General Principles of Disorders of Water Balance (Hyponatremia and Hypernatremia) and Sodium Balance (Hypovolemia and Edema)

General principles of disorders of water balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and edema) 18/01/16
18/01/16 21:23
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General principles of disorders of water balance (hyponatremia and hypernatremia) and sodium balance
(hypovolemia and edema)
Author Section Editor Deputy Editor

Richard H Sterns, MD Michael Emmett, MD John P Forman, MD, MSc
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2015. | This topic last updated: Nov 05, 2014.
INTRODUCTION — Disorders of water balance and sodium balance are common, but the pathophysiology is frequently
misunderstood. As an example, the plasma sodium concentration is regulated by changes in water intake and excretion,
not by changes in sodium balance. As will be described in the following sections, hyponatremia is primarily due to the
intake of water that cannot be excreted, hypernatremia is primarily due to the loss of water that has not been replaced,
hypovolemia represents the loss of sodium and water, and edema is primarily due to sodium and water retention.
Understanding these basic principles is essential for appropriate diagnosis and treatment.
The general principles and disorders of water balance and sodium balance will be reviewed here. The causes and
evaluation of hyponatremia, hypernatremia, hypovolemia, and edema are presented separately. (See "Causes of
hyponatremia in adults" and "Diagnostic evaluation of adults with hyponatremia" and "Etiology and evaluation of
hypernatremia in adults" and "Etiology, clinical manifestations, and diagnosis of volume depletion in adults" and "Clinical
manifestations and diagnosis of edema in adults".)
DEFINITIONS — The following terms are commonly used when discussing disorders of water and sodium balance.
Understanding what these terms represent is essential for appropriate diagnosis and treatment.
Total body water — The total body water (TBW) as a percentage of lean body weight varies with age. Approximate
normal values are 80 percent in premature infants, 70 to 75 percent in term infants, 65 to 70 percent in toddlers, and 60
percent after puberty (figure 1) [1]. These values vary with the amount of fat since fat has a much lower water content
than muscle. Thus, the TBW as a percentage of total body weight is lower in individuals with more fat. As examples, the
TBW as a percentage of total body weight is lower in young adult females than in young adult males (50 versus 60
percent) and becomes progressively lower with increasing obesity or with loss of muscle mass.
The TBW has two main compartments: the extracellular fluid and the intracellular fluid, which are separated by the
cell membrane. The relative size of the two main compartments varies with age. The extracellular fluid component is
increased in infants and young children compared with older patients, which also contributes to the younger patients'
greater TBW percentage of lean body weight (figure 1). The cell membranes are freely permeable to water but not
electrolytes and therefore help to maintain the different solute composition of the two compartments: sodium salts in the
extracellular fluid, with chloride and bicarbonate being the major anions; and potassium salts in the intracellular fluid,
with large macromolecular organic phosphates being the main anions.
Extracellular fluid volume — The extracellular fluid component varies with age and is increased in infants and
young children (figure 1). In normal adults, the extracellular fluid (ECF) volume constitutes approximately 33 to 40
percent of the TBW [2,3] and is determined by the absolute amounts of sodium and water that are present in the ECF.
For the remainder of this discussion, we will use 33 percent (one-third) with the remaining 67 percent (two-thirds) of the
TBW being in the cells. (See 'Intracellular fluid volume' below.)
The ECF volume is regulated by alterations in urinary sodium excretion that are primarily mediated by variations in the
activity of the renin-angiotensin-aldosterone and sympathetic nervous systems, which promote sodium retention, and the
secretion of natriuretic peptides, which promote sodium excretion. (See 'Regulation of effective arterial blood volume'
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General principles of disorders of water balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and edema) 18/01/16 21:23
below.)
Effective arterial blood volume — The hormonal changes that regulate the ECF volume are mediated by
sensors in the renal afferent glomerular arterioles (for renin), carotid sinus (for sympathetic activity), and atria and
ventricles (for natriuretic peptides) that respond to changes in pressure, not volume. In most settings, pressure and
volume change in parallel with changes in sodium intake or with gastrointestinal or renal sodium losses due, for
example, to diarrhea or diuretic therapy.
Loss of ECF volume can lead to a reduction in tissue perfusion. However, the ECF volume and tissue perfusion do not
always change in the same direction. Two common examples are heart failure with edema and cirrhosis with ascites. In
both disorders, the ECF volume is increased, but tissue perfusion is reduced due to a low cardiac output in most cases
of heart failure and to vasodilation in cirrhosis. (See "Pathophysiology and etiology of edema in adults", section on 'Heart
failure' and "Pathogenesis of ascites in patients with cirrhosis".)
Reduced effective arterial blood volume or reduced effective circulating volume are terms that have been used to
describe the discrepancy between hypoperfusion and the increase in extracellular volume in heart failure and cirrhosis.
In both disorders, decreased tissue perfusion activates sodium-retaining hormones, which increase the extracellular
volume but, due to the underlying disease, do not normalize tissue perfusion.
Intracellular fluid volume — In normal adults, the intracellular fluid volume constitutes approximately 60 to 67
percent of the TBW [2,3]. Potassium salts are the main intracellular solutes, and the intracellular fluid volume is larger
than the ECF volume because there are more potassium salts in the cells than sodium salts in the ECF. Changes in the
intracellular fluid volume primarily occur when there are changes in plasma tonicity, resulting in water movement into or
out of the cells. As described below, the intracellular and brain volumes usually increase with hyponatremia and
decrease with hypernatremia (see 'Plasma tonicity' below). Water movement into or out of cells and possible neurologic
symptoms are most pronounced with acute changes in the plasma sodium and often attenuate over time. (See
"Manifestations of hyponatremia and hypernatremia in adults", section on 'Osmolytes and cerebral adaptation to
hyponatremia' and "Manifestations of hyponatremia and hypernatremia in adults", section on 'Cerebral adaptation to
hypernatremia'.)
Plasma osmolality — The plasma osmolality (Posm) is determined by the ratio of plasma solutes and plasma water.
Most of the plasma solutes are sodium salts with lesser contributions from other ions (eg, potassium, calcium), glucose,
and urea. The normal Posm is 275 to 290 mosmol/kg.
The plasma osmolality can be estimated from the following equation (calculator 1):
Posm = 2 x [Na] + [glucose]/18 + blood urea nitrogen/2.8
The multiple of 2 accounts for the anions accompanying sodium, and the divisors of 18 and 2.8 for glucose and the
blood urea nitrogen convert the values in mg/dL to mmol/L. If, as in many countries outside the United States, the
glucose and urea concentrations are reported in mmol/L, the equation becomes (calculator 2):
Posm = 2 x [Na] + [glucose] + [urea]
The contributions of glucose and urea are small when their concentrations are within the normal range; they become
significant when marked elevations develop as with uncontrolled diabetes mellitus or reduced renal function,
respectively.
The plasma and ECF osmolality are the same as the intracellular osmolality since most cell membranes are freely
permeable to water.
Plasma tonicity — Plasma tonicity, also called the effective plasma osmolality, is the parameter sensed by
osmoreceptors and determines the transcellular distribution of water. Water can freely cross almost all cell membranes
and moves from an area of lower tonicity (higher water content) to an area of higher tonicity (lower water content).
The main difference between plasma tonicity and plasma osmolality is that plasma tonicity reflects the concentration of
solutes that do not easily cross cell membranes (mostly sodium salts) and therefore affect the distribution of water
between the cells and the ECF. In contrast, the plasma osmolality also includes the osmotic contribution of urea, which
