AKDH

Etiology and Management of Edema: A Review

Abbal Koirala, Negiin Pourafshar, Arvin Daneshmand, Christopher S. Wilcox,
Sai Sudha Mannemuddhu, and Nayan Arora

The development of peripheral edema can often pose a significant diagnostic and therapeutic challenge for practitioners due to
its association with a wide variety of underlying disorders ranging in severity. Updates to the original Starling’s principle have
provided new mechanistic insights into edema formation. Additionally, contemporary data highlighting the role of hypochlor-
emia in the development of diuretic resistance provide a possible new therapeutic target. This article reviews the pathophys-
iology of edema formation and discusses implications for treatment.
Q 2022 by the National Kidney Foundation, Inc. All rights reserved.
Key Words: Edema, Heart failure, Diuretics, Oncotic pressures, Albumin

T otal body water is calculated as the percentage of the

lean body weight in adults (50% in women and 60%
in men).1 For a 70-kg adult, this would be 42 L. Two-
third of the total body water is intracellular (28 L in a 70-
kg adult), and one-third is extracellular (14 L in a 70-kg
adult).2 Three-fourth of extracellular fluid is in the intersti-
tium (10.5 L in a 70-kg adult), and the rest is in plasma
(3.5 L in a 70-kg adult)2 (Table 1).
ETIOLOGY AND MANAGEMENT OF EDEMA
Classically, edema is defined as the expansion of interstitial
volume resulting in palpable swelling. However, this defi-
nition can be broadened to include fluid accumulation
within cells (cellular edema) or the interstitial space (inter-
stitial edema). Several clinical conditions are associated
with edema development, including heart failure,
cirrhosis, and nephrotic syndrome.
Causes of Edema3
PATHOPHYSIOLOGY OF EDEMA FORMATION
Starling’s forces (hydrostatic and oncotic pressures) operate
across the microvascular walls between the vascular and
interstitial compartments and are responsible for fluid and
solute exchange between the 2 compartments.4,5 Usually,
the balance of forces acting across the microvascular walls
of the capillaries favors the net flux of fluid from the blood-
stream to the interstitium, a process commonly referred to
as capillary filtration. The interstitial fluid drains into the
lymphatics, ultimately returning fluid to the systemic circu-
lation. The flow into the lymphatics is the only route through
which plasma proteins, generally filtered through the capil-
laries, are returned to the blood circulation.
Alterations in the forces across the vascular endothelial
cells, alteration of the capillary surface area, and perme-
ability characteristics of the capillary wall regulate transca-
pillary fluid flow, favoring fluid movement from the
vascular space into the interstitium, resulting in edema.
Edema does not become clinically apparent until the inter-
stitial volume increases by at least 2.5 to 3 L. Therefore, the
initial movement of fluid from the vascular space into the
interstitium cannot sustain edema, as the reduction in
plasma volume would reduce tissue perfusion, resulting
in shock. Activation of the renin-angiotensin-aldosterone
system (RAAS) results in the retention of sodium and wa-
ter by the kidneys to restore tissue perfusion. While some
of this fluid remains in the vascular space, much of it
passes into the interstitial space, resulting in the mainte-
nance of edema.
Capillary Hemodynamics
The exchange of fluid between plasma and interstitium
has been traditionally described by Starling’s law (Fig 1).

Net filtration ¼ Kf 3 ðDelta hydrostatic pressure 2 Delta oncotic pressureÞ

¼ Kf 3 ½ðPc 2 PisÞ 2 sðpp 2 pisÞ

From the Division of Nephrology, University of Washington, Seattle, WA

(A.K., N.A.); Division of Nephrology, MedStar Georgetown University Hospi-
tal, Washington DC (N.P., C.W., A.D.); and Divison of Nephrology, University
of Tennessee, Knoxville, TN (S.M.)
Financial Disclosures: The authors declare that they have no relevant finan-
cial interests.
Address correspondence to Nayan Arora, MD, Division of Nephrology, Uni-
versity of Washington, 1959 NE Pacific Street Box 356521, Seattle, WA 98195.
E-mail: narora@uw.edu
Ó 2022 by the National Kidney Foundation, Inc. All rights reserved.
2949-8139/$36.00
https://doi.org/10.1053/j.akdh.2022.12.002
where Kf is the capillary filtration coefficient (surface area available
for fluid movement 3 hydraulic permeability); Pc and Pis are the
capillary and interstitial fluid hydrostatic pressures, respectively;
pp and pis are the capillary and interstitial fluid oncotic pressures,
respectively; and s represents the reflection coefficient of proteins
across the capillary wall (with values ranging from 0 if completely
permeable to 1 if completely impermeable).
Starling’s forces originally postulated fluid filtration at
the arterial end and fluid resorption at the venular end

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 Etiology and Management of Edema: A Review 111

