Hyponatremia

Hypo-osmolality (serum osmolality < 275 mOsm/kg) always indicates excess total body water relative to body solutes or excess water relative to solute in the extracellular fluid (ECF), as water moves freely between the intracellular and the extracellular compartments. This imbalance can be due to solute depletion, solute dilution, or a combination of both.

Under normal conditions, renal handling of water is sufficient to excrete as much as 15-20 L of free water per day. Further, the body's response to a decreased osmolality is decreased thirst. Thus, hyponatremia can occur only when some condition impairs normal free-water excretion.

Generally, hyponatremia is of clinical significance when it reflects a drop in the serum osmolality (ie, hypotonic hyponatremia), which is measured directly via osmometry or is calculated as 2(Na) mEq/L + serum glucose (mg/dL)/18 + BUN (mg/dL)/2.8. Note that urea is not an ineffective osmole, so when the urea levels are very high (as in azotemia), the measured osmolality should be corrected for the contribution of urea (measured serum osmolality – BUN (mg/dL)/2.8).

The recommendations for treatment of hyponatremia rely on the current understanding of central nervous system (CNS) adaptation to an altered serum osmolality. ^[4]  In the setting of an acute drop in the serum osmolality, neuronal cell swelling occurs due to the water shift from the extracellular space to the intracellular space (ie, Starling forces). Swelling of the brain cells elicits the following two osmoregulatory responses:

• It inhibits arginine vasopressin secretion from neurons in the hypothalamus and hypothalamic thirst center. This leads to excess water elimination as dilute urine.
• There is an immediate cellular adaptation with loss of electrolytes, and over the next few days, a more gradual loss of organic intracellular osmolytes. ^[5]

Therefore, correction of hyponatremia must take into account the chronicity of the condition. Acute hyponatremia (duration < 48 h) can be corrected more quickly than chronic hyponatremia. Most individuals who present with symptomatic hyponatremia (as opposed to those who develop hyponatremia in an inpatient setting) have had hyponatremia for some time, so their condition is chronic, and correction should proceed accordingly. Overly rapid correction of serum sodium levels in these individuals can precipitate a severe neurologic complication, ODS. Consequently, when the duration of hyponatremia is uncertain, the condition should be considered chronic.

Although the differential diagnosis is quite broad, most hyponatremia can be classified as hypertonic, normotonic, or hypotonic in origin.

Hypertonic hyponatremia

Patients with hypertonic hyponatremia often have normal total body sodium levels but a dilutional drop in the measured serum sodium due to the presence of osmotically active molecules in the serum, which causes a water shift from the intracellular compartment to the extracellular compartment.

Glucose reduces the serum sodium level by 1.6 mEq/L for each 100 mg/dL of serum glucose greater than 100 mg/dL. This relationship is nonlinear, with greater reduction in plasma sodium concentrations with glucose concentrations over 400 mg/dL, so a 2.4 mEq/L reduction in sodium for each 100 mg/dL increase in glucose over 100 mg/dL is a more accurate correction factor when the glucose is greater than 400 mg/dL. ^[6]

Other examples of osmotically active molecules include mannitol (often used to treat brain edema) or maltose (used with intravenous immunoglobulin administration).

Normotonic hyponatremia

Severe hyperlipidemia and paraproteinemia can lead to low measured serum sodium concentrations with normal serum osmolality. Normally, water comprises 92-94% of plasma volume. The plasma water fraction falls with an increase in fats and proteins. The measured sodium concentration in the total plasma volume is respectively reduced, although the plasma sodium concentration and plasma osmolality are unchanged. This artifactual low sodium (so-called pseudohyponatremia) is secondary to measurement by flame photometry. It can be avoided by direct ion-selective electrode measurement. Another cause of pseudohyponatremia is seen in patients with cholestatic jaundice secondary to the presence of low-density lipoprotein, lipoprotein X, which can be detected by lipoprotein electrophoresis. ^[7]

Hyponatremia after transurethral resection of the prostate (TURP) or hysteroscopy is caused by absorption of glycine, sorbitol, or mannitol contained in nonconductive flushing solutions used for those procedures. The degree of hyponatremia is related to the quantity and rate of fluid absorbed. The plasma osmolality is also variable and changes over time. The presence of a relatively large osmolal gap due to excess organic solute is diagnostic in the appropriate clinical setting.

