Physiology
Regulation of fluid and
electrolyte balance
Jonathan D Louden
Abstract
The three fluid compartments of the body are interdependent. Their home-
ostasis relies on systems that regulate water balance and, as the princi-
pal extracellular solute, sodium balance. Maintenance of plasma volume
is essential for adequate tissue perfusion. Regulation of plasma osmolal-
ity, which is determined primarily by the serum sodium concentration, is
essential for the preservation of normal cell volume and function. The
importance of osmoregulation is best illustrated by the consequences of
a rapid fall or rise in serum osmolality, which can cause permanent neu-
rological damage and death through shrinkage or swelling of cells. It is
tempting to attribute control of plasma sodium concentration to sodium
balance, but there is no direct relationship ­between plasma sodium and
renal sodium excretion. Osmolality and volume are, therefore, regulated
by separate mechanisms. It is important to recognize that osmoregula-
tion occurs through changes in water balance, whereas volume regula-
tion is principally determined by changes in sodium excretion.
Keywords aldosterone; anti-diuretic hormone; atrial natriuretic peptide;
baroreceptors; osmolality; renin–angiotensin system; sodium balance;
water balance
Distribution of body water and sodium
To address the regulation of water and electrolyte balance, the
processes which govern the distribution of body water must
be considered. Body water constitutes approximately 60% of
total body weight in adults (a higher proportion in infants and
­children).
Movement of water between compartments: osmotic pressure
The concept of osmotic pressure can be explained by considering
two water-containing compartments, separated by a membrane
that is permeable to water but not to solute. Random motion
of water molecules results in movement across the membrane
(­diffusion). The presence of a solute on one side of the mem-
brane decreases random movement on that side owing to inter-
molecular forces. There is, therefore, overall movement of water
molecules into the solute-containing compartment (osmosis).
This process will continue, thereby increasing the hydrostatic
pressure within this compartment. When a steady state has been
Jonathan D Louden FRCP is a Consultant Nephrologist at the James Cook
University Hospital in Middlesbrough, UK. Conflicts of interest: none
declared.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 10:6
Learning objectives
After reading this article, you should be able to:
• recognise the role of water balance in regulation of serum
sodium concentration and osmolality
• appreciate the concept of effective circulating volume
• understand the mechanisms regulating sodium excretion and,
thereby, extracellular volume.
reached, the hydrostatic pressure within the solute-containing
compartment opposing the osmotic movement of water into that
compartment is known as the osmotic pressure of the ­solution.
Osmotically active solutes: effective and ineffective osmoles
The osmotic pressure generated by a solute is proportional to the
number of particles in solution, rather than the molecular weight
or valency. A solute is able to generate an osmotic pressure across
a membrane only if it is unable to cross that membrane.
Sodium and potassium are unable to equilibrate across cell
membranes owing to the Na+/K+-ATPase; therefore, they gen-
erate an osmotic pressure within the extracellular and intracel-
lular compartments respectively. They are examples of effective
osmoles.
Lipid-soluble molecules (e.g. urea) that can pass freely across
cell membranes are unable to generate an osmotic pressure. Such
molecules are known as ineffective osmoles.
Calculated and measured osmolality
In normal circumstances, plasma osmolality can be derived from
the concentrations of the three principal solutes as follows:
Plasma osmolality  =  2  ×  [Na+]  +  [glucose]  +  [urea]
Sodium concentration is multiplied by a factor of 2 to account
for anions.
Measured osmolality incorporates all solutes within the sample
that are capable of generating an osmotic force.
A discrepancy between the calculated and measured osmolalities
indicates the presence of a solute that is not routinely measured
(e.g. ethanol) or an unusually low proportion of plasma water
(e.g. lipaemic blood).
Effective osmolality
The osmolality of a solution is determined by the number of
molecules of osmotically active solute contained in that solution.
Sodium is the major extracellular cation. It is accompanied by
anions, principally chloride and bicarbonate.
Urea is an ineffective osmole and glucose is present at a much
lower concentration than sodium, except during severe hyper­
glycaemia. Therefore,
Effective osmolality  =  2  ×  [Na+]
Fluid compartments
Body water is distributed between two principal compartments:
intracellular and extracellular. Water is able to pass freely between
these compartments and the distribution of water is therefore
determined by osmotic pressure. The extracellular compartment
is subdivided into the interstitial fluid and the intravascular com-
partment (plasma).
279 © 2009 Elsevier Ltd. All rights reserved.
 Physiology

