Measurement of urine sodium helps distinguish renal from nonrenal causes of hyponatremia. Urine sodium exceeding 20 meq/L is consistent with renal salt wasting (diuretics, ACE inhibitors, mineralocorticoid deficiency, salt-losing nephropathy). Hyponatremia in AIDS patients is usually due to the syndrome of inappropriate ADH secretion (SIADH) or gastrointestinal sodium loss but may be due to relative mineralocorticoid or glucocorticoid deficiency. Urine sodium less than 10 meq/L or fractional excretion of sodium less than 1% (unless diuretics have been given) implies avid sodium retention by the kidney to compensate for extrarenal fluid losses from vomiting, diarrhea, sweating, or third-spacing, as with ascites. Fractional excretion (FE) of sodium or urea is calculated using a random urine (U) sample with simultaneously obtained plasma (P) samples for sodium (or urea) and creatinine (Cr).

In hyperlipidemia and hyperproteinemia, the marked increases in lipids (chylomicrons and triglycerides, but not cholesterol) and proteins (> 10 g/dL) occupy a disproportionately large portion of the plasma volume. Plasma osmolality remains normal because its measurement is unaffected by the lipids or proteins. A decreased volume of water results, so that the sodium concentration in total plasma volume is decreased. Because the sodium concentration in the plasma water is normal, hyperlipidemia and hyperproteinemia cause pseudohyponatremia. Most United States laboratories now measure serum electrolytes using ion-specific electrodes and thus avoid misdiagnosis.

The volume status is useful in differentiating the etiology of hypotonic hyponatremia.

A. Hypovolemic Hypotonic Hyponatremia: Hyponatremia with decreased extracellular fluid volume occurs in the setting of renal or extrarenal volume loss. Total body sodium is decreased. To increase intravascular volume, antidiuretic hormone (ADH) secretion increases, and free water is retained. The drive to replenish intravascular volume supersedes the need to maintain osmolality; losses of salt and water are replaced by water alone. Since clinicians frequently fail to recognize hypovolemia, the combination of low fractional excretion of sodium (< 0.5%) and low fractional urea clearance (< 55%) is the best biochemical way to predict saline response. Hyponatremia has been shown to develop in patients with intracranial diseases through renal sodium wasting. Unlike those with SIADH, these patients are hypovolemic, though plasma levels of ADH are inappropriately high. The cause of this syndrome is not known. Treatment consists of replacement of lost volume with isotonic saline or lactated Ringer's infusion. Corticosteroids can be used empirically if hypocortisolism is considered in the differential diagnosis.

B. Euvolemic Hypotonic Hyponatremia: In this setting, determinations of urine osmolality along with urine sodium are useful for appropriate diagnosis.

a. Syndrome of inappropriate ADH secretion (SIADH)–Increased ADH secretion is physiologic in hypovolemic states, so the diagnosis of SIADH is made only if the patient is euvolemic. In SIADH, release of ADH occurs without osmolality-dependent or volume-dependent physiologic stimulation. Normal regulation of ADH release occurs from both the central nervous system and the chest via baroreceptors and neural input. It follows that the causes of SIADH are disorders affecting the central nervous system—structural, metabolic, psychiatric, or pharmacologic—or the lungs. Furthermore, some carcinomas, such as small cell lung carcinoma, synthesize ADH. Other states associated with SIADH include AIDS and administration of drugs that either increase ADH secretion or potentiate its action. Fluoxetine-induced SIADH may be more common in geriatric patients.

b. Postoperative hyponatremia–Severe postoperative hyponatremia can develop in 2 days or less after elective surgery in healthy patients, especially premenopausal women. Most have received excessive postoperative hypotonic fluid in the setting of elevated ADH levels related to pain or surgery. Patients awake normally from general anesthesia but within 2 days develop nausea, headache, seizures, and even respiratory arrest. Serum sodium levels may be less than 110 meq/L. Premenopausal women who develop hyponatremic encephalopathy are about 25 times more likely than menopausal women to die or to suffer permanent brain damage, suggesting a role of estrogen in the pathophysiology of this disorder. Hyponatremia from the absorption of hypotonic fluids through uterine veins during endometrial ablation in menstruating women has been recently described. The mechanism of fluid absorption is similar to one that occurs during transurethral prostate resection in men. These patients can be symptomatic intraoperatively, with tremulousness, hypothermia, or hypoxia, or upon awakening from anesthesia, with headache, nausea, and vomiting.

c. Hypothyroidism–Hyponatremia is not commonly caused by hypothyroidism, but it can occur with serum sodium levels as low as 103 meq/L. Water retention is the cause, probably both from inappropriately elevated ADH levels and from nonhormonal alterations in the handling of water by the kidneys.

d. Psychogenic polydipsia–Marked excess free water intake (generally > 10 L/d) may produce hyponatremia. Euvolemia is maintained through the renal excretion of sodium. Urine sodium is therefore generally elevated (> 20 meq/L), but unlike SIADH, levels of ADH are suppressed. Urine osmolality is appropriately low (< 300 mosm/kg) as the increased free water is excreted. Hyponatremia from bursts of ADH occur in manic-depressive patients with excess free water intake.

e. Beer potomania–Excessive chronic intake of beer (generally at least 8 L daily) can cause hyponatremia as low as 100 meq/L. This disorder occurs primarily in patients with cirrhosis, who have elevated levels of ADH and decreased glomerular filtration rates. Beer generally has a very low content of sodium (< 10 meq/L), and hyponatremia develops through retention of free water (beer).

f. Idiosyncratic diuretic reaction–In addition to hyponatremia that develops from volume contraction due to diuretic therapy (see above), a less common, but severe, diuretic-induced (generally thiazide) hyponatremia can occur in euvolemic patients. This syndrome is most often seen in healthy older women (over 70 years of age). Serious symptoms often develop after only a few days of therapy. The mechanism for the hyponatremia appears to be a combination of excessive renal sodium loss and water retention.

g. Idiosyncratic ACE inhibitor reactions–ACE inhibitors can cause central polydipsia and increased antidiuretic hormone secretion, both of which can cause severe, symptomatic hyponatremia. Patients given ACE inhibitors who develop polydipsia should have their serum Na+ levels checked.

h. Endurance exercise hyponatremia–Hyponatremia after endurance exercise may not be merely secondary to loss of sodium and water with replacement by hypotonic fluid. In the setting of continued ADH secretion after the exercise has stopped, reperfusion of the exercise-induced ischemic splanchnic bed occurs. Thus, there is delayed absorption of previously ingested hypotonic fluid. The retention of hypotonic fluid may be exacerbated by NSAIDs frequently used by athletes.