PHYSIOLOGY
Regulation of fluid and
electrolyte balance
Jonathan D Louden
Abstract
The three fluid compartments of the body are interdependent. Their
homeostasis relies on systems that regulate water balance and, as the prin-
cipal extracellular solute, sodium balance. Maintenance of plasma volume
is essential for adequate tissue perfusion. Regulation of plasma osmolality,
which is determined primarily by the serum sodium concentration, is essen-
tial 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 neurological 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 osmoregulation occurs through changes
in water balance, whereas volume regulation is principally determined by
changes in sodium excretion.
Keywords Aldosterone; anti-diuretic hormone; atrial natriuretic peptide;
baroreceptors; osmolality; renineangiotensin 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
membrane decreases random movement on that side owing to
intermolecular 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 reached, the hydrostatic pressure within the
solute-containing compartment opposing the osmotic movement
of water into that compartment is known as the osmotic pres-
sure of the solution.
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 13:7
Learning objectives
After reading this article, you should be able to:
C recognise the role of water balance in regulation of serum
sodium concentration and osmolality
C appreciate the concept of effective circulating volume
C understand the mechanisms regulating sodium excretion and,
thereby, extracellular volume
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 Naþ/Kþ-adenosine triphosphatase
(ATPase); therefore, they generate an osmotic pressure within
the extracellular and intracellular 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 ¼ 2  ½Naþ  þ ½glucose þ ½urea
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 osmo-
lalities 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 ¼ 2  ½Naþ 
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 com-
302 Ó 2012 Elsevier Ltd. All rights reserved.
 PHYSIOLOGY
partment is subdivided into the interstitial fluid and the intra-
vascular compartment (plasma).
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
Naþ/Kþ-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
balances 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
osmolality. 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 hyper-
natraemia 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
hormone (ADH) and stimulate thirst. Renal water retention,
under the influence of ADH, and increased water intake lower
the elevated osmolality towards normal.
Fluid compartments and the osmotic factors governing
the distribution of body water
H 2O H 2O H 2O
K+
Na+ Plasma
protein
Na+
Na+/K +-ATPase K+
Intracellular fluid Interstitial fluid Plasma
ATPase, adenosine triphosphatase.
Figure 1
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:7
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
different regions of the vasculature.
The differences between osmoregulation and volume regula-
tion are emphasized by considering manoeuvres that would
perturb 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 osmo-
lality 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
principal regulator of so-called free water excretion, with urine
osmolality ranging between extremes of approximately 50 mOs-
mol/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 neu-
rones 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 volume
(perfusion)
Sensory Hypothalamic Baroreceptors and macula
system osmoreceptor cells densa (altered cell volume)
Effector ADH and thirst Sympathetic nervous system
mechanism Renineangiotensin system
ADH
Natriuretic peptides
Pressure natriuresis
Outcome Changes in water Changes in sodium excretion
balance
ADH, anti-diuretic hormone.
Table 1
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 PHYSIOLOGY

Osmoreceptors and the hypothalamo-pituitary tract, Changes in plasma anti-diuretic hormone

which regulates secretion of anti-diuretic hormone a 10

Third ventricle

Plasma ADH (pg/ml)

8
Paraventricular
neurones 6

Supraoptic
4
neurone

2
Optic chiasm
0

Anterior 270 280 290 300 310

hypophyseal Plasma osmolality (mosmol/kg)
artery b
40
Portal venous
system

Plasma ADH (pg/ml)

30
Anterior pituitary
Systemic venous
drainage 20

Posterior pituitary
10
Anti-diuretic hormone, synthesized in the supraoptic (osmoregulatory)
and paraventricular (volume-sensitive) nuclei adjacent to the third ventricle,
is transported along axons and secreted in the posterior pituitary, the 0
portal venous system and into the cerebrospinal fluid 0 5 10 15 20

Blood volume deficit (%)