Each of the compartments contains a principal solute, which
is confined largely to that compartment and therefore acts as
the main osmotic agent. Potassium is the principal intracellular
solute and sodium the principal extracellular solute, owing to the
Na+/K+-ATPase in the cell membrane (Figure 1).
However, sodium is able to move freely across the capillary
walls. Sodium is, therefore, not an effective osmole with respect to
the distribution of water between the interstitial and intra­­vascular
compartments, which is determined by different factors.
Hydrostatic pressure within the leaky capillaries is opposed
by the effect of the plasma proteins. Plasma proteins are too large
to cross the capillary wall freely and act to retain water within
the intravascular compartment. The force that they generate bal-
ances capillary hydrostatic pressure and is known as the plasma
oncotic pressure.
Osmoregulation
Osmoregulation can be considered an essential mechanism to
maintain cell volume. This is well illustrated by considering the
consequences of an abrupt rise or an abrupt fall in plasma osmo-
lality. Rapid onset of severe hyponatraemia causes water to move
into cells, which swell. Within the confined space of the skull,
uncontrolled cerebral oedema results in seizures, coma and death.
Conversely, rapid development of severe hyper­natraemia causes
cells to shrink with potential for permanent neurological damage.
Although plasma osmolality is determined principally by
plasma sodium concentration, osmolality is regulated by changes
in water balance that bring about dilution or concentration of
solute. It is not regulated by changes in sodium excretion.
The mechanism of osmoregulation involves osmoreceptors in
the hypothalamus that control the release of anti-diuretic hor-
mone (ADH) and stimulate thirst. Renal water retention, under
the influence of ADH, and increased water intake lower the
­elevated osmolality towards normal.
Volume regulation
In contrast, volume regulation is brought about largely through
changes in sodium excretion. As the principal solute within the
extracellular compartment, sodium balance is intimately related
to body water content.
Volume regulation is an essential requirement to maintain
perfusion of tissues. Although osmoregulation is managed by a
single sensory arm, volume regulation is governed by multiple
receptors reflecting the potential for variation in perfusion of dif-
ferent regions of the vasculature.
The differences between osmoregulation and volume regula-
tion are emphasized by considering manoeuvres that would per-
turb the homeostasis of the three fluid compartments.
Consider infusion of hypertonic saline. Extracellular volume
increases and, because sodium remains extracellular, the osmo-
lality of the extracellular fluid increases. Osmoregulation results
in water retention through the action of ADH, returning osmolal-
ity to normal but further expanding the extracellular volume.
It can be seen that there is no direct relationship between
plasma sodium concentration (which is the principal determi-
nant of osmolality) and plasma volume. Additional mechanisms
are, therefore, needed to correct the volume excess, through
increased excretion of sodium and water.
The differences between osmoregulation and volume regula-
tion are listed in Table 1.
Anti-diuretic hormone
ADH is a nine-amino-acid peptide that increases the permeability
of the renal collecting ducts to water. Water is thus reabsorbed
without salt, producing a more concentrated urine. ADH is the prin-
cipal regulator of so-called free water excretion, with urine osmo-
lality ranging between extremes of approximately 50 mOsmol/kg
and 1200 mOsmol/kg under the control of ADH.
ADH is produced in the supraoptic and paraventricular nuclei
of the hypothalamus, and then migrates along the axons of these
neurones into the posterior pituitary (Figure 2). The human form
of ADH is known as arginine vasopressin (AVP), reflecting its
pressor effect.
Osmoregulation and volume regulation contrasted
Osmoregulation Volume regulation