of the capillary bed. While this hypothesis is valid in the tion of the sympathetic and renin-angiotensin systems.
kidney cortex and medulla, net filtration continues These neurohumoral activations promote sodium and
throughout the capillary length elsewhere, invalidating water retention, leading to plasma volume expansion.
several assumptions of the Starling relationship.6,7 In a chronic compensated state of heart failure, the resul-
Albumin and sodium ions bound to glycosaminoglycans tant plasma volume expansion leads to the restoration of
in the interstitium contribute to pis and fluid filtration. cardiac output at the expense of an increase in LVEDP. A
Interstitial fluid albumin is recycled back to the systemic new steady state is established in which the stroke vol-
circulation through the lymphatics. The filtration barrier ume and cardiac output are normal, sodium excretion
is formed by a glycocalyx barrier that lines the capillary lu- matches sodium intake, and the activity of the RAAS
mens. The filtration barrier is interrupted by clefts through has returned to normal.9 Decompensation of this new
which filtration occurs. The oncotic pressure difference
7
steady state can occur from increased dietary sodium
across plasma-sub glycocalyx opposes filtration but does load,10 resulting in edema. Additionally, cardiac output
not reverse the filtration rate. Fluid filtration occurs may not be augmented further to support exercise in a
throughout the capillary wall from the arteriolar to the well-compensated state, resulting in decreased tissue
venular end. With the subacute reduction in capillary pres- perfusion and further neurohumoral activation, renal
sure, the glycocalyx model preserves filtration at a very vasoconstriction, sodium retention, and ultimately
low rate without an absorption phase, as the original Star- edema.11
ling equation proposed. This is an essential feature of the In severe chronic heart failure,12 the heart may have
revised paradigm and highlights the limitations of reached its maximum capacity to increase contractility in
attempting to prevent or treat edema by transfusing col- response to increasing stretch. Despite plasma volume
loids. expansion from neurohumoral activation in the face of
Edema is formed when there is either an alteration in low cardiac output, the slight increase in plasma volume
capillary dynamics favoring an increase in net filtration produces a considerable elevation in LVEDP but no in-
or defective removal of addi- crease in cardiac output.
tional filtered fluid by CLINICAL SUMMARY Hence, this leads to edema
lymphatic drainage. formation.
Increased fluid filtration is  The pathophysiology of edema has evolved with greater
In heart failure, cirrhosis,
often due to increased capil- understanding of the glycocalyx, challenging principles of and nephrotic syndrome,
lary hydrostatic pressure or the original Starling’s principle. increased release of natri-
capillary permeability (capil- uretic hormones such as
lary hydraulic permeability).  Advances in mechanisms of diuretic resistance, particularly atrial natriuretic peptide
the role of chloride, provide potential future therapeutic
In addition, it can be due to (ANP) fails to promote
targets for patients with heart failure.
disruption of the endothelial natriuresis due to renal
glycocalyx, decreased inter-  Predominance of the “overfill theory,” particularly in resistance to the action of
stitial compliance, a lower adults, in addition to small clinical trials, does not support ANP13 (see nephrotic syn-
plasma oncotic pressure, or the common practice of infusing albumin with diuretics drome).
a combination of these for the management of refractory edema.
changes (Fig 2). PATHOGENESIS OF
EDEMA IN CIRRHOSIS
PATHOGENESIS OF EDEMA IN HEART FAILURE In liver disease, the development of portal hypertension is
In heart failure, edema is due to an increase in venous pres- necessary for ascites development.14,15 In addition, pa-
sure in the heart (ventricular diastolic pressure), resulting tients with cirrhosis and portal hypertension have hemo-
in back transmission of the pressure to the venous system dynamic, functional, and biochemical abnormalities
(to the peripheral capillaries in right heart failure and pul- contributing to fluid retention.
monary capillaries in left heart failure) resulting in a paral- Cirrhosis with portal hypertension is characterized by a
lel rise in capillary hydrostatic pressure; also, there is marked reduction in systemic vascular resistance (SVR)
volume expansion due to renal sodium retention second- and mean arterial pressure plus an increase in cardiac
ary to activation of the RAAS. The site of edema accumu- output.16 The most commonly affected area is the
8
lation depends on the nature of the cardiac disease. splanchnic circulation. Increased nitric oxide production
Impairment of left ventricular function in coronary artery is most often implicated as the perpetrator for causing
disease, hypertensive heart disease, and left-sided splanchnic vasodilatation.16 Other vasodilators consid-
valvular disease results in a parallel increase in left ventric- ered have been glucagon, vasoactive intestinal peptide,
ular end-diastolic pressure (LVEDP), pulmonary venous substance P, and prostacyclins.17,18 In addition, bacterial
hydrostatic pressure, and pulmonary edema. Right ven- translocation through the gastrointestinal tract and endo-
tricular failure, via similar mechanisms, leads to periph- toxemia has been postulated to cause increased systemic
eral edema in the lower extremities and ascites. prostacyclins19 and nitric oxide.20,21 The other contrib-
In addition to the etiologies mentioned above, plasma uting factors to the decrease in SVR are the opening of por-
volume expansion increases capillary hydrostatic pres- tosystemic shunts.22
sure in chronic heart failure. The reduction in cardiac The decrease in SVR from progressive vasodilation seen in
output decreases tissue perfusion, leading to the activa- cirrhosis leads to the reduced stretch at the carotid and renal

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112 Koirala et al

Table 1. Mechanism of Action of Diuretics

Oral Time to
Diuretic Typical Dose Bioavailability Half Life Onset (IV) Equipotent Doses
Loop diuretics (mechanism of action [MOA]: inhibition of NKCC2 channels)

Furosemide (IV or PO) 20-240 mg (IV) (up to q6 h) 10-100% 1.5-3 h 25 min 40 mg PO furosemide ¼ 20 mg IV
(typical max dose 600 mg) furosemide ¼ 1 mg
Bumetanide (IV or PO) 0.5-10 mg (IV) (up to q6 h) 80-100% 1-1.5 h 25 min bumetanide ¼ 20 mg torsemide
(typical max dose 15 mg)
Torsemide (PO) 10-150 mg (up to TID) 80-100% 3-6 h N/A
(typical max dose 300 mgl)

Thiazide and thiazide-like diuretics. MOA: inhibit NCC channels in the distal tubule

Metolazone (PO) 2.5-10 mg (up to BID) 270% 8-14 h 5 mg metolazone ¼ 50 mg

Chlorthalidone (PO) 50-100 mg (up to BID) 265% 40-60 h chlorthalidone ¼ 500 mg
chlorothiazide ¼ 2.5 mg
indapamide
Chlorothiazide (IV) 500-1000 mg (up to TID) 22 h
Indapamide (PO) 5-10 mg daily 293% 14-24 h