Hemodialysis, which will correct the hyponatremia and remove glycine and its toxic metabolites, can be used in patients with end-stage renal disease. Use of isotonic saline as an irrigant instead of glycine with the new bipolar resectoscope for TURP in high-risk patients (those with large prostates that require lengthy resection) can avoid this complication, making this disorder more a diagnosis of the past. ^[8]

Hypotonic hyponatremia

Hypotonic hyponatremia always reflects the inability of the kidneys to handle the excretion of free water to match the intake. Hypotonic hyponatremia with a urinary osmolality > 100 mOsm/kg (due to presence of inappropriate ADH) can be divided pathophysiologically into the following categories, according to the effective intravascular volume: hypervolemic, euvolemic, and hypovolemic. These clinically relevant groupings aid in determination of likely underlying etiology and guide treatment.

Hypervolemic hypotonic hyponatremia

This is characterized by clinically detectable edema or ascites that signifies an increase in total body water and sodium. Paradoxically, however, a decrease in the effective circulating volume, critical for tissue perfusion, stimulates the same pathophysiologic mechanism of impaired water excretion by the kidney that is observed in hypovolemic hypotonic hyponatremia. Commonly encountered examples include liver cirrhosis, congestive heart failure, nephrotic syndrome, and severe hypoproteinemia (albumin level < 1.5-2 g/dL).

Normovolemic (euvolemic) hypotonic hyponatremia

This is a very common cause of hyponatremia in hospitalized patients. It is associated with non-osmotic and non–volume-related ADH secretion (ie, SIADH) secondary to a variety of clinical conditions, including the following:

• CNS disturbances (eg, hypopituitarism) ^[9]
• Major surgery
• Trauma
• Pulmonary tumors
• Infection
• Stress
• Certain medications
• Uncontrolled pain and nausea
• Idiopathic ^[10]

Some of the common medications associated with SIADH are as follows:

• Chlorpropamide (potentiates the renal action of ADH)
• Carbamazepine (possesses antidiuretic property)
• Cyclophosphamide (marked water retention secondary to SIADH and potentially fatal hyponatremia may ensue in selected cases; use of isotonic saline rather than free water to maintain a high urine output to prevent hemorrhagic cystitis can minimize the risk)
• Vincristine
• Vinblastine
• Amitriptyline
• Haloperidol
• Selective serotonin reuptake inhibitors (particularly in elderly patients)
• Monoamine oxidase inhibitor (MAOI) antidepressants
• Nonsteroidal anti-inflammatory drugs (NSAIDs) (inhibit prostaglandin, which has inhibitory effect on ADH)
• Immune checkpoint inhibitors ^[11]

In those circumstances, the ability of the kidney to dilute urine in the setting of serum hypotonicity is reduced.

Hyponatremia is a relatively common adverse effect of desmopressin, a vasopressin analogue that acts as a pure V2 agonist and is used in the treatment of central diabetes insipidus, von Willebrand disease, nocturia in adults, and enuresis in children. Patients receiving desmopressin require regular monitoring of serum sodium levels. ^[12]

The diagnostic criteria for SIADH are as follows:

• Normal liver, kidney, and heart function - clinical euvolemia (absence of intravascular volume depletion)
• Normal thyroid and adrenal function
• Hypotonic hyponatremia
• Urine osmolality greater than 100 mOsm/kg, generally greater than 400-500 mOsm/kg with normal kidney function

Urinary sodium concentrations are also typically greater than 20 mEq/L on a normal salt diet, as sodium excretion will reflect dietary sodium intake. Serum uric acid levels are generally reduced; this is due to reduced tubular uric acid reabsorption, which parallels the decrease in proximal tubular sodium reabsorption associated with central volume expansion. These findings are also found in a renal salt-wasting process. This similarity makes the differentiation between salt wasting and SIADH difficult except that in renal salt wasting, one would expect to find a hypovolemic state and possibly hypotension.

Reset osmostat is another important, but rare, cause of normovolemic hypotonic hyponatremia. This may occur in the elderly and during pregnancy. These patients regulate their serum osmolality around a reduced set point; however, in contrast to patients with SIADH (who also have a downward resetting of the osmotic threshold for thirst), ^[13]  they are able to dilute their urine in response to a water load to keep the serum osmolality around the preset low point.