Stimulus Plasma osmolality Effective circulating

Fluid compartments and the osmotic factors governing volume (perfusion)
the distribution of body water Sensory system Hypothalamic Baroreceptors
osmoreceptor cells and macula densa
H 2O H 2O H 2O (altered cell volume)
Effector ADH and thirst Sympathetic
mechanism nervous system
Renin–angiotensin
K+
Na+ Plasma system
protein ADH
Natriuretic peptides
Na+ Pressure natriuresis
Na+/K+-ATPase K+ Outcome Changes in water Changes in sodium
balance excretion

Intracellular fluid Interstitial fluid Plasma ADH, anti-diuretic hormone.

Figure 1 Table 1

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 Physiology

Volume receptors for ADH release require substantial deple-

Osmoreceptors and the hypothalamo-pituitary tract, tion of the extracellular compartment, of approximately 10%.2
which regulates secretion of anti-diuretic hormone Such changes in volume will also stimulate the renin–angioten-
sin system (RAS; see below).
Third ventricle
Volume regulation overrides osmoregulation. The hypo­
Paraventricular volaemic stimulus to ADH release is less sensitive than the
neurones osmotic stimulus because it requires a substantial fall in effec-
tive circulating volume (for a definition of effective circulating
Supraoptic
neurone
volume, see later). However, hypovolaemia can generate much
higher ADH levels.
Conditions characterized by a low effective circulating vol-
Optic chiasm ume can lead to water retention in the face of evolving hypo­
natraemia, as seen in cardiac failure and hepatic cirrhosis. In this
Anterior situation, the cells usually have time to adapt to slow develop-
hypophyseal ment of hyponatraemia, by release of osmolytes, thereby avoid-
artery
ing the neurological sequelae of a rapid fall in osmolality as
Portal venous
system
described above.

Anterior pituitary Other factors controlling anti-diuretic hormone release

Systemic venous Nausea causes brief but potent stimulation of ADH release. Hypo-
drainage glycaemia and angiotensin II also stimulate ADH release, but it
Posterior pituitary is not clear whether this has a physiological role. Endo­genous
opiates, high doses of morphine and drugs including chlorprop-
Anti-diuretic hormone, synthesized in the supraoptic (osmoregulatory)
amide stimulate release of ADH, whereas ethanol inhibits it.
and paraventricular (volume-sensitive) nuclei adjacent to the third ventricle,
is transported along axons and secreted in the posterior pituitary, the
portal venous system and into the cerebrospinal fluid

Changes in plasma anti-diuretic hormone

Figure 2
a 10
Control of anti-diuretic hormone release: osmoreceptors and
volume receptors
Plasma ADH (pg/ml)

ADH secretion is controlled by both hyperosmolality and hypo-

volaemia.1 The hypovolaemic stimulus to ADH and thirst is the 6

only effector mechanism common to both osmoregulation and

4
volume regulation. Apart from this, osmolality and volume are
regulated through entirely separate mechanisms.
2

Osmoreceptors 0
The osmoreceptors, located in the supraoptic nuclei of the hypo- 270 280 290 300 310
thalamus, are stimulated by the presence of an osmotic gradient Plasma osmolality (mosmol/kg)
between their cytoplasm and the perfusing plasma, so that water b
40
transits out of or into the cells as serum osmolality rises or falls.
Because sodium is the major solute within the extracellular
Plasma ADH (pg/ml)

compartment, plasma sodium concentration is the principal 30

osmotic factor controlling ADH secretion.

