N@PoC

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

D I 10. 01 pocj. 000204

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 esearch Center I. . echenov First oscow tate edical niversity oscow - ussia
2
Department of Nephrology and Dialysis of Professional ducation Institute I. . echenov First oscow tate edical niversity oscow -
ussia
Department of Internal ccupational Diseases and Pulmonology I. . echenov First oscow tate edical niversity oscow - ussia

ABSTRACT
dema 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 0 year-old
men. The discussion revolves around the following ey uestions on uid 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 under ll theory
2b. The over ll theory
2c. Tubulointerstitial in ammation
2d. ascular permeability
. What are the mechanisms of edema in nephritic syndrome
4. ow can the volume status be assessed in patients with nephrotic syndrome
. What are therapeutic strategies for edema management
6. What are the factors a ecting response to diuretics
. ow can we overcome the diuretics resistance
a. ective doses of loop diuretics
b. Combined diuretic therapy
c. Intravenous administration of diuretics
d. Albumin infusions
e. Alternative methods of edema management
. Conclusion.
Keywords: dema Na C N Na -ATPase Nephrotic syndrome odium retention

Case presentation markable. One month before admission minimal proteinuria

was found.
A 0-year-old male patient was referred to the nephrol- Physical e amination did not reveal any signi cant signs
ogy clinic with massive periorbital upper and lower e trem- and symptoms beyond edema.
ities and scrotal edema 10 g weight gain foamy urine and rinalysis demonstrated nephrotic range proteinuria
reduction of the urine output. is edema was resistant to (10 g day) without any abnormalities of the urinary sedi-
oral furosemid administration ( 0 mg day). is blood pres- ment. Total blood count showed hemoglobin 12. g d
sure was 110 0 mm g. The past medical history was unre- an erythrocyte sedimentation rate of 40 mm h hemato-
crit 4 . The main biochemical data are summari ed in
Table I.
Accepted: eptember 6 2016 No monoclonal component was found either in the serum
Published online: ctober 10 2016 or the urine. Thromboembolic events were not observed.
ltrasonography revealed two normal-si ed idneys and
Corresponding author: presence of ascites. Chest plain radiography revealed bilat-
Irina Bobkova eral hydrothorax.
Gagarina street, 11a imitation of the oral sodium inta e to 2. g daily was
23. Krasnoznamensk
Moscow Region recommended. The intravascular volume was corrected by
Russian Federation intravenous infusions of 20 albumin (2 m min for 1-1.
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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e4 Edema in renal diseases

TABLE I - The biochemical data of the patient with nephrotic TABLE II - ist 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 inta e 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 00-1000
mg day. Side effects Ca+-channel blockers, estrogens, minoxidil,
A idney biopsy was performed and on light microscopy of mediations rosiglitazone, corticosteroids; anabolic
normal glomeruli were found. Immuno uorescent micros- steroids, etc.
copy did not reveal any immune comple deposits. lec- ADH = antidiuretic hormone.
tron microscopy con rmed the absence of electron-dense
deposits and demonstrated hypertrophy and vacuoli ation
of some podocytes and foot process e acement. Based on
these ndings 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 g) while the diuretic therapy was discontinued. A
urinary output of day was observed in a wee a er the dema is one of the cardinal clinical features of nephrotic
initiation of steroids. Two wee s later remission of N was syndrome (N ) and may range from locali ed pu ness to
achieved. The full dose of prednisone was continued for the massive anasarca.
ne t two wee s. A er achieving a complete remission it The pathophysiological mechanisms of edema formation in
was tapered slowly over 6 months. N were discussed over several decades. Abnormal accumula-
tion of interstitial uid results from the combination of
What is edema? What diseases can cause edema?
• abnormal renal sodium retention (primary and secondary)
dema is de ned as an abnormal accumulation of uid in • increased capillary wall permeability (related to the re-
the interstitial space of the body. lease of vascular permeability factor and other cyto ines).
dema is the reason for visiting the doctor and for a care-
ful di erential diagnosis. arious diseases (renal cardiac iven the wide spectrum of renal diseases leading to the
hepatic thyroid glands and others) may be causative (sum- N more than one single mechanism may be responsible
mari ed 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).