Mineralocorticoid receptor antagonists. MOA: inhibit mineralocorticoid receptors

Spironolactone (PO) 100-200 mg 290-95% 17-22 h 25 mg spironolactone ¼ 50 mg

eplerenone
Eplerenone (PO) 200-400 mg Unknown 4-6 h

Direct ENaC inhibitors. MOA: inhibit ENaC channels in the collecting duct

Amiloride (PO) 2.5-10 mg BID 30-90% 6h

Triamterene (PO) 50-100 mg BID 30-70% 2-4 h

Carbonic anhydrase inhibitor. MOA: inhibits carbonic anhydrase, indirectly decreasing sodium reabsorption in the proximal tubule

Acetezolamide (IV or PO) 500-1000 mg (up to BID) .90% 4-8 h

Sodium-glucose cotransporter 2 inhibitors. MOA: inhibit SGTL2 channels in the proximal tubule

Empagliflozin 10-25 mg daily .70% 12 h

Abbreviations: BID, twice daily; IV, intravenous; N/A, not available; NCC, sodium-chloride cotransporter; NKCC, sodium-potassium-chloride
cotransporter; PO, per os; SGLT2, sodium-glucose co-transporter 2; TID, three times daily.

baroreceptors. This results in the activation of sodium- PATHOGENESIS OF EDEMA IN NEPHROTIC

retaining neurohumoral mechanisms (RAAS, sympathetic
nervous system, and antidiuretic hormone) to restore
normal perfusion pressure.23 The downstream effects are
decreased renal sodium and water excretion and expansion
of extracellular volume. In a compensated state of cirrhosis,
plasma volume expansion should reduce the activity of the
endogenous neurohumoral systems, thus establishing a
new steady state with progressive normalization of sodium
and water excretion to match dietary intake.15
Further decompensation of liver disease from the pro-
gression of cirrhosis, infections, gastrointestinal bleeding,
and drugs can decrease effective intravascular volume,
despite having total extracellular volume excess and
increased cardiac output. This results in ongoing activa-
tion of neurohumoral systems, increased renal vasocon-
striction, reduced salt and water excretion, sodium
avidity, and progressive hyponatremia from increased
antidiuretic hormone release,24,25 which can have negative
prognostic implications.24,25
SYNDROME
In nephrotic syndrome, edema formation occurs due to 2
primary mechanisms, and their contribution may vary be-
tween patients.26–28
The Underfill Hypothesis
Under this hypothesis, movement of fluid from the
vascular space into the interstitium, due to a decrease in
plasma colloid oncotic pressure from hypoalbuminemia,
leads to underfilling of the vasculature and activation of
the RAAS resulting in sodium retention by the kidneys
(Fig 3).
Some patients with minimal change disease (MCD),
especially children, have elevated plasma renin activity
and enhanced tubular sodium absorption leading to so-
dium and water retention. These findings suggest under-
filling the circulation due to reduced oncotic pressure
secondary to hypoalbuminemia. In 1 study with 30 chil-
dren with early MCD relapse,29 21 developed edema.

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 Etiology and Management of Edema: A Review 113

A Classic Starling’s Principle Jv = K[(ρc-ρi)-σ(πc- πi)]

Vascular
lumen

Pc c

Pi i

Filtration rate (Jv)

Interstitium

B
Revised Starling’s Principle Jv = (ρc-ρg)-σ(πc- πg)

Vascular Vascular
Pc c lumen Pc c lumen
Intact glycocalyx damaged glycocalyx

Pg g
Small pore Pg g
Large pore network
transporting
plasma
proteins

Intercellular Intercellular
cleft cleft

Pi i Pi i

Filtration rate (Jv) Filtration rate (Jv) Interstitium

Interstitium

Figure 1. Classic versus revised Starling principle. Classic and modified views of starling’s forces along the glomerular capil-
lary wall. (A) The classic theory of continuous endothelium as a semipermeable membrane. This classic model is now consid-
ered flawed and has been superseded by the revised Starling principle. (B) The modified glycocalyx-cleft model depicted in
physiological (left panel) and pathological (right panel) states identifies glycocalyx as a semipermeable layer. Jv, fluid flux
across the capillary membranes; rc, capillary hydrostatic pressure; ri, hydrostatic pressure in the interstitium outside the
capillary; pc, capillary osmotic pressure; pi, interstitial osmotic pressure; s, capillary wall permeability. Revised model: pg, on-
cotic pressure in the sub-glycocalyx space; rg, hydrostatic pressure of the thin layer of interstitial fluid in the sub-glycocalyx
space. Arrow and line weights represent relative changes in effect and direction. Adapted from Finfer and colleagues Nat Rev
Nephrol 14, 541–557 (2018). (For interpretation of the references to color in this figure legend, the reader is referred to the Web
version of this article.)

Sixty-two percent of the children with edema had
biochemical evidence of volume depletion and low frac-
tional excretion of sodium (FENa). Manning and Guyton30
performed plasmapheresis followed by isotonic fluid infu-
sion to reduce plasma protein and noticed that when albu-
min decreased 68% over a 12-day plasmapheresis period
(mean albumin 2.4 g/dL), mean arterial pressure decreased
by 26 mm Hg, plasma renin activity increased 11-fold, and
plasma volume was 66.9 6 2.5% of the control group.
These changes were not seen when plasma albumin
decreased 33% during a 5-day plasmapheresis period.
Vande Walle and colleagues31 reported that in 6 children
with nephrotic syndrome (non-MCD nephrotic syndrome
with hypovolemic symptoms [4 with congenital nephrotic
syndrome of the Finnish type]), FENa was 0.2 6 0.2%.
Lithium clearance and maximal water excretion were

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114 Koirala et al

VASOCONSTRICTION
NFP= Lp S (Pgc-Pbs)- p− bs
(hydraulic pressure) - (oncotic pressure)
+++ NE, NSAIDs
Endothelin +13 mm Hg
++ CNIs, ATP
+ Ang II

VASODILATION
--- ANP, Nitric Oxide
Dopamine
- ARB/ACEi -3 mm Hg
10
46
onc
23 BSonc
gc onc <1
35 0 Pbs
onc
20
35
45
VASOCONSTRICTION 10 onc
+++ Ang II, NE 6
++ CNIs, ANP
8
+ Endothelin