20
Volume receptors controlling anti-diuretic hormone release
Reduced stretch in the carotid sinus baroreceptors feeds back to
10
the vasomotor centre in the brainstem. The signal is relayed to
the paraventricular nuclei of the hypothalamus, resulting in ADH
release. This regulatory system can be regarded as a means of 0
0 5 10 15 20
preserving perfusion of the brain.
Blood volume deficit (%)
Sensitivity of osmoreceptors and volume receptors
Changes in plasma anti-diuretic hormone (ADH) with increasing plasma
The osmotic stimulus for ADH release is much more sensitive osmolality (a) and volume depletion (b). ADH rises abruptly following a 5%
than the volume-directed stimulus. Osmoregulation is triggered increase in osmolality. The ADH response to volume depletion is more
by changes in osmolality of only 1%. ADH is undetectable when pronounced but requires a 10–15% volume deficit
serum osmolality is 280 mOsmol/kg H2O, but rises sharply as
serum osmolality exceeds 295 mOsmol/kg H2O (Figure 3). Figure 3

ANAESTHESIA AND INTENSIVE CARE MEDICINE 10:6 281 © 2009 Elsevier Ltd. All rights reserved.
 Physiology
Actions of anti-diuretic hormone
ADH acts on the principal cells of the renal collecting tubules to
increase water permeability. Several types of ADH receptor have
been characterized. Activation of V2 receptors on the ­basolateral
membrane of principal cells triggers cyclic adenosine mono-
phosphate, causing activation of a protein kinase and insertion
of water channels (aquaporin-CD) into the luminal membrane,
which is otherwise impermeable to water. In the absence of
ADH, these channels are cleared by endocytosis.
These events concentrate the urine, conserving water and
returning osmolality to normal. Consumption of a water load will
bring about the converse, with a reduction in ADH release and
excretion of hypotonic urine, allowing excess water to be cleared
and returning plasma osmolality to normal.
It is not surprising that the osmoreceptors controlling ADH
release are highly sensitive; this is because maintenance of plasma
osmolality within a small range is essential to preserve cell vol-
ume and thus normal function. The system of osmo­­regulation is
highly responsive, a significant water load being largely excreted
within a few hours.
Other actions of anti-diuretic hormone
V2 receptor activation also stimulates renal synthesis of prosta-
glandin E2. This tends to oppose the actions of ADH on the prin-
cipal cells of the distal nephron and might constitute a negative
feedback loop.
V1a receptors have a pressor effect on vascular smooth ­muscle
cells, through activation of phosphoinositol. Activation of V1a
receptors also promotes release of procoagulant factors and
enhances platelet adhesiveness. The actions of V1b receptors
within the hypothalamus is currently unknown.
ADH stimulates potassium excretion in the distal nephron.
This is discussed below.
Thirst
Like ADH release, thirst can be stimulated independently by
either hyperosmolality or hypovolaemia. Increased water intake
driven by thirst, together with water preservation driven by ADH
release, returns elevated osmolality to normal or, if it is volume
driven, helps to correct volume depletion.
The response to ADH can take several hours to restore nor-
mality. It is, therefore, appropriate that thirst tends to be satisfied
quickly by consumption of water but recurs in bursts. If this were
not the case, the thirst stimulus would persist for some hours,
resulting in excess water consumption.
Water intake in the developed world is governed largely by social
factors and habit rather than being driven by thirst. Fortunately,
the capacity to excrete hypotonic urine is so great that it is very dif-
ficult to bring about hyponatraemia from water ­consumption.
Regulation of salt balance and effective circulating volume
Sodium is the principal solute acting to preserve water within the
extracellular compartment. Total body water and ­ extracellular
volume are dependent on total body sodium. Consequently,
maintenance of sodium balance is central to volume regulation.
Changes in sodium balance lead to changes in plasma volume
and are sensed principally through changes in the ­circulation. It is,
ANAESTHESIA AND INTENSIVE CARE MEDICINE 10:6
