Table III summarizes the typical clinical
and laboratory features for distinguishing nephrotic patients
with underfill or overfill physiology. Сlinical characteristics of
© 2016 The Authors. Published by Wichtig International
Bobkova et al
TABLE III - Evaluation of the predominant volemic status in
patients with nephrotic syndrome
Underfill Clinical characteristic:
Low normal or low blood pressure, postural
hypotension, tachycardia, peripheral vasospasm
(pallor, cool extremities), abdominal pain.
Diarrhea and vomiting (may provoke dehydration
and hypovolemia)
Laboratory features:
Serum albumin level <2 g/dL
Urinary sodium concentration <20 mEq/Lb
High urinary potassium concentrationb
FENa+ <1% (often below 0.2%) (on diet without
salt restriction)b
Urinary (K+/K++Na+) >60%
GFR >75% of normal
High hematocrit
Elevated plasma renin, aldosterone, vasopressina
Low atrial natriuretic peptidea
Central venous pressure <5 сm H2O or <2 mmHg
Ultrasonographic determination of inferior vena
cava diameter and its change with respiration:
(d<1.5 cm, inferior vena cava collapsibility index
>50%)
Overfill Clinical characteristic:
Normal or high blood pressure without tachycardia
or orthostatic symptoms and no signs of peripheral
vasospasm
Laboratory features:
Serum albumin level >2 g/dL
GFR <50% of normal
FENa+ >1% (on diet without salt restriction)b
Urinary (K+/K++Na+) <60%b
Elevated blood level of urea disproportionate to
creatinine
Decreased renin, vasopressina
Low or normal plasma aldosteronea
High atrial natriuretic peptidea
Central venous pressure >12 сm H2O or >8 mmHg
Ultrasonographic determination of inferior vena
cava diameter and its respiratory changes:
(d>2.5 cm, inferior vena cava collapsibility index
<20%)
a
Not available for routine practice and quick diagnosis.
b
Influenced by therapy with diuretic.
GFR = glomerular filtration rate; FENa+ = fractional excretion of sodium.
hypovolemia include low blood pressure, postural hypoten-
sion, tachycardia, signs of peripheral vasospasm (pallor, cool
extremities), abdominal pain secondary to decreased intestinal
perfusion. Diarrhea and vomiting, provoking dehydration and
hypovolemia, demand attention from the doctor. By contrast,
in hypervolemic NS, high blood pressure without postural hy-
potension and other signs of volume depletion are found.
Urinary sodium and potassium concentration, fractional
excretion of sodium (FENa+) and index of RAAS axis activation
© 2016 The Authors. Published by Wichtig International
e51
may be useful tests for evaluation of renal sodium handling
and volume status in nephrotic patients.
FENa+ is the ratio of sodium excreted to that filtered by
the renal tubules.
FENa+(%) = (urinary Na+ × serum creatinine/serum Na+ ×
urinary creatinine) × 100.
A urinary sodium concentration below 20 mEq/L and
FENa+ below 1% indicate sodium retaining conditions. The
blockade of sodium reabsorbtion by diuretic increases uri-
nary sodium concentration and fractional sodium excretion
to a greater or lesser extent (38). Loop diuretics can increase
FENa to 30%, thiazides to 5%-10% and potassium sparing
­diuretics to 2%-3% (39).
Vande Walle and coworkers revealed significant positive
correlations between the ratio of urinary concentrations
of K+ to the sum of K+ and Na+ [K+(mEq/L)/K+ (mEq/L) +
Na+(mEq/L)], reflecting of Na+/K+ exchange in the distal neph-
ron, and increased serum concentrations of renin, aldoste-
rone and ADH, which are observed in hypovolemic children
with minimal lesion nephrotic syndrome (8-10). The ratio has
been offered as an index of activation of RAAS axis. A ratio
K+/K++Na+ more than 60% suggests activation of the axis and
renal potassium wasting (8-10).