VASODILATION onc onc

--- ARB/ACEi, 37 25
Dopamine
- Nitric Oxide

20 15

Figure 2. Revised Starling principle. Starling forces (revised view) govern the passive exchange of water between the capil-
lary microcirculation, glycocalyx, and the interstitial fluid by determining the net directionality and rate of water exchange. s,
protein reflection coefficient ¼ 1; pðoncÞbs ¼ 0; pgc, oncotic pressure in the sub-glycocalyx space; rgc, hydrostatic pressure of
the thin layer of interstitial fluid in the sub-glycocalyx space; ACEi, angiotensin-converting enzyme inhibitors; Ang II, angio-
tensin II; ANP, atrial natriuretic peptide; ARB, angiotensin receptor blockers; CNIs, calcineurin inhibitors; Lp, porosity of the
capillary wall; NE, norepinephrine; NFP, net filtration pressure; NSAIDs, nonsteroidal anti-inflammatory drugs; S, surface area
¼ (100x higher than other beds).

suppressed, and plasma aldosterone, renin, and norepi-
nephrine levels were elevated. Among children with
MCD, 12 presented with hypovolemic symptoms and
strong sodium retention (FENa 0.3%), whereas 15 were sta-
ble (FENa 1.1%). In the children with non-MCD lesions, the
plasma colloid osmotic pressure was significantly lower in
the hypovolemic types than in those with stable edema (4.2
vs 13.0 mm Hg; P , 0.05); in MCD, no such difference ex-
isted (8.1 mm Hg and 9.9 mm Hg, respectively).
The Overfill Hypothesis
Primary sodium retention by the kidney due to increased
epithelial sodium channel (ENaC) activity and renal resis-
tance to systemic ANP results in plasma volume expan-
sion (Figs 4 and 5).
Ichikawa and colleagues32 reported a unilateral model
of polyarteritis nodosa (PAN)-induced nephrotic syn-
drome in Munich-Wistar rats. Glomerular filtration rate
(GFR) and single-nephron GFR were reduced selectively
in PAN-perfused kidneys with nephrotic syndrome by
30%. Micropuncture studies revealed decreased sodium
filtration in the nephrotic kidney and less reabsorption
in the proximal convoluted tubule due to reduced oncotic
pressure in the peritubular capillaries and loop of Henle.
However, the quantity of sodium remaining in the
tubular lumen at the end of the late distal tubules re-
mained the same in both PAN-perfused and control kid-
neys, implying increased sodium reabsorption in the
distal tubules.
ANPs are elevated in nephrotic syndrome, but experi-
mental and human data demonstrate markedly blunted
natriuretic and diuretic responses to systemic infusion of
ANP in the nephrotic syndrome. The altered response to
ANP is also related to a defect in the number and affinity
of receptor-binding sites for the peptide and a possible
defect at the intracellular cyclic guanosine monophos-
phate (cGMP) level, the second messenger of ANP.26 In
addition, the gene encoding for a cyclophilin-like protein,
which is increased in sodium-retaining conditions, is upre-
gulated in the kidneys of nephrotic rats, and the infusion of
ANP further increases cyclophilin-like protein mRNA.33
Valentine and colleagues34 revealed a blunted natri-
uretic response to volume expansion with isotonic saline
in proteinuric rats in a rat model of Heymann nephritis.
Plasma ANP concentration was increased to the same
extent in both normal and nephrotic rats compared to hy-
povolemic controls. However, accumulation of cGMP by
isolated glomeruli and inner medullary collecting duct
cells from nephrotic rats after incubation with ANP was
significantly reduced compared with normal rats. This
difference was not related to differences in either density
or affinity of renal ANP receptors but was abolished
when the accumulation of cGMP was measured in the
presence of inhibitors of cyclic nucleotide phosphodies-
terases. Infusion of the phosphodiesterase inhibitor zapri-
nast into 1 renal artery in nephrotic rats normalized both
the natriuretic response to volume expansion and the in-
crease in urinary cyclic guanosine monophosphate excre-
tion from the infused, but not the contralateral, kidney.

