Hyponatremia - Clinical Tree

Sodium and its accompanying anions are the principle osmotically active solutes in extracellular fluid. When extracellular osmolality is low, intracellular osmolality is equally low. Therefore, although there are exceptions (Table 44.1), hyponatremia is usually associated with hypoosmolality and dilution of all body fluids.

The Plasma Sodium Concentration and Body Fluid Tonicity

Sodium and its accompanying anions are the principle osmotically active solutes in extracellular fluid. When extracellular osmolality is low, intracellular osmolality is equally low. Therefore, although there are exceptions ( Table 44.1 ), hyponatremia is usually associated with hypoosmolality and dilution of all body fluids.

Table 44.1

Causes of Non-Hypotonic Hyponatremia

Plasma Osmolality	Disorder	Pathogenesis
Normal	Pseudohyponatremia	Excess non-aqueous material decreases plasma water content; no change in ECF or ICF volume
	Hyperlipidemia
	Multiple myeloma
	Exogenous solutes	Expansion of ECF volume with non-sodium solutes and water; no change in ICF volume
	Isotonic IV mannitol
	Irrigant absorption
Increased	Hyperglycemia, hypertonic IV mannitol, and maltose containing IgG solutions	Initial expansion of ECF volume and shift of water out of cells; decrease in ICF volume

When (as is usually the case) the concentration of non-permeant extracellular solutes other than sodium is very low, the plasma sodium concentration is a function of three variables, as indicated by the following equation:

{Plasma [Na}^{+}] ≅ \frac{{Exchangeable Na}^{+} + {Exchangeable K}^{+}}{Total body water}

${Plasma [Na}^{+}] ≅ \frac{{Exchangeable Na}^{+} + {Exchangeable K}^{+}}{Total body water}$

Only the exchangeable fractions of sodium and potassium are included in the equation, because one-third of body sodium is bound to bone and osmotically inactive. This relationship, which has been validated empirically, indicates that the plasma (or serum) sodium concentration can be reduced by depletion of body cations, by an increase in body water or by a combination of these processes. Recently, it has been emphasized that the original equation describing the relationship between the plasma sodium concentration, exchangeable sodium, exchangeable potassium, and total body water has an intercept that can be explained theoretically. The simplified form of the relationship Eq. (44.1) , which omits the intercept, is useful conceptually, but should not be considered a completely accurate basis for predicting the effect of therapy on the plasma sodium concentration.

It is intuitively obvious that the extracellular sodium concentration should be proportional to the body’s content of water and soluble sodium. The sodium concentration falls when the body retains water (without solute) or when there are net external losses of sodium (without water). The importance of intracellular potassium stores to the plasma sodium concentration is less obvious. In potassium depletion, sodium ions move intracellularly as intracellular potassium is lost, balancing negative charges on intracellular macromolecules. Thus, external loss of exchangeable potassium causes an internal loss of extracellular sodium. Similarly, when intracellular potassium is replaced by hydrogen ions, rather than sodium or when it is lost with phosphate (an intracellular anion), the loss of osmotically active intracellular solute causes a redistribution of water from the intracellular to the extracellular fluid compartments, diluting extracellular sodium ions.

Physiologic Control of Water Excretion

Osmotic Regulation

Controlled by changes in water intake, vasopressin secretion, and water excretion, the plasma sodium concentration is normally prevented from rising above 142 mEq/L or falling below 135 mEq/L. When the plasma sodium concentration changes by as little as 1% (with a corresponding change in plasma osmolality), cell volume receptors (“osmoreceptors”) in the hypothalamus respond, relaying signals to vasopressin-secreting neurons located in the supraoptic and paraventricular nuclei whose axons terminate in secretory bulbs in the neurohypophysis. The antidiuretic hormone, arginine vasopressin, which is released into the systemic circulation by the neurohypophysis, controls water excretion by the kidneys. The hormone activates V ₂ receptors on the basolateral membrane of principal cells in the renal collecting duct, initiating a cyclic AMP-dependent process that culminates in increased production of water channels (aquaporin 2), and their insertion into the cells’ luminal membranes. The effect of vasopressin on water flow is inhibited by locally produced prostaglandin E ₂ , which is stimulated by vasopressin action on V ₁ receptors. Vasopressin’s short half-life in the circulation and continuous shuttling of aquaporins between the collecting duct’s cell membrane and cytosol allow rapid changes in urinary water excretion in response to changes in body fluid tonicity.