Severe hypothyroidism (unknown mechanism, possibly secondary to low cardiac output and glomerular filtration rate) and adrenal insufficiency are also associated with non-osmotic vasopressin release and impaired sodium reabsorption, leading to hypotonic hyponatremia. Hyponatremia associated with cortisol deficiency, such as primary or secondary hypoadrenalism, commonly presents subtly and may go undiagnosed. A random cortisol level check, especially in acute illness, can be misleading if the level is normal (when it should be high). Testing for adrenal insufficiency and hypothyroidism should be part of the hyponatremia workup, as the disorders respond promptly to hormone replacement.

Hospitalized patients who are infected with human immunodeficiency virus (HIV) have a high incidence of hyponatremia. ^[14]  In these cases, hyponatremia is usually due to disorders associated with an increased ADH level:

• Increased release of ADH due to malignancy, occult or symptomatic infection of the central nervous system, or pneumonia from Pneumocystis jirovecii or other organisms.
• Effective volume depletion secondary to fluid loss from the gastrointestinal tract, primarily due to infectious diarrhea. 
• Adrenal insufficiency often due to an adrenalitis, an abnormality that may be infectious in origin, perhaps being induced by cytomegalovirus, Mycobacterium avium-intracellulare, or HIV itself. Affected patients have a high risk of morbidity and mortality

Hypovolemic hypotonic hyponatremia

This usually indicates concomitant solute depletion, with patients presenting with orthostatic symptoms. The pathophysiology underlying hypovolemic hypotonic hyponatremia is complex and involves the interplay of carotid baroreceptors, the sympathetic nervous system, the renin-angiotensin system, antidiuretic hormone (ADH; vasopressin) secretion, and renal tubular function. In the setting of decreased intravascular volume (eg, severe hemorrhage or severe volume depletion secondary to GI or renal loss or diuretic use) owing to a decreased stretch on the baroreceptors in the great veins, aortic arch, and carotid bodies, an increased sympathetic tone to maintain systemic blood pressure generally occurs.

This increased sympathetic tone, along with decreased renal perfusion secondary to intravascular volume depletion, results in increased renin and angiotensin secretion. This, in turn, results in increased sodium absorption in the proximal tubules of the kidney via angiotensin II and consequent decreased delivery of solutes to distal diluting segments, causing an impairment of renal free water excretion. There also is a concomitant increase in serum ADH production that further impairs free water excretion. Because angiotensin is also a very potent stimulant of thirst, free water intake is increased inappropriately at the same time, when water excretion is limited. Together, these changes lead to hyponatremia.

Cerebral salt wasting (CSW) is seen with intracranial disorders, such as subarachnoid hemorrhage, carcinomatous or infectious meningitis, metastatic carcinoma,  traumatic brain injury, and pituitary disorders, but especially after neurologic procedures. ^{[15, 16]} Disruption of sympathetic neural input into the kidney, which normally promotes salt and water reabsorption in the proximal nephron segment through various indirect and direct mechanisms, might cause renal salt wasting, resulting in reduced plasma volume.

Plasma renin and aldosterone levels fail to rise appropriately in patients with CSW despite a reduced plasma volume because of disruption of the sympathetic nervous system. In addition, the release of one or more natriuretic factors could also play a role in the renal salt wasting seen in CSW. Volume depletion leads to an elevation of plasma vasopressin levels and impaired free water excretion.

Distinguishing between CSW and SIADH can be challenging, because there is considerable overlap in the clinical presentation. ^[17]  Vigorous salt replacement is required in patients with CSW, whereas fluid restriction is the treatment of choice in patients with SIADH. Infusion of isotonic saline to correct the volume depletion is usually effective in reversing the hyponatremia in CSW, since euvolemia will suppress the release of ADH. The disorder is usually transient, with resolution occurring within 3-4 weeks of disease onset.

Salt-wasting nephropathy causing hypovolemic hyponatremia may rarely develop in a range of renal disorders (eg, interstitial nephropathy, medullary cystic disease, polycystic kidney disease, partial urinary obstruction) with low salt intake.

