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RENAL PATHOLOGY

ARTICLE

Nephrotic syndrome
and oedema formation:
a new understanding
Nephrotic syndrome is a condition commonly expressed with oedema and
sodium retention. Here, Maria Angela Forneas looks at the pathogenesis
and mechanisms associated with so-called nephrotic oedema.
The term nephrotic syndrome (NS) covers a
collection of clinical findings associated with
massive loss of protein via the kidney. It is
characterised by the presence of
hyperlipidaemia, hypoalbuminaemia,
oedema and nephrotic-range proteinuria
(protein excretion 3.5 g per 24 hours).1,2
Oedema is identified as the generalised or
localised increase in fluid in interstitial
tissues and is attributed to mechanisms
involving sodium retention. In NS,
interstitial oedema is massive and may result
in functional constraints such as restriction
of movement. Oedema is the most common
presenting symptom in about 95% of
children with NS.2 Therefore, understanding
the processes involved is important as this
may lead to the discovery of new therapeutic
options or the application of appropriate
clinical management.

are responsible for sodium and water reabsorption, and potassium secretion, while
intercalated cells are responsible for chloride
transport. These processes in the CCD are
responsible for oedema formation and
increased sodium re-absorption in the PAN
rat, and are involved in the stimulation of the
renal apical epithelial sodium channels
(RENaC).

In addition, sodium retention is attributed


to the induction of basolateral Na, K and
ATPase. In vitro studies have shown that
hydrolytic and transport activities double in
the CCD in cases of proteinuria.
Such irregularities in renal sodium
retention would normally be neutralised by
increased secretion of sodium in the inner
medullary collecting duct, initiated by atrial
natriuretic peptide (ANP); however, this
regulatory process is inhibited in patients with
NS by increased catabolism of cyclic
guanosine monophosphate (cGMP) following
stimulation of phosphodiesterase. Enhanced
cGMP phosphodiesterase activity in the CCD
and glomerulus of proteinuric models has also
been shown to result in resistance to ANP.6

Nephrotic syndrome covers a collection of clinical findings


associated with massive loss of protein via the kidney

Most knowledge about the site and


mechanism of renal sodium retention in
NS has been acquired from experimental
animal models, particularly the puromycin
aminonucleoside (PAN)-treated rat.
Studies3,4 have shown that unilateral renal
PAN results in sodium retention and
unilateral proteinuria. Moreover, it has been
shown that the cortical collecting duct
(CCD) is the site of sodium retention in
a proteinuric kidney.
Cells of the CCD of the PAN nephrotic
rat comprise principal and intercalated cells.
Studies35 have confirmed that principal cells

MAY 2010

Manfred Kage/Science Photo Library

SODIUM RETENTION

The glomerulus and associated tubules comprise the filtration unit (nephron) of the kidney
(original magnification x160).

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351

ARTICLE
UNDERFILL THEORY
Historically, oedema formation in NS was
thought to be due to increased sodium
retention from intravascular volume depletion
as a result of low plasma oncotic pressure. The
mechanism, referred to as the underfill
theory, involves reduced serum albumin
concentration (hypoalbuminaemia)7 and is due
to increased filtration and urinary excretion of
albumin. As this increased interstitial fluid
occurs primarily at the expense of the plasma
compartment, plasma volume contraction
must occur to an extent that activates
secondary sodium-retaining renal mechanisms.
The underfill mechanism is characterised
by several processes. First, hypovolaemia
triggers the sympathetic nervous system,
particularly efferent renal nerve activity
(ERNA),8 after which angiotensin II causes
increased tubular re-absorption in the proximal
tubule. Then, the renin-angiotensinaldosterone (RAA) axis is triggered to increase
renin secretion. Finally, the mechanism covers
the decrease in ANP secretion, facilitating salt
retention.
When renal sodium retention occurs,
and sodium intake is not reduced, a positive
sodium balance results in an increase in
extracellular fluid (ECF) volume. Through
the dilution of plasma albumin, increasing
ECF volume aggravates oedema further.
In general, the underfill theory correlates
with renal sodium retention, the
hyperaldosteronaemia observed in PAN
experimental rats, and the activation of
RENaC and induction of Na, K, ATPase in the
collecting duct; however, these observations
show some inconsistency with clinical
manifestations.

OVERFILL THEORY
The overfill theory postulates the presence
of a primary intrarenal defect in sodium
excretion, and suggests an enhanced plasma
volume that eventually leads to oedema by an
overflow mechanism. The intrarenal element
responsible for the defect has yet to be
confirmed, but it may be linked to tubular
resistance to the natriuretic effect of ANP.9
In this mechanism, enhanced tubular sodium
re-absorption is found specifically in the distal
nephron.
The concept states that an initial rise in
sodium re-absorption results in salt and water
retention, and eventually hypertension.
Moreover, it suggests that the stimulation of
the RAA axis and marked decrease in plasma
volume are not principal determinants of
sodium retention in NS. Irrespective of normal
sodium intake, a positive sodium balance
occurs, leading to progressive ECF volume
expansion.
A body of clinical and experimental
evidence has been provided by clinical studies,
many features of which oppose the underfill
theory. For example:
r no sodium/fluid retention or slight oedema
in analbuminaemic patients with NS
despite low plasma oncotic pressure10

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r no correlation of blood volume with


plasma oncotic pressure in nephrotic
patients11,14 it is only in cases of children
with minimal change disease (MCD) that
plasma volume is observed to be reduced2
r intravenous injection of albumin causes
blood volume expansion but promotes only
mild natriuresis7,12
r natriuresis starts as proteinuria stops,
before the normalisation of albuminaemia
and change in plasma oncotic pressure in
children with steroid-sensitive MCD2,12
r persistent hypertension is present in most
NS patients5,13
r sodium retention persists following
adrenalectomy in PAN-induced nephrotic
rats.14
The overfill theory is more often linked
to patients with high blood pressure and
those with a pronounced tubulointerstitial
inflammatory response. Moreover, the
overflow mechanism does not rely on
reduced plasma oncotic pressure and plasma
volume. Rather, it suggests that plasma and
ECF volume expansion precedes oedema
formation. Unlike the underfill theory, overfill
sees both aldosterone and plasma renin
activity inhibited rather than stimulated.