therefore, not surprising that the systems regulating sodium excre-
tion are closely integrated with those regulating blood ­pressure.
The systems regulating salt balance, and thus volume, are essen-
tially aimed at preservation of tissue perfusion, which is sensed as the
effective circulating volume (see below). The potential for regional
variation in perfusion, for example with a change in posture, and the
primacy of certain organs, such as the brain, accounts for the pres-
ence of multiple volume receptors in various parts of the circulation.
In examining the systems of salt and volume regulation, it is helpful
to consider the concept of the effective circulating volume.
Effective circulating volume
The effective circulating volume refers to the portion of the intra-
vascular volume that is within the arterial system. This param-
eter effectively represents the volume which is perfusing the
tissues. It cannot be measured directly, but changes are sensed
by multiple volume receptors distributed through the arterial
tree. In normal circumstances, the arterial system accounts for
approximately 20% of the intravascular volume.
Volume receptors
The major volume receptors can be divided into extra-renal and
intra-renal groups. Extra-renal baroreceptors are stretch recep-
tors located in the carotid sinuses, the aortic arch and the atria.
The renal volume receptors comprise baroreceptors in the juxta­
glomerular apparatus of the afferent arteriole and the macula
densa in the early part of the distal tubule which sense a fall in
distal delivery of sodium chloride.
Baroreceptors do not sense volume directly; rather, they sense
pressure, through stretch. Pressure is directly related to volume
in most circumstances. Reduced stretch stimulates the effector
response. Extra-renal receptors signal to the vasomotor centre in
the brainstem, increasing sympathetic nervous system activity and
thereby the RAS. The renal receptors influence the RAS directly.
The results of studies of transplanted patients with renal or
cardiac denervation, who are, nevertheless, able to maintain nor-
mal salt and water balance, have shown that these mechanisms
are not interdependent and that no single receptor is dominant.
In some disease states the relationship between effective circu-
lating volume and extracellular volume breaks down. These con-
ditions can promote water retention at the cost of osmoregulation
through the hypovolaemic stimulus to ADH as discussed above.
Cardiac failure
Reduced cardiac output associated with cardiac failure elicits a
response to a perceived reduction in effective circulating volume,
through carotid, aortic and afferent arteriolar baroreceptors. RAS
activation and ADH release result in salt and water retention with
the objective of restoring a perceived volume deficit, although
the result is salt and water overload and sometimes hypona-
traemia (dilutional effect).3 This response can be beneficial
through increased cardiac stretch, which enhances contractility
and thereby increases stroke volume (the Frank–Starling law);
ultimately, however, as ventricular dilation increases, cardiac
output falls (decompensation).
Hepatic cirrhosis
Cirrhosis can be associated with a perceived reduction in effec-
tive circulating volume owing to dilation of the voluminous
282 © 2009 Elsevier Ltd. All rights reserved.
 Physiology
s­ planchnic circulation. Extracellular volume is expanded by asci-
tes and cardiac output can even be increased because of arterio-
venous fistulas (represented by spider naevi in the skin). The
responses to the perceived reduction in effective circulating vol-
ume tend to increase the already expanded extracellular volume,
exacerbating ascites and generating hyponatraemia through ADH
(Table 2).
Renin–angiotensin system
The RAS has several functions, but is principally concerned with
maintenance of pressure and volume. The RAS plays a central
role in regulation of salt excretion and thus in maintenance of
extracellular fluid volume.
Renin is a proteolytic enzyme that is released from the juxta­
glomerular cells in afferent arterioles of the kidney. It cleaves
angiotensinogen to produce the decapeptide angiotensin I. This
is converted enzymatically to an octapeptide, angiotensin II,