is considered an "ineffective" osmole since it can equilibrate across the cell membrane and therefore has little effect on
water movement across the cell membrane. Ethanol is another osmole that rapidly enters cells and therefore has no
tonicity.
The formulas used to estimate plasma tonicity are similar to those for the plasma osmolality with the one exception that
the contribution of urea is not included:
Plasma tonicity = 2 x [Na] + [glucose]/18 (if glucose is measured in mg/dL)
Plasma tonicity = 2 x [Na] + [glucose] (if glucose is measured in mmol/L)
The following examples illustrate the clinical importance of plasma tonicity and the difference between tonicity and
osmolality:
● Hyponatremia is, in most cases, accompanied by a fall in plasma tonicity, which results in osmotic water movement
from the ECF into the cells, including brain cells, and can contribute to the neurologic symptoms of hyponatremia.
In this setting, both the plasma tonicity and plasma osmolality are reduced. (See "Manifestations of hyponatremia
and hypernatremia in adults", section on 'Hyponatremia'.)
● Hypernatremia is accompanied by an increase in plasma tonicity, which results in osmotic water movement out of
the cells, including brain cells, and can contribute to the neurologic symptoms of hypernatremia. In this setting,
both the plasma osmolality and plasma tonicity are increased. (See "Manifestations of hyponatremia and
hypernatremia in adults", section on 'Hypernatremia'.)
● In contrast, urea accumulation in renal failure is associated with urea equilibration across the cell membrane. The
plasma osmolality is increased by the excess urea, but the plasma tonicity is unchanged because urea is an
ineffective osmole. As a result, there is little transcellular water movement. If, however, a patient with renal failure
develops hyponatremia or hypernatremia, the changes in plasma tonicity will result in movement into and out of
cells, respectively, similar to that seen in patients without renal failure. The plasma osmolality may still be elevated
in patients with hyponatremia, but the plasma tonicity will be reduced.
Urea equilibration across the blood-brain barrier occurs much more slowly than water equilibration. Thus, urea can
transiently act as an effective osmole with respect to the brain when its plasma concentration changes rapidly [4].
The most common example of this phenomenon is the rapid fall in plasma urea concentration produced by
hemodialysis in a uremic patient. In this setting, the removal of extracellular urea occurs more quickly than urea
can equilibrate across the cell membrane. Thus, the plasma osmolality falls much more rapidly than the
intracellular osmolality, which promotes osmotic water movement into cells. In the brain, the water shift can result
in cerebral edema and acute neurologic dysfunction, changes that partially explain the dialysis disequilibrium
syndrome [5]. (See "Dialysis disequilibrium syndrome", section on 'Reverse osmotic shift'.)
Urea was previously used to treat cerebral edema and increased intraocular pressure, and is still occasionally
used to treat hyponatremia [6,7]. With rapid administration of urea, an osmotic gradient from plasma to brain
develops, which promotes water movement out of the brain. Over several hours, urea is excreted in the urine with
electrolyte-free water, which increases the serum sodium concentration.
Dehydration — Dehydration is defined as a reduction in TBW below the normal level without a proportional reduction in
sodium and potassium, resulting in a rise in the plasma sodium concentration. (See 'Determinants of the plasma sodium
concentration' below.)
With primary loss of free water (as with unreplaced insensible losses or water loss in diabetes insipidus), the major
biochemical manifestation is hypernatremia. Because water equilibrates across the cell membrane, about two-thirds of
the water losses come from the cells and one-third from the ECF. Thus, 3 L of free water would have to be lost to
produce the same reduction in ECF volume as the loss of 1 L of isotonic saline. Thus, signs of hypovolemia are not
present unless there is a marked degree of free water loss. (See 'Extracellular fluid volume' above and 'Intracellular fluid
volume' above.)
As described in the next section, hypernatremia does not usually occur in patients who have an intact thirst mechanism
and access to water since stimulation of thirst can replace most of the water deficit. (See 'Regulation of plasma tonicity'
below.)
REGULATION OF WATER AND SODIUM BALANCE — The kidney regulates water and sodium balance
independently since water can be taken in without salt and salt can be taken in without water (eg, pretzels or potato
chips). Regulation of plasma tonicity and of the effective arterial blood volume involve different hormones, although there
are some areas of overlap, such as the hypovolemic stimulus to the release of antidiuretic hormone (ADH). (See
'Combined regulation of plasma tonicity and effective arterial blood volume' below.)
Regulation of plasma tonicity — As mentioned above, it is the plasma tonicity (also called effective plasma osmolality)
that is of primary importance in osmoregulation. Plasma osmolality measurement may include a high concentration of
solutes that do not affect tonicity (eg, urea in renal failure or ethanol in intoxicated patients). These "ineffective" osmoles
do not affect fluid movement into or out of cells unless there is a change in concentration that is more rapid than the time
required for equilibration with the cells, as can occur with hemodialysis in patients with renal failure. (See 'Plasma
tonicity' above.)
Changes in plasma tonicity are sensed by osmoreceptors in the hypothalamus. These receptors affect both water intake
and water excretion by influencing thirst and the release of ADH, respectively (figure 2 and table 1). ADH is the primary
physiologic determinant of the rate of free water excretion. Its major renal effect is to augment the water permeability of
the luminal membranes of principal cells in the cortical and medullary collecting tubules [8], thereby promoting water
reabsorption via osmotic equilibration with the hypertonic interstitium.
Signaling by ADH via the vasopressin 2 (V2) receptor initiates a sequence of intracellular events culminating in
increased water permeability (figure 3). Under the influence of ADH, preformed cytoplasmic vesicles that contain unique
water channels (aquaporin-2) move to and fuse with the luminal membrane [8-13], thereby allowing water to be
reabsorbed down the favorable osmotic gradient [14,15]. Once the water channels span the luminal membrane and
permit osmotic water movement into the cells [16], water is then rapidly returned to the systemic circulation across the
basolateral membrane, which is both water permeable (even in the absence of ADH) and has a much greater surface
area than the luminal membrane [17]. When the ADH effect has worn off, the water channels aggregate within clathrin-
coated pits, from which they are removed from the luminal membrane by endocytosis and returned to the cytoplasm
[13,16].
Thus, regulation of plasma tonicity is achieved by alterations in water balance. Suppression of ADH release is the
primary protective mechanism against water retention and the development of hyponatremia, while thirst is the primary
protective mechanism against water loss and the development of hypernatremia. The osmoreceptors are extremely
sensitive, responding to alterations in the plasma tonicity of as little as 1 percent [18-20]. In humans, the osmotic
threshold for ADH release is about 280 to 290 mosmol/kg (figure 2) [18,19]. Below this level, there is little if any
circulating ADH, and the urine should be maximally dilute with an osmolality below 100 mosmol/kg. Above the osmotic
threshold, there is a progressive and relatively linear rise in ADH secretion. This system is so efficient that the plasma
osmolality usually does not vary by more than 1 to 2 percent, despite wide fluctuations in water intake.
Persistent water retention resulting in hypoosmolality and hyponatremia occurs, with rare exceptions, only in patients
with an impairment in renal water excretion due either to an inability to suppress the release of ADH (most often due to
reduced effective arterial blood volume, as seen in true hypovolemia, heart failure, cirrhosis, or the syndrome of
inappropriate ADH secretion) (SIADH), or to advanced renal failure in which water retention is largely independent of
ADH. (See "Causes of hyponatremia in adults".)
On the other hand, correction of a water deficit (caused, for example, by sweating on a hot day) requires the intake and
retention of exogenous water. This is achieved by increases in thirst and ADH release, which are induced by the
elevation in plasma tonicity (figure 4). Even though thirst is regulated centrally (including cortical areas that influence