Patients with NS and hypovolemia typically show low
FENa+ (often below 0.2%) and a high urinary K+/K++Na+ in-
dex (greater than 60%) (8, 39-43). Management of edema
in such patients demands correction of the intravascular
volume with infusion of albumin ore non-protein colloids
before initiation of diuretic therapy. Active usage of diuret-
ics without adequate volume correction poses a risk to hy-
povolemic shock. In hypovolemic patients with relapse of
steroid responsive NS treatment with corticosteroids leads to
rapid decrease of proteinuria, steroid-induced diuresis within
7-10 days. It may be better to avoid giving furosemide to
these patients if possible and wait for the diuretic effects of
remission due to corticosteroid treatment.
Patients with edema and clinical and/or laboratory fea-
tures of hypervolemia (FENa+>1% and urinary K+/K++Na+
index <60%) can safely be treated with diuretics (8, 39-43).
Intravascular infusion of albumin and colloids in such patients
put them at risk of volume overload and lung edema.
It should be noted that the prior therapy with diuretic
may limit the practical utility of these urinary tests for distin-
guishing patients with underfill or overfill physiology. There-
fore, close monitoring of both clinical and laboratory features
(Tab. III), are required for evaluation of predominant mecha-
nism of nephrotic edema formation and therapeutic decision.
What are therapeutic strategies for edema
management?
Treatment of renal edema is directed to the limitation of
further sodium retention, and to the enhancement of the so-
dium and water excretion, sequestered in the interstitial com-
partment. Diuretics are fundamental for edema treatment in
NS; this type of medication ensures diuresis by inhibiting of
sodium reabsorption in the different segments of the renal
tubular system (2, 39).
The efficacy of diuretics is determined by site of their
action in the nephron. Major proportion of filtered Na+ is
e52
reabsorbed in the proximal tubule (55%-60%) and in the loop
of Henle (25%-30%); only 5%-7% of filtered sodium is reab-
sorbed in the distal segments of the renal tubular system. How-
ever, in NS the efficacy of diuretics acting in proximal segments
is hampered by compensatory increase of sodium and water
by distal reabsorption in the ascending limb of Henle’s loop.
Therefore, loop diuretics, which can increase FENa+ up to 30%,
remain the first choice for edema treatment in patients with
NS. Nevertheless, the treatment of edematous patients should
be individualized according to their clinical manifestations.
The general principles of edema management are as
follows:
• Sodium intake restriction to 100 mEq Na+/day should be
recommended to all patients with edema (1 mEq Na+ =
23 mg Na+ = 58.3 mg of NaCl)
• Strict limiting sodium intake (to 1 mEq/kg/day) is neces-
sary only in subjects with refractory edema
• Diuretics are not required for minimal periorbital puffi-
ness or feet edema. Most of such patients demonstrate
reduction of edema with moderate restriction of sodi-
um intake
• Mild edema in patients with steroid responsive NS resolve
under treatment with corticosteroids, which usually leads
to steroid-induced diuresis within 7-10 days
• Patients with moderate-to-severe edema, beyond so-
dium restriction, also need treatment with one or more
diuretic agents
• Evaluation of volume status is necessary for edema man-
agement
• Albumin infusions with diuretic co-administration should
be recommended to subjects with hypovolemia or re-
fractory severe edema.
In the absence of emergency situations, the body-weight re-
duction under the diuretic treatment should be targeted to
1% of body weight.
Edema in renal diseases
Fig. 3 - The algorithm for edema man-
agement in patients with nephrotic
syndrome.
Edema is considered refractory if therapy with maximum
doses of diuretics results in the daily weight loss less than 1%
of body weight.
The algorithm of edema management in patients with NS
is shown in Figure 3.
What are the factors affecting response to diuretics?
The efficacy of loop diuretics is restricted by the function-
al resistance of nephrotic patients to the natriuretic effect of
these drugs (2, 39, 44, 45).
Several mechanisms may contribute to diuretic resistance
in patients with NS, including:
• Decreased gastro-intestinal drug absorption.