Another rare cause of hypovolemic hyponatremia secondary to solute loss in body fluid is high biliary fluid loss due to external biliary drainage—for example, in the setting of acalculous cholecystitis.The drained biliary fluid has a high sodium concentration, ranging between 122-164 mmol/L. The significant sodium loss in bile fluid results in hypotension and renal free-water retention in response to increased ADH secretion. ^[18]

Diuretics may induce hypovolemic hyponatremia. Note that thiazide diuretics, in contrast to loop diuretics, impair the diluting mechanism without limiting the concentrating mechanism, thereby impairing the ability to excrete a free-water load. Thus, thiazides are more prone to causing hyponatremia than are loop diuretics. This is particularly so in elderly persons, who already have impaired diluting ability.

Other causes

There are other causes that do not fit in any of the above categories and may or may not be associated with elevated levels of ADH or may simply overwhelm the capacity of the kidneys to properly excrete excess water.

The most common precipitant of hyponatremia in patients after surgery is the iatrogenic infusion of hypotonic fluids. ^[19]  Inappropriate administration of hypotonic intravenous fluids after surgery increases the risk of hyponatremia in these vulnerable patients, who retain water due to non-osmotic release of ADH, which can be elevated for a few days after most surgical procedures.

In severely malnourished individuals with a low-protein but high-water diet, diminished intake of solutes limits the ability of the kidney to handle free water. This is similar to the known condition of beer potomania, which occurs in individuals whose main source of calories is alcohol. ^[20]  In these patients, the urinary osmolality will typically be < 100 mOsm/kg.

Compulsive intake of large amounts of water exceeding the diluting capacity of the kidneys (> 20 L/d), despite a normal solute intake of 600-900 mOsm/d can result in hyponatremia. These patients will have a maximally dilute urine (urinary osmolality < 100 mOsm/kg), unlike those with SIADH. In primary polydipsia, there is a defect in thirst regulation due to a psychiatric illness, with different abnormalities in ADH regulation identified in psychotic patients. Transient stimulation of ADH release during acute psychotic episodes, an increase in the net renal response to ADH, downward resetting of the osmostat, and antipsychotic medication may contribute. Limiting water intake will rapidly raise the plasma sodium concentration as the excess water is readily excreted in dilute urine. ^[21]

Acute hyponatremia is not an uncommon occurrence in ultra-endurance athletes and marathon runners, with women being at higher risk. ^[22] The strongest single predictor of hyponatremia in these cases is weight gain during the race correlating with excessive fluid intake. Longer race time and lower body mass index extremes are also associated with hyponatremia, whereas the composition of fluids consumed (plain water rather than sports drinks containing electrolytes) is not. Oxidization of glycogen and triglyceride during a race is associated with the production of "bound" water, which then becomes an endogenous, electrolyte-free water infusion contributing to hyponatremia induced by water ingestion in excess of water losses.

It should be noted that some runners who collapse during a race are normonatremic or even hypernatremic, ^[23]  making blanket recommendations difficult. However, fluid intake to the point of weight gain should be avoided. ^[24]  Athletes should rely on thirst as their guide for fluid replacement and avoid global recommendations for water intake. Symptomatic patients with documented hyponatremia should receive 100 mL of 3% sodium chloride over 10 minutes in the field before transportation to hospital. This maneuver should raise the plasma sodium concentration an average of 2-3 mEq/L. ^[25]

By inhibiting prostaglandin formation, NSAID use may increase the risk of hyponatremia developing during strenuous exercise. Prostaglandins have a natriuretic effect. Prostaglandin depletion increases NaCl reabsorption in the thick ascending limb of Henle (ultimately increasing medullary tonicity) whereby ADH action in the collecting duct can lead to increased free water retention. ^[26]

Symptomatic and potentially fatal hyponatremia can develop with rapid onset after ingestion of the amphetamine derivative methylenedioxymethamphetamine (MDMA; ecstasy, Molly). ^[27]  A marked increase in water intake via direct thirst stimulation, as well as inappropriate secretion of ADH, contributes to the hyponatremia seen with even a low dose of this drug.

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is an SIADH-like clinical and laboratory picture seen in male infants who present with neurologic symptoms secondary to hyponatremia in the setting of undetectable plasma arginine vasopressin (AVP) levels. This hereditary disorder is secondary to a gain-of-function mutation in the V2 vasopressin receptor, resulting in constitutive activation of the receptor with elevated cyclic adenosine monophosphate (cAMP) production in the collecting duct principal cells.