Vasopressin levels are normally unmeasurable when the plasma sodium concentration falls to approximately 135 mEq/L. Low levels of the hormone allow the excretion of large volumes of a maximally dilute urine (≈50 mOsm/kg) which reduces body water content and restores the plasma sodium concentration to normal. At higher plasma sodium levels, plasma vasopressin is directly related to the plasma sodium concentration, reaching levels that are high enough to promote the excretion of maximally concentrated urine (≈1200 mOsm/kg) at a plasma sodium concentration of approximately 142 mEq/L. A rising plasma sodium concentration also stimulates thirst. Ingested water is retained, returning the plasma sodium concentration back towards normal.

Hemodynamic Regulation

Under day-to-day conditions, vasopressin secretion, urinary free water excretion, and thirst respond primarily to changes in body fluid tonicity. Under pathologic conditions, osmotic control of vasopressin secretion and thirst can be overridden by hemodynamic stimuli. In addition to input from osmoreceptors, the hypothalamic neurons that secrete vasopressin also receive neural input from baroreceptors in the great vessels, and volume receptors in the atria. When these receptors are stimulated by hypotension or by a major reduction in plasma volume, impulses are carried via cranial nerves IX and X to the hypothalamus. The thirst center in the hypothalamus responds to similar non-osmotic stimuli. Vasopressin and thirst responses to hypovolemia and hypotension lead to water retention, despite hypotonicity of body fluids. These hemodynamic responses can be regarded as back-up systems that serve to maintain arterial blood volume under emergency conditions, sacrificing tonicity to tissue perfusion. Although high levels of vasopressin occur in response to hypovolemia, under experimental conditions, a rather large stimulus is required; while plasma vasopressin is measurably increased by a 1% change in plasma osmolality, a 10% change in extracellular fluid volume is required to elicit the same response. However, these experimental findings are difficult to reconcile with clinical observations, suggesting that non-osmotic vasopressin secretion occurs with more subtle volume depletion.

Hypotonic Hyponatremia: Classification and Pathogenesis

Traditionally, patients with hyponatremia are divided into categories according to their body sodium content and/or intravascular volume: low body sodium content (volume depletion); high body sodium content (edematous conditions) or normal body sodium content (euvolemic hyponatremia or SIADH). Although this time-honored approach is often helpful to clinicians, intravascular volume and body sodium content do not always change in parallel (e.g., self-induced water intoxication), and some causes of hyponatremia (e.g., diuretic-induced and cerebral salt-wasting) may be difficult to classify by intravascular volume. Moreover, physiologic responses to extracellular volume expansion and contraction often create ambiguities in volume status. Thus, secondary water retention in response to volume depletion and secondary natriuresis in response to water overload may ultimately yield similar values for total body sodium and water ( Figure 44.1 ).

Figure 44.1, Body water and cation content in hyponatremia.

Table 44.2 classifies hyponatremia by the physiologic mechanism underlying the electrolyte disturbance. As the plasma sodium concentration is proportional to the ratio of exchangeable cations and total body water, it follows that changes in sodium concentration are related to external balances of sodium, potassium, and water. However, because the plasma sodium concentration is normally maintained within a narrow physiologic range by control systems which regulate water balance, hypotonic hyponatremia can only occur if water excretion is impaired or overwhelmed. The various causes of hyponatremia are therefore divided according to the status of urinary water excretion. Disordered water balance is often accompanied by changes in cation balance, which also play a pivotal role in the pathogenesis of hyponatremia.

Table 44.2

Pathophysiologic Classification of Hypotonic Hyponatremia

Urine Diluting Ability	Cause of Hyponatremia
Unimpaired	Psychotic polydipsia
	Beer potomania
	Infantile water intoxication
Impaired: vasopressin-independent	Oliguric renal failure
	Tubular interstitial renal disease
	Diuretics
	Nephrogenic syndrome of antidiuresis ^a
Impaired: vasopressin-dependent	Hemodynamically-mediated
	Volume-depletion
	Spinal cord disease
	Congestive heart failure
	Cirrhosis
	Addison’s disease ^b
	Cerebral salt-wasting ^b
	SIADH (see Table 44.3 )

a Hereditary disorder of the V2 receptor with clinical features of SIADH, but with undetectable plasma vasopressin levels.

b Disorders with both hemodynamic and non-hemodynamic bases for vasopressin release.