(Bowel wall edema impairs absorption of oral medica-
tions)
• Decreased diuretic entry into the tubular lumen.
(Loop diuretics are highly bound to proteins, and signifi-
cant hypoalbuminemia results in the reduced free drug
secretion into the tubules)
• Increased distal sodium reabsorption, so called rebound
effect or braking phenomenon.
(With long-term use of loop diuretics sodium, that origi-
nates from Henle’s loop to the distal segments, causes
hypertrophy of distal nephron cells with concomitant in-
crease of the sodium reabsorption)
• Use of non-steroidal anti-inflammatory drugs (NSAIDs)
(Through blocking the synthesis of prostaglandins,
NSAIDs can cause vasoconstriction, reduction of renal
perfusion and sodium retention. In addition, NSAIDs can
competitively inhibit the secretion of diuretic into proxi-
mal tubule, preventing their effects).
The binding of furosemide to albumin in the tubular fluid has
been demonstrated in the experiment, but has not been con-
firmed in the human study.
© 2016 The Authors. Published by Wichtig International
Bobkova et al
How can we overcome the diuretics resistance?
Effective doses of loop diuretics
The diuretic effect relies on an adequate amount of the
drug reaching its site of action in the renal tubules. Primarily,
in patients with NS and edema it is necessary to increase the
dose of loop diuretics to maximally effective oral dose (furose-
mide 480 mg/day, torasemide 50 mg/day, bumetanide 6 mg/
day). Higher doses of oral diuretics do not exert any additional
effect, while the frequency of side effects is greatly increased.
Diuretics with a high bioavailability are preferred (50% for furo-
semide, 80% for torasemide, 90% for bumetanide).
Second, to overcome the sodium reabsorption in the dis-
tal tubules after the termination of the loop diuretic’s action,
they can be prescribed more than once per day. The daily
dose may be divided into two parts, provided that each dose
reaches an effective concentration.
Combined diuretic therapy
In patients with NS adding thiazides (hydrochlorothiazide
25-100 mg/day or metolazone 100 mg/day) on top of furose-
mide markedly increases the natriuresis (46).
First off all, thiazide diuretics have a longer half-life and
prevent or reduce the sodium retention after termination of
the loop diuretic’s action, prolonging its natriuretic effect.
Second, administration of the thiazide may interfere with
the so-called rebound effect, following loop diuretic treat-
ment. Thiazide diuretics block the nephron sites, prone to
sodium-induced hypertrophy, accounting for the synergistic
response of the combination of thiazide and loop diuretics.
In the combined administration, thiazide diuretics have to
be prescribed 1 hour before the loop diuretics in order to
achieve full blockade of the distal tubules.
Nephrotic patients also demonstrate intensive sodium re-
absorption in the connecting and cortical collecting tubules.
Thus, co-administration of furosemide and amiloride in pa-
tients with NS increases urinary sodium excretion and pro-
motes edema resolution (47). Amiloride inhibits the above-
mentioned Na+/H+exchanger in the proximal tubules and
ENa+C in the distal tubules. Moreover, amiloride has recently
been shown to inhibit the synthesis of the urokinase recep-
tor uPAR. This molecule converts plasminogen to plasmin at
the cell surface of distal tubular cells, which subsequently up-
regulates ENa+C activity, resulting in salt and water retention
and edema formation (47, 48).
Spironolactone, the inhibitor of mineralocorticoid receptors
in the collecting tubules, is used to counteract aldosterone-me-
diated sodium reabsorption. The presence of hyperreninemic
hyperaldosteronism in patients with NS and hypovolemia is an
indication to spironolactone’s administration. Adding spirono-
lactone (2-3 mg/kg/day) to loop diuretics in patients with NS
and hypovolemia increases urinary sodium excretion, reduces
refractory edema, and prevents hypokalemia.