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 Etiology and Management of Edema: A Review
Increased activity of ENaCs has been noted in nephrotic
syndrome (Fig 5).35,36 One of the serine proteases filtered
in patients with nephrotic syndrome, plasminogen, gets
activated to plasmin by a tubular urokinase-type plasmin-
ogen activator (uPA). Plasmin has been known to cause
proteolytic cleavage of the gamma chain of ENaCs, lead-
ing to its activation and sodium retention.
Staehr and colleagues37 administered amiloride, which
inhibits the ENaCs and uPA activity. Amiloride reduced
urine uPA activity, plasminogen activation, protease activ-
ity, and sodium retention in PAN rats, while proteinuria
was not altered. In paired urine samples,37 uPA protein
level was significantly elevated in urine from children
with active nephrotic syndrome compared with the remis-
sion phase. In addition, in 6 adult nephrotic patients, urine
uPA protein and activity correlated positively with
24-hour urine protein excretion.
MANAGEMENT OF EDEMA
Diuretics are ubiquitous in the management of congestion
and edema, but the response is often inadequate.38–40
Diuretic resistance (DR), commonly defined qualitatively
as a decreased natriuretic response necessitating
progressive increases in diuretic dosing and/or variations
in medication combination, is a major clinical challenge
and often portends a poor prognosis.41 At this time, there
is no standardization of diuretic therapy following identi-
fication of DR. This review covers the etiology of DR from
a physiological standpoint, focusing on novel
mechanisms.
DIURETIC BRAKING
DR mechanisms have been coalesced under the term
“diuretic braking,” a descriptive term for the progressive
decrease in response to the same dose of diuretic
throughout therapy.42 Diuretic braking is beneficial as it al-
lows a wider therapeutic window but, at the same time,
can result in impaired decongestion. The term diuretic
braking in clinical practice fails to recognize a specific
mechanism of resistance; however, one explanation for
this phenomenon could be enhanced distal sodium chlo-
ride (NaCl) reabsorption.43 This is often in the setting of
intermittent diuretic dosing.44 Diuretic dose and fre-
quency are interdependent in DR, and both must be
considered.45 Herein, we further discuss the roles of so-
dium and chloride in resistance to diuretic therapy. Mech-
anisms of diuretic braking are displayed in Figure 6.
SODIUM AVIDITY AND SALT INTAKE
Sodium has been understood to play a paramount role in
fluid homeostasis in the setting of congestion.46,47 The
importance of kidney sodium avidity in determining
diuretic response has been highlighted by recent studies
reporting that healthy individuals on a very-low-salt diet
had a noticeable decrease in response to loop diuretics.48
Enhanced sodium avidity may also explain excessive so-
dium retention in the absence of diuretics.49 As such, var-
iations in diuretic responsiveness, despite a similar
estimated GFR (eGFR), may be a result of differences in
basal sodium avidity.45,50
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115
Several studies have shown that concomitant use of
intravenous (IV) hypertonic saline solution with high
doses of loop diuretics for the management of persistent
congestion improves diuresis and clinical outcomes.47,51
The exact mechanisms for the benefit of hypertonic saline
remain elusive. It was initially hypothesized that mobiliza-
tion of fluid from the interstitial space to the intravascular
compartment through osmotic forces would restore effec-
tive intravascular volume, with resultant enhanced renal
blood flow (RBF) and delivery of diuretic agents to the
loop of Henle.52,53 However, this hypothesis was chal-
lenged by a study involving slow infusion of hypertonic
saline and minimal osmotic improvement but with similar
beneficial results.54 Therefore, a definitive mechanism ex-
plaining the reported benefits of hypertonic saline in
decongestive therapy remains unclear and needs to be
further evaluated.
ROLE OF CHLORIDE
Chronic diuretic use may lead to chloride depletion via
chloriuresis, which in turn plays an often overlooked
role in DR.55 Chloride (Cl2) signals the macula densa to
respond to volume overload via tubuloglomerular feed-
back, thus mediating renin release.56 As such, chloride
levels are strongly linked to diuretic responsiveness,
with chloride-containing solutions in turn increasing renal
NaCl excretion.57–59 Prior animal studies explored this
phenomenon by directly infusing hypertonic or
hypotonic NaCl into the renal artery while maintaining
plasma Na1 and Cl2 levels via hemodialysis.60 Results
showed that increases in renal plasma sodium and chlo-
ride [P[NaCl]] led to increased sodium excretion despite re-
ductions in eGFR, RBF, and intrarenal RAAS
activation.60,61 While hypertonic saline or ammonium
chloride reduced RBF and GFR and increased urine so-
dium volume (UNaV), intrarenal infusion of sodium ace-
tate actually increased RBF and GFR and reduced
UNaV.48,59,61 These results relate renal vasoconstriction
and natriuresis to increased Cl2, independent of Na1 or
plasma osmolality. Tubular fluid Cl2 plays a dominant
role in the reduction of eGFR and RBF via the tubuloglo-
merular feedback mechanism and increases in afferent
arteriolar resistance.62 The effect of increased Cl2 in
increasing UNaV was independent of renal hemody-
namics. This natriuresis may be partially explained by
chloride-induced metabolic acidosis, resulting in
respiratory compensation and resultant decrease in
PCO2, which in turn reduces proximal tubule NaCl and
fluid reabsorption.63,64
Thus, an increase in Cl2, independent of sodium or os-
molarity, has a potent effect to induce renal vasoconstric-
tion, reduce intrarenal angiotensin II, and increase renal
NaCl and fluid excretion. Indeed, acute hyperchloremia
in human subjects reduces RBF and renal renin and angio-
tensin release.65 Moreover, hypochloremic metabolic alka-
losis during loop diuretic administration reduces the
diuretic response by up to 40%.66 This may be because de-
livery of Cl2 to the loop of Henle determines the activity of
the Na1/2Cl2/K1 (NKCC2) cotransporter, which is the site
of action of loop diuretics.66,67 In contrast, depletion of
116 Koirala et al

Underfill Theory of Edema

↓ Plasma blood and Plasma Restoration of Blood &

Kidney Damage
volume Plasma Volume
↓ Blood Pressure ↑ ECF
Proteinuria Orthostatic Hypotension Normal Blood Pressure

Normal levels
Hypoalbuminemia ↑Renin ↑ Aldo
↓ ANP Renin Aldo
↑ NE ↑ ADH
NE ADH ANP

↓ Oncotic Pressure
↓ GFR, & ↓ FF
↑ Sodium reabsorption in
Shift of PCT & DCT
intravascular fluid ↑ Water reabsorption
into Interstitium
Hyponatremia

EDEMA FORMATION

Figure 3. Underfill theory of edema. Proteinuria, depleted intravascular volume, and decreased blood pressure can activate
the renin-angiotensin-aldosterone (Aldo) system, increase anti-diuretic hormone (ADH) and norepinephrine (NE) secretion,
decrease norepinephrine (NE) and atrial natriuretic peptide (ANP). These changes decrease glomerular filtration rate (GFR)
and filtration fraction (FF) and increase sodium reabsorption in the proximal and distal convoluted tubules (PCT and DCT).
This restores blood, plasma, and extracellular fluid (ECF) volume. (For interpretation of the references to color in this figure
legend, the reader is referred to the Web version of this article.)

intracellular Cl2 activates NKCC2 via effects in WNK3, a
chloride-sensitive kinase.66,67
Chloride has also been shown to reduce renin release in
contrast to non–chloride-containing sodium salts, which
do not affect renin levels.59 Previous studies of patients
admitted with acute decompensated heart failure
(ADHF) have shown that low serum chloride, but not
serum sodium, was strongly associated with impaired
decongestion and increased mortality.55,68 Moreover, hy-
pochloremia was associated with poor diuretic response
in patients with HF while its correction, independent of
serum sodium with lysine chloride, improved clinical
responses to diuretics.69 Therefore, repletion of chloride
may be considered in patients with DR.