Water Intoxication with Maximally Dilute Urine

Pathophysiology

Rarely, fluid intake can overwhelm normal mechanisms for water excretion. In the absence of vasopressin, urine osmolality falls to approximately 50 mOsm/kg. A typical American diet provides a daily load of 600 to 900 milliosmoles of solute (electrolytes and urea) that must be excreted. At this rate of solute excretion, the volume of maximally dilute urine equals 12 to 18 liters per day or 500 to 750 ml/hour. Water intake can occasionally exceed this large excretory capacity. Patients with severe acute water intoxication are truly “water-logged,” and susceptible to pulmonary edema due to retained water.

Self-Induced Water Intoxication in Psychotic Polydipsia

Polydipsia and polyuria are extremely common among institutionalized patients with mental illness. Many patients with polydipsia have frequent episodes of hyponatremia, which may present with seizures. About half the reported cases have had maximally dilute urine (urine osmolalities below 100 mOsm/kg) at presentation. In others, inappropriately concentrated urine was present immediately following seizures or in association with nausea, but the rate of correction of hyponatremia indicates that the urine became dilute soon afterwards.

In most psychotic water drinkers, hyponatremia can be ascribed to a generalized dilution of body solutes by retained water; thus, body weight increases in proportion to the severity of hyponatremia. Patients gain weight and become hyponatremic during the course of the day, and then spontaneously diurese, normalizing their plasma sodium concentration and body weight during the night. Caregivers in psychiatric hospitals routinely monitor weight changes in patients who are habitual water drinkers to determine when access to water must be rigidly restricted to avoid severe symptomatic hyponatremia.

Agents that interfere with the ability to maximally dilute the urine (e.g., diuretics or carbamazepine) should be avoided in polydipsic patients, as they can precipitate a rapid onset of life-threatening hyponatremia.

Water Intoxication in Infants

Acute water intoxication is common among infants who are given excessively dilute formula. The hungry infant ingests large volumes of fluid leading to water retention, despite the excretion of maximally dilute urine. Once water is restricted, the plasma sodium concentration self-corrects as large volumes of urine are excreted.

Beer Drinkers Potomania

Alcoholics who eat little and subsist on large volumes of beer may also become hyponatremic while excreting maximally dilute urine. Beer’s low protein content and the protein-sparing effect of its carbohydrate result in profoundly reduced blood urea nitrogen concentrations and urinary urea excretion. The total daily excretion of urinary solute may be only 200 to 300 milliosmoles. Thus, even at a urine osmolality of 50 mOsm/kg, urine output is limited to 4 to 6 liters per day, an amount that fails to match the enthusiastic beer drinker’s intake of electrolyte free water. A similar phenomenon has been reported in non-beer drinkers with a high fluid and low protein intake. Volume-depletion from gastrointestinal losses, and transient vasopressin release caused by nausea or alcohol withdrawal, may further limit the beer drinker’s ability to excrete free water, contributing to the development and persistence of hyponatremia.

Vasopressin-Independent Defects in Water Excretion

Pathophysiology

Maximal free water excretion depends on adequate delivery of glomerular filtrate to the renal diluting segments (the ascending limb of the loop of Henle and the distal tubule), reabsorption of salt without water by the diluting segments to create hypotonic fluid within the tubular lumen, and a collecting duct that is relatively impermeable to water, so that the dilute tubular fluid formed “upstream” can be eliminated in the final urine. Hyponatremia occurs when water is taken in at a time when these mechanisms are not functioning normally.

Renal Failure

The most obvious cause of impaired water excretion is oliguric renal failure. Even when nonoliguric, patients with advanced renal failure have fixed isosthenuria, and are unable to excrete dilute urine despite normally suppressed vasopressin secretion. In the absence of renal failure, urinary dilution can still be impaired, despite low levels of vasopressin, by two mechanisms: (1) enhanced proximal reabsorption of the glomerular filtrate, limiting fluid delivery to the renal diluting segments (as in volume depletion, congestive heart failure, and cirrhosis) ; and (2) impaired sodium reabsorption in the renal diluting segments (by diuretics or tubular interstitial disease).