nonessential or social drinking), it is sensed peripherally as the sensation of a dry mouth [21,22]. The cessation of thirst
(satiety) is also mediated initially in the periphery by oropharyngeal mechanoreceptors [23,24] that are stimulated by
swallowing relatively large volumes of fluid [25].
In contrast to the response to hypotonicity, in which renal water excretion is of primary importance, thirst is the major
defense against hypertonicity and hypernatremia. Hypernatremia generally will not occur in a patient with a normal thirst
mechanism and access to water. It is primarily seen in patients with impaired mental status (elderly or critically ill) who
do not experience thirst or in infants who can experience thirst but require others to provide fluid intake. (See "Etiology
and evaluation of hypernatremia in adults", section on 'The importance of thirst'.)
Regulation of effective arterial blood volume — Changes in body sodium content lead to changes in extracellular
fluid (ECF) volume and effective arterial blood volume, which is defined above. (See 'Effective arterial blood volume'
above.)
Changes in effective arterial blood volume are sensed by three major pressure receptors which activate specific systems
that regulate both systemic vascular resistance and sodium excretion (table 1):
● Receptors in specialized cells in the afferent glomerular arteriole (called juxtaglomerular cells) sense the perfusion
pressure in the kidney and are an important determinant of the activity of the renin-angiotensin-aldosterone
system, which increases with renal hypoperfusion (figure 5 and figure 6).
● Receptors in the carotid sinus and aorta regulate the activity of the sympathetic nervous system [26,27]. Increased
sympathetic activity also increases renin release (figure 6).
● Cardiac receptors regulate the release of atrial natriuretic peptide (mostly from the atria) and brain natriuretic
peptide (mostly from the ventricles).
Angiotensin II and norepinephrine are vasoconstrictors; aldosterone, angiotensin II, and norepinephrine also promote
sodium reabsorption. The natriuretic peptides are vasodilators that increase sodium excretion. (See "Natriuretic peptide
measurement in heart failure".)
In response to volume expansion due to a high salt intake, natriuretic peptide secretion is increased while the renin-
angiotensin-aldosterone system is suppressed (figure 7), changes that promote urinary excretion of the larger sodium
load.
In contrast, volume contraction will have the opposite effect. In addition, a reduced effective arterial blood volume (even
in a hypervolemic patient) activates the renin-angiotensin-aldosterone and sympathetic nervous systems. These
hormonal changes result in both sodium retention and vasoconstriction, thereby maintaining the ECF volume and
systemic blood pressure. However, when the renin-angiotensin-aldosterone system is markedly activated in these
conditions, vasodilatory and natriuretic peptides as well as other hormones (such as prostaglandins) are often also
increased. These counterregulatory factors act to moderate the degree of vasoconstriction and salt retention [28,29].
The importance of these moderating factors is evident, for example, when prostaglandin inhibitors (such as nonsteroidal
antiinflammatory drugs) are given to a patient with cirrhosis or severe heart failure. The inhibition of vasodilatory
prostaglandins leads to marked salt retention and acute kidney dysfunction. These adverse effects are due to the
development of unopposed vasoconstriction and salt retention.
The diagnosis of reduced effective arterial blood volume is usually made from the history, physical examination (postural
hypotension or poor skin turgor with true volume depletion, edema in heart failure, ascites in cirrhosis), and by
demonstrating renal sodium retention as evidenced by a urine sodium concentration below 25 meq/L unless there is
renal sodium wasting (most often due to diuretic therapy or underlying renal disease).
Later role of ADH — In addition to the primary role of volume-regulating hormones, a substantial reduction in the
effective arterial blood volume can also lead to the release of ADH (figure 8) [30], indicating the existence of nonosmolal,
volume-sensitive receptors for ADH release. The sensitivity of the volume receptors is different from that of the
osmoreceptors. The latter respond to alterations in plasma osmolality of as little as 1 percent (figure 2); in comparison,
small, acute reductions in volume that are sufficient to increase the secretion of renin and norepinephrine have little
effect on the release of ADH. Acutely, ADH is secreted nonosmotically in humans only if there is a large enough change
in the effective arterial blood volume to produce a reduction in the systemic blood pressure [31,32]. Once hypotension
occurs, there may be a marked rise in ADH secretion, resulting in circulating hormone levels that can substantially
exceed that induced by hypertonicity (figure 8) [18,32].
In addition to increasing water reabsorption by the distal nephron (an effect mediated by V2 receptors), ADH acts to
increase vascular resistance via the V1 receptors (hence the name "vasopressin") [33]. These actions of ADH will
partially restore the ECF volume and increase blood pressure; however, as noted above, most (about two-thirds) of the
retained water will move osmotically into the cells. (See 'Extracellular fluid volume' above.) Water retention will also
lower the plasma sodium concentration.
In patients with heart failure and cirrhosis, the severity of the hyponatremia is related to the severity of the underlying
disease. As a result, hyponatremia is an independent predictor of an adverse prognosis (figure 9), with the prognosis
becoming progressively worse at lower plasma sodium concentrations [34,35]. In a study of patients with cirrhosis who
were candidates for liver transplantation, the hazard ratio for death was 1.05 per 1 meq/L decrease in plasma sodium at
values between 140 and 125 meq/L [34]. (See 'Hyponatremia' below and "Hyponatremia in patients with heart failure",
section on 'Predictor of adverse prognosis' and "Hyponatremia in patients with cirrhosis", section on 'Predictor of
adverse prognosis'.)
Combined regulation of plasma tonicity and effective arterial blood volume — The preceding discussion dealt with
regulation of plasma tonicity (and osmolality) and the effective arterial blood volume as isolated events. However,
changes often occur in both parameters. In these settings, the hormonal response results in the excretion of urine with a
composition that is similar to what has been taken in. (See 'Effective arterial blood volume' above and 'Plasma tonicity'
above.)
A simple example is the intravenous administration of one-half isotonic saline (sodium concentration 77 meq/L), which
will produce both volume expansion and, because it is a solution that is dilute to plasma, a reduction in the plasma
sodium concentration. This will lead to the following changes in hormone secretion and urine composition:
● The ensuing volume expansion induced by saline administration will reduce the activity of the renin-angiotensin-
aldosterone system and increase the secretion of natriuretic peptides, both of which will promote the appropriate
excretion of the excess sodium.
● The reduction in plasma sodium concentration and plasma tonicity induced by the infusion of a dilute fluid will
suppress the release of ADH, resulting in a reduction in urine osmolality and an appropriate increase in water
excretion.
The changes are in the opposite direction with exercise on a hot day that leads to the loss of dilute sodium-containing
fluid as sweat. The net effect is a rise in the plasma sodium concentration and a fall in the extracellular volume. This will
lead to the following changes in hormone secretion and urine composition:
● The increase in plasma sodium concentration and plasma tonicity will stimulate both ADH release and thirst; the
ensuing rise in urine osmolality and subsequent water retention return the plasma sodium concentration toward
normal.
● The associated hypovolemia will activate the renin-angiotensin-aldosterone system and suppress the release of
natriuretic peptides, resulting in a fall in urinary sodium excretion.
● The net effect is that the urine will initially be concentrated (to prevent further water loss) and contain relatively little
sodium, an appropriate response to hypertonicity and volume depletion.
A third example is the ingestion of salted pretzels without intake of water. The following sequence would occur:
● Salt intake will raise the plasma sodium concentration, plasma osmolality, and tonicity. (See 'Plasma tonicity'
above.)
● The increase in plasma tonicity will stimulate ADH release (figure 2), reducing water excretion to prevent a further
rise in the plasma sodium concentration.
● The increase in plasma tonicity will also cause osmotic water movement from the cells into the ECF. The ensuing