SODIUM-HYDROGEN EXCHANGER
Sodium-hydrogen exchanger type 3 (NHE3)
is a protein found in the apical membrane
of the proximal tubule and thick ascending
limb cells where it has physiological functions
in sodium and bicarbonate absorption.15
Changes in NHE3 transport between
intracellular compartments causes increased
sodium re-absorption accompanied by
expansion of extracellular volume. Such
changes, specifically movement of NHE3
protein from the plasma membrane microvilli
and a subapical compartment, are controlled
by stimuli such as albumin, osmolarity,
andothelin-1, parathyroid hormone and
dopamine.15 Thus, metabolic and hormonal
elements play an important part in the
management of renal proximal tubular apical
membrane NHE3.
Other studies15,16 have shown some
involvement between increased albumin
endocytosis (protein overloading) in the
proximal tubule and NHE3; in vitro, however,
suspension of NHE3 decelerates albumin
endocytosis. The role of NHE3 in maintaining
ECF volume is supported by the presence of

Sodium-hydrogen
exchanger type 3 is a
protein found in the
apical membrane of the
proximal tubule and thick
ascending limb cells

'Diuretics are the foundation


of treatment for oedema
in nephrotic syndrome
as they prevent renal
sodium retention
hypovolaemia and hypotension in NHE3-null
mice.15
Salt retention, as well as renal disease,
progresses with activation of NHE3 by
albumin in the presence of fibrosis and renal
inflammation. A small association has also
been shown for NHE3 with the activation of
nuclear factor-B, which is involved in
cellular inflammation and disease processes.

A BETTER UNDERSTANDING
Nephrotic syndrome is always connected with
renal sodium retention, irrespective of its
aetiology, and eventually this results in
asymmetric expansion of the interstitial
tissue. Underfill or overfill concepts
notwithstanding, interstitial inflammation is
the stimulus for oedema formation.
Aside from the basic pathogenic
mechanisms postulated, new mechanistic
components have been identified, particularly
the effect of increased NHE3. In studying
the role of NHE3 in oedema formation,
it is logical to use an in vitro model of
microperfusion to study nephrotic
pathogenesis other than the PAN-nephrotic
experimental model.
The pathophysiology of NS includes
changes in the intrinsic properties of
endothelial capillary permeability in control of
the asymmetry of volume expansion,
alteration of the glomerular filtration barrier
causing hypoalbuminaemia and proteinuria,
and activation of distal nephron Na, K,
ATPase responsible for sodium retention in
the kidney. A relationship between these three
elements is not fully elucidated but they help
to explain the proposed mechanisms of
oedema formation.
In addition, it has been shown that
decreased plasma oncotic pressure plays a key
role in the development of oedema. Together
with primary sodium retention, it overwhelms
the mechanisms that inhibit alterations in
interstitial volume. In spite of this, low plasma
oncotic pressure cannot be used as a
determinant of oedema resorption.
Diuretics are the foundation of treatment
for oedema in NS as they prevent renal
sodium retention; however, individual
patients will be treated differently according
to the manifestation of their symptoms. Thus,
laboratory testing is critical in the monitoring
of oedema and in research into its
pathogenesis.
Research into the signalling mechanisms
in the renal collecting duct continue in
order to understand the process of sodium

MAY 2010

ARTICLE
re-absorption during the formation of oedema
in NS to better understand the dysregulation
of Na, K, ATPase activity and the surface
expression of RENaC.
r

REFERENCES

Available online at www.bjbs-online.org

BJBS

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MAY 2010

Oedema is the generalised


or localised increase in fluid
in interstitial tissues and is
attributed to mechanisms
involving sodium retention
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Maria Angela Forneas LIBMS
(angela.forneas@royalsurrey.nhs.uk) is a
biomedical scientist at the Royal Surrey
County Hospital, Guildford, Surrey GU2 7XX.

Papers appearing
in Volume 67,
Number 1, 2010
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of penicillin-susceptible and penicillin-resistant isolates of
Streptococcus pneumoniae in transport medium
Staphylococcus aureus nasal and hand carriage among students
from a Portuguese health school
Clinical and epidemiological characterisation of Burkitts
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Teaching Hospital, Ghana
Nitric oxide scavenging by food: implications for in vivo
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Protective effects of Nigella sativa oil and thymoquinone
against toxicity induced by the anticancer drug
cyclophosphamide
Phenotypic diversity of Campylobacter isolates from sporadic
cases of acute human gastroenteritis in Northern Ireland
Do equine strains of Pseudomonas aeruginosa carry the
Liverpool epidemic strain markers relevant to patients with
cystic fibrosis?
Molecular characterisation and diagnosis of Hb J-Taichung
(129[H7]AlaAsp) in a Taiwanese family subject
Infective endocarditis: changing aetiology of disease

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