ANP

2 ANP (Atrial Natriuretic

• Increased afferent and 1 peptide) Resistance
efferent arteriolar
resistance due to
increased sympathetic ↑ open channel
activity probability of ENaC
• Increased sympathetic (Epithelial Sodium Channel)
activityÆ activation of 3 4
tubular adrenergic
receptorsÆ Sodium and
water reabsorption
throughout the nephron
↑ Number and activity
of Na-K-ATPase

Figure 4. Overfill theory of edema. Mechanisms supporting overfill theory of edema. 1. Increased sympathetic activity leads
to arteriolar resistance, activation of adrenergic receptors, and increased sodium and water reabsorption; 2. resistance to
atrial natriuretic peptide (ANP) and decreased sodium excretion; 3. increased probability of ENaC opening and increased
number and activity of sodium potassium ATPase (Na-K-ATPase). Aldo, aldosterone; ECF, extracellular fluid; ENaC, epithelial
sodium channel; FF, filtration fraction; GFR, glomerular filtration rate; NE, norepinephrine; PCT and DCT, proximal and distal
convoluted tubule. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version
of this article.)

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 Etiology and Management of Edema: A Review 117

Overfill Theory of Edema

Kidney Damage Lumen Cortical Collecting Duct Blood
Principal Cell
Proteinuria

Plasminogen excretion
& conversion to Plasmin Plasminogen

Urokinase-type plasminogen
activator
Inhibition of domain Plasmin
by Plasmin Closed ENaC due to the
presence of the domain
’

ENaC (Epithelial
Sodium Channel) O
Open ENaC
activation

Sodium retention &

edema

Figure 5. Overfill theory of edema. Mechanism of epithelial sodium channel (ENaC) opening. Proteinuria and plasminogen
excretion increases the concentration of plasminogen in the lumen, which converts to plasmin. Plasmin inhibits a part of
the gamma (gÞ domain of the ENaC channel that has an inhibitory effect on the channel, which leads to persistent activation
of ENaC and sodium retention. (For interpretation of the references to color in this figure legend, the reader is referred to the
Web version of this article.)

A family of serine-threonine kinases (with no lysine
[WNK]) have been shown to play a key role in regulation
of electrolyte homeostasis and the transporters where loop
and thiazide diuretics function.70,71 Hypochloremia is
sensed by specific WNKs that regulate the sodium-
potassium-chloride cotransporter and thereby modify
salt and water retention.72
WNK kinases play a central role in intracellular signaling
and regulation of ion transport and neurohormonal
pathways in response to hypochloremia73 as they regulate
the targets of both loop and thiazide diuretics.74
It has been shown that reduced chloride levels activate the
WNK1 kinase through autophosphorylation. Once acti-
vated, WNK1 kinase activates and upregulates NKCC2

Diuretic Resistance Mechanisms

Prolonged use of loop or Thiazide diuretics

Low Plasma Potassium Low Plasma Chloride

Autophosphorylation & activation Decreased Cl delivery to Metabolic Alkalosis

of WNK Kinases Macula Densa
Increased delivery of bicarbonate
to NKCC2

Upregulation of Upregulation of Increased Renin, Angiotensin II

NKCC2 in TAL NCC in DCT & Aldosterone Activation of NDBCE in DCT

Increased Electrolyte & Fluid Reabsorption

Decreased Effect of Diuretic Therapy

Figure 6. Diuretic resistance mechanisms. Multiple mechanisms of diuretic resistance in patients with edema. DCT, distal
convoluted tubule; NCC, sodium-chloride cotransporter; NDBCE, sodium-dependent bicarbonate-chloride exchanger;
NKCC, sodium-potassium-chloride cotransporter; TAL, thick ascending loop of Henle. (For interpretation of the references
to color in this figure legend, the reader is referred to the Web version of this article.)

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118 Koirala et al

(Continued )
Mechanism of Edema
Causes of Edema Formation Mechanism of Edema
Causes of Edema Formation
Heart failure Decreased EF and forward
flow results in decreased  Wet beriberi  Thiamine deficiency
effective intravascular leading to high-output
volume and activation of heart failure
SNS, RAAS and ADH Refeeding edema Patients who have fasted for
leading to sodium and some time when fed a
water retention. Increased carbohydrate-rich diet
LVEDP leads to pulmonary retain sodium in response
venous congestion. to insulin-induced sodium
Increased right-sided reabsorption in the
filling pressures contribute proximal convoluted
to hepatic congestion, tubule.
ascites, and peripheral Lymphatic obstruction Impaired lymphatic drainage
edema. of interstitial fluid back to
Nephrotic syndrome Overfill hypothesis: primary the systemic circulation
renal sodium retention by (eg, radical lymph node
activation of RAAS and dissection for breast
ENaC activation resulting cancer).
in volume expansion and Drug-induced edema
edema. NSAIDs Depletion of vasodilatory
Underfill hypothesis: prostaglandins leads to
Underfilling of the increased renal sodium
circulation by a decreased retention. NSAIDs
plasma oncotic pressure exacerbate volume
leads to secondary renal salt overload in heart failure
and water retention. and cirrhosis and can
Chronic kidney disease Decreased GFR results in salt cause diuretic resistance.
and water retention Antihypertensive agents
Cirrhosis Portal hypertension leads to  Direct arterial/  Arteriolar vasodilatation
ascites. Decreased arteriolar leads to increased
effective intravascular vasodilators: capillary hydrostatic
volume results in the hydralazine, pressure and increased
activation of SNS, RAAS clonidine, filtration at the capillary
and ADH leading to methyldopa level. Direct vasodilators
sodium and water guanethidine, also lead to a drop in
retention. minoxidil systemic blood pressure,
Localized edema RAAS activation, and renal
 Venous obstruction  Increased venous sodium retention.
(DVT or venous stasis) hydrostatic pressure  Adrenergic
leading to increased antagonists
ultrafiltrate formation.  Calcium channel  CCB-induced edema is due
 Allergic reactions  Loss of vascular integrity, blockers (CCB) to arteriolar vasodilatation
(laryngeal edema) allowing fluid to move into leading to increased
the interstitial tissues due formation of capillary
to the presence of ultrafiltrate. It is more
inflammatory mediators common with
(due to mast cell-mediated dihydropyridine than with
angioedema, bradykinin- nondihydropyridines. CCB
mediated angioedema, and RAAS blockers
and from unknown improve edema by
mechanisms). causing capillary
Nutritional deficiencies venodilatation.
 Kwashiorkor  Increased generation of Thiazolidinediones Edema formation by an
cysteinyl leukotrienes that unknown mechanism.
increase capillary Contraindicated in NYHA
permeability and class 3 and 4 heart failure.
hypoalbuminemia, DPP4 inhibitors Angioedema either alone or
leading to decreased in combination with RAAS
plasma colloid oncotic inhibitors due to reduced
pressure. clearance of bradykinin by
(Continued ) DPP4 inhibitors.
(Continued )