primarily by angiotensin-converting enzyme in the pulmonary
capillaries.
Angiotensin II has a pressor effect and stimulates sodium
retention, both directly and through aldosterone secretion. It also
stimulates thirst and ADH release.
Control of renin secretion
Salt intake is the principal regulator of renin secretion. Dietary
salt content varies considerably and, to maintain sodium bal-
ance, excretion must be capable of adjustment to match intake.
Salt loading expands the extracellular volume, decreasing
renin secretion, whereas salt deprivation causes contraction of
the extracellular volume, stimulating renin secretion. The con­
sequent changes in angiotensin II and aldosterone activity result
in sodium excretion or retention respectively, correcting the
extracellular volume.
Renin secretion is also stimulated whenever effective circulat-
ing volume falls, and is suppressed when it is restored. The sen-
sory limb of these feedback loops comprises direct ­ stimulation
by intra-renal baroreceptors and the macula densa of the dis-
tal tubule and indirect stimulation by extra-renal baroreceptors.
These relay through the vasomotor centre in the brainstem to
the sympathetic nervous system. Increased sympathetic outflow
stimulates renin secretion.
Actions of angiotensin II
Angiotensin II has two principal effects: vasoconstriction of arte-
rioles and sodium retention. Both actions tend to correct hypo-
volaemia and hypotension, supporting tissue perfusion. These
effects are mediated by specific angiotensin II receptors on the
surface of target cells.
Relationships between effective circulating volume and extracellular volume in disease states
Effective circulating volume Extracellular volume
Severe volume depletion ↓ ↓
Cardiac failure ↓ ↑
Hepatic cirrhosis ↓ ↑
Table 2
ANAESTHESIA AND INTENSIVE CARE MEDICINE 10:6 283
Sodium retention is achieved through two mechanisms: a
direct action of angiotensin II on the proximal tubule and an indi-
rect action by stimulation of adrenocortical aldosterone synthesis
and secretion. Aldosterone acts on the distal nephron to promote
sodium reabsorption (see below).
Aldosterone
Aldosterone, which is synthesized in the zona glomerulosa of
the adrenal cortex, is a steroid hormone with mineralocorticoid
activity. Unlike the other adrenal cortical hormones, aldosterone
is not regulated by adrenocorticotropic hormone, but by the RAS
and also by plasma potassium.
Control of aldosterone secretion
Aldosterone plays a central role in salt balance and potassium
excretion. Volume depletion results in aldosterone secretion,
mediated by the RAS; angiotensin II promotes synthesis and
secretion of aldosterone in the adrenal zona glomerulosa.
The distal nephron regulates renal potassium excretion under
the control of aldosterone. As plasma potassium concentration
increases, aldosterone secretion is stimulated in a linear fashion.
Potassium excretion is increased, correcting the plasma potas-
sium concentration.
Actions of aldosterone
Aldosterone acts on the principal cells of the cortical collecting
tubule in the distal nephron. It increases the permeability of the
luminal membrane to sodium, thereby increasing passive diffusion
of sodium into the cells. Electroneutrality is preserved either by
passive reabsorption of chloride or by secretion of potassium into
the tubular lumen. Activity of the basolateral Na+/K+-ATPase is
increased, promoting the passage of sodium into the circulation.
Like other steroid hormones, aldosterone enters the cytosol
of its target cell, where it attaches to its receptor then enters
the nucleus. Transcription and translation of RNA produces
new sodium channels, which are inserted into the luminal
­membrane.
Aldosterone also acts on the intercalated cells of the cortical
collecting tubule to increase acid excretion through stimulation
of H+-ATPase.
See Figure 4 for a summary of the neural and humoral mecha-
nisms discussed so far in the regulation of sodium and water
balance.
Natriuretic peptides
Sodium loading results in an appropriate increase in sodium
excretion. Experiments inhibiting the effects of salt loading on
Plasma volume Cardiac output
↓ ↓
↑ ↓
↑ ↑/unchanged
© 2009 Elsevier Ltd. All rights reserved.
 Physiology