Treatment of NSIAD poses a challenge. Water restriction improves serum sodium levels and osmolality in infants, but it limits calorie intake in formula-fed infants. The use of demeclocycline or lithium is potentially limited due to their adverse effects. The current therapy of choice is fluid restriction and the use of oral urea to induce obligatory free water excretion via osmotic diuresis. ^[28]

Hyponatremic-hypertensive syndrome, a rare condition, consists of severe hypertension associated with renal artery stenosis, hyponatremia, hypokalemia, severe thirst, and kidney dysfunction characterized by natriuresis, hypercalciuria, renal glycosuria, and proteinuria. Angiotensin-mediated thirst coupled with non-osmotic release of vasopressin provoked by angiotensin II and/or hypertensive encephalopathy are likely mechanisms for this syndrome. Sodium depletion due to pressure natriuresis and potassium depletion due to hyperaldosteronism with high plasma renin activity are also likely to play a role in the pathogenesis of hyponatremia. The abnormalities resolve with correction of the renal artery stenosis. ^[29]

United States

The incidence of hyponatremia depends largely on the patient population and the criteria used to establish the diagnosis. Among hospitalized patients, 15-20% have a serum sodium level of < 135 mEq/L, while only 1-4% have a serum sodium level of less than 130 mEq/L. The prevalence of hyponatremia is lower in the ambulatory setting.

The US armed forces reported 1579 incident diagnoses of exertional hyponatremia among active service members from 2003 through 2018, for a crude overall incidence rate of 7.2 cases per 100,000 person-years. Cases occurred both in training facilities and theaters of war. Diagnosis and treatment without hospitalization was accomplished in 86.3% of cases. ^[30]

Mortality/morbidity

Severe hyponatremia (< 125 mEq/L) has a high mortality rate. In patients whose serum sodium level falls below 105 mEq/L, and especially in persons with alcohol use disorder, the mortality is over 50%. ^[31]

In patients with acute ST-elevation myocardial infarction (MI), the presence of hyponatremia on admission or early development of hyponatremia is an independent predictor of 30-day mortality, and the prognosis worsens with the severity of hyponatremia. ^[32] In hospitalized survivors of acute MI, the presence of hyponatremia at discharge is an independent predictor of 12-month mortality. ^[33]

Similarly, cirrhotic patients with persistent ascites and a low serum sodium level who are awaiting liver transplantation have a high mortality risk despite low- severity Model for End-Stage Liver Disease (MELD) scores (see the MELD Score calculator). The independent predictors—ascites and hyponatremia—are findings indicative of hemodynamic decompensation. ^{[34, 35, 36]}

In patients with chronic kidney disease, hyponatremia and hypernatremia are associated with an increased risk for all-cause mortality and for deaths unrelated to cardiovascular problems or malignancy. Hyponatremia is also linked to an increased risk for cardiovascular- and malignancy-related mortality in these patients. ^[37]

Race-, sex-, and age-related demographics

Hyponatremia affects all races.

No sexual predilection exists for hyponatremia. However, symptoms are more likely to occur in young women than in men. Hyponatremia is more common in elderly persons partially because of higher rate of comorbid conditions (eg, heart, liver, or kidney failure) that can lead to hyponatremia.

The prognosis for patients with hyponatremia is predicated upon the underlying etiology. Hyponatremia in patients with cancer is associated with extended hospital stays and higher mortality rates; however, whether long-term correction of hyponatremia would improve these outcomes is unclear. ^[38]

In patients with end-stage renal disease who are receiving hemodialysis or peritoneal dialysis, evidence suggests that the risk of death rises with incrementally lower sodium levels. Causes of hyponatremia-related mortality in the dialysis population remain uncertain, but possibilities include central nervous system toxicity, falls and fractures, infection-related complications, and impaired cardiac function. ^[39]

A meta-analysis of 15 studies encompassing 13,816 patients found that any improvement in hyponatremia was associated with a reduced risk of overall mortality (odds ratio [OR]=0.57). With the eight studies that reported a threshold for serum sodium improvement to > 130 mmol/L, the association was even stronger (OR=0.51). The reduction in mortality risk persisted at 12-month follow-up (OR=0.55). Reduced mortality was more evident in older patients and in patients with lower serum sodium levels at enrollment. ^[40]

Patients who are to be treated with fluid restriction often require education regarding the free-water content of foods and an explanation of the need to limit the intake of liquids to a predetermined level.