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 Etiology and Management of Edema: A Review 119

(Continued ) A reduction in chloride delivery to the loop of Henle

Mechanism of Edema (such as during volume depletion) increases absorption
Causes of Edema Formation of NaCl via upregulation of NKCC2 and NCCs, whereas
low chloride delivery to the macula densa stimulates
Steroid hormones Primary renal salt and water renin secretion from the juxtaglomerular apparatus.67,68
 Glucocorticoids retention through the
Hyperactivity of the RAAS has long been known to
 Anabolic steroids mineralocorticoid receptor
 Estrogens and activation of ENaC
portend an unfavorable impact on ADHF and is a vital
 Progestins channels in principal cells. treatment target in these patients.69 The ROSE-AHF
Cyclosporine Renal vasoconstriction and (Renal Optimization Strategies Evaluation in Acute Heart
stimulation of thiazide- Failure) trial reported that although baseline chloride
sensitive NaCl channels levels did not correlate with worsening HF, hypochlore-
lead to salt and water mia had a negative association with response to diuretics
retention. and diuretic efficiency, increased mortality, and rehospi-
Growth hormone Primary renal salt and water talization rate.80
retention by growth The chloride-bicarbonate exchanger pendrin, located on
hormone and through IGF-
ß-intercalated cells in the kidney cortical collecting duct
1 by activation of ENaC
channels in principal cells.
and connecting tubules, which mediates the secretion of
Immunotherapies bicarbonate and reabsorption of chloride and plays an
 Interleukin 2  Increased capillary important role in vascular homeostasis, has been sug-
permeability from high- gested as a target for diuretic therapy.81,82 Pendrin elimi-
dose IL-2. nates excess bicarbonate during alkalosis and is a novel
 OKT3 monoclonal  Depletion of T cells by therapeutic target for diuretics.81,82 Chloride can be
antibody OKT3 leads to paradoxical directly reabsorbed in exchange for bicarbonate by pen-
(Muromonab-CD3) T-cell activation resulting drin, or chloride absorption can be coupled to sodium ab-
in cytokine release sorption by driving the activity of another transporter, the
syndrome and increased
Na1-dependent bicarbonate-chloride exchanger, replac-
capillary permeability.
ing one intracellular chloride for one extracellular bicar-
Abbreviations: ADH, anti-diuretic hormone; DPP4, Dipeptidyl pepti- bonate plus one sodium. This results in the net
dase 4; DVT, deep venous thrombosis; EF, ejection fraction; ENaC, absorption of NaCl.83
epithelial sodium channels; GFR, glomerular filtration rate; IGF-1, in-
sulin-like growth factor 1; LVEDP, left ventricular end-diastolic pres-
Administration of a selective pendrin inhibitor as mono-
sure; NSAIDs, nonsteroidal anti-inflammatory drugs; NYHA, New therapy to rodents results in no change in electrolyte
York Heart Association; OKT3, Muromonab-CD3; RAAS, renin- handling or urine output unless the rat has been chroni-
angiotensin-aldosterone system; SNS, sympathetic nervous sys- cally treated with furosemide, which causes increases in
tem. urine output.84 As such, pendrin is an excellent candidate
for human DR in that it offers a salvage pathway when
and the NaCl cotransporter (NCC) in the thick ascending distal delivery of sodium is increased.
limb and distal convoluted tubule, respectively, which are
the primary targets of loop and thiazide diuretics, thereby Renal Venous Congestion
enhancing renal electrolyte and fluid reabsorption. The A small increase in renal interstitial pressure, such as that
numbers of NKCC2 and NCC receptors are thought to following renal lymphatic ligation, enhances renal sodium
have an inverse relationship with diuretic efficiency. Activa- excretion.85 In addition, a modest increase in renal venous
tion of chloride-sensing WNKs by hypochloremia with pressure that increases the renal interstitial pressure in-
initiation of the downstream signaling cascade and upregu- duces a brisk natriuresis.86 However, steeper increases in
lation of NKCC2 and NCC may impair diuretic response renal venous pressure can collapse capillaries and tubules
and inhibit the treatment of congestion.67,75 in the encapsulated kidney, thereby reducing RBF, GFR,
Reports of WNK4’s effect over NCC activity were and the excretion of fluid and sodium.87 A fall in GFR dur-
initially discordant, as evidence showed inhibitory modu- ing diuretic therapy is generally attributed to volume
lation in vitro,71,76 while in vivo evidence demonstrated depletion88; however, an abrupt and considerable increase
WNK4 as an activator of NCC.77 Later, it was explained in intrarenal pressure could be accompanied by a fall in
that this discrepancy could be supported by WNK4 regu- RBF and GFR.89 Because the main intranephron hydro-
lation by chloride. One study showed that while WNK4 static resistance to flow is downstream from the loop of
coexpression does not upregulate NCC in basal condi- Henle,90 inhibition of fluid reabsorption within the loop
tions, decreasing plasma chloride promotes WNK4s acti- of Henle will considerably increase intratubular and renal
vating phosphorylation and WNK4-mediated NCC interstitial fluid pressure. Indeed, furosemide causes a
activation.78 Mutation of the WNK4 chloride binding site sharp rise in the volume of the distal, but not the proximal,
changed it into an active kinase that upregulated NCC ac- tubules in the rat,91 likely because it reduces fluid reab-
tivity. These series of trials not only assisted understanding sorption in the ascending limb of the loop of Henle, the
the effects of WNK4 over NCC function but also estab- thin loops of Henle, and the collecting ducts that are in
lished WNK kinases as key chloride-sensing proteins either side of the loop of Henle, which are the major
that regulate the activity of the transporters.79 nephron segments contributing to intratubular fluid