ECF volume expansion will increase the release of natriuretic peptides and suppress the renin-angiotensin-
aldosterone system, resulting in increased sodium excretion.
● The net effect is excretion of urine with a high sodium concentration and low volume, similar to what was taken in.
In addition, the increase in plasma tonicity will increase thirst leading to water intake.
Isotonic saline in SIADH — Combined regulation of water and sodium balance may produce unintentional and
undesirable consequences in the treatment of hyponatremia due to the SIADH. The mainstay of therapy is fluid
restriction and, in symptomatic patients, hypertonic saline. In patients who are not symptomatic, there may be a
tendency to give isotonic saline. However, in most patients with SIADH, isotonic saline will not raise the plasma sodium
and will often worsen the hyponatremia. This issue is discussed in detail elsewhere, but why this occurs can be
illustrated by the following scenario. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone
secretion (SIADH) and reset osmostat", section on 'Intravenous saline'.)
Suppose a patient with SIADH has a plasma sodium concentration of 120 meq/L and a urine osmolality that is
substantially higher than plasma due to the persistent effect of ADH (eg, urine sodium plus potassium concentration of
258 meq/L and total urine osmolality of 616 mosmol/kg):
● If the patient is given 1000 mL of isotonic saline (which contains 154 meq each of sodium and chloride or 308
mosmol), the plasma sodium will initially rise because isotonic saline has a higher sodium concentration than the
plasma.
● However, all 154 meq of infused sodium will be excreted (since sodium handling is intact in SIADH) but in only 600
mL of water (258 meq/L x 0.6 L ≈ 154 meq).
The net effect will be retention of 400 mL of water and worsening of the hyponatremia. To raise the plasma sodium
concentration with intravenous saline in patients with SIADH, the concentration of sodium plus potassium (ie, tonicity) of
the infused solution must exceed the concentration of sodium plus potassium of the urine, not simply the plasma (see
'Determinants of the plasma sodium concentration' below). Since the urine osmolality is almost always above 300
mosmol/kg in hyponatremic patients with SIADH, urine electrolyte concentrations often equal or exceed the plasma
sodium concentration so that isotonic saline alone is not an effective therapy. If salt is to be given to raise the plasma
sodium concentration, hypertonic saline or oral salt tablets are required.
Hypertonic saline in SIADH — Suppose the patient in the preceding section who had hyponatremia due to SIADH
and a concentrated urine is treated with hypertonic (3 percent) saline, which has a sodium concentration of 513 meq/L.
Even if the urine is maximally concentrated, the sodium plus potassium concentration is not usually much higher than
250 meq/L. Thus:
● If 1000 mL of 3 percent sodium chloride is given (513 meq of sodium), the plasma sodium will initially rise because
hypertonic saline has a higher sodium concentration than the plasma.
● All 513 meq of the infused sodium will be excreted (since sodium handling is intact in SIADH). If the sodium plus
potassium concentration in the urine is, for example, 258 meq/L, the infused sodium will be excreted in
approximately 2 L of urine.
● The net effect is the loss of roughly 1000 mL of water, which will tend to raise the plasma sodium by about 5
meq/L.
When the urine osmolality is very high in SIADH, relatively large volumes of hypertonic saline may be required to
achieve the desired increase in serum sodium. In such patients, concurrent use of furosemide, which blocks the renal
concentrating mechanism, with hypertonic saline [36] or, alternatively, a vasopressin antagonist instead of hypertonic
saline may be considered. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion
(SIADH) and reset osmostat", section on 'Therapies to raise the serum sodium'.)
THE STEADY STATE — The preceding section described the mechanisms by which sodium and water balance are
regulated. The hormonal changes that occur allow the effective arterial blood volume and plasma tonicity to be
maintained within a narrow range even in the presence of wide variations in intake from day to day. (See 'Effective
arterial blood volume' above and 'Plasma tonicity' above.)
An important related issue is how balance (defined as intake and net losses being equal) is maintained with changes in
water or sodium (or potassium) intake or excretion in patients without advanced renal failure or an edematous state such
as heart failure or cirrhosis. There are two mechanisms by which this might occur:
● A set point which acts to maintain the plasma sodium and potassium concentrations and the extracellular fluid
(ECF) volume at specific levels.
● A steady state in which intake and output are maintained at an equal level. In contrast to the set point mechanism,
the plasma sodium, potassium concentration, and the ECF volume vary in the steady state to provide the signal
that intake or urinary excretion (eg, with diuretic therapy) has changed.
Water, sodium, and potassium balance are primarily achieved by maintenance of the steady state as illustrated by the
following observations from different studies:
● Progressively increasing sodium intake from 10 up to 350 meq/day (which is well above the 100 to 250 meq per
day sodium intake on a typical American diet) is associated with an appropriate equivalent increase in sodium
excretion (figure 10) that is mediated by increased release of atrial natriuretic peptide and decreased activity of the
sodium-retaining renin-angiotensin-aldosterone system (figure 7) [37]. The signal that drives the hormonal
response is a mild, and usually subclinical retention of sodium during the first few days before balance between
intake and excretion is restored (figure 10). The degree of volume expansion that occurs is proportional to the
magnitude of the increase in sodium intake.
A similar sequence occurs when sodium reabsorption is increased in primary aldosteronism: initial sodium
retention, with the ensuing extracellular volume expansion providing the signal to increase sodium excretion back
to the level of sodium intake (at least in part mediated by increased natriuretic peptide secretion) (figure 11) [38].
The net effect of this phenomenon, which is called aldosterone escape, is reattainment of the steady state with no
edema. Similar considerations apply to the plasma potassium concentration. The initial urinary potassium wasting
induced by hyperaldosteronism returns to the level of intake due to the direct potassium-conserving effect of
hypokalemia. (See "Pathophysiology and clinical features of primary aldosteronism", section on 'The steady state'.)
● When a thiazide diuretic is given to nonedematous patients (eg, for the treatment of hypertension or nephrolithiasis
associated with hypercalciuria), the initial diuresis and kaliuresis are, within a period of days, counterbalanced by
sodium-retaining forces (eg, aldosterone and possibly the reduction in blood pressure) and potassium-retaining
forces (eg, the direct effect of the fall in plasma potassium) that limit further sodium and potassium excretion in
excess of intake. In a study evaluating the urinary responses to 100 mg of hydrochlorothiazide per day (much
higher than usual current dosing), the sodium wasting (ie, excretion greater than intake) ceased by day 4, and the
potassium wasting ceased by day 10 (figure 12) [39]. At this point, sodium and potassium intake and excretion are
in balance, but the previous losses will persist at that level unless the diuretic dose or sodium or potassium intake
is changed.
Similarly, when an intravenous loop diuretic is given at a constant dose to stable patients, the maximum diuresis
occurs after the first dose with bolus therapy and in the first few hours with an intravenous infusion (figure 13) [40].
(See "Time course of loop and thiazide diuretic-induced electrolyte complications".)
● The urine output can exceed 10 L/day in normal individuals if water intake is increased to that level. This response
is mediated by reduced secretion of antidiuretic hormone (ADH), which permits excretion of the excess water in a
dilute urine. The signal for this response is retention of some of the excess water in the first day, resulting in a fall
in the plasma sodium concentration and therefore the plasma osmolality (figure 2). A clinical setting in which
increased fluid intake is recommended is for the prevention of recurrent kidney stones. (See "Prevention of
recurrent calcium stones in adults", section on 'Increase fluid intake'.)
OVERVIEW OF DISORDERS OF WATER AND SODIUM BALANCE — Abnormalities in plasma tonicity and the
extracellular volume lead to the following four basic disorders of water and sodium balance [41]:
● Hyponatremia (too much water)