Con rmation of the renal nature of the edema re uires 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 under ll hy-
important for de ning 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 tarling forces (Fig. 1). These
events lead to uid redistribution from the intravascular space
towards the interstitial space causing the decrease in e ec-
tive arterial blood volume. The plasma volume contraction
triggers adaptive neurohumoral responses through activation
of the sympathetic nervous system (particularly e erent renal
nerves) stimulation of the renin-angiotensin-aldosterone sys-
tem ( AA ) an increase of antidiuretic hormone (AD ) release
renal sodium and water retention. The decrease in atrial na-
triuretic peptide (ANP) secretion facilitates salt retention and
subse uent edema formation (Fig. 1).
owever there are many arguments against this theory.
Clinical observations indicate that most of the edematous
patients with the di erent histological forms of N have either
a normal or even e panded intravascular volume whereas
only a minority of nephrotic patients have a depleted intra-
vascular volume ( ). o some patients with early phases
of severe N (usually in rapidly developing relapse of minimal
changes disease ( -11)) demonstrate a temporary hypovole-
mia because the mobili ation of interstitial albumin to the
blood is not su ciently fast to prevent it there is dise ui-
librium between plasma and e travascular albumin stores.
ater when the albumin redistribution becomes complete a
new e uilibrium is established during which blood volume is
maintained.
There is increasing e perimental and clinical evidence
that hypoalbuminemia cannot e plain the development of
edema in N (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
e4
Fig. 1 - Pathophysiological mech-
anism of edema formation in
nephrotic syndrome.
phenomenon has also been demonstrated in humans with N
(1 14).
Furthermore decrease in plasma oncotic pressure does
not a ect the volume of the intravascular space in N (1
16) and intravenous administration of albumin to induce vol-
ume e pansion promotes only mild natriuresis (12).
These data suggest that there might have been sodium
retention in patients with N not mediated by volume
depletion.
The “overfill” theory
nli e the under ll hypothesis the over ll concept
presumes a primary intrinsic defect of salt and water excre-
tion in the nephrotic idney (1 2). This theory postulates that
there are also conse uences of the proteinuria other than
just hypoalbuminemia which lead to enhanced tubular so-
dium reabsorption progressive e tracellular uid volume
e pansion and edema formation by an over ow mechanism
(Fig. 1).
The cellular mechanisms of this primary sodium retention
in N are associated with
activation of the e pression of Na e changer
(N ) in the apical membrane of the pro imal tubules
by the tubular albumin (1 -1 )
proteinuria-induced stimulation of the basolateral Na -
ATPase pump in the collecting ducts (20-22)
activation of the apical epithelial amiloride-sensitive so-
dium channels ( Na C) in the collecting ducts induced by
urine proteases (plasminogen plasmin) (2 2 -26)
e 0
• tubular resistance to ANP (the result of an increased
cyclic guanosine monophosphate (c P) phosphodies-
terase activity and depletion of c P which is the ANP
second messenger) (2 2 -2 ).
Tubulointerstitial inflammation
There is also strong evidence that tubulointerstitial inflam-
mation and glomerulo-interstitial cross-tal s are involved in
sodium retention and nephrotic edema formation ( 0). It has
been demonstrated that proteinuria induces in ltration of the
interstitium by in ammatory cells (T-cells and monocyte mac-
rophages). Production of vasoactive mediators by these cells (in-
crease of angiotensin II and decrease of nitric o ide) can cause
a reduction in glomerular ultra ltration coe cient and single
nephron F ( 0 1) as well as a decline in sodium ltration
with an increase of tubular reabsorption resulting in primary
sodium retention (Fig. 2). Interstitial in ammation in longstand-
ing N stimulating tubulointerstitial brosis and atubular glom-
eruli formation can lead to a more permanent decrease in
glomerular ltration rate ( F ) and thus to sodium retention.