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120
resistance to flow.92 Moreover, furosemide activates renal
afferent nerves likely by activation of renal baroreceptors
and chemoreceptors.93 Interestingly, the falls in RBF and
GFR with IV furosemide are dependent on renal afferent,
but not efferent, nerves.94 Therefore, acute renal conges-
tion accompanying IV loop diuretics may contribute to
adverse renal hemodynamics and DR via direct effects of
the rise in intrarenal pressure and via afferent renal neural
mechanisms rather than by volume depletion. Indeed, the
acute falls in RBF and GFR with IV furosemide persist un-
modified if the NaCl and fluid excreted is replaced quan-
titatively by a matching saline infusion.94 Similarly, the
sharp fall in Na1 and fluid excretion that occurs after the
loop diuretic effect has abated and is considered to be
“compensatory” in healthy human volunteers in whom
all salt and water loss is prevented by a saline infusion.95
In ADHF, postdiuretic sodium and fluid retention is not
compensatory for diuretic-induced salt loss, with basal so-
dium avidity being a stronger driver of spontaneous natri-
uresis.96 Thus, renal congestion can be both a consequence
of volume overload and a consequence of the use of IV
loop diuretics for its treatment. In both settings, the
congestion is associated with impaired renal hemody-
namics and renal sodium and fluid retention.
ALBUMIN FOR REFRACTORY EDEMA
The cornerstone of therapy for edema, other than reversing
the underlying disorder when possible, involves achieving
net negative sodium balance,97 typically with the initiation
of a loop diuretic. Loop diuretics are highly protein-bound
and, therefore, have a low volume of distribution; however,
in hypoalbuminemic patients, the volume of distribution
can increase substantially. This concept provides a potential
mechanism for diuretic hyporesponsiveness in this popula-
tion and suggests that albumin infusion, concurrent with
loop diuretic administration, may be an attractive therapeu-
tic intervention by improving drug delivery to the kidney.
This concept was demonstrated in analbuminemic rats
who had a 10-fold higher volume of distribution of furose-
mide than normal animals. This resulted in insufficient con-
centration of diuretics at secretory sites in the proximal
tubule and little drug secreted in the urine, hence a negli-
gible diuretic response, which was restored after infusion
of an albumin/furosemide mixture.98 Unfortunately, this
has not consistently translated to human studies. A small
study of 13 patients with biopsy-proven cirrhosis demon-
strated no difference in furosemide pharmacokinetics, urine
furosemide excretion, or urine sodium excretion with albu-
min administration (either premixed with furosemide
ex vivo or infused simultaneously) versus furosemide
alone.99 A study of 9 patients with nephrotic syndrome
demonstrated a modest increase in sodium excretion and
urine volume with coadministration of furosemide plus al-
bumin, compared to furosemide alone, in the absence of dif-
ferences in urinary furosemide excretion; however, the
increased natriuresis can be explained by desalination of
the sodium content of the infused colloid.100 A meta-
analysis of 10 studies (including 8 trials with a cross-over
design) found a modest increase in urinary sodium excre-
tion at 8 hours (15 mmol sodium) although there were no
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Koirala et al
difference in natriuresis or urine volume at 24 hours.101 Al-
bumin administration has been insufficiently studied in pa-
tients with a serum albumin concentration less than 2.0 g/
dL; therefore, it remains possible that a combination of
loop diuretics with albumin remains a viable option for
those with severe hypoalbuminemia. One such study as-
sessed the efficacy of furosemide with or without albumin
in patients with severe hypoalbuminemia (mean serum al-
bumin 1.7 g/dL) and acute lung injury. The authors reported
a significant improvement in cumulative fluid balance in
the treatment group; however, the control group received
significantly more fluid boluses, likely explaining the
difference.102 Thus, coadministration of albumin and loop
diuretics for the treatment of refractory edema in patients
with hypoalbuminemia is not currently supported by pub-
lished literature. An exception to this may be in patients
with MCD, particularly in children. Concurrent administra-
tion of albumin with furosemide may result in transient im-
provements in weight loss although at the expense of
possible worsening hypertension and respiratory failure.103
A proposed management strategy is to utilize a FENa to
identify patients who were volume-contracted (supported
by the underfill theory) with those who were volume-
expanded (supported by the overfill theory). Administra-
tion of albumin with furosemide to the volume-contracted
patients, defined as a FENa , 0.2%, led to an improvement
in biochemical parameters and no difference in hospital
length of stay or weight loss compared to furosemide alone
for patients identified as volume-expanded.104
CONCLUSION
Despite recent advancements in the management of
congestion and volume overload, there remains a gap in
our understanding of diuretic therapy and how it may
be optimized in the setting of chronic disease. Mechanisms
for DR should be more thoroughly investigated, and po-
tential therapeutic targets identified. Moreover, modifica-
tion of the existing therapy to match discoveries in
electrolyte pathophysiology is integral to provide effective
diuresis and improve outcomes.
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