glomerular filtration rate (GFR) and aldosterone secretion indi-
cate the presence of additional factors promoting sodium excre-
tion. The physiological role of the various natriuretic peptides is
not known.
Atrial natriuretic peptide
This is a polypeptide hormone consisting of 28 amino acids
that is synthesized in myocardial cells by cleavage of a precur-
sor (pro-ANP). Most atrial natriuretic peptide (ANP)-producing
cells are within the atria, responding to an increase in stretch.
The ventricles and vascular smooth muscle cells have also been
shown to produce ANP.
Brain natriuretic peptide: this seems to have similar proper-
ties to ANP. It might be responsible for the cerebral salt wasting
sometimes seen after severe neurological damage.
Pressure natriuresis
Changes in blood volume directly alter cardiac output and blood
pressure. This results in increased renal excretion of sodium
and water, independent of neural and humoral mechanisms.
Pressure natriuresis might explain why patients with excessive
­inappropriate aldosterone secretion (primary hyperaldosteron-
ism) are not usually severely volume ­overloaded.

Actions of atrial natriuretic peptide

The physiological role of ANP is not well understood. It causes vaso-
dilation and increases urinary excretion of sodium and water. Experi­
mental evidence indicates that ANP effects an increase in sodium
and water excretion by increasing GFR and decreasing sodium
absorption in both the proximal and distal nephron ­segments.
ANP seems to inhibit renin release and might therefore play
a part in the suppression of the renin–angiotensin system during
volume expansion.
Other natriuretic peptides
Urodilatin: this is cleaved from pro-ANP and has ANP-like prop-
erties. It seems to act on the distal nephron and there is some
evidence that it might be more important than ANP.
The steady state
The discussions so far have dealt principally with responses of
the regulatory systems for water and salt balance to acute per-
turbations. These systems must also be able to accommodate
changes in salt intake. This is achieved by reaching a new steady
state.
An abrupt and maintained increase in sodium intake causes
extracellular volume to rise, owing to a rise in osmolality. This
stimulates ADH secretion and thirst; a fall in renin secretion and
aldosterone concentration and a rise in ANP ensue, stimulating
increased sodium excretion.
Assuming that sodium intake remains elevated, it will take
several days for sodium excretion to increase to the new level of

The humoral and neural mechanisms involved in regulation of water and sodium balance

Hyperosmolality Hypovolaemia
or 10% volume depletion

Vasomotor
centre
ADH
Paraventricular nuclei Baroreceptors (↓ stretch)
(osmoreceptors and Carotid Sympathetic outflow*
volume receptors) Aortic and cardiopulmonary
+ thirst
Afferent arteriolar

Macula densa
Increased water intake (↓ NaCl delivery)
+
Angiotensinogen
decreased water excretion Vasoconstriction Renin
Angiotensin I
ACE
Angiotensin II
Anti-diuretic hormone (ADH) is released in
response to increased osmolality or a Aldosterone
Sodium retention
marked fall in effective circulating volume.
Multiple receptors respond to alterations in
regional perfusion pressure to influence
excretion of sodium, maintaining
extracellular volume. *Increased sympathetic
outflow also causes: venoconstriction which
increases venous return; increased cardiac
contractility; increased heart rate