Diuretic-Induced Hyponatremia

Both thiazides and loop diuretics interfere with the ability to maximally dilute the urine. Thus, both classes of diuretic can lead to water intoxication in patients who habitually ingest extremely large volumes of water. Diuretics are one of the most important causes of hyponatremia. Most cases are caused by thiazide or thiazide-like agents; loop diuretics are implicated much less commonly. Thiazides may be the sole factor responsible for causing hyponatremia, and they may also exacerbate hyponatremia in patients with disorders associated with SIADH. The mechanism of thiazide-induced hyponatremia remains somewhat unclear; however, as for all causes of hyponatremia, water retention and/or cation depletion must be responsible. There is evidence that thiazides have a direct antidiuretic effect mediated by upregulation of aquporin 2 (AQP2).

Most cases of thiazide-induced hyponatremia have occurred in elderly small women who have been prescribed diuretics for the treatment of hypertension. The impairment of renal diluting ability caused by thiazides is more pronounced in elderly people, especially those who have previously experienced thiazide-induced hyponatremia. The predisposition of elderly women to severe hyponatremia may be explained by body size, in that small changes in body water and electrolyte content can lead to marked changes in serum sodium.

In susceptible individuals, the serum sodium may fall within hours of diuretic ingestion, and severe hyponatremia can develop in less than two days. While in many cases the diuretic had been recently prescribed, in others thiazides had been used chronically without incident until, for some reason, water intake increased, dietary salt and protein intake decreased or an intercurrent illness led to “inappropriate” antidiuretic hormone secretion. Mild hyponatremia often persists for a few weeks when diuretic therapy is withdrawn from patients with diuretic-induced hyponatremia, apparently reflecting temporary “resetting” of the osmostat or alternatively, slow restoration of depleted cation stores.

Although thiazide diuretics do not inhibit the ability to concentrate the urine, they do impair diluting ability in several ways : inhibition of electrolyte transport at the cortical diluting sites; direct stimulation of vasopressin release; direct upregulation of AQP2; reduction of glomerular filtration; and enhancement of fractional proximal water reabsorption, reducing delivery to diluting sites.

Positive water balance during the onset of thiazide-induced hyponatremia and negative balance during its correction have been documented. Some patients with thiazide-induced hyponatremia have low serum uric acid levels and high uric acid clearances (markers of volume expansion) which return to normal as the serum sodium normalizes. Most affected patients drink large amounts of water, and the superimposed diuretic prevents urine output from keeping pace with water intake.

Although increased total body water often contributes to the pathogenesis of thiazide-induced hyponatremia, there are many cases in which body weight decreased or remained the same during the fall in serum sodium. In others, direct measurements of total body water in affected patients have been normal. In these cases, other explanations for hyponatremia must be sought.

Negative cation balance plays a major role in the pathogenesis of diuretic-induced hyponatremia. Rejected cations may be excreted at a total concentration which exceeds that of plasma, directly “desalinating” the plasma even in the absence of water intake. Potassium depletion is an important factor in many cases; treatment of hypokalemia has been shown to increase the plasma sodium concentration with no change in body weight. Magnesium repletion may act similarly, presumably through an effect on skeletal muscle Na-K-ATPase. Surprisingly, despite negative cation balance, many patients appear to be euvolemic. Apparently, enough water is retained to offset the initial tendency toward hypovolemia. Once diuretics are withdrawn, urinary sodium excretion falls to very low levels.

Vasopressin-Dependent Defects in water Excretion

Pathophysiology

Normally, in response to hypotonicity, vasopressin secretion is suppressed, the collecting duct is impermeable to water, and a maximally dilute urine is formed. In two large surveys of hospitalized patients with hyponatremia, over 90% of cases were associated with elevated vasopressin levels. Vasopressin levels are rarely elevated into pathologic ranges, even in cases associated with ectopic secretion by tumors. Rather, vasopressin levels are inappropriately high relative to the plasma osmolality. Non-osmotic vasopressin secretion may be an adaptive response driven by hemodynamic stimuli or it may be “inappropriate” and independent of any of the usual physiologic mechanisms which regulate water excretion. Persistent vasopressin secretion despite hypoosmolality allows ingested or infused free water to be retained, causing hypotonic hyponatremia. Vasopressin-mediated hyponatremia is characterized by urine which is more concentrated (usually much more) than 100 mOsm/kg and which becomes more dilute after administration of a V2 receptor antagonist (see section “V ₂ -Receptor Antagonists”).