Figure 2
Control of anti-diuretic hormone release: osmoreceptors and
volume receptors
ADH secretion is controlled by both hyperosmolality and hypo-
volaemia.1 The hypovolaemic stimulus to ADH and thirst is the
only effector mechanism common to both osmoregulation and
volume regulation. Apart from this, osmolality and volume are
regulated through entirely separate mechanisms.
Osmoreceptors
The osmoreceptors, located in the supraoptic nuclei of the hypo-
thalamus, are stimulated by the presence of an osmotic gradient
between their cytoplasm and the perfusing plasma, so that water
transits out of or into the cells as serum osmolality rises or falls.
Because sodium is the major solute within the extracellular
compartment, plasma sodium concentration is the principal
osmotic factor controlling ADH secretion.
Volume receptors controlling anti-diuretic hormone release
Reduced stretch in the carotid sinus baroreceptors feeds back to
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
preserving perfusion of the brain.
Sensitivity of osmoreceptors and volume receptors
The osmotic stimulus for ADH release is much more sensitive
than the volume-directed stimulus. Osmoregulation is triggered
by changes in osmolality of only 1%. ADH is undetectable when
serum osmolality is 280 mOsmol/kg H2O, but rises sharply as
serum osmolality exceeds 295 mOsmol/kg H2O (Figure 3).
Changes in plasma anti-diuretic hormone (ADH) with increasing plasma
osmolality (a) and volume depletion (b). ADH rises abruptly following a 5%
increase in osmolality. The ADH response to volume depletion is more
pronounced but requires a 10–15% volume deficit
Figure 3
Volume receptors for ADH release require substantial depletion
of the extracellular compartment, of approximately 10%.2 Such
changes in volume will also stimulate the renineangiotensin
system (RAS; see below).
Volume regulation overrides osmoregulation. The hypo-
volaemic stimulus to ADH release is less sensitive than the
osmotic stimulus because it requires a substantial fall in effective
circulating volume (for a definition of effective circulating
volume, see later). However, hypovolaemia can generate much
higher ADH levels.
Conditions characterized by a low effective circulating volume
can lead to water retention in the face of evolving hyponatraemia, as
seen in cardiac failure and hepatic cirrhosis. In this situation, the
cells usually have time to adapt to slow development of hypona-
traemia, by release of osmolytes, thereby avoiding the neurological
sequelae of a rapid fall in osmolality as described above.
Other factors controlling anti-diuretic hormone release
Nausea causes brief but potent stimulation of ADH release.
Hypoglycaemia and angiotensin II also stimulate ADH release,
but it is not clear whether this has a physiological role. Endog-
enous opiates, high doses of morphine and drugs including
chlorpropamide stimulate release of ADH, whereas ethanol
inhibits it.