Vascular permeability
The asymmetric e pansion of the interstitial volume in
N is e plained 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 tarling forces (2 2- 4). Increase of capil-
lary permeability could be related to the release of numerous
vascular permeability factors and other cyto ines from im-
mune cells including histamine endoto ins anaphylato ins
catecholamines vascular endothelial growth factor interleu-
in-1 interleu in-2 and tumor necrosis factor-alpha.
Edema in renal diseases
Fig. 2 - The role of tubulointerstitial
in ammation in the pathogenesis
of nephrotic edema. Adapted from
odrigue -Iturbe et al ( 0). f
ultra ltration coe cient F glo-
merular ltration rate AT-II angio-
tensin II N nitric o ide.
What are the mechanisms of edema in nephritic
syndrome?
Acute glomerulonephritis is the prototypical form of ne-
phritic edema ( ). vere pansion of the vascular compart-
ment is responsible for the hemodynamic characteristics of
patients with nephritic syndrome (increased e ective arterial
blood volume plasma volume blood pressure and cardiac
output) ( 6). ypervolemia and edema in such patients re-
sult from primary salt retention and F 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 f which is driven by the e ective capillary
wall hydraulic permeability and total capillary surface area
per glomerulus ( ). At the onset of the disease the F re-
mains normal for some period of time. The initially preserved
F is maintained by the e uilibrium between the increased
transcapillary hydraulic pressure which is the driving force
for ltration and the reduced f. The progressive F dete-
rioration observed in more advanced stages of this disorder
is the conse uence of the further reduction of f. The signi -
cant fall of f leading to subse uent reduction of F results
in the decrease of sodium ltration with sodium and water
retention.
How can the volume status be assessed in patients
with nephrotic syndrome?
valuation of the volume status is crucially important for
edema management. Table III summari es the typical clinical
and laboratory features for distinguishing nephrotic patients
with under ll or over ll physiology. linical characteristics of
© 2016 The Authors. Published by Wichtig International
Bobkova et al
TABLE III - valuation 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
e tremities) abdominal pain secondary to decreased intestinal
perfusion. Diarrhea and vomiting provo ing dehydration and
hypovolemia demand attention from the doctor. By contrast
in hypervolemic N high blood pressure without postural hy-
potension and other signs of volume depletion are found.
rinary sodium and potassium concentration fractional
e cretion of sodium (F Na ) and inde of AA a is activation
© 2016 The Authors. Published by Wichtig International
e 1
may be useful tests for evaluation of renal sodium handling
and volume status in nephrotic patients.
F Na is the ratio of sodium e creted to that ltered by
the renal tubules.
F Na ( ) (urinary Na serum creatinine serum Na
urinary creatinine) 100.
A urinary sodium concentration below 20 m and
F Na below 1 indicate sodium retaining conditions. The
bloc ade of sodium reabsorbtion by diuretic increases uri-
nary sodium concentration and fractional sodium e cretion
to a greater or lesser e tent ( ). oop diuretics can increase
F Na to 0 thia ides to -10 and potassium sparing
diuretics to 2 - ( ).
ande Walle and cowor ers revealed signi cant positive
correlations between the ratio of urinary concentrations
of to the sum of and Na (m ) (m )
Na (m ) re ecting of Na e change in the distal neph-
ron and increased serum concentrations of renin aldoste-
rone and AD which are observed in hypovolemic children
with minimal lesion nephrotic syndrome ( -10). The ratio has
been o ered as an inde of activation of AA a is. A ratio
Na more than 60 suggests activation of the a is and
renal potassium wasting ( -10).
Patients with N and hypovolemia typically show low
F Na (o en below 0.2 ) and a high urinary Na in-
de (greater than 60 ) ( -4 ). anagement 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 ade uate volume correction poses a ris to hy-
povolemic shoc . In hypovolemic patients with relapse of
steroid responsive N treatment with corticosteroids leads to
rapid decrease of proteinuria steroid-induced diuresis within
-10 days. It may be better to avoid giving furosemide to
these patients if possible and wait for the diuretic e ects of
remission due to corticosteroid treatment.