Patients with inappropriate vasopressin secretion must take in water to become hyponatremic. In some cases, hyponatremia develops when electrolyte-free water is administered parenterally. More commonly, patients become hyponatremic while ingesting water. Theoretically, osmotic inhibition of thirst should prevent water ingestion when the ability to excrete water is impaired. However, patients with SIADH continue to drink despite plasma osmolalities below the normal osmotic threshold for thirst. Formal testing has shown that there is downward resetting of the osmotic threshold for thirst in SIADH, but that thirst responds to osmotic stimulation and is suppressed by drinking around the lowered set-point.

Escape from Vasopressin-Induced Water Retention

Experimentally, after several days of constant vasopressin infusion and constant water intake, there is an escape from the antidiuretic effect of vasopressin. With the onset of vasopressin escape, the urine becomes less concentrated, allowing water balance to be re-established at a new steady-state in which the plasma sodium concentration stabilizes at a level lower than normal. In experimental models, escape is temporally associated with a marked decrease in renal aquaporin-2 protein, accompanied by suppression of aquaporin-2 mRNA levels ( Figure 44.2 ). V2-receptor mRNA expression and binding are decreased, as is c-AMP production in response to vasopressin, Plasma and urine aldosterone and mean arterial pressure are increased as are thiazide-sensitive Na-Cl co-transporter and ENaC proteins in the distal nephron that are known to be upregulated by aldosterone. Inhibition of nitric oxide synthase or prostaglandin synthesis synergistically inhibit the escape phenomenon, supporting a role for nitric oxide and prostaglandins in mediating vasopressin escape.

In conditions characterized by vasopressin-mediated water retention, (e.g., SIADH, congestive heart failure), renal escape from vasopressin-induced antidiuresis (along with decreased water intake in some cases) permits patients with vasopressin-mediated hyponatremic states to manifest a relatively stable level of hyponatremia, despite continued water intake and continued presence of vasopressin.

Hemodynamic Causes of Vasopressin-Mediated Hyponatremia

Pathophysiology

Hypovolemia, heart failure, and cirrhosis are the most common non-osmotic stimuli for antidiuretic hormone secretion. In a series of 100 consecutive hospitalized patients with hypotonic hyponatremia, volume contraction (29%), advanced heart failure (25%), and liver cirrhosis (16%) were identified as the cause of hyponatremia in a high percentage of cases. The hemodynamic abnormalities that stimulate vasopressin release in these conditions also promote sodium reabsorption by the renal tubules (mediated by aldosterone, increased sympathetic nervous system activity, peritubular Starling forces, etc.), causing both sodium and water retention. In volume-depletion, sodium retention serves to replace a sodium deficit; in heart failure and cirrhosis, sodium retention serves to compensate for the circulatory abnormality, but it also causes edema.

Volume-Depletion

Sodium and potassium losses associated with gastrointestinal fluids (or with urinary losses caused by osmotic or loop diuretics) do not directly lower the plasma sodium concentration, because these fluids are either hypotonic or isotonic. However, the intravascular volume-depletion caused by such losses is a hemodynamic stimulus for thirst and vasopressin secretion; as a result, ingested water is retained, lowering the plasma sodium concentration. Thus, hyponatremia in these conditions is associated with a reduced content of both total body cations and water. However, in many patients, compensatory water retention makes it difficult to detect the underlying volume depletion. Laboratory clues, including a low urine sodium concentration and elevated serum uric acid levels, can be helpful diagnostically.

Spinal Cord Disease

Hyponatremia is very common after spinal cord injury, particularly among patients with complete quadriplegia. Contributing factors include a large water intake (reflecting physician recommendations, angiotensin II-mediated thirst, and loss of pharyngeal and gastric satiety signals), and baroreceptor-mediated vasopressin release. One study showed normal osmoregulation of vasopressin secretion and excretion of a water-load when subjects were supine, but with the subjects in a sitting position, there was a reduced osmotic threshold and increased sensitivity for vasopressin release, and urine diluting ability and free water clearance were markedly impaired.

Edematous Conditions

Severe hyponatremia can occur despite increased body sodium content if retained sodium is offset by a disproportionate increase in body water.

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