Figure 4

ANAESTHESIA AND INTENSIVE CARE MEDICINE 10:6 284 © 2009 Elsevier Ltd. All rights reserved.
 Physiology
intake. A new steady state is achieved, with expanded extracellu-
lar volume accompanied by equal sodium intake and excretion.
The converse occurs if sodium intake falls.
Volume expansion is the sensor for sodium intake and results
in increased sodium excretion. It is in proportion to the increase
in sodium intake.
The response to diuretics
The concept of the steady state is helpful in examining the actions
of diuretics and the timescale of the response. Diuretics decrease
sodium reabsorption, resulting in increased excretion of sodium
and water and a fall in extracellular volume.
This stimulates renin secretion, leading to an increase in circu-
lating aldosterone and sodium reabsorption in the distal nephron.
Thirst is also stimulated. A new steady state is achieved over the
course of several days, after which net salt and water loss ceases.
Renal potassium handling
Most filtered potassium is reabsorbed in the proximal tubule.
Only approximately 5% of the filtered load reaches the distal
nephron, but this is the principal site at which potassium excre-
tion is controlled.
Aldosterone has a major role in potassium balance, stimu-
lating potassium secretion from the luminal membrane of the
principal cells of the cortical collecting duct. ADH also stimulates
distal tubular potassium excretion.
Potassium excretion and distal tubular flow
Potassium excretion seems to be closely related to distal tubu-
lar flow, increasing with a rise in flow and decreasing as flow
falls. The mechanisms are not fully understood, but increased
flow, by removing luminal potassium more efficiently, would be
expected to promote further potassium secretion by maintenance
of a favourable electrochemical gradient.
Conversely, low distal flow and less efficient clearance of
secreted potassium within the lumen would be expected to
­produce a less favourable electrochemical gradient for continued
potassium secretion.
Physiological role of the relationship between distal flow and
potassium excretion
Volume expansion results in decreased activity of the RAS and a
decrease in aldosterone-driven potassium secretion, alongside an
increase in sodium and water excretion. This might be expected
to carry a risk of potassium accumulation.
Conversely, volume depletion stimulates RAS activity and
aldosterone in order to increase sodium and water retention,
but aldosterone-driven potassium secretion might be expected to
cause potassium depletion.
The relationship between distal flow and potassium excretion
counteracts these effects, thereby allowing aldosterone to regu-
late sodium excretion independently of potassium and maintain-
ing potassium balance.
Anti-diuretic hormone, distal flow and potassium excretion
Distal potassium excretion is stimulated by ADH. This is prob-
ably an important mechanism for avoidance of potassium
ANAESTHESIA AND INTENSIVE CARE MEDICINE 10:6
a­ ccumulation when distal flow is low as a result of ADH-driven
water reabsorption.
Magnesium balance
Bone is the main reservoir of magnesium, but there is almost no
exchange with circulating magnesium. Regulation of magnesium
balance is unusual in that no hormones influence magnesium
excretion. Daily intake is approximately 15 mmol, of which only
approximately 30% is absorbed. Because there is no appreciable
exchange with bone stores, balance is maintained by renal excre-
tion of the 5 mmol absorbed.
Unlike other electrolytes, filtered magnesium is reabsorbed
principally in the thick ascending limb of the loop of Henle, as
opposed to the proximal tubule. Magnesium transport in this
limb is believed to be by passive diffusion, dependent on sodium
and chloride reabsorption. Therapy with loop diuretics, by inhibi-
tion of sodium and chloride reabsorption, can therefore decrease
magnesium reabsorption, resulting in magnesium depletion.
Magnesium reabsorption in the ascending limb is also inhib-
ited by hypercalcaemia and is dependent on potassium secretion.
Binding of calcium to a receptor on the basolateral membrane
inhibits luminal potassium channels through a series of sec-
ondary messengers. Potassium secretion into the lumen of the
thick ascending limb provides a substrate for the Na–K–2Cl co-
transporter and provides an electrochemical gradient favouring
magnesium (and calcium) reabsorption. The requirement for
potassium secretion in order to reabsorb the greater part of the
filtered load of magnesium might explain the severe potassium
wasting that can occur in states of magnesium depletion.
Processing of magnesium in the distal nephron is incom-
pletely understood. Magnesium depletion can occur with ­thiazide
diuretic therapy and in Gitelman’s syndrome (owing to an abnor-
mality of the thiazide-sensitive co-transporter).
There seems to be no mechanism to protect against hyper­
magnesaemia, which occurs if intake is maintained in the face of
declining renal function. ◆
References
1 Leaf A, Mamby AR. An antidiuretic mechanism not regulated by
extracellular fluid tonicity. J Clin Invest 1952; 31: 60–71.
2 Dunn FL, Brennan TJ, Nelson AE, et al. The role of blood osmolality
and volume in regulating vasopressin secretion in the rat. J Clin Invest
1973; 52: 3212–9.
3 Mettauer B, Roleau J-L, Bichet D, et al. Sodium and water excretion
abnormalities in congestive heart failure. Ann Intern Med 1986;
105: 161–7.
Further reading
Rennke HG, Denker BM. Renal pathophysiology. Baltimore, MD:
Lippincott Williams & Wilkins, 1994.
Robertson GL. Regulation of vasopressin secretion. In: Seldin DW,
Giebisch G, eds. The kidney: physiology and pathophysiology,
2nd edn. New York: Raven Press, 1992: p. 1595–613.
Rose BD, Post TW. Clinical physiology of acid-base and electrolyte
disorders, 5th edn. New York: McGraw-Hill, 2001.
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