Patients with edema and clinical and or laboratory fea-
tures of hypervolemia (F Na 1 and urinary Na
inde 60 ) can safely be treated with diuretics ( -4 ).
Intravascular infusion of albumin and colloids in such patients
put them at ris 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 under ll or over ll physiology. There-
fore close monitoring of both clinical and laboratory features
(Tab. III) are re uired 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 e cretion se uestered in the interstitial com-
partment. Diuretics are fundamental for edema treatment in
N this type of medication ensures diuresis by inhibiting of
sodium reabsorption in the di erent segments of the renal
tubular system (2 ).
The e cacy of diuretics is determined by site of their
action in the nephron. ajor proportion of ltered Na is
e 2
reabsorbed in the pro imal tubule ( -60 ) and in the loop
of enle (2 - 0 ) only - of ltered sodium is reab-
sorbed in the distal segments of the renal tubular system. ow-
ever in N the e cacy of diuretics acting in pro imal segments
is hampered by compensatory increase of sodium and water
by distal reabsorption in the ascending limb of enle’s loop.
Therefore loop diuretics which can increase F Na up to 0
remain the rst choice for edema treatment in patients with
N . Nevertheless the treatment of edematous patients should
be individuali ed according to their clinical manifestations.
The general principles of edema management are as
follows:
odium inta e restriction to 100 m Na day should be
recommended to all patients with edema (1 m Na
2 mg Na . mg of NaCl)
trict limiting sodium inta e (to 1 m g day) is neces-
sary only in subjects with refractory edema
Diuretics are not re uired for minimal periorbital puffi-
ness or feet edema. ost of such patients demonstrate
reduction of edema with moderate restriction of sodi-
um intake
ild edema in patients with steroid responsive N resolve
under treatment with corticosteroids which usually leads
to steroid-induced diuresis within -10 days
Patients with moderate-to-severe edema beyond so-
dium restriction also need treatment with one or more
diuretic agents
valuation 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.
dema is considered refractory if therapy with ma imum
doses of diuretics results in the daily weight loss less than 1
of body weight.
The algorithm of edema management in patients with N
is shown in Figure .
What are the factors affecting response to diuretics?
The e cacy of loop diuretics is restricted by the function-
al resistance of nephrotic patients to the natriuretic e ect of
these drugs (2 44 4 ).
everal mechanisms may contribute to diuretic resistance
in patients with N including
• Decreased gastro-intestinal drug absorption.
(Bowel wall edema impairs absorption of oral medica-
tions)
• Decreased diuretic entry into the tubular lumen.
( oop 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 enle’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 bloc ing 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 uid has
been demonstrated in the e periment but has not been con-
rmed 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 e ect relies on an ade uate amount of the
drug reaching its site of action in the renal tubules. Primarily
in patients with N and edema it is necessary to increase the
dose of loop diuretics to ma imally e ective oral dose (furose-
mide 4 0 mg day torasemide 0 mg day bumetanide 6 mg
day). igher doses of oral diuretics do not e ert any additional
e ect while the fre uency of side e ects is greatly increased.
Diuretics with a high bioavailability are preferred ( 0 for furo-
semide 0 for torasemide 0 for bumetanide).
econd to overcome the sodium reabsorption in the dis-
tal tubules a er 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 e ective concentration.
Combined diuretic therapy
In patients with N adding thia ides (hydrochlorothia ide
2 -100 mg day or metola one 100 mg day) on top of furose-
mide mar edly increases the natriuresis (46).
First o all thia ide diuretics have a longer half-life and
prevent or reduce the sodium retention a er termination of
the loop diuretic’s action prolonging its natriuretic e ect.
econd administration of the thia ide may interfere with
the so-called rebound e ect following loop diuretic treat-
ment. Thia ide diuretics bloc the nephron sites prone to
sodium-induced hypertrophy accounting for the synergistic
response of the combination of thia ide and loop diuretics.