Intravenous administration of diuretics
Intravenous administration of loop diuretics is preferred
in patients with refractory edema, where high doses of oral
© 2016 The Authors. Published by Wichtig International
e53
diuretics are ineffective. The maximal natriuretic response
occurs by intravenous furosemide boluses 1-2 mg/kg, or
the equivalent doses of bumetanide and torasemide, which
should be administered slowly over 10-15 minutes (not ex-
ceeding the rate 4 mg/min). However, bolus diuretic therapy
may be associated with a higher incidence of diuretic resis-
tance due to prolonged intervals of sub-therapeutic drug con-
centrations in the kidney.
In patients poorly responding to bolus doses of the
loop diuretics, a continuous intravenous infusion can be
­recommended. After an initial bolus of 1-2 mg/kg, furosemide,
continuous infusion should be started with a dose of 0.1 mg/
kg/h, which may be increased up to 1 mg/kg/h. Continuous
infusions of furosemide result in a more constant delivery of
diuretic to the tubules and more substantial natriuresis. More-
over, infusions of diuretics are associated with lower peak plas-
ma concentrations and a lower incidence of side effects.
Albumin infusions
Treatment of edema in severe resistant NS and hypovo-
lemia requires high doses of loop diuretics combined with
albumin infusions. Volume repletion in this type of nephrotic
patients plays a pivotal role in the management of edema.
In order to achieve a temporary increase of intravascular
volume and to facilitate binding of the diuretic to albumin,
an intravenous infusion of 5% albumin (10-20 mL/kg over 30-
60 minutes, infusion rate 5 mL/min) or 20% albumin (1 g/kg
over 1-4 h) in combination with maximum doses of furose-
mide (120 mg) may be performed. The 20% albumin solution
increases the vascular volume to 3-4 mL per 1 mL of infused
solution. The rate of 20% albumin infusion should not exceed
2-3 mL/min. Usually albumin is administered as an undiluted
solution, but it may be diluted with isotonic saline or 5% dex-
trose to increase the infused volume. Furosemide may be ad-
ministered as a bolus in the midst or after the end of albumin
infusion. To achieve a maximum effect, both medications may
be mixed before intravenous administration. Since the effect
of albumin infusion is transient the infusion should be re-
peated for achieving a sustained reduction in edema. On the
other hand, infusion of hyperoncotic albumin in nephrotic pa-
tients without decrease of intravascular volume may trigger
the development of pulmonary edema and congestive heart
failure. Therefore, albumin infusions should be restricted to
subjects with hypovolemia or refractory severe edema.
Alternative methods of edema management
Excess of fluid in patients with refractory edema and oli-
guria can be removed by prolonged veno-venous ultrafiltra-
tion with highly permeable membranes, or by hemofiltration.
These methods are more effective and safe compared to a
further increase of the doses of diuretics. If these methods
are not available, it is also possible to use intermittent hemo-
dialysis with isolated ultrafiltration.
Head-out water immersion (3-4 h/day) is a quite physiologi-
cal method for management of patients with massive edema.
There is perfect distribution of gravity on the surface surround-
ing the body in water immersion. Increased venous return due
to hydrostatic pressure results in release of ANP, increasing
e54
natriuresis and diuresis, with a reduction of edema. However,
this procedure is not widely applicable in current renal practice.
Conclusion
Renal edema is associated with renal sodium retention as
a result of different pathogenetic mechanisms, including “un-
derfill” and “overfill” pathways.
In a great number of patients with NS, the pathophysiology
of edema is not related to hypoalbuminemia, hypovolemia and
secondary RAAS activation, but is associated with a primary re-
nal defect in sodium excretion. Proteinuria itself up-regulates
the tubular sodium reabsorption through stimulation of NHE3
expression in the apical membrane of the proximal tubules and
thick ascending limb cells, induction of Na,K-ATPase synthesis
and activation of apical amiloride-sensitive ENa + C in the corti-
cal collecting ducts.
Proteinuria-induced interstitial inflammation in persis-
tent NS is also involved in edema formation. Both a decrease
in sodium filtration and increase in sodium reabsorption
occur due to production of vasoconstrictive substances
in the interstitium, driven by the inflammatory cell infil-
trate. Another mechanism of sodium and water retention
in NS is associated with markedly blunted diuretic and
natriuretic response of medullar collecting ducts to ANP.