● Hypernatremia (too little water)
● Hypovolemia (too little sodium, the main extracellular solute)
● Edema (too much sodium with associated water retention)
Disorders of water balance — The general principles that underlie the primary disorders of water balance
(hyponatremia and hypernatremia) are briefly described in the ensuing sections. The etiology and evaluation of these
disorders are reviewed elsewhere. (See "Causes of hyponatremia in adults" and "Diagnostic evaluation of adults with
hyponatremia" and "Etiology and evaluation of hypernatremia in adults".)
Before discussing hyponatremia and hypernatremia, it is useful to review the determinants of the plasma sodium
concentration.
Determinants of the plasma sodium concentration — Sodium and accompanying anions (mostly chloride and
bicarbonate) are the main determinants of the plasma and extracellular fluid (ECF) osmolality. In contrast, intracellular
potassium and accompanying anions are the main determinant of the intracellular osmolality.
Since water freely crosses most cells, the osmolality is the same in the extracellular and intracellular fluids. Thus, the
plasma sodium concentration reflects the osmolality in both compartments even though potassium is the major
intracellular cation. These relationships lead to the following formula:
(Nae + Ke)
Plasma sodium ≈ --------------------
Total body water
The subscript "e" refers to exchangeable sodium since approximately 30 percent of total body sodium and a smaller
fraction of total body potassium are bound in areas such as bone where they are nonexchangeable and osmotically
inactive.
This relationship applies over a wide range of plasma sodium concentrations (figure 4). The derivation of this formula is
presented elsewhere. (See "Etiology and evaluation of hypernatremia in adults", section on 'Determinants of the plasma
sodium concentration'.)
Hyponatremia — Hyponatremia is almost always due to the oral or intravenous intake of water that cannot be
completely excreted. Normal individuals can excrete more than 10 L of urine per day (and more than 400 mL per hour)
and therefore will not develop hyponatremia unless water intake exceeds this value, which occurs most often in
psychotic patients with primary polydipsia. Hyponatremia caused by massive water intake rapidly resolves as soon as
water intake stops, provided that the ability to dilute the urine is intact. (See "Causes of hyponatremia in adults", section
on 'Hyponatremia with a low serum osmolality'.)
Persistent hyponatremia is associated with impaired water excretion that is most often due to an inability to suppress
the release of antidiuretic hormone (ADH) or to advanced renal failure. The two major causes of persistent ADH
secretion are the syndrome of inappropriate ADH secretion (SIADH) and reduced effective arterial blood volume. The
latter can be due to true volume depletion (eg, diuretics, vomiting, or diarrhea) or to decreased tissue perfusion in heart
failure or cirrhosis. In the last two disorders, the severity of the hyponatremia parallels the severity of the underlying
disease. (See "Causes of hyponatremia in adults", section on 'Hyponatremia with a low serum osmolality' and
"Hyponatremia in patients with heart failure", section on 'Predictor of adverse prognosis' and "Hyponatremia in patients
with cirrhosis", section on 'Predictor of adverse prognosis'.)
Although water is retained in patients with hyponatremia, the degree of ECF volume expansion is not clinically important.
The cell membranes are permeable to water, and approximately two-thirds of the excess fluid moves into the cells.
Hyponatremia due to water retention is typically associated with a reduction in plasma osmolality and tonicity (see
'Plasma tonicity' above). This initially creates an osmotic gradient that favors water movement from the ECF into cells
and the brain. Water movement into the brain can lead to cerebral edema and potentially severe neurologic symptoms,
particularly if the hyponatremia is acute. In addition, overly rapid correction of severe chronic hyponatremia can lead to
potentially irreversible neurologic injury. These issues are discussed in detail elsewhere. (See "Manifestations of
hyponatremia and hypernatremia in adults", section on 'Hyponatremia' and "Osmotic demyelination syndrome and overly
rapid correction of hyponatremia".)
Although hyponatremia is usually associated with a reduction in plasma osmolality, this is not always the case as
illustrated by the following examples:
● Hyponatremia can be caused by osmotic water movement out of the cells, which increases the extracellular
volume and, by dilution, lowers the plasma sodium concentration. This phenomenon can occur when
hyperosmolality is induced by hyperglycemia or the administration of hypertonic mannitol. Because plasma tonicity
is increased, these patients do not experience an increase in intracellular and brain volume caused by water
movement into the cells. To the contrary, hypertonicity results in water movement out of the cells and the brain.
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The movement of water out of the brain with hypertonic mannitol provides the rationale for its use in the treatment
of cerebral edema and increased intracranial pressure. The plasma sodium rises toward its baseline value as the
hyperglycemia is treated or the mannitol is excreted in the urine. (See "Evaluation and management of elevated
intracranial pressure in adults", section on 'Mannitol' and "Causes of hyponatremia in adults", section on
'Hyponatremia with a high or normal serum osmolality' and "Elevated intracranial pressure (ICP) in children",
section on 'Mannitol'.)
● Hyponatremia may be associated with a normal or high plasma osmolality in patients with renal failure in whom the
osmotic effect of urea retention counterbalances the reduction in plasma osmolality induced by the hyponatremia.
However, urea readily diffuses into cells and is considered an ineffective osmole. The plasma tonicity (ie,
effective plasma osmolality) is equal to the plasma osmolality minus the contribution of urea and is reduced in
proportion to the reduction in plasma sodium. Thus, these patients can develop the manifestations of
hyponatremia. (See "Causes of hyponatremia in adults", section on 'Advanced renal failure' and 'Plasma tonicity'
above and "Manifestations of hyponatremia and hypernatremia in adults", section on 'Hyponatremia'.)
The evaluation and treatment of hyponatremia varies with the cause and is discussed elsewhere. (See "Diagnostic
evaluation of adults with hyponatremia" and "Overview of the treatment of hyponatremia in adults" and "Treatment of
hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat".)
Hypernatremia — Hypernatremia is most often caused by the failure to replace water losses due to impaired thirst
or lack of access to water. It can also be induced by the intake of salt in excess of water or the administration of a
hypertonic salt solution. (See "Etiology and evaluation of hypernatremia in adults".)
In contrast to hyponatremia in which water moves into the cells, the increase in plasma tonicity in hypernatremia usually
pulls water out of the cells, resulting in a decrease in intracellular volume.
The clinical manifestations that may be associated with hypernatremia and the evaluation and treatment of
hypernatremia are discussed separately. (See "Manifestations of hyponatremia and hypernatremia in adults", section on
'Hypernatremia' and "Etiology and evaluation of hypernatremia in adults", section on 'Evaluation of hypernatremia' and
"Treatment of hypernatremia".)
Disorders of sodium balance — The two disorders of sodium balance are hypovolemia and edema.
Hypovolemia — Hypovolemia refers to any condition in which the ECF volume is reduced and, when severe, can
lead to hypotension or shock. Hypovolemia is usually induced by salt and water losses that are not replaced (eg,
vomiting, diarrhea, diuretic therapy, bleeding, or third-space sequestration). In contrast, primary water loss, due to
insensible loss by evaporation from the skin and respiratory tract or to increased urinary water loss due to diabetes
insipidus, does not usually lead to hypovolemia for two reasons: the associated rise in plasma tonicity stimulates thirst,
leading to replacement of most of the lost water; and water is lost disproportionately from the intracellular fluid
compartment which contains approximately two-thirds of the total body water. (See 'Intracellular fluid volume' above.)
True hypovolemia due to fluid losses should be distinguished from decreased tissue perfusion in heart failure and
cirrhosis in which cardiac dysfunction and systemic vasodilation, respectively, are the major hemodynamic
abnormalities. (See 'Effective arterial blood volume' above.)
Concurrent changes in plasma sodium concentration — The plasma sodium concentration in hypovolemic
patients may be normal, low (most often due to hypovolemia-induced release of ADH, which limits urinary water
excretion), or high (if water intake is impaired). The effect on the plasma sodium concentration depends upon both the
composition of the fluid that is lost and fluid intake.
In true hypovolemia due to vomiting, diarrhea, or diuretic therapy, the direct effect of fluid loss on the plasma sodium
concentration depends upon the concentration of sodium plus potassium in the fluid that is lost (figure 4). The
rationale for including the potassium concentration is discussed above. (See 'Determinants of the plasma sodium
concentration' above.)
● If, as occurs in most cases of vomiting and diarrhea, the sodium plus potassium concentration in the fluid that is
lost is less than the plasma sodium concentration, water is lost in excess of sodium plus potassium which will tend
to increase the plasma sodium concentration. As an example, suppose that one liter of diarrheal fluid has a
sodium plus potassium concentration of 75 meq/L. This represents the electrolytes contained in 500 mL of isotonic
saline (sodium concentration 154 meq/L). The loss of 500 mL of isotonic electrolytes will have no effect on the
plasma sodium concentration. In addition, 500 mL of electrolyte-free water is excreted, which will raise the plasma
sodium concentration. (See "Etiology and evaluation of hypernatremia in adults", section on 'Determinants of the
plasma sodium concentration'.)
● If the sodium plus potassium concentration is the same as the plasma sodium concentration (as with bleeding),
there will be no change in plasma sodium concentration induced by the fluid loss.
● If the sodium plus potassium concentration is greater than the plasma sodium concentration, as can occur with
thiazide diuretics, the plasma sodium concentration will fall. The high urine sodium plus potassium concentration
(which exceeds the sodium concentration of the plasma) is produced because thiazide diuretics act in the distal
tubule and therefore do not interfere with urinary concentrating ability, which depends upon sodium chloride
reabsorption in the loop of Henle. The high ADH levels induced by the hypovolemia result in water reabsorption