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 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 volume and thus normal function. The system of osmoreg-
ulation 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
principal 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
normality. 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 difficult 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 13:7
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
essentially 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 presence 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
intravascular volume that is within the arterial system. This
parameter 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 jux-
taglomerular 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
normal salt and water balance, have shown that these mecha-
nisms are not interdependent and that no single receptor is
dominant.
In some disease states the relationship between effective
circulating volume and extracellular volume breaks down. These
conditions can promote water retention at the cost of osmoreg-
ulation 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 hyponatraemia
(dilutional effect).3 This response can be beneficial through
increased cardiac stretch, which enhances contractility and
thereby increases stroke volume (the FrankeStarling law); ulti-
mately, however, as ventricular dilation increases, cardiac output
falls (decompensation).
305 Ó 2012 Elsevier Ltd. All rights reserved.
 PHYSIOLOGY
Hepatic cirrhosis
Cirrhosis can be associated with a perceived reduction in effec-
tive circulating volume owing to dilation of the voluminous
splanchnic circulation. Extracellular volume is expanded by
ascites and cardiac output can even be increased because of
arteriovenous fistulas (represented by spider naevi in the skin).
The responses to the perceived reduction in effective circulating
volume tend to increase the already expanded extracellular
volume, exacerbating ascites and generating hyponatraemia
through ADH (Table 2).
Renineangiotensin 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 jux-
taglomerular 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
balance, 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
consequent 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 circu-
lating volume falls, and is suppressed when it is restored. The
sensory limb of these feedback loops comprises direct stimula-
tion by intra-renal baroreceptors and the macula densa of the
distal tubule and indirect stimulation by extra-renal barorecep-
tors. These relay through the vasomotor centre in the brainstem
Relationships between effective circulating volume and
extracellular volume in disease states
Effective Extracellular Plasma Cardiac
circulating volume volume output
volume
Severe volume Y Y Y Y
depletion
Cardiac failure Y [ [ Y
Hepatic cirrhosis Y [ [ [/unchanged
Table 2
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:7
to the sympathetic nervous system. Increased sympathetic
outflow stimulates renin secretion.
Actions of angiotensin II
Angiotensin II has two principal effects: vasoconstriction of
arterioles and sodium retention. Both actions tend to correct
hypovolaemia and hypotension, supporting tissue perfusion.
These effects are mediated by specific angiotensin II receptors on
the surface of target cells.
Sodium retention is achieved through two mechanisms:
a direct action of angiotensin II on the proximal tubule and an
indirect 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 diffu-
sion 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 Naþ/Kþ-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 Hþ-ATPase.
See Figure 4 for a summary of the neural and humoral
mechanisms 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
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.
306 Ó 2012 Elsevier Ltd. All rights reserved.
 PHYSIOLOGY

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

Atrial natriuretic peptide Pressure natriuresis

This is a polypeptide hormone consisting of 28 amino acids that
is synthesized in myocardial cells by cleavage of a precursor
(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.
Actions of atrial natriuretic peptide
The physiological role of ANP is not well understood. It causes
vasodilation and increases urinary excretion of sodium and
water. Experimental 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 renineangiotensin system during
volume expansion.
Other natriuretic peptides
Urodilatin: this is cleaved from pro-ANP and has ANP-like
properties. It seems to act on the distal nephron and there is
some evidence that it might be more important than ANP.
Brain natriuretic peptide: this seems to have similar properties
to ANP. It might be responsible for the cerebral salt wasting
sometimes seen after severe neurological damage.
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 inappro-
priate aldosterone secretion (primary hyperaldosteronism) are
not usually severely volume overloaded.
The steady state
The discussions so far have dealt principally with responses of the
regulatory systems for water and salt balance to acute perturba-
tions. 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
intake. A new steady state is achieved, with expanded extracel-
lular 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.

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 PHYSIOLOGY
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
circulating 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
excretion 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 tubular
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 main-
taining 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 accu-
mulation when distal flow is low as a result of ADH-driven water
reabsorption.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:7
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
excretion 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 inhibition
of sodium and chloride reabsorption, can therefore decrease
magnesium reabsorption, resulting in magnesium depletion.
Magnesium reabsorption in the ascending limb is also
inhibited 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 secondary messengers. Potassium secretion into the lumen of
the thick ascending limb provides a substrate for the NaeKe2Cl
co-transporter and provides an electrochemical gradient favour-
ing 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 thia-
zide diuretic therapy and in Gitelman’s syndrome (owing to an
abnormality 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. A
REFERENCES
1 Leaf A, Mamby AR. An antidiuretic mechanism not regulated by
extracellular fluid tonicity. J Clin Invest 1952; 31: 60e71.
2 Dunn FL, Brennan TJ, Nelson AE, et al. The role of blood osmolality and
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3 Mettauer B, Roleau J-L, Bichet D, et al. Sodium and water excretion
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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; 1595e1613.
Rose BD, Post TW. Clinical physiology of acid-base and electrolyte
disorders. 5th edn. New York: McGraw-Hill, 2001.
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