Finally, increased capillary hydraulic conductivity and hy-
perpermeability to proteins play an important role in the
pathophysiology of nephrotic edema.
In patients with nephritic syndrome, overexpansion of
the vascular compartment and edema formation result
from primary salt retention and reduction in Kf and GFR.
The understanding of the mechanisms involved in edema
formation is important for efficient treatment strategy. Treat-
ment with diuretics for minimal edema is not required, and
salt restriction should be recommended to such patients.
Mild edema in patients with steroid-responsive NS resolves
promptly upon the initiation of corticosteroid therapy. Evalu-
ation of volemic status is necessary for rational diuretic usage.
In the majority of patients, edema can be managed adequately
with oral administration of an effective dose of loop diuretics.
The treatment of patients with refractory edema is more dif-
ficult and comprises a strong salt restriction, treatment with
intravenous furosemide, additional use of thiazide, amiloride,
spironolactone and intravenous albumin. Albumin infusions
should be restricted to patients with hypovolemia or refractory
severe edema. Infusion of hyperoncotic albumin in nephrotic
patients without decrease of intravascular volume may trigger
the development of pulmonary edema and congestive heart
failure.
Further clarification of sites and cellular mechanisms
of primary sodium retention in patients with renal edema
should be continued to create new therapeutic options.
Key messages
- Assessment of circulatory volume is the key to determin-
ing management approaches to reduce edema and avoid
common complications in NS - acute kidney insufficiency
in patients with “underfill”, or hypertensive and pulmo-
nary complications in patients with “overfill”.
Edema in renal diseases
- Albumin infusions with diuretics co-administration should
be recommended to patients with hypovolemia or refrac-
tory severe edema.
- Mild edema in patients with steroid-responsive NS re-
solves promptly following therapy with corticosteroids.
- Edema in patients with NS and hypervolemia can safely
be treated with diuretics.
Disclosures
Financial support: No grants or funding have been received for this
study.
Conflict of interest: None of the authors has any financial interest
related to this study to disclose.
References
1. Rondon-Berrios H. [New insights into the pathophysiology
of oedema in nephrotic syndrome]. Nefrologia. 2011;31(2):
148-154.
2. Doucet A, Favre G, Deschênes G. Molecular mechanism of
edema formation in nephrotic syndrome: therapeutic implica-
tions. Pediatr Nephrol. 2007;22(12):1983-1990.
3. Siddall EC, Radhakrishnan J. The pathophysiology of edema
formation in the nephrotic syndrome. Kidney Int. 2012;82(6):
635-642.
4. Bockenhauer D. Over- or underfill: not all nephrotic states are
created equal. Pediatr Nephrol. 2013;28(8):1153-1156.
5. Hamm LL, Batuman V. Edema in the nephrotic syndrome:
new aspect of an old enigma. J Am Soc Nephrol. 2003;14(12):
3288-3289.
6. Schrier RW, Fassett RG. A critique of the overfill hypothesis of
sodium and water retention in the nephrotic syndrome. Kidney
Int. 1998;53(5):1111-1117.
7. Geers AB, Koomans HA, Boer P, Dorhout Mees EJ. Plasma and
blood volumes in patients with the nephrotic syndrome. Neph-
ron. 1984;38(3):170-173.
8. Vande Walle JGJ, Donckerwolcke RA, Koomans HA. Patho-
physiology of edema formation in children with nephrotic syn-
drome not due to minimal change disease. J Am Soc Nephrol.
1999;10(2):323-331.
9. Vande Walle JG, Donckerwolcke RA, van Isselt JW, Derkx FHM,
Joles JA, Koomans HA. Volume regulation in children with early
relapse of minimal-change nephrosis with or without hypovo-
laemic symptoms. Lancet. 1995;346(8968):148-152.