and high urine osmolality and electrolyte concentrations. Loop diuretics are much less likely to have this effect
because they block sodium reabsorption in the thick ascending limb of the loop of Henle, which impairs the
countercurrent mechanism. As a result, the urine osmolality will be closer to isosmotic despite high ADH levels,
and the sodium plus potassium concentration will be less than the plasma sodium concentration since urea also
contributes to the urine osmolality. (See "Diuretic-induced hyponatremia", section on 'Pathogenesis'.)
The changes in plasma sodium concentration directly induced by fluid loss do not necessarily represent the final
outcome. Hypovolemia stimulates nonosmotic release of ADH, which will promote retention of ingested water or infused
electrolyte-free water, which will lower the plasma sodium concentration, independent of the composition of the fluid lost.
(See 'Later role of ADH' above and "Causes of hyponatremia in adults", section on 'True volume depletion'.)
Edema — Edema (including ascites) is a manifestation of sodium excess and an expanded ECF volume. Movement
of fluid out of the vascular space into the interstitium is most often mediated by an increase in capillary hydraulic
pressure. The pathophysiology of edema formation is discussed in detail elsewhere. (See "Pathophysiology and etiology
of edema in adults", section on 'Edema formation'.)
Tissue perfusion is variable in these disorders, depending upon the cause of edema:
● When due to renal failure or glomerulonephritis, tissue perfusion may be increased if cardiac function is intact.
● When due to heart failure or cirrhosis, tissue perfusion is often reduced due to decreased cardiac function and
vasodilation, respectively. (See 'Effective arterial blood volume' above.)
● When due to the nephrotic syndrome, tissue perfusion may be reduced due to hypoalbuminemia or increased due
to primary renal sodium retention. (See "Pathophysiology and treatment of edema in patients with the nephrotic
syndrome", section on 'Underfilling versus renal sodium retention'.)
Effect on plasma sodium concentration — The sodium retention in edematous patients is not associated with
hypernatremia since a proportionate amount of water is retained. However, hyponatremia can occur if there is a
concurrent reduction in the ability to excrete water. As an example, hyponatremia is common in patients with heart
failure and cirrhosis because the reduction in tissue perfusion increases the secretion of ADH, thereby limiting the
excretion of ingested water. In these disorders, the severity of hyponatremia is directly related to the severity of the
underlying disease and is therefore a predictor of an adverse prognosis. (See 'Hyponatremia' above and "Hyponatremia
in patients with heart failure", section on 'Predictor of adverse prognosis' and "Hyponatremia in patients with cirrhosis",
section on 'Predictor of adverse prognosis'.)
SUMMARY
● The following terms are commonly used when discussing disorders of water and sodium balance (see 'Definitions'
above):
• Total body water (TBW) – A percentage of lean body weight that varies with age; approximate normal values
are 80 percent in premature infants, 70 to 75 percent in term infants, 65 to 70 percent in toddlers, and 60
percent after puberty (figure 1). TBW as a percentage of total body weight is lower in young adult females
than in young adult males (50 versus 60 percent) and becomes progressively lower with increasing obesity or
with loss of muscle mass. The TBW has two main compartments: the extracellular fluid (ECF) and the
intracellular fluid, which are separated by the cell membrane. (See 'Total body water' above.)
• Extracellular fluid (ECF) volume – The ECF component is greater in infants and young children compared
with older patients (figure 1). In normal adults, the ECF constitutes approximately 33 to 40 percent of the
TBW in normal adults and is determined by the absolute amounts of sodium and water that are present in the
ECF. (See 'Extracellular fluid volume' above.)
• Effective arterial blood volume – The hormonal changes that regulate the ECF volume are mediated by
sensors that respond to changes in pressure and tissue perfusion, not volume. In most settings, pressure and
volume change in parallel with changes in sodium intake or with sodium losses. However, the ECF volume
and tissue perfusion do not always change in the same direction. Two common examples are heart failure
with edema and cirrhosis with ascites. In both disorders, the ECF volume is increased, but tissue perfusion is
reduced. Reduced effective arterial blood volume is a term that has been used to describe the discrepancy
between hypoperfusion and the increase in extracellular volume in heart failure and cirrhosis. (See 'Effective
arterial blood volume' above.)
• Intracellular fluid volume – In normal adults, the intracellular fluid volume constitutes approximately 60 to 67
percent of TBW. Potassium salts are the main intracellular solutes, and the intracellular fluid volume is larger
than the ECF volume because there are more potassium salts in the cells than sodium salts in the ECF.
Changes in the intracellular fluid volume primarily occur when there are changes in plasma tonicity, resulting
in water movement into or out of the cells. (See 'Intracellular fluid volume' above.)
• Plasma osmolality (Posm) – The Posm is determined by the ratio of plasma solute particles and plasma
water. Most of the plasma solutes are dissociated sodium salts with lesser contributions from other ions (eg,
potassium, calcium), glucose, and urea. The normal Posm is 275 to 290 mosmol/kg. The plasma osmolality
can be estimated (calculator 1) or measured. The plasma and ECF osmolality are the same as the
intracellular osmolality since most cell membranes are freely permeable to water, which flows from areas of
lower osmolality to those with higher osmolality. (See 'Plasma osmolality' above.)
• Plasma tonicity – Plasma tonicity is the effective plasma osmolality, which is sensed by osmoreceptors and
determines the transcellular distribution of water. Water can freely cross almost all cell membranes and
moves from an area of lower tonicity (higher water content) to an area of higher tonicity (lower water content).
The main difference between plasma tonicity and plasma osmolality is that plasma tonicity reflects the
concentration of solutes that do not easily cross cell membranes (mostly sodium salts) and therefore affect
the distribution of water between the cells and the ECF. The plasma osmolality includes the osmotic
contribution of urea, which is considered an "ineffective" osmole since it can equilibrate across the cell
membrane and therefore has little effect on water movement across the cell membrane. (See 'Plasma
tonicity' above.)
• Dehydration versus hypovolemia – Dehydration is defined as a reduction in TBW below the normal level
without a proportional reduction in sodium and potassium, resulting in a rise in the plasma sodium
concentration (hypernatremia). Because water equilibrates across the cell membrane, about two-thirds of
water losses come from the cells, and only one-third come from the ECF, thereby preserving effective arterial
blood volume. Thus, signs of hypovolemia are not present in patients with dehydration unless there is a
marked degree of free water loss. (See 'Dehydration' above.)
● The kidney regulates water and sodium balance independently since water can be taken in without salt and salt
can be taken in without water. Regulation of plasma tonicity and of the effective arterial blood volume involve
different hormones, although there are some areas of overlap. (See 'Regulation of water and sodium balance'
above.)
● Osmoregulation (regulation of the plasma tonicity) is achieved by alterations in water balance. Suppression of ADH
release is the primary protective mechanism against water retention and the development of hyponatremia, while
thirst is the primary protective mechanism against water loss and the development of hypernatremia. (See
'Regulation of plasma tonicity' above.)
● Changes in effective arterial blood volume are sensed by three major pressure receptors which activate specific
systems that regulate both systemic vascular resistance and sodium excretion (table 1) (see 'Regulation of
effective arterial blood volume' above):
• Juxtaglomerular cells, which sense the perfusion pressure in the kidney, are an important determinant of the
activity of the renin-angiotensin-aldosterone system, which increases with renal hypoperfusion (figure 5 and
figure 6).
• Receptors in the carotid sinus and aorta regulate the activity of the sympathetic nervous system. Increased
sympathetic activity also increases renin release (figure 6).
• Cardiac receptors regulate the release of atrial natriuretic peptide (mostly from the atria) and brain natriuretic
peptide (mostly from the ventricles).
● In response to volume expansion due, for example, to a high salt intake, natriuretic peptide secretion is increased
while the renin-angiotensin-aldosterone system is suppressed (figure 7); these changes promote urinary sodium
excretion and a reduction in the ECF volume. In contrast, a reduction in effective arterial blood volume due, for
example, to volume contraction will activate the renin-angiotensin-aldosterone and sympathetic nervous systems.
These hormonal changes result in both sodium retention and vasoconstriction, thereby maintaining the ECF and
systemic blood pressure. (See 'Regulation of effective arterial blood volume' above.)
● Regulation of plasma tonicity and the effective arterial blood volume occur simultaneously; the hormonal response
normally results in the excretion of urine with a composition that is similar to what has been taken in. (See
'Combined regulation of plasma tonicity and effective arterial blood volume' above.)
● The hormonal changes that occur allow the effective arterial blood volume and plasma tonicity to be maintained
within a narrow range even in the presence of wide variations in intake from day to day. (See 'The steady state'
above.)
● Abnormalities in plasma tonicity and the extracellular volume lead to the following four basic disorders of water and
sodium balance (see 'Overview of disorders of water and sodium balance' above):
• Hyponatremia (too much water or overhydration). (See 'Disorders of water balance' above.)
• Hypernatremia (too little water or dehydration). (See 'Disorders of water balance' above.)
• Hypovolemia (too little sodium, the main extracellular solute or volume contraction). (See 'Disorders of
sodium balance' above.)
• Hypervolemia (too much sodium, the main extracellular solute, with expansion of the effective arterial blood
volume and hypertension). (See 'Disorders of sodium balance' above.)
• Edema or hypervolemia (too much sodium with associated water retention in interstitial spaces). (See
'Disorders of sodium balance' above.)
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Topic 2307 Version 13.0
GRAPHICS
Total body water and its major subdivisions as a function of