In the combined administration thia ide diuretics have to
be prescribed 1 hour before the loop diuretics in order to
achieve full bloc ade 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 N increases urinary sodium e cretion and pro-
motes edema resolution (4 ). Amiloride inhibits the above-
mentioned Na e changer in the pro imal tubules and
Na C in the distal tubules. oreover amiloride has recently
been shown to inhibit the synthesis of the urokinase recep-
tor uPA . This molecule converts plasminogen to plasmin at
the cell surface of distal tubular cells which subse uently up-
regulates Na C activity resulting in salt and water retention
and edema formation (4 4 ).
pironolactone 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 N and hypovolemia is an
indication to spironolactone’s administration. Adding spirono-
lactone (2- mg g day) to loop diuretics in patients with N
and hypovolemia increases urinary sodium e cretion reduces
refractory edema and prevents hypo alemia.
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
e
diuretics are ine ective. The ma imal natriuretic response
occurs by intravenous furosemide boluses 1-2 mg g or
the e uivalent doses of bumetanide and torasemide which
should be administered slowly over 10-1 minutes (not e -
ceeding the rate 4 mg min). owever 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 idney.
In patients poorly responding to bolus doses of the
loop diuretics a continuous intravenous infusion can be
recommended. A er an initial bolus of 1-2 mg g furosemide
continuous infusion should be started with a dose of 0.1 mg
g h which may be increased up to 1 mg g h. Continuous
infusions of furosemide result in a more constant delivery of
diuretic to the tubules and more substantial natriuresis. ore-
over infusions of diuretics are associated with lower pea plas-
ma concentrations and a lower incidence of side e ects.
Albumin infusions
Treatment of edema in severe resistant N and hypovo-
lemia re uires high doses of loop diuretics combined with
albumin infusions. olume 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 albumin (10-20 m g over 0-
60 minutes infusion rate m min) or 20 albumin (1 g g
over 1-4 h) in combination with ma imum doses of furose-
mide (120 mg) may be performed. The 20 albumin solution
increases the vascular volume to -4 m per 1 m of infused
solution. The rate of 20 albumin infusion should not e ceed
2- m min. sually albumin is administered as an undiluted
solution but it may be diluted with isotonic saline or de -
trose to increase the infused volume. Furosemide may be ad-
ministered as a bolus in the midst or a er the end of albumin
infusion. To achieve a ma imum e ect both medications may
be mi ed before intravenous administration. ince the e ect
of albumin infusion is transient the infusion should be re-
peated for achieving a sustained reduction in edema. n 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
cess of uid in patients with refractory edema and oli-
guria can be removed by prolonged veno-venous ultra ltra-
tion with highly permeable membranes or by hemo ltration.
These methods are more e ective 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 ultra ltration.
ead-out water immersion ( -4 h day) is a uite 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
e 4 Edema in renal diseases

natriuresis and diuresis with a reduction of edema. owever - Albumin infusions with diuretics co-administration should
this procedure is not widely applicable in current renal practice. be recommended to patients with hypovolemia or refrac-
tory severe edema.
Conclusion - ild edema in patients with steroid-responsive N re-
solves promptly following therapy with corticosteroids.
enal edema is associated with renal sodium retention as - dema in patients with N and hypervolemia can safely
a result of di erent pathogenetic mechanisms including un- be treated with diuretics.
der ll and over ll pathways.
In a great number of patients with N the pathophysiology Disclosures
of edema is not related to hypoalbuminemia hypovolemia and Financial support No grants or funding have been received for this
secondary AA activation but is associated with a primary re- study.
nal defect in sodium e cretion. Proteinuria itself up-regulates Con ict of interest None of the authors has any nancial interest
the tubular sodium reabsorption through stimulation of N related to this study to disclose.
expression in the apical membrane of the proximal tubules and
thic ascending limb cells induction of Na -ATPase synthesis
and activation of apical amiloride-sensitive Na C in the corti- References
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