10. Van de Walle JGJ, Donckerwolcke RAMG, Greidanus TB, Joles
JA, Koomans HA. Renal sodium handling in children with ne-
phrotic relapse: relation to hypovolaemic symptoms. Nephrol
Dial Transplant. 1996;11(11):2202-2208.
11. Vande Walle J, Donckerwolcke R, Boer P, van Isselt HW,
Koomans HA, Joles JA. Blood volume, colloid osmotic pres-
sure and F-cell ratio in children with the nephrotic syndrome.
Kidney Int. 1996;49(5):1471-1477.
12. Joles JA, Willekes-Koolschijn N, Braam B, Kortlandt W, Koomans
HA, Dorhout Mees EJ. Colloid osmotic pressure in young anal-
buminemic rats. Am J Physiol. 1989;257(1 Pt 2):F23-F28.
13. Lecomte J, Juchmès J. [So-called absence of edema in analbu-
minemia]. Rev Med Liege. 1978;33(21):766-770.
14. Koomans HA, Geers AB, vd Meiracker AH, Roos JC, Boer P,
Dorhout Mees EJ. Effects of plasma volume expansion on re-
nal salt handling in patients with the nephritic syndrome. Am J
Nephrol. 1984;4(4):227-234.
15. Manning RD Jr, Guyton AC. Effects of hypoproteinemia on flu-
id volumes and arterial pressure. Am J Physiol. 1983;245(2):
H284-293.
© 2016 The Authors. Published by Wichtig International
Bobkova et al
16. Camici M. Molecular pathogenetic mechanisms of nephrotic
edema: progress in understanding. Biomed Pharmacother.
2005;59(5):215-23.
17. Besse-Eschmann V, Klisic J, Nief V, Le Hir M, Kaissling B,
Ambuhl P. Regulation of the proximal tubular sodium/­proton
exchanger NHE3 in rats with puromycin aminonucleoside
(PAN) induced nephrotic syndrome. J Am Soc Nephrol. 2002;
13(9):2199-2206.
18. Klisic J, Zhang J, Nief V, Reyes L, Moe OW, Ambuhl PM. Albumin
regulates the Na+/H+ exhanger in OKP cells. J Am Soc Nephrol.
2003;14(12):3008-3016.
19. Deschenes G, Feraille E, Doucet A. Mechanisms of oedema in
nephrotic syndrome: Old theories and new ideas. Nephrol Dial
Transplant. 2003;183:454-456.
20. Deschenes G, Doucet A. Collecting duct (Na+/K+)-ATPase activ-
ity is correlated with urinary sodium excretion in rat nephrotic
syndromes. J Am Soc Nephrol. 2000,11(4):604-615.
21. Feraille 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;91:1295-1300.
22. Vogt B, Favre H. Na+,K+-ATPase activity and hormones in single
nephron segments from nephrotic rats. Clin Sci. 1991;80:599-604.
23. De Santo NG, Pollastro RM, Saviano C, et al. Nephrotic edema.
Semin Nephrol. 2001;21(3): 262-268.
24. De Seigneux S, Kim SW, Hemmingsen SC, et al. Increased ex-
pression but not targeting of ENaC in adrenalectomized rats
with PAN-induced nephrotic syndrome. Am J Physiol Renal
Physiol. 2006;291:F208-217.
25. Kim SW, de Seigneux S, Sassen MC, et al. Increased apical
targeting of renal ENaC subunits and decreased xpression of
11betaHSD2 in HgCl2-induced nephrotic syndrome in rats. Am
J Physiol Renal Physiol. 2006;290:F674-F687.
26. Svenningsen P, Bistrup C, Friis UG, et al. Plasmin in nephrot-
ic urine activates the epithelial sodium channel. J Am Soc
Nephrol. 2009;20:299-310.
27. Plum J, Mirzaian Y, Grabensee B. Atrial natriuretic peptide,
sodium retention, and proteinuria in nephritic syndrome.
Nephrol Dial Transplant. 1996;11:1034-1042.
