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 hypotonic hyponatremia in adults".)
●(See "Diagnostic evaluation of adults with hyponatremia".)
●(See "Etiology and evaluation of hypernatremia in adults".)
●(See "Etiology, clinical manifestations, and diagnosis of volume depletion in adults".)
●(See "Clinical manifestations and evaluation 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' 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]. (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 kidney 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. By 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'.)
●By contrast, urea accumulation in kidney 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 kidney 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 kidney 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 'Pathogenesis'.)
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, approximately 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 kidney 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 kidney 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 kidney 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 approximately 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 to:
●An inability to suppress the release of ADH due to reduced effective arterial blood volume (as seen in true hypovolemia, heart failure, or cirrhosis)
or
●The syndrome of inappropriate ADH secretion (SIADH) or advanced kidney disease in which water retention is largely independent of ADH. (See "Causes of hypotonic hyponatremia in adults".)
Water is continuously lost in sweat, and these water losses increase with higher environmental temperature. Avoidance of hyperosmolality and hypernatremia 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 (older adult 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 kidney 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.
By contrast, volume contraction will have the opposite effect. In addition, a reduced effective arterial blood volume (even in an edematous 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.
Role of ADH in volume regulation — A substantial reduction in the effective arterial blood volume can lead to the release of ADH mediated by volume-sensitive receptors rather than osmoreceptors (figure 8) [30]. In humans, nonosmotic release of ADH only occurs acutely if the reduction in effective arterial blood volume is sufficiently large as to lower systemic blood pressure [31,32]; small, acute reductions in plasma volume that are sufficient to increase the secretion of renin and norepinephrine have little effect on the release of ADH. Once hypotension occurs, there may be a marked rise in ADH secretion (in addition to renin and norepinephrine), 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 (approximately 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.
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. The hormonal response to intake that alters both tonicity and effective arterial blood volume 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.)
As an example, the intravenous administration of one-half isotonic saline (sodium concentration of 77 mEq/L) will result in volume expansion and, because it is a solution that is dilute to plasma, will also cause a reduction in the plasma sodium concentration. These changes in body composition and volume will lead to the following changes in hormonal secretion and urine composition:
●Expansion of the extracellular volume 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.
●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 ADH release, resulting in a rise in urine osmolality and a reduction in urinary water loss.
●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 be concentrated (to prevent further water loss) and contain relatively little sodium, an appropriate response to hypertonicity and volume depletion.
The increase in plasma sodium concentration and plasma tonicity will also increase thirst and water intake. Retention of ingested water (due to reduced water excretion in the urine) will return the plasma sodium concentration toward normal. Retention of ingested salt (due to reduced sodium excretion in the urine) will return the extracellular volume toward normal.
A third example is the ingestion of salted pretzels without intake of water. The following sequence would occur:
●Salt intake will transiently 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.
Retention of ingested water (due to reduced water excretion in the urine) will return the plasma sodium concentration toward normal and shift water back into cells. Excretion of ingested salt (due to increased sodium excretion in the urine) will return the extracellular volume toward normal.
Isotonic saline in SIADH — It is important to understand the regulation of water and sodium balance in order to avoid unintentional and undesirable consequences when treating hyponatremia due to the SIADH. The mainstay of therapy in this disorder 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 hypertonic saline'.)
Suppose a patient with SIADH has a plasma sodium concentration of 120 mEq/L, a urine osmolality that is substantially higher than plasma due to the persistent effect of ADH, and a urine sodium plus potassium concentration of 258 mEq/L:
●If the patient is given 1000 mL of isotonic saline (which contains 154 mEq of sodium), 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, 257 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 approximately 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 plasma sodium. In such patients, concurrent use of furosemide, which blocks the renal concentrating mechanism, with hypertonic saline [34] 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 normal subjects. 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 is associated with an appropriate equivalent increase in sodium excretion (figure 9) that is mediated by increased release of atrial natriuretic peptide and decreased activity of the sodium-retaining renin-angiotensin-aldosterone system (figure 7) [35]. 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 9). 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 10) [36]. 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.
●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 11) [37]. At this point, sodium and potassium intake and excretion are in balance, but body stores of sodium and potassium will persist at their depleted levels 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 12) [38]. (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 few hours, 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 "Kidney stones in adults: Prevention of recurrent kidney stones", section on '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 [39]:
●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 hypotonic 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. By 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 hypotonic hyponatremia in adults".)
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 kidney 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 "Hyponatremia in patients with heart failure", section on 'Predictor of adverse prognosis' and "Causes of hypotonic hyponatremia in adults" and "Hyponatremia in patients with cirrhosis", section on 'Prognosis'.)
The term "nephrogenic syndrome of inappropriate antidiuresis (NSIAD)" was coined to describe patients with gain-of-function mutations in the vasopressin receptor V2R whose clinical and laboratory evaluations were consistent with SIADH despite undetectable plasma ADH levels [40]. Several drugs cause hyponatremia in a similar manner [41].
Although water is retained in patients with hyponatremia caused by SIADH or NSIAD, 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 (ODS) 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. 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 "Elevated intracranial pressure (ICP) in children: Management", section on 'Mannitol' and "Causes of hypotonic hyponatremia in adults".)
●Hyponatremia may be associated with a normal or high plasma osmolality in patients with kidney 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 'Plasma tonicity' above and "Manifestations of hyponatremia and hypernatremia in adults", section on 'Hyponatremia' and "Causes of hypotonic hyponatremia in adults".)
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 in adults".)
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). By contrast, unreplaced 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, because 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, high urine osmolality, and high urine 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 'Role of ADH in volume regulation' above and "Causes of hypotonic hyponatremia in adults".)
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 kidney 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 adults 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 'Prognosis'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyponatremia".)
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, approximately 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 kidney 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. By 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.)