age
Data from: Friis-Hansen B. Body water compartments in children: changes during growth
and related changes in body composition. Pediatrics 1961; 28:169.
Graphic 56512 Version 2.0
Osmotic regulation of ADH release and thirst
Relation between plasma antidiuretic hormone (ADH) concentration

and plasma osmolality in normal humans in whom the plasma
osmolality was changed by varying the state of hydration. The osmotic
threshold for thirst is a few mosmol/kg higher than that for ADH.
Data from Robertson GL, Aycinena P, Zerbe RL. Am J Med 1982; 72:339.
Differences between osmoregulation and volume regulation
Osmoregulation Volume regulation

What is being sensed Plasma osmolality Effective circulating volume
Sensors Hypothalamic osmoreceptors Carotic sinus
Afferent glomerular arteriole
Atria
Effectors Antidiuretic hormone Sympathetic nervous system
Renin-angiotensin-aldosterone
Natriuretic peptides
Pressure natriuresis
Antidiuretic hormone
What is affected Water excretion (via ADH) Sodium excretion
Water intake (via thirst)
Effect of arginine vasopressin on water permeability in the

collecting duct
Binding of arginine vasopressin (AVP) to the vasopressin V2 receptor in principal cells of the
collecting ducts begins a succession of intracellular processes culminating in increased water
permeability. These steps include the activation of adenylyl cyclase via the stimulation of G-
alpha-s heterometric proteins, increased levels of cAMP, activation of protein kinase A, and
the fusion of vesicles consisting of water channel proteins (AQP2) with the luminal
membrane.
Reproduced with permission from: Bichet DG. Nephrogenic and central diabetes insipidus. In:
Schrier's Diseases of the Kidney, 9th ed, Coffman TM, Falk RJ, Molitoris BA, et al (Eds), Lippincott
Williams & Wilkins, Philadelphia 2012. Copyright © 2012 Lippincott Williams & Wilkins.
www.lww.com.
Determinants of the plasma sodium concentration
Among both normal subjects and patients with a variety of diseases,