28. Perico N, Delaini F, Lupini C, et al. Blunted excretory response
to atrial natriuretic peptide in experimental nephrosis. Kid-
ney Intern. 1989; 36:57-64.
29. Valentin JP, Ying WZ, Sechi LA, et al. Phosphodiesterase inhibi-
tors correct resistance to natriuretic peptides in rats with Hey-
mann nephritis. J Am Soc Nephrol. 1996;7:582-593.
30. Rodriguez-Iturbe B, Herrera-Acosta J, Johnson RJ. Interstitial
inflammation, sodium retention, and the pathogenesis of ne-
phrotic edema: A unifying hypothesis. Kidney Intern. 2002;62:
1379-1384.
© 2016 The Authors. Published by Wichtig International
e55
31. Franco M, Tapia E, Santamarıa J, et al. Renal cortical vasocon-
striction contributes to the development of salt-sensitive hy-
pertension after Angiotensin II exposure. J Am Soc Nephrol.
2001;12:2263-2271.
32. Rostoker G, Behar A, Lagrue G. Vascular hyperpermeability in
nephrotic dema. Nephron. 2000;85(3):194-200.
33. Brenchley PE. Vascular permeability factors in steroid-sensitive
nephrotic syndrome and focal segmental glomerulosclerosis.
Nephrol Dial Transplant. 2003;18 (6):21-25.
34. He P, Curry FE. Albumin modulation of capillary permeability:
role of endothelial cell [Ca2+]. Am J Physiol. 1993;265:H74-H82
35. Vinen CS, Oliveira DBG. Acute glomerulonephritis. Postgrad
Med J. 2003;79:206-213.
36. Kurtzman NA. Nephritic edema. Seminars in Nephrology. 2001;
21(3):257-261.
37. Maddox DA, Bennett CM, Deen WM, et al. Determinants of
glomerular filtration in experimental glomerulonephritis in the
rat. J Clin Invest. 1975;55:305-318.
38. Bohlin AB, Berg U. Renal sodium handling in minimal change
nephrotic syndrome. Arch Dis Child 1984;59:825-83.
39. Vasudevan A, Mantan M, Bagga A. Bagga A. Management of
edema in nephrotic syndrome. Indian Pediatr. 2004;41:787-795.
40. Donckerwolcke RAMG, France A, Raes A, Vande Walle J. Distal
nephron sodium-potassium exchange in children with nephrotic
syndrome. Clin ephrol. 2003;59:259-266.
41. Iyengar AA, Kamath N, Vasudevan A, Phadke KD. Urinary indi-
ces during relapse of childhood nephrotic syndrome. Indian J
Nephrol. 2011;21:172-176. 41.
42. Matsumoto H, Miyaoka Y, Okada T, et al. Ratio of urinary potas-
sium to urinary sodium and the potassium and edema status in
nephrotic syndrome. Intern Med. 2011;50:551-555.
43. Vande Walle J, Donckerwolcke R. Pathogenesis of edema for-
mation in the nephrotic syndrome. Pediatr Nephrol. 2001;16:
283-293.
44. Brater DC. Resistance to loop diuretics: Why it happens and
what to do about it. Drugs. 1985;35:27-43.
45. Loon NR, Wilcox CS, Unwin RJ. Mechanism of impaired natri-
uretic response to furosemide during prolonged therapy. Kid-
ney Int. 1989;36:682-689.
46. Oster JR. Epstein M, Smoller S. Combined therapy with thiazide
type and loop diuretic agents for resistant sodium retention.
Ann Intern Med. 1983;99:405-406.
47. Deschenes G, Wittner M, Stefano A, Jounier S, Doucet A. Collect-
ing duct is a site of sodium retention in PAN nephrosis: a ratio-
nale for amiloride therapy. J Am Soc Nephrol. 2001;12: 598-601.
48. Warnock D, Kusche-Virog K, Tarjus A, et al. Blood pressure
and amiloride-sensitive sodium channels in vascular and renal
cells. Nat Rev Nephrol. 2014;10:146-157.