there is a very close correlation between the plasma water sodium
concentration and the ratio of total body exchangeable solutes
(primarily Na salts in the extracellular fluid + K salts in the cells) to the
total body water (TBW). The exchangeable portion is used since about
30 percent of the body Na and a smaller fraction of the body K are
bound in areas such as bone where they are "nonexchangeable" and
therefore osmotically inactive.
Adapted from Edelman I, Leibman J, O'Meara MP, et al. J Clin Invest 1958;
37:1236, by copyright permission of the American Society for Clinical
Investigation.
Anatomy of the juxtaglomerular apparatus
The juxtaglomerular cells in the wall of the afferent arteriole secrete

renin into the lumen of the afferent arteriole and the renal lymph.
Stretch receptors in the afferent arteriole, the sympathetic nerves
ending in the juxtaglomerular cells, and the composition of the tubular
fluid reaching the macula densa all contribute to the regulation of renin
secretion.
Adapted from Davis JO, Am J Med 1973; 55:333.
Regulation of renin release
The renin-angiotensin-aldosterone system and the maintenance of sodium

and volume balance.
Hormonal response to increasing sodium intake
Increasing plasma levels of atrial natriuretic peptide (ANP) and falling

plasma renin activity in normal subjects given a progressively
increasing sodium intake from 10 to 350 meq/day after a 5-day
equilibration period. These hormonal responses promote urinary
excretion of the excess sodium.
Data from Sagnella GA, Markandu ND, Buckley MG, et al. Am J Physiol 1989;
256:R1171.
Hypovolemic stimulus to ADH release
Relationship of plasma antidiuretic hormone (ADH) concentrations to

isosmotic changes in blood volume in the rat. Much higher ADH levels
can occur with hypovolemia than with hyperosmolality, although a
relatively large fall in blood volume is required before this response is
initiated.
Data from Dunn FL, Brennan TJ, Nelson AE, et al. J Clin Invest 1973;
52:3212.
Hyponatremia associated with reduced survival in

patients with severe chronic heart failure
Survival over time in patients with severe chronic heart failure and a
left ventricular ejection fraction less than 30 percent who, at study
entry, had either a normal plasma sodium concentration (greater than
137 meq/L, solid line) or hyponatremia (plasma sodium less than or
equal to 137 meq/L, dashed line). Survival was significantly reduced in
the patients with hyponatremia. The survival rate was very low
(approximately 15 percent at 12 months) in those with a baseline
plasma sodium concentration less than or equal to 130 meq/L.
Data from: Lee WH, Packer M. Circulation 1986; 73:257.
Relationship between sodium intake and excretion

in the steady state
Relation between sodium intake (solid line) and urinary sodium

excretion (dashed line) as sodium intake is progressively increased
from 10 to 350 meq/day in normal subjects. Although excretion rises
in parallel to intake, there is a slight lag in equilibration, and the area
under the curve represents the net amount of sodium retained. This
volume expansion constitutes the signal to maintain sodium excretion
at a high level.
Data from Sagnella GA, Markandu ND, Buckley MG, et al. Am J Physiol 1989;
256:R1171.
Resumption of the steady state in primary

aldosteronism
The combination of aldosterone administration and the ingestion of a

high Na+ diet leads initially to Na+ retention, volume expansion, and a
rise in systemic blood pressure. After several days, however, there is a
spontaneous diuresis, resulting in the return of Na+ balance toward
normal but persistent hypertension.
From Hall JE, Granger JP, Smith MJ Jr, Premen AJ, Hypertension 1983; 6(2
Pt 2):I-183. By permission of the American Heart Association, Inc.
Steady state after initiation of a thiazide diuretic
Changes in sodium and potassium balance (intake minus excretion)

after the administration of 100 mg of hydrochlorothiazide to three
normal subjects. Negative balance persisted for only three days for
sodium and six days for potassium before a steady state was
reestablished, in which intake and excretion were roughly equal.
Data from Maronde RF, Milgrom M, Vlachakis ND, et al. JAMA 1983;
249:237.
Peak diuresis after first dose of loop diuretic
Increase in urinary sodium excretion (UNa) after intravenous

bumetanide, given as a continuous infusion (solid line) or as a bolus
(dashed line), in patients with stable chronic kidney disease. The
continuous infusion produced a 30 percent greater increase in sodium
excretion than bolus therapy due to a more favorable rate of diuretic
excretion. In addition, the natriuretic response declined over time with
both regimens. With the bolus, for example, the peak natriuretic
response to the second dose was 25 percent less than that to the first.
Data from Rudy DW, Voelker JR, Greene PK, et al. Ann Intern Med 1991;
115:360.
Disclosures
Disclosures: Richard H Sterns, MD Nothing to disclose. Michael Emmett, MD Consultant/Advisory Boards: ZS Pharma [treatment of
hyperkalemia (potassium binder, zirconium silicate)]. John P Forman, MD, MSc Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a
multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is
required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

General Principles of Disorders of Water Balance (Hyponatremia and Hypernatremia) and Sodium Balance (Hypovolemia and Edema)

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Posm = 2 x [Na] + [glucose]/18 + blood urea nitrogen/2.8

Posm = 2 x [Na] + [glucose] + [urea]

Plasma tonicity = 2 x [Na] + [glucose]/18 (if glucose is measured in mg/dL)

Plasma tonicity = 2 x [Na] + [glucose] (if glucose is measured in mmol/L)

magnitude of the increase in sodium intake.

● Hyponatremia (too much water)

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tonicity. J Clin Invest 1952; 31:54.

Topic 2307 Version 13.0

Total body water and its major subdivisions as a function of

Graphic 56512 Version 2.0

Osmotic regulation of ADH release and thirst

Relation between plasma antidiuretic hormone (ADH) concentration

Graphic 65195 Version 2.0

Differences between osmoregulation and volume regulation

Osmoregulation Volume regulation

Sensors Hypothalamic osmoreceptors Carotic sinus

Afferent glomerular arteriole

Effectors Antidiuretic hormone Sympathetic nervous system

What is affected Water excretion (via ADH) Sodium excretion

Water intake (via thirst)

Graphic 51153 Version 2.0

Effect of arginine vasopressin on water permeability in the

Graphic 51077 Version 9.0

Determinants of the plasma sodium concentration

Among both normal subjects and patients with a variety of diseases,

Graphic 71817 Version 2.0

Anatomy of the juxtaglomerular apparatus

The juxtaglomerular cells in the wall of the afferent arteriole secrete

Adapted from Davis JO, Am J Med 1973; 55:333.

Graphic 69949 Version 1.0

Regulation of renin release

The renin-angiotensin-aldosterone system and the maintenance of sodium

Graphic 65116 Version 1.0

Hormonal response to increasing sodium intake

Increasing plasma levels of atrial natriuretic peptide (ANP) and falling

Graphic 53243 Version 2.0

Hypovolemic stimulus to ADH release

Relationship of plasma antidiuretic hormone (ADH) concentrations to

Graphic 58012 Version 2.0

Hyponatremia associated with reduced survival in

Data from: Lee WH, Packer M. Circulation 1986; 73:257.

Graphic 55554 Version 2.0

Relationship between sodium intake and excretion

Relation between sodium intake (solid line) and urinary sodium

Graphic 58458 Version 3.0

Resumption of the steady state in primary

The combination of aldosterone administration and the ingestion of a

Graphic 62044 Version 3.0

Steady state after initiation of a thiazide diuretic

Changes in sodium and potassium balance (intake minus excretion)

Graphic 74940 Version 4.0

Peak diuresis after first dose of loop diuretic

Increase in urinary sodium excretion (UNa) after intravenous

Graphic 75714 Version 3.0

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